Rutgers The State University

CANCER CENTER SUPPORT GRANT

UMDNJ/RUTGERS UNIVERSITY COUNTERACT RESEARCH CENTER OF EXCELLENCE

WORKER HEALTH AND SAFETY TRAINING COOPERATIVE AGREEMENT

RESEARCH CENTER IN ENVIRONMENTAL HEALTH SCIENCES

NEW JERSEY ALLIANCE FOR CLINICAL AND TRANSLATIONAL SCIENCE: NJ ACTS

NOVEL MOLECULAR MECHANISMS PROMOTE GPCR-INDUCED BRONCHODILATION IN ASTHMA

FEND FOR TB

MYOCARDIAL ISCHEMIA AND TRANSFUSION (MINT) - CCC

NJ ACTS: A PLATFORM FOR TRANSLATIONAL SCIENCE IN NEW JERSEY

AFRICAN ANCESTRY GENOMIC PSYCHIATRY COHORT

BACTERIAL AND HOST HETEROGENEITY IN TB LATENCY, PERSISTENCE AND PROGRESSION - ABSTRACT - OVERALL UNTIL RECENTLY, TUBERCULOSIS (TB) HAS BEEN VIEWED AS A DISEASE THAT PROGRESSES OVER SEVERAL DISCRETE STAGES, PRINCIPALLY CONSISTING OF A PERIOD OF INFECTION FOLLOWED BY EITHER ACTIVE TB DISEASE OR A LATENT STATE WITH THE POTENTIAL FOR REACTIVATION. SIMILARLY, MYCOBACTERIUM TUBERCULOSIS (MTB), THE CAUSATIVE AGENT OF TB, HAS BEEN VIEWED AS A RELATIVELY STABLE BACTERIUM WITH LITTLE GENOMIC DIVERSITY, PREDICTABLE CAUSES OF ANTIBIOTIC RESISTANCE, AND PHENOTYPIC UNIFORMITY BOTH DURING CULTURE AND WITHIN ITS INFECTED HOST. HOWEVER, RECENT FINDINGS, MANY SPEARHEADED BY THE MEMBERS OF THIS APPLICATION, HAVE BEGUN TO DISCOVER UNEXPECTED HETEROGENEITY IN TB DISEASE STATES, HOST RESPONSES, THE GENOTYPES AND PHENOTYPES OF THE BACTERIA, AND AMONG THE APPARENTLY CLONAL INFECTING POPULATION OF MTB. THE PREMISE FOR THIS PROGRAM IS THAT THE HETEROGENOUS OUTCOMES OF TB INFECTIONS AND TREATMENTS ARE DETERMINED BY THE INTERPLAY BETWEEN HETEROGENEOUS HOST-BACTERIA TRANSCRIPTIONAL AND METABOLIC PROGRAMS. HOST AND BACTERIA MAY BE PRE-PROGRAMMED PHENOTYPICALLY OR GENETICALLY TO PROGRESS FROM TB INFECTION TO TB DISEASE; AND TO DO SO RAPIDLY OR SLOWLY; AND, WITH OR WITHOUT EXTENSIVE INFLAMMATION AND LUNG DAMAGE. IMMUNE TOLERANCE, EVASION OR SUBVERSION MAY BE ANOTHER RESULT OF THESE INTERACTIONS, WHICH COULD LEAD TO WORSENING DISEASE AND ADVERSE TREATMENT OUTCOMES INCLUDING RELAPSE. DRUG TOLERANCE OR RESISTANCE IS ANOTHER RESULT OF THESE INTERACTIONS THAT MAY HAVE WIDESPREAD EFFECTS ON TREATMENT RESPONSES. ALTHOUGH MTB-HOST AND MTB-DRUG INTERACTIONS WOULD SEEM TO BE UNRELATED, WE WILL ALSO STUDY THE POSSIBILITY THAT IMMUNE AND DRUG TOLERANT MTB SHARE A NUMBER OF TRANSCRIPTIONAL AND METABOLIC PROGRAMS; AND THUS, ALSO SHARE SOME OF THE SAME VULNERABILITIES THAT COULD PROVIDE THERAPEUTIC TARGETS. CONSISTING OF 4 PROJECTS AND 3 CORES, THIS PROGRAM WILL BE ACCOMPLISHED IN THE FOLLOWING SPECIFIC AIMS: 1) TO DETERMINE THE EFFECTS OF BACTERIAL AND HOST HETEROGENEITY ON THE MANIFESTATIONS, PROGRESSION AND CONSEQUENCES OF CLOSE EXPOSURE TO TB IN THE HOUSEHOLD, AND OF ACTIVE TB. ADDRESSED IN PROJECT 1: BACTERIAL AND HOST DETERMINANTS OF PROGRESSION, MANIFESTATIONS AND CONSEQUENCES OF TB. 2) TO UNCOVER THE IMMUNOLOGICAL MECHANISMS UNDERLYING THE DIVERSE CLINICAL OUTCOMES IN HOSTS INFECTED WITH HIGH AND LOW TRANSMISSION STRAINS OF MTB. ADDRESSED IN PROJECT 2: IMMUNE DETERMINANTS OF THE COURSE OF MTB INFECTION AND DISEASE. 3) TO DEFINE THE HOST IMMUNE PATHWAYS THAT INDUCE DRUG TOLERANCE AND IDENTIFY POTENTIAL ROUTES TO THERAPEUTIC INTERVENTION. ADDRESSED IN PROJECT 3: MINIMIZING IN VIVO DRUG TOLERANCE INDUCTION IN TB. 4) TO DEFINE BACTERIAL FACTORS THAT CONTRIBUTE TO THE HETEROGENEOUS EXPRESSION OF DRUG TOLERANCE AND CHARACTERIZE LINKS WITH ADVERSE TREATMENT OUTCOMES. ADDRESSED IN PROJECT 4. DRUG TOLERANCE, BACTERIAL HETEROGENEITY AND ADVERSE TB TREATMENT OUTCOMES.

BIOMEDICAL SCIENCE EDUCATION POSTDOCTORAL TRAINING PROGRAM

RESOURCES, WORKFORCE DEVELOPMENT, AND ANIMAL MODELS FOR THE RUTGERS RBL - OVERALL ABSTRACT THE RUTGERS UNIVERSITY REGIONAL BIOCONTAINMENT LABORATORY (RBL) SERVES AS A CENTRAL FACILITY TO PERFORM BIOSAFETY LEVEL THREE (BSL3) THERAPEUTIC, PATHOGENESIS, AND DIAGNOSTIC RESEARCH ON HIGH THREAT BIOLOGICAL AGENTS WITH A FOCUS ON MYCOBACTERIUM TUBERCULOSIS AND SARS-COV-2, AS WELL AS OTHER CATEGORY A, B, AND C PATHOGENS. THE RBL SERVES ACADEMIC AND COMMERCIAL ENTITIES WITHIN RUTGERS UNIVERSITY, THE NORTHEAST UNITED STATES AND NATIONALLY, WHILE ALSO ENGAGING GLOBALLY WITH COMPANIES AND ACADEMIC INSTITUTIONS THROUGH COLLABORATIONS AND RESEARCH CONTRACTS. THIS PROPOSAL WILL PROVIDE SUPPORT THAT ENHANCES THE RBL’S ABILITY TO FULFILL ITS RESEARCH AND BIOTHREAT RESPONSE/PANDEMIC PREPAREDNESS MISSIONS WHILE ALSO SUPPORTING AN EXPANDING FACULTY/STAFF. WE PROPOSE TO ACCOMPLISH THESE GOALS BY IMPROVING THE RBL FACILITIES, SUPPORT SERVICES, BSL3 PRACTICE DEVELOPMENT AND IMPLEMENTATION AND SPECIAL SERVICES OFFERINGS THOUGH THE EXECUTION OF THREE AIMS: AIM 1. ESTABLISH A FACILITY MANAGEMENT, MAINTENANCE AND OPERATIONS (FMMO) CORE. AIM 2. ESTABLISH A BSL-3 PRACTICES CORE (PRACTICE CORE). AIM 3. ESTABLISH A BIOCONTAINMENT RESEARCH SUPPORT SERVICE CORE DEVOTED TO DEVELOPING ANIMAL MODELS OF BSL3 PATHOGENS AND ASSOCIATED SUPPORT SERVICES (ANIMAL MODELS AND RELATED SERVICES, OR AMRS CORE). THE FMMO CORE WILL PROVIDE BSL3 AND ABSL3 SERVICES, MANAGEMENT AND OVERSIGHT, FOR ROUTINE ANIMAL HUSBANDRY, MICROBIOLOGY AND VIROLOGY SERVICES IN SUPPORT OF INVESTIGATORS GRANT FUNDED RESEARCH PROJECTS WHILE ENSURING EFFICIENT OPERATIONS AND MAINTENANCE OF THE BSL3 FACILITIES AND PROVIDING TRAINED STAFF TO SUPPORT THE BSL3 BUILDING SYSTEMS AND EQUIPMENT. THE PRACTICE CORE WILL DEVELOP AND MAINTAIN STANDARD OPERATING PROCEDURES AND TRAINING FOR RESEARCH IN THE RBL BSL3 LABORATORIES INCLUDING BEST PRACTICES, EMERGENCY RESPONSE, WASTE MANAGEMENT, SHIPPING, HUSBANDRY, SELECT AGENT-SPECIFIC PRACTICES AND INVENTORY. IT WILL ALSO DEVELOP AND CONDUCT BIOSECURITY AND DISASTER DRILLS AND LIAISE WITH OTHER BSL3 LABORATORIES WITHIN THE RBL NETWORK AS WELL AS LOCAL, STATE AND FEDERAL HEALTH AGENCIES TO COORDINATE OPERATIONS AND PLAN FOR JOINT RESPONSES TO NEW INFECTIOUS DISEASE THREATS. THE AMRS CORE WILL DEVELOP CRITICAL ANIMAL MODELS INCLUDING THOSE OF SARS-COV2 AND HIGHLY PATHOGENIC INFLUENZA VIRUS TRANSMISSION, COVID-19 PASC, PULMONARY IMPAIRMENT AFTER TB (PIAT), AND DRUG TREATMENT MODELS, AND THEN SUPPORT GRANT FUNDED INVESTIGATORS IN THE PERFORMANCE OF THESE MODELS ALONG WITH THE ADVANCED INSTRUMENTATION NEEDED TO ANALYZE THESE INFECTED MODELS AND THEIR TISSUES/CELLS IN A BSL3 ENVIRONMENT. TOGETHER, THESE THREE CORES WILL SIGNIFICANTLY ENHANCE THE NEAR- AND LONG-TERM ABILITIES OF THE RBL TO ADDRESS CRITICAL BIOTHREATS AND EMERGING INFECTIOUS DISEASES REQUIRING STUDY IN A BSL3 LABORATORY SETTING, WHILE ALSO INCREASING OUR CAPACITY TO RESPOND TO THE NEXT PUBLIC HEALTH EMERGENCY OR PANDEMIC.

TB-RICC 3.0 - TB-RICC 3.0 IS DESIGNED TO SUPPORT THE REGIONAL PROSPECTIVE OBSERVATIONAL RESEARCH TUBERCULOSIS (REPORT) CONSORTIUM TO PRODUCE THE HIGHEST QUALITY OBSERVATIONAL AND INTERVENTIONAL RESEARCH ON TUBERCULOSIS (TB), TB-HIV, AND TB-COVID-19. TO ACCOMPLISH THIS GOAL, TB-RICC 3.0 WILL: I) COLLABORATE WITH REPORT COUNTRY-NETWORK DATA CENTERS AND BIOREPOSITORIES TO ENSURE THAT COMMON DATA ELEMENTS (CDE) OF THE COMMON PROTOCOL AND SPECIMEN TRACKING ARE ACCESSIBLE THROUGH THE GLOBAL DATA TEMPLATE; II) ORGANIZE AND/OR STRENGTHEN SELECT SITES TO PARTICIPATE IN DIAGNOSTIC STUDIES AND CLINICAL TRIALS; AND III) SUPPORT THE REPORT COUNTRY-NETWORKS TO ENSURE FURTHER DEVELOPMENT OF TB DIAGNOSTIC LABORATORIES, TB- RICC 3.0 SPECIALIZED LABORATORIES, AND BIOREPOSITORIES. AIMS OF TB-RICC 3.0 ARE: COORDINATING CENTER STRUCTURE AND FUNCTION: DEVELOP A LEADERSHIP GROUP AND EXECUTIVE COMMITTEE; ASSURE EFFECTIVE COMMUNICATION INTERNALLY AND EXTERNALLY; ESTABLISH A DATA HUB TO PROVIDE SEAMLESS DATA MANAGEMENT FROM COLLECTION TO ANALYSIS; ESTABLISH SCIENTIFIC WORKING GROUPS; A SCIENTIFIC REVIEW COMMITTEE AND AN ADMINISTRATIVE CORE; FACILITATE GRANT SUBMISSIONS TO POTENTIAL FUNDERS AND PARTNERS. DATA HARMONIZATION: DEVELOP A DATA HUB TO COLLABORATE WITH COUNTRY-LEVEL DATA CENTERS TO FACILITATE MULTIREGIONAL DATA WORKFLOW USING THE REDCAP HARMONIST PLATFORM AND OTHER TOOLS; RESEARCH: CATALYZE TB, TB/HIV AND TB/COVID-19 RESEARCH WITHIN AND ACROSS REPORT COUNTRY NETWORKS, AND WITH EXTERNAL PARTNERS; PRIORITIZE STUDY OF TB CLOSE CONTACTS TO EVALUATE BIOMARKERS PREDICTIVE OF PROGRESSION TO TB ACROSS THREE “OMICS” PLATFORMS AND THREE CONTINENTS; CAPACITY BUILDING: DEVELOP MODULAR REMOTE COURSES FOR CAPACITY BUILDING IN THE COMPONENTS OF TB RESEARCH; MENTOR EARLY-STAGE INVESTIGATOR (ESI) DEVELOPMENT. TB-RICC 3.0 WILL DELIVER HIGH-IMPACT INNOVATIVE RESEARCH TO ADVANCE TB SCIENCE AND TB CONTROL

HEALTH CENTER PROGRAM

RUTGERS-NYU CENTER FOR ASIAN HEALTH PROMOTION AND EQUITY - OVERALL – ABSTRACT IN RESPONSE TO RFA-MD-21-007, WE PROPOSE THE RUTGERS-NYU CENTER FOR ASIAN HEALTH PROMOTION AND EQUITY (CAHPE) TO ADVANCE INTERDISCIPLINARY RESEARCH ON COMORBID CARDIOMETABOLIC DISEASE AND MENTAL HEALTH OF ASIAN ADULTS. THERE ARE CURRENTLY SIGNIFICANT DISPARITIES IN RELATIONSHIP TO HEART AND MIND, WITH LOWER THRESHOLDS FOR BMI FOR ASIANS AND DISPROPORTIONATE DISPARITIES RELATED TO CARDIOMETABOLIC DISEASE AND MENTAL HEALTH. SUCH AN IMPORTANT FOCUS IN RESEARCH, POPULATION AND INVESTIGATORS WILL INFORM BOTH PRACTICE AND POLICY AT COMMUNITY, REGIONAL AND NATIONAL LEVELS. ASIANS ARE THE FASTEST GROWING YET MOST UNDERSTUDIED US MINORITY GROUP AT 23 MILLION PEOPLE AND GROWING 26% FROM 2010-2019. YET, < 1% OF NIH RESEARCH FUNDING IN THE LAST 10 YEARS WERE FOCUSED ON US ASIAN POPULATIONS. MOREOVER, THIS POPULATION EXPERIENCES THE “ASIAN PARADOX”: WHILE ON AVERAGE, US ASIANS, ARE THE HIGHEST-INCOME EARNERS AND THE MOST HIGHLY EDUCATED, MORE ASIANS, ESPECIALLY OLDER ADULTS, LIVE BELOW THE POVERTY LINE, ARE LESS LIKELY TO PARTICIPATE IN BIOMEDICAL RESEARCH, AND SUFFER DISPROPORTIONAL HEALTH DISPARITIES COMPARED TO WHITE AMERICANS. THESE HEALTH INEQUITIES ARE FURTHER COMPLICATED BY THE HETEROGENEITY OF THESE IMMIGRANT POPULATIONS, ESPECIALLY WITH RESPECT TO CULTURE, RELIGION, LANGUAGE, SEXUAL IDENTITY, AND TRAUMA EXPOSURE, MANY OF WHICH CHALLENGE OUR ASSUMPTIONS ABOUT THE “MODEL MINORITY” STEREOTYPE. BUILDING ON TWO DECADES OF RIGOROUS AGING RESEARCH IN MINORITY POPULATIONS AND TRACK RECORDS OF SUCCESSFUL ACADEMIC ACHIEVEMENTS, WE HAVE LEVERAGED STRONG EXISTING TRANSDISCIPLINARY PARTNERSHIPS ACROSS MULTIPLE ACADEMIC AND COMMUNITY INSTITUTIONS TO BUILD A CENTER DESIGNED TO FOSTER THE NEXT GENERATION OF DIVERSE RESEARCHERS IN A NURTURING ENVIRONMENT THAT IS CONDUCIVE TO SUCCESS AND PROMOTES HIGHLY RELEVANT AND RIGOROUS TRANSLATIONAL RESEARCH ON CARDIOMETABOLIC AND MENTAL HEALTH OUTCOMES AMONG US ASIANS. WITH STRONG INSTITUTIONAL SUPPORT OF $3 MILLION IN MATCHING FUNDS, OUR CENTER WILL HAVE FIVE INTER-CONNECTED AIMS: 1) PROVIDE LEADERSHIP, ORGANIZATIONAL COMMUNICATION, AND EVALUATION SYSTEMS DESIGNED TO ACHIEVE THE OVERARCHING GOALS OF SUPPORTING HIGH QUALITY AND ENDURING INTER-DISCIPLINARY RESEARCH ON CARDIOMETABOLIC AND MENTAL HEALTH OUTCOMES AMONG ASIAN ADULTS; 2) GUIDE SOLICITATION AND SELECTION OF 6 PILOT STUDIES PER YEAR; 3) IMPLEMENT THE THREE INTERDISCIPLINARY, TRANSLATIONAL, AND SYNERGISTIC R01-LIKE PROJECTS WITH SPECIFIC FOCUS ON: NUTRITIONAL, POSITIVE AFFECT, AND DEMENTIA CAREGIVING INTERVENTIONS TO MULTI-PRONG TARGET DIVERSE ASIAN POPULATION AT HIGH RISK; 4) ENHANCE, TRACK, AND EVALUATE EXISTING INFRASTRUCTURE TO SUPPORT AND SYNCHRONIZE THE PILOT AND CENTER PROJECTS; AND 5) DISSEMINATE THESE FINDINGS TO THE LOCAL, REGIONAL, AND NATIONAL LEVELS IN ORDER TO INFORM THE DESIGN OF FUTURE PREVENTION/INTERVENTION RESEARCH COMMODITIES. THE OVERALL AIMS OF THIS APPLICATION REFLECT THE SYNERGISTIC WORK OF THE ADMINISTRATIVE CORE (AC), INVESTIGATOR DEVELOPMENT CORE (IDC), COMMUNITY ENGAGEMENT CORE (CEC), AND RESEARCH PROJECTS.

MECHANISMS OF THE BRCA-NETWORK IN TUMORIGENESIS AND THERAPEUTIC RESPONSE - MECHANISMS OF THE BRCA-NETWORK IN TUMORIGENESIS AND THERAPEUTIC RESPONSE (OVERALL) ABSTRACT: THE FAITHFUL REPAIR OF DNA DAMAGE AND EFFICIENT RESOLUTION OF STALLED REPLICATION FORKS ARE FUNDAMENTAL MECHANISMS BY WHICH MAMMALIAN CELLS MAINTAIN DNA SEQUENCE FIDELITY AND CHROMOSOMAL INTEGRITY DURING DNA REPLICATION AND IN RESPONSE TO EXOGENOUS DNA DAMAGE. DEFECTS IN DNA REPAIR MECHANISMS NOT ONLY CONTRIBUTE TO GENOMIC INSTABILITY AND SUBSEQUENT TUMORIGENESIS, BUT ALSO CAN ALTER THE EPIGENETIC LANDSCAPE OF CELLS AND IMPART THERAPEUTIC VULNERABILITIES THAT CAN BE EXPLOITED CLINICALLY. THE INVESTIGATORS PARTICIPATING IN THIS P01 PROJECT SHARE COMMON INTERESTS IN UNDERSTANDING THE MECHANISMS BY WHICH CELLS MAINTAIN GENOMIC INTEGRITY TO SUPPRESS TUMORIGENESIS, AND IN EXPOSING TUMOR VULNERABILITY TO THERAPY BASED ON MECHANISTIC UNDERSTANDINGS OF THE GENOMIC CONSEQUENCES OF IMPAIRED DNA REPAIR. ONE PARTICULARLY STRONG AREA OF RESEARCH OFFERED BY THIS TEAM IS A MULTI-DISCIPLINARY APPROACH TO UNDERSTANDING THE BASIC MECHANISMS BY WHICH THE BRCA1-PALB2-BRCA2 COMPLEX AND ASSOCIATED REGULATORS PARTICIPATE IN REGULATING DNA REPLICATION AND REPAIR CHOICE. REGULATORS OF THE BRCA-NETWORK INCLUDE, 53BP1, RNF4, BARD1, TOPBP1, EHMT2 (G9A), MCM10, SLFN11 (MOUSE SLFN9), AND BCCIP. SOME OF THESE FACTORS HAVE BEEN A LONG-STANDING RESEARCH FOCUS FOR INVESTIGATORS IN THE PROJECT TEAM. THE RESEARCH COLLABORATION IS FORMED AROUND THE CENTRAL THEMES OF HOW MEMBERS OF THIS LARGE NETWORK OF PROTEINS INTERFACE WITH EACH OTHER TO MAINTAIN GENOME INTEGRITY, SUPPRESS TUMOR DEVELOPMENT AND MODULATE TUMOR RESPONSE TO CANCER THERAPY. FOUR PROJECTS, TWO SHARED RESOURCE CORES, AND AN ADMINISTRATIVE CORE ARE PROPOSED TO ACHIEVE THREE SCIENTIFIC GOALS: 1) TO REVEAL NOVEL MECHANISMS BY WHICH THE RECRUITMENT AND FUNCTION OF THE BRCA1-PALB2-BRCA2 NETWORK IS REGULATED BY CHROMATIN CONTEXT MEDIATED BY METHYLATION, SUMOYLATION, AND UBIQUITINATION; 2) TO REFINE THE ROLES OF THE BRCA NETWORK IN DNA REPLICATION, TUMOR SUPPRESSION AND DEFINE THE GENOMIC CONSEQUENCES OF BRCA DYSFUNCTION; AND 3) TO EXPLORE NEW OPPORTUNITIES TO TARGET DEFECTS IN THE BRCA NETWORK FOR THERAPEUTICS IN MEDULLOBLASTOMA AND BREAST CANCER.

OPIOD ANALGESIC REDUCTION STUDY (OARS): MANAGING ACUTE POST-OPERATIVE SURGICAL PAIN

RUTGERS CENTER OF EXCELLENCE IN RAPID SURVEILLANCE OF TOBACCO - ABSTRACT THE 2009 TOBACCO CONTROL ACT (TCA) GAVE THE FDA AUTHORITY TO REGULATE TOBACCO PRODUCTS TO PROTECT PUBLIC HEALTH BUT INITIALLY EXTENDED ONLY TO CIGARETTES. BY THE TIME OTHER PRODUCTS WERE DEEMED UNDER FDA AUTHORITY IN 2016, THE TOBACCO LANDSCAPE HAD CHANGED DRAMATICALLY, MAKING MODERN TOBACCO SURVEILLANCE INCREASINGLY COMPLEX. UNFORTUNATELY, THE CIGARETTE-CENTRIC TOBACCO SURVEILLANCE SYSTEMS IN THE US HAVE BEEN SLOW TO RESPOND TO THESE CHANGES. EVEN AFTER FORMAL CALLS FOR IMPROVEMENTS IN SMOKELESS TOBACCO AND CIGAR MEASUREMENT MORE THAN 20 YEARS AGO, STANDARDIZED MEASURES OF THESE PRODUCTS REMAIN SPARSE AND INSUFFICIENT. MOREOVER, DESPITE NUMEROUS EARLY WARNING SIGNALS, QUESTIONS ABOUT JUUL DID NOT APPEAR ON MAJOR NATIONAL SURVEYS SUCH AS NATIONAL YOUTH TOBACCO SURVEY UNTIL 2019, TWO FULL YEARS AFTER IT BECAME THE TOP- SELLING ENDS BRAND ON THE MARKET AND ENDS USE AMONG YOUTH HAD REACHED CONCERNING LEVELS. INDEED, RAPID ASSESSMENT AND RESPONSE TO CHANGES IN THE TOBACCO MARKET ARE ESSENTIAL TO INFORMING AND EVALUATING FDA’S CURRENT AND PENDING REGULATORY ACTIONS, INCLUDING PROPOSED PRODUCT STANDARDS (E.G., BANNING MENTHOL), PENDING MARKETING AUTHORIZATIONS FOR E-CIGARETTES, AND THE MODIFIED RISK TOBACCO PRODUCTS (MRTPS) PATHWAY. THEREFORE, INFORMED BY A CONCEPTUAL FRAMEWORK WHICH DRAWS UPON A TRADITIONAL PUBLIC HEALTH SURVEILLANCE PERSPECTIVE AS WELL AS FDA’S SENTINEL INITIATIVE, THIS U01 PROPOSAL ASSEMBLES A LARGE COLLABORATIVE NETWORK, WHICH INCLUDES A NETWORK OF SIX SENTINEL STATES THAT TRIANGULATES MULTIPLE DATA SOURCES TO ESTABLISH THE CENTER FOR RAPID SURVEILLANCE OF TOBACCO (CRST). THE CRST AIMS TO PERFORM RAPID SURVEILLANCE OF: 1) TOBACCO PRODUCT MARKETING, TO GENERATE SIGNALS OF INTEREST; 2) THE TOBACCO PRODUCT MARKETPLACE, TO GENERATE AND REFINE SIGNALS OF INTEREST; AND 3) CHANGES IN TOBACCO PRODUCT USE BEHAVIORS, TO GENERATE, REFINE, AND EVALUATE SIGNALS OF INTEREST. WE WILL IMPLEMENT AN OPTIMAL RAPID SURVEILLANCE SYSTEM OF TOBACCO THAT WILL ENHANCE FDA’S REGULATION OF TOBACCO PRODUCTS USING A RANGE OF METHODS AND SUBJECT MATTER EXPERTS TO RAPIDLY ASSESS MEANINGFUL CHANGES IN TOBACCO MARKETING, THE TOBACCO MARKETPLACE, AND TOBACCO USE. THE TEAM ASSEMBLED HAS DEEP EXPERIENCE WITH TOBACCO REGULATORY SCIENCE, SURVEILLANCE AND ANALYSES OF THESE DATA. WE ALSO HAVE EXTENSIVE EXPERIENCE OVERSEEING MULTI-SITE PROJECTS IN COLLABORATION WITH FEDERAL PARTNERS THAT SUPPORT OUR ABILITY TO CARRY OUT THE ADMINISTRATIVE ASPECTS OF CRST. OUR ONGOING ENGAGEMENT WITH FDA CTP, FEDERAL PARTNERS, AND CASEL AND DEEP KNOWLEDGE OF FDA’S REGULATORY AUTHORITY AND PROCESSES ENSURE THAT WE WILL NOT ONLY CONDUCT RAPID SURVEILLANCE, BUT ANTICIPATE CHANGES IN THE MARKET VIA EARLY SIGNAL DETECTION, AND DELIVER MEANINGFUL DATA TO INFORM FDA’S ACTIVITIES AND SUPPORT A SUBSTANTIAL PUBLIC HEALTH IMPACT. IN DOING SO, WE WILL ESTABLISH A NEW PARADIGM OF TOBACCO SURVEILLANCE, SERVE AS A RESOURCE ON SURVEILLANCE METHODS AND MEASURES, SUPPORT EVOLUTIONS IN TRADITIONAL SURVEILLANCE MEASURES, AND MEANINGFULLY ADVANCE THE FIELD OF TOBACCO REGULATORY SCIENCE.

REGULATION OF GENETIC COMPETENCE IN BACILLUS SUBTILIS

CARDIOPROTECTIVE EFFECTS OF THIOREDOXIN 1

BACTERIA AND HOST IN TB TRANSMISSION

TRAINING IN ENVIRONMENTAL TOXICOLOGY

IBD GENE MAPPING BY CLINICAL AND POPULATION SUBSETS

MECHANISTIC STUDIES OF NUCLEIC ACID ENZYMES INVOLVED IN DNA REPLICATION, TRANSCRIPTION, AND INNATE IMMUNITY

TRANSGENERATIONAL INHERITANCE OF A COCAINE RESISTANCE PHENOTYPE

LATINO ANCESTRY GENOMIC PSYCHIATRY COHORT

AIDS EDUCATION AND TRAINING CENTERS PROGRAM

ASSAY AND DATA GENERATION CENTER (ADGC) FOR THE MODEL OF IPSC-DERIVED NEURONS FOR NPD (MINND) - PROJECT SUMMARY/ABSTRACT IN THE PAST DECADE, THE SCIENTIFIC COMMUNITY HAS WITNESSED ACCELERATED GENETIC DISCOVERIES FOR NEURODEVELOPMENTAL AND PSYCHIATRIC DISORDERS (NPD) SUCH AS SCHIZOPHRENIA (SZ), AUTISM SPECTRUM DISORDER (ASD), BIPOLAR DISORDER, AND MAJOR DEPRESSION. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND WHOLE-EXOME SEQUENCING (WES) HAVE IDENTIFIED A MOUNTING NUMBER OF NPD RISK GENES. HOWEVER, TRANSLATING THESE EXCITING GENETIC DISCOVERIES INTO CLINICALLY ACTIONABLE BIOLOGY HAS BEEN IMPEDED BY OUR LIMITED KNOWLEDGE OF GENE FUNCTION AND RELATED DISEASE MECHANISMS. A BOTTLENECK IN THE FIELD IS THAT MOST BIOLOGICAL CHARACTERIZATION HAS FOCUSED ON VERY FEW NPD GENES, WHICH HAVE NOT NECESSARILY BEEN SELECTED FOR STUDY BASED ON PATHOPHYSIOLOGICAL IMPORTANCE. FURTHERMORE, GENES ARE OFTEN STUDIED ONE AT A TIME, HINDERING THE PACE OF OUR UNDERSTANDING OF DISEASE MECHANISMS. WE PROPOSE AN ALTERNATIVE STRATEGY: LARGE-SCALE, UNBIASED, PARALLEL STUDY OF NPD GENES IN DISEASE-RELEVANT MODEL SYSTEMS, IN RESPONSE TO THE RFA-MH-22-111 (SCALABLE AND SYSTEMATIC NEUROBIOLOGY OF PSYCHIATRIC AND NEURODEVELOPMENTAL DISORDER RISK GENES-SSPSYGENE). WE PROPOSE TO ESTABLISH THE ASSAY AND DATA GENERATION CENTER (ADGC) FOR THE MODEL OF INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED NEURONS FOR NPD (MINND), WHERE WE WILL IMPLEMENT AND OPTIMIZE NOVEL SCALABLE AND SYSTEMATIC ASSAYS FOR INTERROGATING THE MOLECULAR AND NEUROBIOLOGICAL FUNCTIONS OF UP TO 200 NPD RISK GENES. TEAMING UP WITH THE SSPSYGENE CONSORTIUM AND LEVERAGING OUR TEAM’S RESPECTIVE EXPERTISE IN STEM CELL BIOLOGY, FUNCTIONAL GENOMICS, NEUROSCIENCE, AND FUNCTIONAL ANALYSIS, OUR MINND-ADGC WILL GENERATE LOSS-OF-FUNCTION (LOF) IPSC HUMAN NEURAL MODELS, AND PERFORM HIGH-CONTENT MORPHOMETRIC AND SINGLE-CELL TRANSCRIPTOMIC (SCRNA-SEQ) ANALYSES OF NPD LOF ALLELES. WE WILL ALSO ASSAY SYNAPTIC FUNCTIONS USING OPTICAL SENSORS IN A HIGH-THROUGHPUT FASHION AND CARRY OUT MULTIMODAL PATCHSEQ ANALYSES AND MODELING TO PREDICT NEURONAL PROPERTIES FROM SCRNA-SEQ DATA. FINALLY, WORKING WITH THE SSPSYGENE CONSORTIUM, WE WILL CONDUCT DATA INTEGRATION, CURATION, AND DISSEMINATION TO THE RESEARCH COMMUNITY AND PUBLIC FOR FURTHER ANALYSIS. OUR MINND-ADGC WILL BUILD A VALUABLE RESOURCE AND INTEGRATED KNOWLEDGE BASE THAT WILL PROVIDE A FERTILE FOUNDATION FOR FUTURE STUDIES OF DISEASE MECHANISMS. THE DATA FROM STUDYING THE SELECTED NPD RISK GENES ON MULTIPLE GENETIC BACKGROUNDS, INCLUDING THE UNDERSTUDIED AFRICAN AMERICAN IPSC LINES, WILL ENABLE ROBUST INFERENCES OF POTENTIAL CROSS-DISORDER AND CROSS-POPULATION BIOLOGICAL CONVERGENCE AND DIVERGENCE RELEVANT TO NPD.

SPECIAL PROJECTS OF NATIONAL SIGNIFICANCE

REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY

AIDS EDUCATION AND TRAINING CENTERS PROGRAM

ACTIVATED MACROPHAGES AND OZONE TOXICITY

NOVEL AND OPTIMIZED DIAGNOSTICS FOR PEDIATRIC TB

MULTILEVEL STRATEGIES TO UNDERSTAND AND MODIFY THE ROLE OF STRUCTURAL AND ENVIRONMENTAL CONTEXT ON HIV INEQUITIES FOR SEXUAL AND GENDER MINORITIES OF COLOR - PROJECT SUMMARY/ABSTRACT BLACK, LATINO/A/E/X, AND MULTIRACIAL (BLM) SEXUAL AND GENDER MINORITIES WHO HAVE SEX WITH MEN (SGMSM) IN THE U.S. CONTINUE TO EXPERIENCE A HIGH AND DISPROPORTIONATE BURDEN OF HIV, PARTICULARLY YOUNGER BLM SGMSM FOR WHOM HIV INCIDENCE CONTINUES TO RISE DESPITE ADVANCES IN HIV PREVENTION. EVIDENCE SUGGESTS THAT DIFFERENCES IN INDIVIDUAL RISK BEHAVIORS DO NOT ACCOUNT FOR HIV INEQUITIES, AND UNDERSCORE THE NEED TO MOVE BEYOND MODELS OF INDIVIDUAL-LEVEL RISK FACTORS TO IDENTIFY AND INTERVENE UPON THE SOCIO-STRUCTURAL FACTORS THAT CREATE AND MAINTAIN INEQUITABLE RISK ENVIRONMENTS. HOWEVER, MUCH OF THE RESEARCH TO DATE IS LIMITED IN SCOPE AND FOCUSES INDIVIDUAL-LEVEL RISK OR ON CROSS-SECTIONAL HIV PREVALENCE, WHICH LIMITS THE ABILITY TO TREAT SOCIO- STRUCTURAL FACTORS AS DYNAMIC OR TO INVESTIGATE THE ENVIRONMENTS WITHIN WHICH RISK BEHAVIORS OCCUR. WE ARE SUBMITTING THIS APPLICATION IN RESPONSE TO RFA-AI-21-018 LIMITED INTERACTION TARGETED EPIDEMIOLOGY TO ADVANCE HIV PREVENTION (UG3/UH3). WE PROPOSE TO ENROLL A COHORT OF APPROXIMATELY 5,500 BLM SGMSM AGES 16 AND OLDER IN THE U.S. AND PUERTO RICO WHO ARE AT HIGH RISK FOR HIV INFECTION. WE WILL USE A COMBINED APPROACH TO RECRUITMENT (SEXUAL NETWORKING APPS, SOCIAL MEDIA, AND OTHER DIGITAL RECRUITMENT TECHNIQUES) THAT IS ADAPTIVE TO KNOWN SHIFTS IN DIGITAL TECHNOLOGY. PARTICIPANTS WILL COMPLETE A SURVEY AND HOME-BASED SAMPLING FOR LAB-BASED HIV TESTING AT ENROLLMENT AND ANNUALLY THEREAFTER FOR THREE YEARS AND AN ECOLOGICAL MOMENTARY ASSESSMENT (EMA) FOR SIX WEEKS AFTER ENROLLMENT. CONCORDANT WITH STUDY ENROLLMENT, WE WILL DEVELOP NOVEL METRICS TO QUANTIFY SOCIO-STRUCTURAL FACTORS (STATE-LEVEL POLICY AND SOCIAL CLIMATE INDICATORS) THAT CREATE INTERSECTIONAL OPPRESSION FOR BLM SGMSM, SPECIFICALLY STRUCTURAL RACISM, ANTI-LGBTQ STIGMA, AND RESTRICTIVE HIV-RELATED HEALTHCARE (AIM 1A). WE WILL SUBSEQUENTLY UTILIZE THE NEWLY DEVELOPED METRICS FROM AIM 1A ALONG WITH LOCAL SOCIO-STRUCTURAL FACTORS (LOCAL-LEVEL HIV PREVALENCE AND SOCIOECONOMIC INDICATORS) AND BASELINE AND EMA DATA TO TEST THE INEQUITABLE RISK ENVIRONMENTS HYPOTHESIS TO UNDERSTAND THE ROLE OF STATE AND LOCAL SOCIO- STRUCTURAL RISK FACTORS IN HIV RISK—THIS HYPOTHESIS WILL SPECIFICALLY TEST BOTH THE IMPACT OF SOCIO-STRUCTURAL FACTORS ON DAILY EXPOSURE TO INTERSECTIONAL STIGMA AND THE INTERACTION OF SOCIO-STRUCTURAL RISK WITH INDIVIDUAL BEHAVIORS ON UNDIAGNOSED HIV INFECTION AT BASELINE (AIM 2). THESE DATA WILL ALSO BE USED TO TEST A LONGITUDINAL MODEL OF MECHANISMS THROUGH WHICH STATE AND LOCAL SOCIO-STRUCTURAL FACTORS DIRECTLY AND INDIRECTLY INFLUENCE HIV SEROCONVERSION AND ACCESS TO EMERGING HIV PREVENTION TECHNOLOGIES (E.G., EMERGING PREP MODALITIES) (AIM 3). STUDY FINDINGS WILL BE SYSTEMATICALLY REVIEWED AND TRANSLATED INTO GUIDELINES FOR ENDING THE HIV EPIDEMIC- RELATED PUBLIC HEALTH POLICY AND COMMUNITY-LEVEL INTERVENTIONS TO REDUCE HIV INEQUITIES (AIM 1B). DEVELOPING AND TESTING A SOCIO-STRUCTURAL MODEL OF HIV RISK HAS STRONG POTENTIAL TO MOVE THE FIELD BEYOND INDIVIDUALLY- FOCUSED MODELS OF RISK AND IMPROVE THE NEXT GENERATION OF HIV PREVENTION INTERVENTIONS AIMED AT REDUCING DISPARITIES FOR THIS POPULATION.

NUCLEAR EVENTS IN PTH ACTION ON BONE CELLS

AIDS EDUCATION AND TRAINING CENTERS PROGRAM

ROLE OF INTEGRIN A5 IN THE DEVELOPMENT OF AORTIC ARCH ARTERIES.

IDENTIFICATION OF METABOLIC VULNERABILITIES OF RAS-DRIVEN CANCER CELLS

ROLE OF PALB2 IN THE DNA DAMAGE RESPONSE AND BREAST CANCER SUPPRESSION

TARGETING RETROVIRAL AND VIRUS-LIKE PARTICLES FOR GENE AND PROTEIN DELIVERY

HIV-1 REVERSE TRANSCRIPTASE STRUCTURE: FUNCTION, INHIBITION, AND RESISTANCE

THE ROLE OF INOSITOL IN CRYPTOCOCCUS BIOLOGY AND PATHOGENESIS

NOVEL LYSOSOMAL ENZYME DEFICIENT IN BATTEN DISEASE

REGULATION OF THE INTESTINAL CA2+ CHANNELS TRPV6

MICROBIAL, IMMUNE, METABOLIC PERTURBATIONS BY ANTIBIOTICS (MIME STUDY)

AIR POLLUTION PARTICLE EFFECTS ON HUMAN ANTIMYCOBACTERIAL IMMUNITY

FUNCTIONAL GENOMICS OF THE HUMAN CONNECTOME IN PSYCHIATRIC ILLNESS

DECIPHERING THE NEURAL BASIS OF ALCOHOL USE DISORDERS USING HUMAN AND MOUSE NEURONS

REMOVAL OF DAMAGED MITOCHONDRIA BY ALTERNATIVE AUTOPHAGY

ADOPTION, DIFFUSION, AND IMPLEMENTATION OF TOBACCO 21 POLICIES TO ADDRESS HEALTH DISPARITIES

MECHANISMS OF VACCINE PROTECTION AGAINST AIDS-ASSOCIATED CRYPTOCOCCUS INFECTION

TB CENTERS OF EXCELLENCE FOR TRAINING, EDUCATION, AND MEDICAL CONSULTATION - OBJECTIVE IS TO INCREASE, EXPAND, AND UTILIZE RUTGERS GLOBAL TUBERCULOSIS INSTITUTE'S CURRENT INFRASTRUCTURE AND PROGRAMMING TO MEET THE PROJECT GOAL. CURRENT PROGRAMS INCLUDE TRAINING ACTIVITIES, PRODUCT DEVELOPMENT, COLLABORATING WITH OTHER CENTERS OF EXCELLENCE TO OPTIMIZE RESOURCES, AND PROVIDING MEDICAL CONSULTATION TO HEALTHCARE PROVIDERS AND THOSE SERVICING HIGH RISK POPULATIONS FOR TB AND LATENT TB INFECTION (LTBI). OUTCOMES 1) AN INCREASED NUMBER OF EDUCATED AND TRAINED HEALTH CARE WORKERS IN PUBLIC HEALTH PROGRAMS, THE COMMUNITY, AND INPATIENT SETTINGS WHO WORK WITH PERSONS WITH TB OR THOSE AT RISK OF LTBI 2) INCREASED ACCESS AND USE OF TB EDUCATIONAL RESOURCES THROUGH THE DEVELOPMENT OF RELEVANT, NEEDS BASED COURSES AND MATERIALS IN USER FRIENDLY FORMATS WHICH INCLUDES MATERIALS FOR PROVIDERS TO EDUCATE PERSONS WITH TB AND LTBI 3) INCREASED AND EXPANDED AVAILABILITY OF EXPERT CONSULTATIONS TO COMMUNITY PROVIDER NETWORKS SERVING POPULATIONS AT HIGH RISK FOR TB AND LTBI AND 4) INCREASED UNDERSTANDING OF NATIONAL TRENDS OF TB PATIENT CARE NEEDS THROUGH THE ASSESSMENT OF PROGRAM DATA AND DATA COLLECTED AND ANALYZED FROM THE MEDICAL CONSULTATION SYSTEM (ID CROWD) FOR ONE TIME AND LONGITUDINAL CONSULTATIONS.

STIMULUS CONTROL REFINEMENTS OF FCT INTERVENTIONS FOR DESTRUCTIVE BEHAVIOR IN ID

THE RV2623-RV1747 INTERACTION: REGULATION OF THE IN VIVO FATE OF M. TUBERCULOSIS

ROLE OF OREXIN IN COCAINE DEMAND AND ADDICTION

MITOCHONDRIA-CYTOPLASM INTERACTIONS FOR CYTOSOLIC FE-S CLUSTER ASSEMBLY

BRIGHT IDEAS-YOUNG ADULTS: PROBLEM-SOLVING SKILLS TRAINING TO REDUCE DISTRESS AMONG YOUNG ADULTS WITH CANCER

THE ADAPTOR PROTEIN CRK IN IMMUNE RESPONSES

MECHANISM OF ECM REGULATION OF ACTIN NUCLEATION DURING MORPHOGENESIS.

SPECIAL PROJECTS OF NATIONAL SIGNIFICANCE

EXPOSURE TO PFNA AND OTHER PFAS IN DRINKING WATER AND ASSOCIATIONS WITH HEALTH-RELATED OUTCOMES IN GLOUCESTER COUNTY NJ

RUTGERS OPTIMIZES INNOVATION (ROI) PROGRAM

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

NUTRIGENOMICS OF INTESTINAL VITAMIN D ACTION

DRUG TARGET VALIDATION OF THE ENTEROVIRUS D68 2A PROTEASE

STUDIES OF DEMENTIA PATHOGENESIS IN GENETICALLY FAITHFUL RAT MODELS OF FAMILAL ALZHEIMER DISEASE

ENHANCED POC ASSAY FOR TB IN HIV-INFECTED CHILDREN BASED ON THE ULTRASENSITIVE DETECTION OF THE URINARY FORM OF THE LIPOARABINOMANNAN ANTIGEN

ARE MECHANISMS LEADING TO FAD, SAD AND AGE-ASSOCIATED COGNITIVE DECLINE SIMILAR?

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

TREM2-MEDIATED MICROGLIA-NEURONAL AXIS IN ALZHEIMER DISEASE PATHOGENESIS - ABSTRACT ALZHEIMER’S DISEASE (AD) IS THE MOST COMMON CAUSE OF AGEING-DEPENDENT DEMENTIA IN THE WORLD AND IS ASSOCIATED WITH CEREBRAL AMYLOID PLAQUES, MOSTLY COMPOSED OF ASS PEPTIDES, AND INTRANEURONAL NEUROFIBRILLARY TANGLES, MOSTLY COMPOSED BY HYPERPHOSPHORYLATED TAU. THE IMPACTS OF AD ON PATIENTS, FAMILIES, CAREGIVERS AND SOCIETY ARE SHATTERING. REGRETTABLY, AD-MODIFYING DRUGS ARE UNAVAILABLE UNDERSCORING THE SCANT UNDERSTANDING OF AD PATHOGENESIS. ~5% OF AD CASES HAVE EARLY ONSET (<65 YO) AND ARE DUE TO FAMILIAL AUTOSOMAL DOMINANT MUTATIONS IN APP, PSEN1 AND PSEN2 (FAD); ~95% OF CASES ARE SPORADIC WITH LATE ONSET (>65 YO, SAD). YET, COMMONLY USED ANIMAL ORGANISMS MODEL FAD. THIS MAY BE AN ISSUE IF FAD AND SAD PRESENT SIGNIFICANT PATHOGENIC DIFFERENCES. IF SO, THERAPEUTICS EFFECTIVE IN FAD ANIMALS MAY HAVE LIMITED EFFICACY IN SAD PATIENTS. THUS, MODELS THAT REPRODUCE THE PATHOGENESIS OF SAD ARE NEEDED TO IDENTIFY THERAPEUTIC TARGETS AND TEST SAD-MODIFYING THERAPEUTICS. VARIANTS OF THE MICROGLIA GENE TREM2 INCREASE THE RISK OF SAD BY 3 FOLD. TO GAIN INSIGHTS INTO THE PATHOGENIC MECHANISMS OF SAD, WE GENERATED RATS CARRYING THE P.R47H PATHOGENIC VARIANT IN THE RAT TREM2 GENE (TREM2R47H). RAT AND HUMAN APP DIFFER BY 3 AMINO ACIDS IN THE ASS REGION. THESE DIFFERENCES MAY BE CRUCIAL IN THIS MODEL ORGANISM BECAUSE: 1) HUMAN ASS POSSESSES HIGHER PROPENSITY TO FORM TOXIC SPECIES AS COMPARED TO RODENT ASS; 2) THE PATHOGENIC ROLE OF THE P.R47H TREM2 VARIANT MAY BE LINKED TO DEFICITS IN MICROGLIA-MEDIATED HUMAN ASS CLEARANCE. TO OVERCOME THIS ISSUE, WE HUMANIZED THE RAT ASS SEQUENCE (APPH ALLELE); THUS, OUR RAT MODELS PRODUCE HUMAN ASS FROM THE ENDOGENOUS RAT APP GENE. WE CHOOSE A KNOCK IN (KI) APPROACH RATHER THAN THE MORE COMMON TRANSGENIC OVEREXPRESSION APPROACH BECAUSE KI MODELS MAKE NO PRECONCEIVED ASSUMPTION ABOUT PATHOGENIC MECHANISMS, EXCEPT THE UNBIASED GENETIC ONE. IN CONTRAST, TRANSGENIC MODELS, WHICH PRODUCE HIGH LEVELS OF AB AND CAN READILY DEPOSIT AMYLOID PLAQUES, ARE BASED ON THE HYPOTHESIS THAT PLAQUES AND/OR OTHER FORMS OF TOXIC AB HAVE A CENTRAL PATHOGENIC ROLE. WE PROPOSE TO DISSECT PATHOGENIC MECHANISMS TRIGGERED BY THE P.R47H PATHOGENIC VARIANT USING THESE KI RAT MODELS. WE WILL ALSO STUDY THE IMPACT OF TREM2R47H ON THE PATHOLOGICAL PROCESSES TRIGGERED BY THE APPS AND PSEN1LF FAD MUTATIONS. WE WILL ANALYZE MICROGLIA FUNCTION, CELL-TO-CELL TRANSCRIPTOMIC CHANGES IN THE BRAIN, APP PROCESSING, BRAIN PATHOLOGY, NEURO-INFLAMMATION AND NEURODEGENERATION, SYNAPTIC TRANSMISSION/PLASTICITY, LEARNING & MEMORY. DISSECTING PATHOGENIC PATHWAYS SET OFF BY THE TREM2R47H VARIANT MAY PAVE THE WAY TO THERAPEUTIC APPROACHES THAT CAN PREVENT/DELAY SPORADIC AD.

ADVANCED DEVELOPMENT OF DRUGS TO MITIGATE PARATHION INTOXICATION

ADVANCED DEVELOPMENT AND UTILIZATION OF ASSEMBLED AGING TRAJECTORY FILES FROM MULTIPLE DATASETS - PROJECT SUMMARY THIS GOAL OF THIS PROJECT IS TO CREATE A UNIQUE AND COMPREHENSIVE RESEARCH REPOSITORY OF AGING TRAJECTORY DA- TASETS, RELATED RESOURCES, AND ANALYTIC METHODS THAT CAN BE USED TO ANSWER NEW AND IMPORTANT QUESTIONS IN AGING AND RELATED SCIENCES. SPECIFICALLY, BY HARMONIZING AND MERGING MULTIPLE DATA SETS THIS PROJECT WILL GENER- ATE THE DATA INFRASTRUCTURE NEEDED TO UNDERSTAND CHANGE OVER TIME IN CARE SETTINGS, GERIATRIC SYNDROMES, PHYSI- CAL FUNCTIONING, AND SHARED RISK FACTORS AT MULTIPLE LEVELS (PATIENT, PROVIDER, COMMUNITY, HEALTHCARE SYSTEM, AND SOCIETY) AND ACROSS MULTIPLE DOMAINS (BIOLOGICAL, BEHAVIORAL, SOCIOCULTURAL, AND PHYSICAL/BUILT ENVIRONMENTS) INCLUDING CHRONIC CONDITIONS AND HISTORY OF ACUTE ILLNESS SUCH AS COVID-19, EXPOSURE TO AIR POLLUTION, NEIGHBOR- HOOD SOCIOECONOMIC, AND HEALTH CARE SYSTEM FACTORS (AIM 1). ANALYTIC STRATEGIES WILL BE DEVELOPED FOR USER- DEFINED COHORTS AND THEIR PROPENSITY SCORE-MATCHED CONTROLS, E.G., OLDER ADULTS WHO WERE LIVING WITH CHRONIC CONDITIONS INCLUDING ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD), DIABETES, HEART FAILURE, END-STAGE RE- NAL DISEASE, METASTATIC CANCER, AND HIV. STATE-OF-THE-ART ANALYTIC METHODS ARE USED TO IDENTIFY PATTERNS OF AG- ING TRAJECTORIES (CARE SETTING, GERIATRIC SYNDROMES, PHYSICAL FUNCTIONING) EXPERIENCED BY OLDER ADULTS DURING THE FINAL YEARS OF LIFE AND THEIR ASSOCIATION WITH SHARED RISK FACTORS AND DISTAL OUTCOMES (AIM 2). FROM THE ASSEM- BLED TRAJECTORY FILE IN AIM 1, COHORTS ARE DERIVED BY ALIGNING AN ORIGINATING INDEX TIME SUCH AS AGE CUTOFF POINT AND TIME AT DIAGNOSIS (E.G., ADRD, STROKE, CHRONIC KIDNEY DISEASE). BOTH A MODEL-BASED APPROACH AND MA- CHINE LEARNING ALGORITHMS ARE THEN USED TO DISCOVER MULTILEVEL AND POTENTIALLY INTERACTIVE PREDICTORS OF TRAJECTO- RIES (E.G., RAPID FUNCTIONAL DECLINE IN INDEPENDENT LIVING BENEFICIARIES) AND SPECIFIC OUTCOMES (E.G., RESPIRATORY VENTILATOR USAGE AMONG MEDICARE BENEFICIARIES DIAGNOSED WITH COVID-19) (AIM 3). THE UNIQUE RESOURCES ARE THEN SHARED TO DISSEMINATE RESOURCES INCLUDING DATASETS, DOCUMENTATION, SOURCE CODE, AND METHODOLOGY (AIM 4). AT THE END OF THIS PROJECT, THE RESEARCH INFRASTRUCTURE TO INVESTIGATE THE RELATIONSHIP BETWEEN SHARED RISK FACTORS AND AGING TRAJECTORIES WILL BE READY TO USE AND REPLICATE, GIVING INVESTIGATORS UNPRECEDENTED ABILITY TO SOLVE NEW CHALLENGES IN AGING SCIENCE. THIS WILL ALLOW RESEARCHERS TO UNDERSTAND THE UNDERLYING PROCESSES AND SYSTEMS ASSOCIATED WITH REVERSIBLE PERIODS OF DISABILITY ACROSS CARE SETTINGS, AND INTERVENTIONS THAT MAY BE USED TO SUPPORT RECOVERY OF FUNCTION AND REDUCTION OF GERIATRIC SYNDROMES INCLUDING COGNITIVE DECLINE, FOR THE PURPOSE OF REDUCING BURDENSOME CARE TRANSITIONS, AND MAINTENANCE OF FUNCTIONAL INDEPENDENCE. THIS PROJECT WILL ALSO CREATE THE RESOURCES AND METHODS NEEDED TO EVALUATE THE IMPACT OF INNOVATIONS AND INTERVENTIONS IM- PLEMENTED AT THE PATIENT, PROVIDER, COMMUNITY, HEALTHCARE SYSTEM, AND SOCIETY/POLICY LEVELS TO IMPROVE CARE QUALITY AND OUTCOMES FOR OLDER ADULTS.

INNATE IMMUNE MECHANISMS AT THE MATERNAL-FETAL INTERFACE IN NORMAL AND SUPEROVULATORY PREGNANCY

PROVIDE TECHNICAL ASSISTANCE IN SUPPORT OF HIV PREVENTION, CARE AND TREATMENT

ROLE OF PDE2A IN MITOCHONDRIAL DYSFUNCTION IN ALZHEIMER?S DISEASE - PROJECT SUMMARY/ABSTRACT COMPELLING EVIDENCE SUGGESTS THAT MITOCHONDRIAL DYSFUNCTION IS AN EARLY FEATURE IN SUSCEPTIBLE NEURONS IN THE BRAINS OF PATIENTS WITH ALZHEIMER’S DISEASE (AD) AND PLAYS A CRITICAL ROLE IN PATHOGENESIS, YET THE UNDERLYING MOLECULAR MECHANISMS REMAIN INCOMPLETELY UNDERSTOOD. PHOSPHODIESTERASES (PDES) ARE A SUPERFAMILY OF ENZYMES RESPONSIBLE FOR THE HYDROLYSIS OF CAMP AND CGMP, SECOND MESSENGERS THAT REGULATE IMPORTANT CELLULAR FUNCTIONS. INTERESTINGLY, RECENT STUDIES DEMONSTRATED THAT CAMP/CGMP-PKA/PKG SIGNALING IS INVOLVED IN THE REGULATION OF MITOCHONDRIAL DYNAMICS AND EXPRESSION/ASSEMBLY OF KEY ENZYMES IN THE ELECTRON TRANSPORT CHAIN (ETC) AND MITOCHONDRIAL RESPIRATION. AMONG THE MANY PDES, PDE2A IS THE MOST HIGHLY EXPRESSED PDE IN THE HIPPOCAMPUS AND FRONTAL/TEMPORAL CORTEX, BRAIN REGIONS VULNERABLE TO AD. OUR PRELIMINARY STUDIES FOUND INCREASED PDE2A EXPRESSION IN THE BRAINS OF AD PATIENTS AND APP/PS1 MICE (AN AD MODEL), ACCOMPANIED BY DECREASED CAMP AND CGMP IN BOTH CYTOSOL AND MITOCHONDRIA MATRIX, IMPLICATING THE POTENTIAL INVOLVEMENT OF AN ABERRANT PDE2A-CAMP/CGMP SIGNALING IN THE PATHOGENESIS OF AD. MULTIPLE STUDIES, INCLUDING OURS, DEMONSTRATED COGNITIVE ENHANCING EFFECT OF PDE2A INHIBITORS, ALTHOUGH THE UNDERLYING MECHANISM REMAINS ELUSIVE. IN THIS REGARD, OUR PRELIMINARY STUDIES REVEALED THAT PDE2A OVEREXPRESSION IMPAIRED MITOCHONDRIAL FUNCTION ACCOMPANIED BY EXTENSIVE MITOCHONDRIAL FRAGMENTATION. IMPORTANTLY, ASS-INDUCED MITOCHONDRIAL FRAGMENTATION AND RESPIRATORY DEFICITS COULD BE RESCUED BY A PDE2A INHIBITOR, SUGGESTING MITOCHONDRIAL DYNAMICS AND FUNCTION COULD BE MECHANISM OF ACTION FOR PDE2A TO INFLUENCE COGNITION. BASED ON THESE STUDIES, WE HYPOTHESIZED THAT ABERRANT PDE2A SIGNALING CAUSED MITOCHONDRIAL DYSFUNCTION WHICH ADVERSELY IMPACTED NEURONAL/SYNAPTIC FUNCTION AND CAUSED PATHOLOGICAL/COGNITIVE DEFICITS IN AD. NOVEL ANIMAL MODELS WITH PDE2A CONDITIONAL KNOCKOUT IN THE FOREBRAIN WILL BE CROSSED WITH DIFFERENT AD TRANSGENIC MOUSE MODELS AND CAREFULLY CHARACTERIZED. THE ROLE OF PDE2A2, THE PDE2A ISOFORM UNIQUELY LOCALIZED TO MITOCHONDRIA, IN BRAIN FUNCTION AND BEHAVIOR IN AD MOUSE MODELS WILL ALSO BE DETERMINED. FINALLY, BASED ON THE LITERATURE AND OUR PRELIMINARY STUDY, WE PROPOSE TO EXPLORE THE MECHANISM UNDERLYING THE EFFECTS OF ABERRANT PDE2A EXPRESSION ON MITOCHONDRIAL DYSFUNCTION WITH A FOCUS ON MITOCHONDRIAL DYNAMICS AND THE EXPRESSION/ASSEMBLY OF MITOCHONDRIAL ETC COMPLEXES. OUR PROPOSED STUDIES WILL PROVIDE MECHANISTIC INSIGHTS INTO MOLECULAR MECHANISMS UNDERLYING MITOCHONDRIAL DYSFUNCTION IN AD AND DEEPEN OUR UNDERSTANDING OF PDE2A IN THE REGULATION OF COGNITION IN THE BRAIN. THE SUCCESSFUL COMPLETION OF THIS STUDY WILL LIKELY PAVE THE WAY FOR FUTURE DRUG DEVELOPMENT OF PDE2A INHIBITORS, SPECIFICALLY FOR THE MITOCHONDRIAL PDE2A2 ISOFORM, AS A PROMISING TREATMENT FOR AD.

MECHANISM OF PROTEOTOXICITY AND EXPERIMENTAL THERAPEUTIC APPROACHES IN PORPHYRIA

SEX DIFFERENCE IN INTESTINAL IMMUNE DYSFUNCTION, SHIV INFECTION AND RESERVOIR - PROJECT SUMMARY GASTROINTESTINAL MALFUNCTIONS AND IMMUNE ACTIVATION REMAIN SIGNIFICANT HEALTH ISSUES FOR PEOPLE LIVING WITH HIV/AIDS IN THE ERA OF ANTI-RETROVIRAL THERAPY (ART). IMMUNE ACTIVATION FUELS HIV RESERVOIRS THAT ARE ESTABLISHED EARLY DURING INFECTION AND SUPPORT VIRUS REBOUND AFTER ART INTERRUPTION (ATI). INCREASING EVIDENCE POINTS TOWARD SEX DIFFERENCES IN HIV PATHOGENESIS, DISEASE PROGRESSION, AND PERSISTENCE. IDENTIFYING SEX-SPECIFIC IMMUNE PARAMETERS ASSOCIATED WITH VIRAL PERSISTENCE AND REBOUND WILL BE CRITICAL TO OUR LONG TERM GOAL OF DEVELOPING PERSONALIZED THERAPEUTIC STRATEGIES TO RELIABLY HALT HIV-ASSOCIATED CHRONIC DISEASES, AND TO TARGET HIV RESERVOIRS. IN SUBJECTS WITHOUT ART, WOMEN HAVE HIGHER LEVELS OF IMMUNE ACTIVATION THAN MEN AND HAVE A HIGHER RISK OF DEVELOPING AIDS. SEX DIFFERENCES IN IMMUNE ACTIVATION IN HIV-INFECTED SUBJECTS ON ART ARE LESS DEFINITIVE, POSSIBLY DUE TO CONFOUNDING FACTORS, INCLUDING GENDER (INVOLVING SOCIAL/BEHAVIOR FACTORS) DIFFERENCES IN SEEKING TREATMENT. RECENT EVIDENCE IDENTIFYING ESTROGEN RECEPTOR 1 AS A KEY REGULATOR OF HIV LATENCY IN CD4+ T CELLS SUGGESTS THE INVOLVEMENT OF ESTROGEN SIGNALING IN SEX-BASED DIFFERENCES IN HIV PERSISTENCE. HOWEVER, THE ROLE OF ESTROGEN IN HIV PERSISTENCE IN VIVO REMAINS UNKNOWN, AS ESTROGEN INDUCES TYPE I IFNS AND OTHER PRO- INFLAMMATORY CYTOKINES, RESULTING IN IMMUNE ACTIVATION. RESEARCH IN THIS AREA HAS BEEN LACKING A RELIABLE ANIMAL MODEL. IN THAT REGARD, WE HAVE DEVELOPED A RHESUS MACAQUE (RM) MODEL THAT MIMICS KEY FEATURES OF HUMAN HIV INFECTION PROVIDING PROMISING AVENUES FOR PURSUING SEX-BASED DIFFERENCE STUDIES. THE MODEL, WHICH EMPLOYS R5 SHIV C109 INTRARECTAL CHALLENGE, DISPLAYS A SPECTRUM OF DISEASE OUTCOMES SIMILAR TO HUMAN AIDS. IN THIS MODEL, FAST DISEASE PROGRESSION OCCURS IN FEMALES ONLY, AND IS ACCOMPANIED BY AN UNCONTROLLED ROBUST MUCOSAL IMMUNE RESPONSE. ALL MALE RMS TESTED TO DATE EXHIBIT NORMAL (SLOW/CHRONIC) PROGRESSION. WE HYPOTHESIZE THAT KINETICS AND MAGNITUDE OF IMMUNE DYSREGULATION THAT DRIVE VIRAL REPLICATION, PERSISTENCE, AND REBOUND EXHIBIT SEX-BASED DIFFERENCES AND THAT ESTROGEN MAY PARTIALLY CONTRIBUTE TO SEX DIFFERENCE IN IMMUNE RESPONSES AND VIRAL PERSISTENCE. WE WILL DETERMINE SEX-SPECIFIC IMMUNE CELLULAR AND MOLECULAR DETERMINANTS RELEVANT TO HIV RESERVOIRS AND REBOUND LONGITUDINALLY. THE CONTRIBUTION OF ESTROGEN TO SEX DIFFERENCES IN IMMUNE REGULATION AND VIRAL PERSISTENCE WILL ALSO BE EXAMINED. THE PROPOSED WORK IS SIGNIFICANT BECAUSE IT PROMISES TO PROVIDE NEW INSIGHTS INTO THE CROSS-TALK BETWEEN INTESTINAL IMMUNE ACTIVATION AND VIRAL PERSISTENCE THAT ARE DIFFERENTIALLY REGULATED IN MALE AND FEMALE RMS, WHICH WILL BE CRITICAL FOR DEVELOPING PERSONALIZED THERAPEUTIC STRATEGIES TO RELIABLY HALT HIV-ASSOCIATED CHRONIC DISEASE, AND TO TARGET HIV RESERVOIRS.

OUTCOME ASSESSMENTS OF DEMOGRAPHICALLY DIVERSE LONG-TERM COHORTS OF PERSONS AT HIGH HIV RISK ENROLLED FROM DRUG ABUSE TREATMENT PROGRAMS IN THE 1980S ACROSS THE U.S.

THE SCHIZOPHRENIA-ASSOCIATED 3Q29 DELETION: GENETIC ARCHITECTURE OF BEHAVIORAL PHENOTYPES - SUMMARY 3Q29 DELETION SYNDROME IS CAUSED BY A TYPICALLY DE NOVO 1.6 MB DELETION OF 21 GENES. THE SYNDROME IS ASSOCIATED WITH AN ASTONISHING 40-FOLD INCREASED RISK FOR SCHIZOPHRENIA, AS WELL AS COGNITIVE DISABILITY, A HIGH RATE OF AUTISM AND SOCIAL DISABILITY, EXECUTIVE FUNCTION DEFICITS AND PRONOUNCED PREVALENCE OF ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), CLINICALLY SIGNIFICANT GRAPHOMOTOR WEAKNESS, AND MANIFESTATION OF ANXIETY DISORDERS. THE FACTORS THAT CONTRIBUTE TO THIS PHENOTYPIC HETEROGENEITY ARE NOT UNDERSTOOD. WE PROPOSE TO EVALUATE 200 INDIVIDUALS WITH THE 3Q29 DELETION, TO BETTER DEFINE PHENOTYPIC MANIFESTATIONS AND IDENTIFY RISK MODIFIERS FOR KEY PHENOTYPES. IN PARTICULAR, WE SEEK TO UNDERSTAND HOW POLYGENIC BACKGROUND AND SEX OF THE PROBAND MAY MODIFY RISK FOR PSYCHOSIS, COGNITIVE DISABILITY, SOCIAL FUNCTIONING, AND OTHER PHENOTYPES. TO FACILITATE OUR EVALUATION AND ATTENUATE ASCERTAINMENT BIAS, WE HAVE DEVELOPED A REMOTE PHENOTYPING BATTERY, WHICH DOES NOT REQUIRE TRAVEL TO A TESTING SITE. THIS REMOTE BATTERY REMOVES BARRIERS TO PARTICIPATION FOR OUR STUDY SUBJECTS AND DRAMATICALLY REDUCES COSTS, IMPROVING THE EFFICIENCY OF OUR STUDY. USING THIS VALIDATED PHENOTYPING PROTOCOL, WE WILL CHARACTERIZE 200 NEW STUDY SUBJECTS WITH THE 3Q29 DELETION, AND IDENTIFY THE FULL PHENOTYPIC SPECTRUM, SEX-DEPENDENT PHENOTYPIC RISKS AND SIGNIFICANT COMORBID RELATIONSHIPS. WE WILL ALSO PHENOTYPE BIOLOGICAL PARENTS TO CONTEXTUALIZE THE BURDEN OF ILLNESS IN 3Q29 DELETION SYNDROME RELATIVE TO DEPARTURE FROM MID-PARENTAL PHENOTYPE, AND CLARIFY THE RANGE OF PHENOTYPIC HETEROGENEITY IN 3Q29 DELETION SYNDROME. WE WILL COLLECT DNA FROM OUR STUDY SUBJECTS, TO DIRECTLY TEST THE CONTRIBUTION OF POLYGENIC RISK TO SELECTED PHENOTYPES. FINALLY, IN A COLLABORATION WITH THE NIMH-SPONSORED GENES 2 MENTAL HEALTH NETWORK, WE WILL COMPARE THE PHENOTYPIC SPECTRUM AND RISK MODIFIERS OF 3Q29 DELETION SYNDROME WITH >2,000 SAMPLES FROM OTHER GENOMIC DISORDERS ASSOCIATED WITH NEURODEVELOPMENTAL AND NEUROPSYCHIATRIC DISORDERS, INCLUDING 22Q11.2 DELETION AND DUPLICATION, 16P11 DELETION AND DUPLICATION, 1Q21 DELETION, AND OTHERS. AT THE END OF THIS PROJECT, WE WILL HAVE A COMPREHENSIVE SURVEY OF 3Q29 DELETION ASSOCIATED PHENOTYPES, AN UNDERSTANDING OF HOW SEX AND POLYGENIC BACKGROUND MAY INCREASE OR ATTENUATE PHENOTYPIC RISKS IN 3Q29 DELETION SYNDROME, AND AN APPRECIATION FOR HOW THE 3Q29 DELETION COMPARES TO THE BROADER LANDSCAPE OF RARE GENETIC DISORDERS ASSOCIATED WITH DEVELOPMENTAL BRAIN DISORDERS. ALL GENOTYPE AND PHENOTYPE DATA FROM THIS STUDY WILL BE SHARED IN PUBLICLY-AVAILABLE DATABASES, INCLUDING DBGAP AND NDAR.

CELLULAR CONSEQUENCES AND CONVERGENT BIOLOGY OF SCHIZOPHRENIA-ASSOCIATED RARE VARIANTS IN THE DIVERSE GPC COHORT - PROJECT SUMMARY / ABSTRACT RECENT DISCOVERIES IMPLICATE SPECIFIC GENETIC VARIANTS THAT CONFER EXTREMELY HIGH RISK FOR SCHIZOPHRENIA (SZ), A DEVASTATING PSYCHIATRIC SYNDROME. ALONGSIDE THESE GENETIC DISCOVERIES THERE HAVE BEEN PARALLEL ADVANCES IN MOLECULAR NEUROSCIENCE, INCLUDING INDUCED PLURIPOTENT STEM (IPS) CELL TECHNOLOGY; HIGH-THROUGHPUT CELLULAR TECHNOLOGIES SUCH AS HIGH CONTENT IMAGING AND SINGLE CELL GENOMICS; AND MULTIPLEX “CELL VILLAGE” APPROACHES. THESE TECHNIQUES ALLOW FOR RIGOROUS YET EFFICIENT INTERROGATION OF COMPLEX BIOLOGICAL PROCESSES IN PREVIOUSLY INACCESSIBLE HUMAN NEURONAL CELL TYPES. THE COMBINATION OF GENETIC FINDINGS AND TECHNOLOGICAL ADVANCES ARE POWERFUL TOOLS FOR ADDRESSING WHAT HAS BECOME THE “GREAT WHITE WHALE” OF MODERN PSYCHIATRY: WHAT IS THE UNDERLYING PATHOPHYSIOLOGY THAT GIVES RISE TO A SZ PHENOTYPE? WE PROPOSE THAT HIGH PENETRANCE OF RARE SZ MUTATIONS DERIVE FROM LARGE EFFECTS AT THE MOLECULAR AND CELLULAR LEVELS. WE WILL IDENTIFY DOWNSTREAM TARGETS AND PATHWAYS IMPACTED BY FIVE RARE SZ-ASSOCIATED VARIANTS WITH LARGE EFFECT SIZES: DELETIONS AT CHROMOSOMAL LOCATIONS 2P16 (LOCALIZED TO THE NRXN1 GENE), 3Q29, 15Q13.3, 22Q11.2, AND DUPLICATION AT 16P11. A KEY STRENGTH OF THIS PROPOSAL IS OUR ACCESS TO THE GENOMIC PSYCHIATRY COHORT (GPC). IMPORTANTLY, THE GPC IS A DIVERSE COHORT WITH SIGNIFICANT REPRESENTATION OF AFRICAN ANCESTRY. WE WILL SELECT FOR STUDY PREVIOUSLY-BANKED CRYOPRESERVED LYMPHOCYTES FROM INDIVIDUALS WITH SZ WHO CARRY ONE OF THESE FIVE DEFINED VARIANTS (N=20 EACH GENOTYPE), PRIORITIZING UNDERREPRESENTED MINORITIES, TO GENERATE IPS CELL LINES. A CLEAR ADVANTAGE OF THE GPC IS ITS LARGE DIVERSE CONTROL SAMPLE, ALLOWING US TO SELECT CONTROLS (N=40) THAT ARE MATCHED BY GENOMIC BACKGROUND TO THE SZ CASES, INCREASING THE RIGOR OF OUR STUDY. A CONSISTENT BUT SURPRISING OBSERVATION ABOUT THESE SZ-ASSOCIATED RARE VARIANTS IS THEIR SIMILARITY IN BOTH EFFECT SIZE AND PHENOTYPIC CHARACTERISTICS, GIVING RISE TO THE HYPOTHESIS THAT THESE VARIANTS CONVERGE ON DOWNSTREAM MOLECULAR TARGETS AND/OR CELLULAR PATHWAYS. WE WILL TEST THE HYPOTHESIS THAT SZ-ASSOCIATED RARE MUTATIONS CAUSE MOLECULAR PERTURBATIONS IN NEURONS AT THE LEVEL OF CHROMATIN ACCESSIBILITY AND GENE EXPRESSION AND THAT GENES OR PATHWAYS IMPACTED BY TWO OR MORE OF THESE SZ-ASSOCIATED VARIANTS CONVERGE, WITH MORE OVERLAP THAN EXPECTED BY CHANCE. FINALLY, WE WILL VALIDATE MOLECULAR PATHWAYS USING MULTIMODAL CELLULAR PHENOTYPIC LEVELS OF ANALYSIS. IDENTIFYING THE SPECIFIC BIOLOGICAL PROCESSES THAT ARE DISRUPTED BY SZ-ASSOCIATED LOCI WILL OPEN A WINDOW INTO THE COMPLEX MOLECULAR BIOLOGY OF THIS DISORDER. THE SUBSTRATE FOR OUR MECHANISTIC STUDIES WILL INCLUDE SUBJECTS WITH DIVERSE GENETIC BACKGROUNDS THAT HAVE BEEN HISTORICALLY UNDERREPRESENTED IN GENETIC STUDIES, ENSURING THAT OUR RESULTS ARE GENERALIZABLE TO THESE COMMUNITIES, WHO SUFFER DISPROPORTIONATELY FROM ADVERSE MENTAL HEALTH OUTCOMES. THE TOOLS AND DATA GENERATED HEREIN WILL SUPPORT THE MENTAL HEALTH FIELD ALIGNING WITH NIMH PRIORITIES, LEAD TO TRANSFORMATIVE INSIGHTS INTO THE NEUROBIOLOGY OF SZ, AND UNCOVER NOVEL TARGETS THAT MAY BE A LAUNCH POINT FOR THERAPEUTIC DISCOVERY.

SIMPLE AND RAPID POC DETECTION FOR FUNGEMIA

ADAPTING AND IMPLEMENTING EVIDENCE-BASED BREAST CANCER FOLLOW-UP IN PRIMARY CARE - PROJECT SUMMARY/ABSTRACT BREAST CANCER SURVIVORS ARE A GROWING POPULATION AND THEIR SYMPTOM BURDEN IS SIGNIFICANT. DESPITE GROWING EVIDENCE ON SPECIFIC SYMPTOMS AND RISK MANAGEMENT STRATEGIES, EFFORTS TO TRANSLATE KNOWLEDGE INTO PRACTICE HAVE PRODUCED SUBOPTIMAL RESULTS. PRIMARY CARE IS AN IDEAL RECEPTOR SITE FOR BREAST CANCER SURVIVORS, WITH STUDIES DEMONSTRATING THE EFFECTIVENESS OF PRIMARY CARE BASED SURVIVORSHIP CARE. NEVERTHELESS, OVER THE PAST DECADE, THE EMPHASIS ON SURVIVORSHIP CARE PLANS AND SURVIVORSHIP MODELS HAS NOT HAD AN EVIDENT IMPACT ON PRIMARY CARE BREAST CANCER SURVIVORSHIP CARE PROCESSES. OVER THE PAST TWO DECADES, PRIMARY CARE PRACTICES HAVE REDESIGNED STRUCTURES AND CARE PROCESSES TO DELIVER CARE TO DIFFERENT COMPLEX POPULATIONS; HOWEVER, BREAST CANCER SURVIVORS ARE NOT AMONG THEM. MANY CURRENTLY PROPOSED AND TESTED STRATEGIES ARE CONSIDERED ONCOLOGY-CENTRIC AND DO NOT FIT WELL WITHIN THE REAL WORLD CONTEXTS OF PRIMARY CARE PRACTICES. RESULTS FROM OUR RECENT RESEARCH STUDIES INDICATE THAT BREAST CANCER SURVIVORSHIP IS NOT CONSIDERED CLINICALLY ACTIONABLE EVEN AMONG PRIMARY CARE PRACTICES WITH ADVANCED STAFFING MODELS. THEREFORE, CAPACITY BUILDING AND STAKEHOLDER- INFORMED STRATEGIES ARE NEEDED TO ENHANCE THE TRANSLATIONAL POTENTIAL OF SURVIVORSHIP EVIDENCE INTO PRIMARY CARE PRACTICES. THIS PROJECT USES A “DESIGNING FOR DISSEMINATION” PERSPECTIVE, BLENDING THE IMPLEMENTATION EXPLORATION, PLANNING, IMPLEMENTATION AND SUSTAINMENT (EPIS) FRAMEWORK AND THE PRIMARY CARE PRACTICE CHANGE MODEL (PCM) AS A THEORETICAL BASIS FOR UNDERSTANDING MULTILEVEL FACTORS IMPACTING THE IMPLEMENTATION OF CANCER SURVIVORSHIP GUIDELINES IN PRIMARY CARE. THESE PERSPECTIVES HELP FRAME AND IDENTIFY MISMATCHES AMONG EXISTING POLICY, PRACTICE, PROVIDER, AND PATIENT MOTIVATORS TO TRANSLATE THE EVIDENCE INTO CLINICALLY ACTIONABLE PRIMARY CARE PRACTICE CHANGE STRATEGIES. USING A BLENDED IMPLEMENTATION/PRIMARY CARE PRACTICE CHANGE CONCEPTUAL FRAMEWORK, THIS PROJECT AIMS TO: (1) ENGAGE DIVERSE PRIMARY CARE STAKEHOLDERS IN IDENTIFYING ACTIONABLE, PRACTICE-BASED ACTIVITIES FOR PROVISION OF LONG-TERM BREAST CANCER SURVIVORSHIP CARE IN PRIMARY CARE USING DEPTH INTERVIEWS; (2) PRIORITIZE, SYNTHESIZE, AND IDENTIFY ACTIONABLE ACTIVITIES FOR PROVIDING CARE TO LONG- TERM CANCER SURVIVORS IN PRIMARY CARE BY ENGAGING KEY STAKEHOLDERS USING MODIFIED ONLINE DELPHI METHODS AND CONCEPT MAPPING; AND (3) IMPLEMENT AND EVALUATE ACTIONABLE BREAST CANCER SURVIVORSHIP SYMPTOM AND RISK MANAGEMENT ACTIVITIES USING A HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION CLUSTER STUDY DESIGN WITH WAITLIST CONTROL IN 26 PRIMARY CARE PRACTICES. STUDY RESULTS ARE POISED TO HAVE PROFOUND IMPACT ON IMPLEMENTATION STRATEGIES USED THROUGHOUT THE U.S. TO PROVIDE LONG-TERM CARE FOR PATIENTS WITH A HISTORY OF BREAST CANCER.

MOLECULAR MODULATORS OF RADIATION-INDUCED CHROMOSOME INSTABILITY

IGM IN THE REGULATION OF TB IMMUNITY

SYSTEMIC AND DIETARY ADVANCED GLYCATION END PRODUCTS IN TYPE 2 DIABETES-RELATED COGNITIVE DECLINE AND INCIDENT DEMENTIA: EFFECTS ON ALZHEIMER'S PATHOLOGY AND CEREBROVASCULAR DISEASE

NO SIGNALING BY A SOLUBLE GUANYLYL CYCLASE-THIOREDOXIN TRANSNITROSATION COMPLEX

MICROVASCULAR MECHANISMS OF GROWTH RESTRICTION AFTER ENVIRONMENTAL TOXICANT EXPOSURE - ABSTRACT THE UTERINE CIRCULATION AND PLACENTA ARE SPECIFICALLY DESIGNED TO REGULATE THE FLOW OF BLOOD AND TRANSPORT OF ES- SENTIAL NUTRIENTS TO THE FETUS. DISRUPTION OF MATERNAL HEMODYNAMIC REGULATION DURING PREGNANCY CAN ADVERSELY IMPACT FETAL HEALTH, RESULTING IN MISCARRIAGE AND INTRAUTERINE GROWTH RESTRICTION (IUGR). CURRENT TREATMENT OP- TIONS FOR IUGR PATIENTS ARE EXTREMELY LIMITED, FOCUSING PRIMARILY ON EARLY DELIVERY; THUS, PUTTING THE MOTHER AND CHILD AT RISK FOR COMPLICATIONS ASSOCIATED WITH PRETERM BIRTH. EPIDEMIOLOGICAL STUDIES INDICATE THAT PREGNANT WOMEN EXPOSED TO FINE PARTICULATE MATTER (PM) HAVE A HEIGHTENED RISK OF FETAL LOSS AND DEVELOPMENT OF IUGR. WE HAVE REPRODUCED THIS PHENOMENON IN LABORATORY RODENT MODELS, WHEREIN ANIMALS EXPOSED TO NANOSIZED TITANIUM DIOXIDE (NANO-TIO2) AEROSOLS DEVELOP IUGR AND SUFFER A GREATER NUMBER OF ‘MISCARRIAGES’ (FETAL REABSORPTIONS). WE HAVE DEMONSTRATED THAT ACUTE AND CHRONIC EXPOSURES SIGNIFICANTLY IMPAIR UTERINE VASCULAR ENDOTHELIUM-DEPENDENT DILATION, SEVERELY LIMITING MATERNAL-TO-FETAL BLOOD FLOW AND IMPACTING FETAL GROWTH. AN UNDERSTANDING OF THE MECHANISMS UNDERLYING DYSREGULATION IN UTERINE AND PLACENTAL BLOOD FLOW IS CRITICAL FOR DEVELOPING TREATMENTS AND REDUCING IUGR. BASED ON PREVIOUS FINDINGS, WE HYPOTHESIZE THAT MATERNAL INHALATION OF NANO-TIO2 AEROSOLS DURING PREGNANCY PROMOTES THE DEVELOPMENT OF IUGR BY DISRUPTING ENDOTHELIUM-DEPENDENT NO AND AA SIGNALING CASCADES, RESULTING IN REDUCED UTERINE VASODILATION AND BLOOD FLOW. MOREOVER, FOLIC ACID (FA) SUPPLEMENTATION WILL RESCUE THIS UTERO-PLACENTAL HEMODYNAMIC IMBALANCE AND PREVENT IUGR THROUGH ITS ACTION IN NO SIGNALING. USING NOVEL APPROACHES AND METHODOLO- GIES, THESE STUDIES WILL: (1) EVALUATE UTERINE NITRIC OXIDE-DRIVEN VASODILATION, (2) DETERMINE WHETHER ALTERATIONS IN ARACHIDONIC ACID METABOLISM IMPAIR UTERINE VASCULAR REACTIVITY AND IMPACT PLACENTAL PERFUSION, AND (3) ASSESS THE THERAPEUTIC BENEFIT OF DIETARY FOLIC ACID SUPPLEMENTATION TO IMPROVE UTERO-PLACENTAL BLOOD FLOW AND ATTENUATE THE DEVELOPMENT OF IUGR AFTER MATERNAL EXPOSURE TO NANO-TIO2 AEROSOLS. THESE STUDIES ARE CONCEPTUALLY INNOVATIVE AS WE WILL UTILIZE OUR UNIQUE RESOURCES TO IDENTIFY MECHANISTIC TARGETS WITHIN THE UTERO-PLACENTAL MI- CROCIRCULATION AND TEST DIRECTED NUTRITIONAL INTERVENTIONS FOR IUGR. THIS WORK IS TECHNICALLY INNOVATIVE AS WE WILL USE NOVEL METHODOLOGIES DEVELOPED FOR THE EVALUATION OF ENVIRONMENTAL TOXICITY IN MATERNAL-FETAL MEDICINE. OVERALL, THE SUCCESSFUL COMPLETION OF THESE STUDIES WILL: (1) CREATE THE CONCEPTUAL FRAMEWORK TO IDENTIFY ENVIRONMENTAL EXPOSURE AS A RISK FACTOR FOR THE DEVELOPMENT OF IUGR; (2) REVEAL NEW MECHANISTIC INSIGHT INTO THE VASCULAR PATHOGENESIS RESULTING FROM NANOMATERIAL EXPOSURE; (3) PROVIDE A MOLECULAR BASIS TO IDENTIFY HOW NANOMATERIAL EXPOSURE MANIFESTS AS VASCULAR DISRUPTIONS; AND (4) IDENTIFY MECHANISTIC TARGETS FOR THERAPEUTIC STRATEGIES TO AMELIORATE MICROVASCULAR DYSFUNCTION AND IMPROVE UTERO-PLACENTAL BLOOD FLOW. THESE INTERVENTION- AL STRATEGIES ARE NOT ONLY LIMITED TO PM, BUT ARE WIDELY APPLICABLE TO UNDERSTANDING THE ROLE OF A SPECTRUM OF ENVIRONMENTAL TOXICANTS IN THE PATHOPHYSIOLOGICAL DEVELOPMENT OF IUGR.

TELEHEALTH SHARED DECISION-MAKING COACHING FOR LUNG CANCER SCREENING IN PRIMARY CARE (TELESCOPE) - ABSTRACT SCREENING WITH LOW-DOSE CT (LDCT) SCANS REDUCES LUNG CANCER MORTALITY. HOWEVER, THE POTENTIAL HARMS ASSOCIATED WITH SCREENING INCLUDE FALSE-NEGATIVE AND FALSE-POSITIVE RESULTS, INCIDENTAL FINDINGS, OVERDIAGNOSIS, RADIATION EXPOSURE, AND COMPLICATIONS FROM INVASIVE DIAGNOSTIC PROCEDURES AND TREATMENTS. GIVEN THE COMPLEXITY OF LUNG CANCER SCREENING (LCS) DECISIONS, THE UNITED STATES PREVENTIVE SERVICES TASK FORCE STRONGLY RECOMMENDS THAT PATIENTS RECEIVE COUNSELING ABOUT SMOKING CESSATION AND SHARED DECISION-MAKING (SDM) WITH A HEALTH CARE PROVIDER BEFORE BEING REFERRED FOR LDCT. THE SDM DISCUSSION ABOUT LCS SHOULD ADDRESS THE BENEFITS AND HARMS OF SCREENING, THE IMPORTANCE OF ADHERING TO ANNUAL LUNG CANCER LDCT SCREENING AND RECOMMENDED DIAGNOSTIC TESTING AND TREATMENT, AND TOBACCO AVOIDANCE. YET, THERE IS UNCERTAINTY ABOUT HOW TO MOST EFFECTIVELY ENGAGE PATIENTS IN SDM FOR LCS. BOTH PATIENTS AND PRIMARY CARE CLINICIANS PERCEIVE IMPORTANT BARRIERS TO LCS DECISION MAKING AND ACCESSING HEALTH SERVICE. WHEN SCREENING DISCUSSIONS ARE CONDUCTED, THEY OFTEN FAIL TO MEET EXPECTATIONS FOR SDM. WE PROPOSE TO ADDRESS THESE DEFICIENCIES BY IMPLEMENTING A WORKFLOW AWARE TELEMEDICINE SDM INTERVENTION THAT INCLUDES DECISION COACHING AND PATIENT NAVIGATION THAT IS A POTENTIALLY SCALABLE AND EFFICIENT APPROACH TO MEETING NATIONAL SCREENING RECOMMENDATIONS. THE STUDY’S LONG-TERM GOAL IS TO REDUCE DISPARITIES AND THE BURDEN OF LUNG CANCER AMONG HEAVY SMOKERS BY SUPPORTING HIGH-QUALITY DECISION MAKING ABOUT LCS AND SMOKING CESSATION AND ABSTINENCE. OUR SHORT-TERM GOAL IS TO IDENTIFY AN EFFECTIVE INTERVENTION THAT CAN READILY BE IMPLEMENTED IN REAL-WORLD PRIMARY CARE SETTINGS TO SUPPORT HIGH-QUALITY SDM IN RACIALLY AND ETHNICALLY DIVERSE POPULATIONS. WE WILL CONDUCT AN EFFECTIVENESS-IMPLEMENTATION HYBRID TYPE I TRIAL GUIDED BY THE PRACTICAL, ROBUST IMPLEMENTATION AND SUSTAINABILITY MODEL (PRISM). A CLUSTER RANDOMIZED TRIAL DESIGN INCLUDING 40 PRIMARY CARE PRACTICES, 100 PROVIDERS AND 400 PATIENTS WILL EVALUATE WHETHER A TELEMEDICINE DECISION COACHING AND NAVIGATION INTERVENTION (TELESCOPE) COMPARED TO ENHANCED USUAL CARE (EUC) WILL IMPROVE THE QUALITY OF DECISION MAKING, INCREASE ADHERENCE WITH SCREENING AND DIAGNOSTIC TESTING, AND GENERATE MORE REFERRALS FOR SMOKING CESSATION. THE SPECIFIC AIMS ARE TO: 1) TEST THE EFFECTIVENESS OF A DECISION COACHING INTERVENTION FOR LCS DELIVERED BY NURSE NAVIGATORS VS. EUC ON THE QUALITY OF PATIENT DECISION MAKING ABOUT LCS, SUBSEQUENT SCREENING AND DIAGNOSTIC TESTING, AND SMOKING CESSATION REFERRALS FOR CURRENT SMOKERS; 2) EVALUATE THE IMPLEMENTATION POTENTIAL OF NAVIGATOR-LED DECISION COACHING FOR LCS; AND 3) DETERMINE THE RESOURCES AND COSTS REQUIRED TO IMPLEMENT THE NAVIGATOR-LED DECISION COACHING INTERVENTION FOR LCS. THIS HIGHLY IMPACTFUL RESEARCH HAS THE POTENTIAL TO GREATLY ADVANCE THE FIELD OF SDM IMPLEMENTATION AND IMPROVE QUALITY OF CARE BY PROVIDING PATIENTS WITH HIGH-QUALITY DECISION SUPPORT ABOUT LCS, TESTING FEASIBLE STRATEGIES FOR BUSY PCPS TO SUPPORT SDM FOR THEIR HIGH-RISK PATIENTS, AND DEMONSTRATING FOR POLICY MAKERS AND PAYORS NEW MODELS FOR EFFECTIVE DELIVERY OF SDM FOR LCS.

INTEGRATED TRANSPORTER ELUCIDATION CENTER - PROJECT SUMMARY/ABSTRACT GIVEN THEIR PHYSIOCHEMICAL PROPERTIES, MEDICATIONS AND DIETARY SUPPLEMENTS OFTEN REQUIRE ACTIVE TRANSPORT USING SOLUTE CARRIERS (SLC) AND ATP-BINDING CASSETTE (ABC) TRANSPORTERS TO CROSS TROPHOBLAST BARRIERS. THESE SAME TRANSPORTERS ARE ALSO INVOLVED IN THE DELIVERY OF NUTRIENTS TO THE FETUS AND ONE UNINTENTIONAL CONSEQUENCE OF DRUG THERAPY DURING PREGNANCY CAN BE DISRUPTION OF THESE SHARED SYSTEMS. THEREFORE, UNDERSTANDING THE INTERPLAY BETWEEN SLC AND ABC TRANSPORTERS IN THE PLACENTAL DISPOSITION OF DRUGS AND NUTRIENTS IS ONE KEY STEP TO OPTIMIZING THERAPEUTIC INTERVENTIONS THAT IMPROVE PERINATAL HEALTHCARE. OUR RESEARCH TEAM HAS CHAMPIONED THE ADVANCEMENT OF NOVEL APPROACHES TO STUDY SLC AND ABC TRANSPORTERS IN THE PLACENTA. TO EXPAND THESE EFFORTS, WE HAVE CREATED THE INTEGRATED TRANSPORTER ELUCIDATION CENTER (INTEC) WHICH LEVERAGES TRANSLATIONAL RESEARCH EXPERTISE ACROSS 4 ACADEMIC INSTITUTIONS. OUR CENTRAL HYPOTHESIS IS THAT NOVEL REGULATION AND FUNCTIONS OF PLACENTAL TRANSPORTERS CAN BE ELUCIDATED USING INTEGRATED EXPERIMENTAL, EPIDEMIOLOGICAL, AND MODELING APPROACHES. TOGETHER, DATA AND MODELS GENERATED CAN PREDICT THE PLACENTAL DISPOSITION OF THERAPEUTICS AND NUTRIENTS AND THEIR SUBSEQUENT EFFECTS ON FETAL DEVELOPMENT. TO ACCOMPLISH THIS GOAL, WE WILL 1) IDENTIFY CRITICAL FACTORS THAT REGULATE PLACENTAL TRANSPORTERS USING STATE-OF-THE-ART QUANTITATIVE TARGETED ABSOLUTE PROTEOMICS AND GENETICS IN A US-BASED BIRTH COHORT; 2) DEVELOP A NOVEL COMPUTATIONAL MODELING FRAMEWORK THAT PREDICTS MATERNAL-FETAL CHEMICAL DISPOSITION ACCORDING TO PLACENTAL TRANSPORTER FUNCTIONS AND REGULATION; AND 3) EVALUATE SLC AND ABC TRANSPORT IN NOVEL PLACENTA-ON-A-CHIP MICROPHYSIOLOGICAL SYSTEMS. WE WILL TEST NUTRIENTS, SUPPLEMENTS, DRUGS, AND TOXICANTS AS SUBSTRATES AND INHIBITORS OF PLACENTAL TRANSPORTERS. INTEC WILL ENABLE RAPID ACCELERATION OF PLACENTA TRANSPORTER RESEARCH AND ESTABLISH BEST PRACTICES FOR TRANSPORTER BIOLOGY. RESOURCES AND DATASETS WILL BE DISSEMINATED VIA OUR CIIPRO WEBPORTAL CREATED IN 2017. UNIQUE TRAINING OPPORTUNITIES WILL BE PROVIDED TO EARLY CAREER SCIENTISTS (UNDERGRADUATE STUDENTS, MS/MPH/PHD STUDENTS, AND POSTDOC FELLOWS) AND CLINICIANS (OBSTETRICS RESIDENTS AND FELLOWS) AT THE INTERSECTIONS OF PHARMACOLOGY, COMPUTATIONAL BIOLOGY, PUBLIC HEALTH, MATERNAL-FETAL MEDICINE, AND BIOMEDICAL ENGINEERING. THROUGH INNOVATIVE RESEARCH AND TRAINING, INTEC WILL LEAD TO NOVEL BREAKTHROUGHS IN THE FIELD OF PLACENTAL TRANSPORT AND ENSURE A WELL-TRAINED WORKFORCE TO IMPROVE MATERNAL AND PERINATAL HEALTH.

ROLE OF MYCOBACTERIAL DYNAMIN-LIKE PROTEINS IN THE BIOGENESIS OF MEMBRANE VESICLES, AND HOST-PATHOGEN INTERACTIONS - DESPITE THE WIDESPREAD USE OF AN ATTENUATED VACCINE AND SEVERAL ANTIBIOTICS, TUBERCULOSIS (TB) CONTINUES TO BE A GLOBAL PUBLIC HEALTH PROBLEM. OVER 1.2 MILLION PEOPLE DIED FROM TB IN 2019. THIS DIRE SITUATION IS COMPOUNDED BY INCREASING PREVALENCE OF ANTIBIOTIC RESISTANT STRAINS OF MYCOBACTERIUM TUBERCULOSIS (MTB), THE MAIN ETIOLOGICAL AGENT OF HUMAN TB. CENTRAL TO MTB SUCCESS IS ITS ABILITY TO EVADE, MODULATE, AND EVEN MANIPULATE HOST IMMUNE DEFENSE RESPONSE. CONSEQUENTLY, BACTERIAL FACTORS INVOLVED IN UNDERMINING THE IMMUNE SYSTEM ARE POTENTIALLY GOOD TARGETS FOR TB INTERVENTION. LIKE MANY OTHER BACTERIA, MTB ACTIVELY PRODUCES EXTRACELLULAR VESICLES (EVS) IN VITRO AND IN VIVO. THESE ARE MEMBRANE ENCLOSED SPHERICAL STRUCTURES THAT ALLOW THE BACTERIA TO CONCENTRATE AND SECRETE A VARIETY OF MOLECULES, AND COMMUNICATE WITH OTHER CELLS IN THEIR ENVIRONMENT. THE RELEASE OF EVS BY MTB INFECTING MACROPHAGES ENABLES THE DELIVERY OF PATHOGENICITY FACTORS AND IMMUNOMODULATORY MOLECULES INTO THE HOST CELL, AND THE EXTRACELLULAR MILIEU. STRONG EVIDENCE FROM IN VITRO STUDIES INDICATES THAT EVS MAY ALLOW MTB TO REMOTELY INFLUENCE BYSTANDER IMMUNE CELLS. HOWEVER, THE LIMITED UNDERSTANDING OF THE MOLECULAR MECHANISMS INVOLVED IN VESICLE BIOGENESIS, AND THE LACK OF MUTANTS DEFICIENT IN VESICLE PRODUCTION HAVE IMPEDED PROGRESS IN ELUCIDATING THE RELEVANCE OF VESICLE SECRETION TO MTB VIRULENCE. OUR PRELIMINARY WORK IDENTIFIED THE DYNAMIN-LIKE PROTEINS (DLP) OF MTB AS ESSENTIAL FACTORS FOR EFFICIENT EVS RELEASE AND CHARACTERIZED A DLP MUTANT DEFICIENT IN VESICLE BIOGENESIS. WE ARE NOW WELL POSITIONED TO DISSECT DLP'S FUNCTION IN VESICLE FORMATION AND ASSESS THE ROLE OF EV PRODUCTION DURING INFECTION, USING A MOUSE MODEL OF TB; THOSE ARE THE MAIN GOALS OF THIS PROPOSAL. WE ANTICIPATE THE FINDINGS WILL ADVANCE THE TB FIELD BY HIGHLIGHTING WAYS TO TARGET VESICLE RELEASE, OR DISRUPT THE EFFECTS OF VESICLES IN HOST-RESISTANCE TO TB.

INSTITUTIONAL CAREER DEVELOPMENT CORE

THE ROLE OF SLEEP IN CARDIOVASCULAR HEALTH AMONG MEN LIVING WITH HIV - PROJECT SUMMARY CARDIOVASCULAR DISEASE (CVD) IS A MAJOR HEALTH CONCERN FACING THE U.S. POPULATION, WITH THE IMPACT OF RISK FACTORS ACCUMULATING OVER THE LIFESPAN AND BEGINNING WELL BEFORE OLDER AGE. INCREASINGLY, THE STUDY OF CARDIOVASCULAR HEALTH FOR PEOPLE LIVING WITH HIV IS VITAL GIVEN THE GROWING NUMBER OF MIDDLE- AND OLDER-AGED ADULTS LIVING WITH HIV AS A CHRONIC CONDITION AND ITS COMPLEX EFFECTS ON CARDIOVASCULAR HEALTH DIRECTLY, AND INDIRECTLY THROUGH HIV'S IMPACT ON INFLAMMATION. IN THE GENERAL POPULATION, POOR OR INADEQUATE SLEEP HAS BEEN LINKED WITH INCREASED RISK FOR CVD, IN PART THROUGH ITS IMPACT ON INFLAMMATION AND OTHER PHYSIOLOGICAL MECHANISMS. IN OUR OWN WORK, AMONG SEXUAL MINORITY MEN LIVING WITH HIV, POOR SLEEP HAS ALSO BEEN LINKED WITH LOWER RATES OF ADHERENCE TO ANTIRETROVIRAL (ART) MEDICATIONS. THEREFORE, THE STUDY OF CARDIOVASCULAR HEALTH AMONG PEOPLE LIVING WITH HIV REQUIRES SPECIAL CONSIDERATION OF THE PATHWAYS FROM POOR SLEEP THROUGH WORSENED HIV HEALTH TO INCREASED CVD RISK BOTH DIRECTLY, AND INDIRECTLY THROUGH INFLAMMATION (PRINCIPALLY, IL-6, TNF-ALPHA, AND CRP). FURTHER, WE HYPOTHESIZE THAT, CONTRIBUTING TO THIS LARGER PICTURE OF PHYSIOLOGICAL PATHWAYS FROM SLEEP TO CVD RISK, IS A DAY-LEVEL PSYCHOSOCIAL-BEHAVIORAL DYNAMIC WHEREBY EXPERIENCES OF MINORITY STRESS AFFECT SUBSEQUENT ART ADHERENCE THROUGH THE IMPACT OF MINORITY STRESS ON SLEEP. ACCORDINGLY, IN THE PROPOSED OBSERVATIONAL, LONGITUDINAL STUDY OF 240 RACIALLY-DIVERSE SEXUAL MINORITY MEN LIVING WITH HIV, AGED 45-64, WE AIM TO USE LONGITUDINAL DATA TO TEST THE HYPOTHESES THAT POOR SLEEP LONGITUDINALLY PREDICTS GREATER CVD RISK AMONG SMM-LWH AGED 45-64, IN PART THROUGH THE IMPACT OF POOR SLEEP ON HIV HEALTH, AND IN PART THROUGH THE IMPACT OF POOR SLEEP ON INFLAMMATION. ADDITIONALLY, WE AIM TO TEST THE DAY-LEVEL HYPOTHESIS THAT THE IMPACT OF MULTIPLE, INTERSECTING SOURCES OF MINORITY STRESS (SEXUAL MINORITY STRESS, RACIAL/ETHNIC MINORITY STRESS, AND/OR HIV-RELATED STRESS) ON NEXT-DAY ART ADHERENCE IN SMM-LWH OPERATES, IN PART, THROUGH THE DAY-LEVEL IMPACT OF MINORITY STRESS ON POOR SLEEP. THIS PROPOSED STUDY ALIGNS WITH THE GROWING RECOGNITION OF THE IMPORTANCE OF SLEEP IN NUMEROUS MENTAL, BEHAVIORAL, AND PHYSICAL HEALTH OUTCOMES, AND ALSO CONTRIBUTES TO OUR UNDERSTANDING OF HOW MINORITY STRESS “GETS UNDER THE SKIN” (HERE, THROUGH ITS IMPACT ON SLEEP) TO AFFECT PHYSICAL HEALTH OUTCOMES IN INDIVIDUALS WITH MARGINALIZED IDENTITIES.

REGULATION OF TH2 DIFFERENTIATION BY SKIN-RESIDENT DENDRITIC CELLS

IDENTIFYING CHILDREN WITH SUBCLINICAL NEUROCOGNITIVE DECLINE AND SUSCEPTIBILITY TO OXIDATIVE DAMAGE DURING THE EARLY MONTHS OF THERAPY FOR ALL

SAFETY OF DRUGS COMMONLY USED OFF-LABEL IN CHILDREN DESPITE INSUFFICIENT EVIDENCE OF EFFICACY AND SAFETY - DRUG SAFETY AND EFFECTIVENESS IN ADULTS DOES NOT ASSURE SAFETY AND EFFECTIVENESS OF THE SAME DRUGS IN CHILDREN. IN THE UNITED STATES, >40% OF SYSTEMIC DRUGS ORDERED FOR CHILDREN ARE OFF-LABEL (USED OUTSIDE OF AN FDA- APPROVED AGE, INDICATION, ETC.). FURTHERMORE, RATES OF OFF-LABEL USE IN CHILDREN ARE RISING, PARTICULARLY FOR TREATMENT INDICATIONS UNAPPROVED AT ANY AGE. USE, OVERUSE, AND COMBINED USE (POLYPHARMACY) OF OFF-LABEL MEDICINES FOR UNSUPPORTED INDICATIONS MAY PUT MILLIONS OF CHILDREN AT RISK EACH YEAR FOR SERIOUS DRUG-RELATED HARMS THAT OUTWEIGH UNCERTAIN BENEFITS OF TREATMENT. THIS TEAM’S LONG-TERM GOAL IS TO IMPROVE THE JUDICIOUS, EVIDENCE-BASED USE OF MEDICINES THAT WILL INFORM CLINICAL DECISION-MAKING AND MAKE CHILDREN HEALTHIER AND SAFER. THE SPECIFIC OBJECTIVE OF THIS PROJECT IS TO CHARACTERIZE THE RISKS FOR SERIOUS DRUG-RELATED HARMS IN CHILDREN FROM SOME OF THE DRUGS USED MOST COMMONLY DESPITE INSUFFICIENT EVIDENCE OF EFFICACY AND SAFETY: PSYCHOTROPIC DRUGS. THE CENTRAL HYPOTHESIS IS THAT USE OF CERTAIN PSYCHOTROPIC DRUGS IN CHILDREN IS ASSOCIATED WITH INCREASED RISKS OF SERIOUS HARMS. PSYCHOTROPIC DRUGS ARE USED AS APPLIED EXAMPLES FOR MANY REASONS: 1) HIGH AND RISING PREVALENCE OF UNSUPPORTED OFF-LABEL USE IN CHILDREN; 2) INSUFFICIENT EVIDENCE OF EFFICACY IN CHILDREN; 3) POTENTIAL FOR SERIOUS OR FATAL HARMS; 4) POTENTIALLY GREATER HARMS IN CHILDREN THAN IN ADULTS; 5) CRITICAL THERAPEUTIC NEEDS; 6) AVAILABLE THERAPEUTIC ALTERNATIVES (E.G., SAFER DRUGS, NON-PHARMACOLOGIC INTERVENTIONS); AND 7) MEASURABLE OUTCOMES. BASED ON THESE CRITERIA, GAPS IN THE LITERATURE, AND PRELIMINARY DATA, THIS PROPOSAL FOCUSES ON SELECTED SERIOUS HARMS (NAMELY, SUICIDE, ARRHYTHMIAS, AND SEVERE SKIN REACTIONS) POSSIBLY ASSOCIATED WITH ANTIDEPRESSANTS (E.G., VENLAFAXINE) AND ANTIEPILEPTIC DRUGS/MOOD STABILIZERS (AEDS) (E.G., LAMOTRIGINE). SPECIFICALLY, THIS PROPOSAL AIMS TO EVALUATE THE EXTENT TO WHICH: 1) CERTAIN ANTIDEPRESSANTS AND AEDS INCREASE OR DECREASE THE RISK OF DEATH BY SUICIDE IN CHILDREN (AIM 1); 2) CERTAIN ANTIDEPRESSANTS AND AEDS INCREASE OR DECREASE THE RISK OF VENTRICULAR ARRHYTHMIAS, CARDIAC ARREST, OR SUDDEN DEATH IN CHILDREN (AIM 2); AND 3) CERTAIN ANTIEPILEPTIC DRUGS/MOOD STABILIZERS OR DRUG COMBINATIONS INCREASE OR DECREASE THE RISK OF SEVERE SKIN REACTIONS IN CHILDREN (AIM 3). THE PROJECT TEAM WILL STUDY DISTINCT PEDIATRIC POPULATIONS WITHIN TWO NATIONAL CLAIMS AND ELECTRONIC HEALTH RECORDS DATABASES TO ACCOMPLISH THESE AIMS. THIS RESEARCH WILL PRODUCE GENERALIZABLE, ACTIONABLE, CLINICALLY RELEVANT EVIDENCE NOW LACKING ON RELATIVE AND ABSOLUTE RISKS OF SERIOUS HARMS FROM DRUGS AND DRUG COMBINATIONS INCREASINGLY USED OFF-LABEL AND WITH INSUFFICIENT EVIDENCE IN CHILDREN. THESE RARE OUTCOMES CANNOT BE FEASIBLY STUDIED WITH CLINICAL TRIALS DUE TO THE NEED FOR PROHIBITIVELY LARGE SAMPLE SIZES. COMPARISONS ACROSS AGE GROUPS, DIAGNOSES, DRUG DOSES, AND CONCOMITANT DRUGS WILL NOT ONLY QUANTIFY RISKS IN KEY SUBGROUPS BUT WILL ALSO SHED LIGHT ON UNDERLYING BIOLOGY AND MECHANISMS. THIS PROJECT ALSO BEGINS AN IMPORTANT NEW LINE OF WORK THAT WILL INFORM IMPROVEMENTS THE OVERALL QUALITY OF EVIDENCE FOR DRUGS THAT CHILDREN COMMONLY USE DESPITE INSUFFICIENT EVIDENCE OF EFFICACY AND SAFETY.

FY 2021 COMMUNITY MENTAL HEALTH CENTERS (CMHC) GRANT PROGRAM - PROJECT NAME: FY 2021 COMMUNITY MENTAL HEALTH CENTERS (CMHC) GRANT PROGRAM ABSTRACT THE PURPOSE OF THIS PROGRAM IS TO PROVIDE SERVICES TO ADDRESS THE UNMET NEEDS OF THE BLACK AND LATINO/HISPANIC COMMUNITIES IN MIDDLESEX COUNTY, NEW JERSEY WITH SERIOUS EMOTIONAL DISTURBANCE (SED), SERIOUS MENTAL ILLNESS (SMI), AND CO-OCCURRING DISORDERS WHOSE NEEDS HAVE NOT BEEN MET DURING THE PANDEMIC. OUR GOALS ARE: GOAL 1: TIMELY ACCESS TO EARLY INTERVENTION AND TREATMENT FOR MENTAL HEALTH AND ADDICTION OBJECTIVE 1A/B: CMHC STAFF WILL PROVIDE IN-PERSON SOCIALLY DISTANCED OR VIRTUAL OUTREACH TO 100% OF INDIVIDUALS SERVED AND WILL OFFER LINKAGE TO EVIDENCE-BASED INTERVENTIONS. OBJECTIVE 1C: TIMELY MEDICATIONS WILL BE AVAILABLE TO 100% OF INDIVIDUALS SERVED. GOAL 2: INCREASE ACCESS TO MEDICAL SERVICES OBJECTIVE 2A/B: 100% OF INDIVIDUALS SERVED WILL BE PROVIDED WITH EDUCATION AROUND THE COVID VIRUS AND VACCINE AND OFFERED ASSISTANCE WITH SCHEDULING AND ACCESSING COVID VACCINATIONS. OBJECTIVE 2C: 100% OF INDIVIDUALS WITH MEDICAL CONDITIONS WITH BE OFFERED EDUCATION AND THE OPPORTUNITY TO EXPLORE TREATMENT OPTIONS WITH THE CMHC MEDICAL STAFF. OBJECTIVE 2D: 100 % OF INDIVIDUALS WITH MEDICAL CONDITIONS WILL BE OFFERED LINKAGE TO A PCP. GOAL 3: INCREASE ACCESS TO EMPLOYMENT AND EDUCATIONAL OPPORTUNITIES OBJECTIVE 3A: 100% OF UNEMPLOYED INDIVIDUALS WILL BE OFFERED SUPPORTED EMPLOYMENT AND EDUCATION SERVICES. OBJECTIVE 3B/C: 25% INDIVIDUALS WHO LOST THEIR JOBS DUE TO THE PANDEMIC WILL FIND FULL TIME OR PART TIME EMPLOYMENT AND LINKED TO EDUCATIONAL/VOCATIONAL TRAINING GOAL 4: INCREASE ACCESS TO PERMANENT HOUSING AMONG INDIVIDUALS EXPERIENCING MARGINAL HOUSING OR HOMELESSNESS. OBJECTIVE 4A: 100% OF HOMELESS INDIVIDUALS SERVED WILL BE OFFERED DIRECT SUPPORT AND ASSISTANCE TO SUCCESSFULLY SECURE A STABLE LIVING ENVIRONMENT. OBJECTIVE 4B: 90% OF HOMELESS INDIVIDUALS SERVED WILL BE SAFELY SHELTERED GOAL 5: PEER STAFF WILL RECEIVE TRAINING OBJECTIVE 5A/B: 100% OF PEER SUPPORT STAFF WILL RECEIVE TRAINING ABOUT MENTAL HEALTH, ADDICTION AND CO-OCCURRING DIAGNOSIS, AND THE EFFECTS OF THE PANDEMIC ON INDIVIDUALS SERVED TO INCLUDE TRAUMA GRIEF, LONELINESS AND ISOLATION GOAL 6: AVAILABILITY OF IN-PERSON SOCIALLY DISTANCED OR VIRTUAL SUPPORT SERVICES THAT ARE ATTUNED TO THE CULTURE, LANGUAGE AND PAST EXPERIENCES OF THE TARGETED POPULATION OBJECTIVE 6A/B: 100 % OF STAFF WILL RECEIVE TRAINING ON CULTURAL COMPETENCE AND STRATEGIES TO ENGAGE THE TARGET POPULATIONS OBJECTIVE C: 50% OF STAFF HIRED WILL REFLECT THE POPULATIONS SERVED. THE PROGRAM WILL SERVE 500 UNDUPLICATED INDIVIDUALS ANNUALLY, AND 1,000 UNDUPLICATED INDIVIDUALS OVER THE ENTIRE PROJECT PERIOD.

BAYESIAN MACHINE LEARNING FOR CAUSAL INFERENCE WITH INCOMPLETE LONGITUDINAL COVARIATES AND CENSORED SURVIVAL OUTCOMES - PROJECT SUMMARY POPULATION COHORT STUDIES FUNDED BY THE NATIONAL INSTITUTE OF HEALTH, INCLUDING THE ATHEROSCLEROSIS RISK IN COM- MUNITIES (ARIC) STUDY AND MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), ARE WIDELY USED IN CARDIOVASCULAR RESEARCH AND HAVE PROVIDED FUNDAMENTAL KNOWLEDGE FOR CARDIOVASCULAR DISEASE (CVD) PREVENTION STRATEGIES AND PUBLIC HEALTH POLICIES. POOLING DATA ACROSS MULTIPLE COHORTS PROVIDES A UNIQUE OPPORTUNITY FOR IN-DEPTH INVESTIGA- TIONS OF EMERGING CVD RESEARCH QUESTIONS, SUCH AS OPTIMAL BLOOD PRESSURE THRESHOLD VALUES TRIGGERING INITIATION OF ANTIHYPERTENSIVE TREATMENT FOR YOUNG ADULTS, THAT HERETOFORE WOULD NOT HAVE BEEN POSSIBLE. WHILE FORMING A FERTILE GROUND FOR INNOVATIVE RESEARCH, THE METHODOLOGICAL ISSUES ASSOCIATED WITH THE POOLED COHORTS DATA CANNOT BE AS EFFECTIVELY ADDRESSED BY EXISTING STATISTICAL METHODS. THERE ARE THREE MAIN ANALYTIC CHALLENGES. FIRST, MANY DISCRETE OR CONTINUOUS LONGITUDINAL VARIABLES HAVE MISSING VALUES WITH VARIOUS MISSING DATA PATTERNS. EXISTING METHODS EITHER ARE SUSCEPTIBLE TO MISSPECICATION BIASES OR DO NOT PROVIDE COHERENT ESTIMATES OF IMPUTATION UN- CERTAINTY, AND CANNOT HANDLE MISSING NOT AT RANDOM. SECOND, CURRENT CAUSAL INFERENCE METHODS EITHER REQUIRE ALIGNED MEASUREMENT TIME POINTS OR PARAMETRIC ASSUMPTIONS ABOUT FORMS OF CAUSAL PATHWAYS, NEITHER OF WHICH CAN BE SATISED IN COMPLEX LONGITUDINAL HEALTH DATA. THIRD, VIOLATIONS OF THE “SEQUENTIAL IGNORABILITY” ASSUMPTION EMBEDDED IN CAUSAL INFERENCE METHODOLOGY CAN BE A POTENTIAL SOURCE OF BIAS. THE SENSITIVITY ANALYSIS METHODS FOR TIME-VARYING CONFOUNDING WITH CENSORED SURVIVAL OUTCOMES ARE UNDERDEVELOPED. TO OVERCOME THESE CHAL- LENGES AND IMPROVE STATISTICAL AND CVD RESEARCH, WE PROPOSE A SUITE OF GENERALIZABLE STATISTICAL METHODS UTILIZING MACHINE LEARNING. WE PROPOSE TO DEVELOP A SCALABLE BAYESIAN NONPARAMETRIC (BNP) FRAMEWORK TO IMPUTE CON- TINUOUS OR DISCRETE MISSING AT RANDOM LONGITUDINAL COVARIATES WHILE PROVIDING COHERENT UNCERTAINTY INTERVALS, AND ADDRESS THE MISSING NOT AT RANDOM MECHANISM VIA SENSITIVITY ANALYSIS. WE WILL APPLY THE DEVELOPED METHOD TO ADDRESS MISSING DATA ISSUES FOR SEVERAL LONGITUDINAL CVD RISK FACTORS SUCH AS BLOOD PRESSURE, CHOLESTEROL LEVELS (SPECIC AIM 1); TO DEVELOP A ROBUST AND COMPUTATIONALLY EFCIENT BNP CAUSAL INFERENCE METHOD (SPECIC AIM 2) AND A NEW CONTINUOUS-TIME MARGINAL STRUCTURAL SURVIVAL MODEL FROM A BAYESIAN PERSPECTIVE (SPECIC AIM 3) TO STUDY AND VALIDATE THE SURVIVAL EFFECTS OF TIME-VARYING ANTIHYPERTENSIVE TREATMENTS FOR YOUNG ADULTS AND THE FRAIL ELDERLY; TO DEVELOP A EXIBLE AND INTERPRETABLE SURVIVAL SENSITIVITY ANALYSIS METHOD TO ASSESS THE SENSITIVITY OF THE CAUSAL EFFECT ESTIMATES TO VARYING DEGREES OF SEQUENTIAL UNMEASURED CONFOUNDING (SPECIC AIM 4); AND TO CREATE USABLE R SOFTWARE PACKAGES FOR ALL PROPOSED METHODS AND DEVELOP TUTORIAL PAPERS AND SHORT COURSES TO BRIDGE THEORETICAL AND PRACTICAL KNOWLEDGE AND PROMOTE USE OF OUR METHODS (SPECIC AIM 5).

TWO-COMPONENT SYSTEM DESIGN PRINCIPLES

NEUROPEPTIDE-MEDIATED REGULATION OF ANTIHELMINTH IMMUNITY

MODELING THE HUMAN NEURONAL PHENOTYPE OF THE SCHIZOPHRENIA-ASSOCIATED 3Q29 DELETION

NEW JERSEY ECHO - PROJECT SUMMARY/ABSTRACT EARLY ENVIRONMENTAL EXPOSURES ARE STRONGLY IMPLICATED IN THE DEVELOPMENT OF LATER DISEASES. THE EARLY LIFE MICROBIOME PROVIDES A DEVELOPMENTAL CONTEXT FOR UNDERSTANDING HEALTH AND DISEASE ACROSS THE LIFE COURSE. IN THE MODERN ERA, MOTHERS AND CHILDREN ROUTINELY ENCOUNTER MICROBIOME PERTURBING EXPOSURES INCLUDING CESAREAN SECTION, INFANT FORMULA, AND ANTIBIOTICS DURING PREGNANCY AND IN THE CHILD'S FIRST YEAR AFTER BIRTH. COMPELLING BASIC SCIENCE AND EPIDEMIOLOGICAL RESEARCH FROM OUR GROUP AND OTHERS SHOWS THAT PERTURBATION OF THE PRE-CONCEPTION, PRENATAL, AND EARLY CHILDHOOD MICROBIOME CONTRIBUTES TO ADVERSE HEALTH OUTCOMES. THESE CONNECTIONS ARE PARTICULARLY STRONG FOR UPPER AND LOWER AIRWAY HEALTH. POPULATION-BASED STUDIES DOCUMENT ASSOCIATIONS BETWEEN ASTHMA AND EARLY ANTIBIOTIC EXPOSURE, AND CHILDREN WITH ASTHMA HAVE DISTINCT MICROBIOME SIGNATURES FROM UNAFFECTED CHILDREN. COMPLEMENTARY MOUSE MODELS SHOW A CAUSAL ASSOCIATION BETWEEN PERTURBED MICROBIOTA AND AIRWAY DISEASE. HOWEVER, KEY KNOWLEDGE GAPS REMAIN. FIRST, EXISTING STUDIES LACK DIVERSITY AND ARE OFTEN UNDERPOWERED TO EVALUATE THE EXTENT TO WHICH MICROBIOME-PERTURBING EXPOSURES SUCH AS MEDICATION USE, CESAREAN SECTION, AND INFANT FORMULA UNDERLIE RACIAL/ETHNIC DISPARITIES IN OUTCOMES SUCH AS THE HIGHER PREVALENCE OF ASTHMA IN BLACK AND HISPANIC CHILDREN COMPARED TO WHITE CHILDREN. SECOND, FEW STUDIES HAVE EXAMINED THE MICROBIOME ACROSS CRITICAL TIME WINDOWS (PRECONCEPTION, PREGNANCY, DELIVERY, INFANCY, AND EARLY CHILDHOOD). ECHO PROVIDES A UNIQUE OPPORTUNITY TO ADDRESS THESE GAPS AND STUDY THE DEVELOPMENTAL ROLE OF THE EARLY LIFE MICROBIOME IN LATER HEALTH IN A LARGE, DIVERSE U.S. COHORT. WE WILL RECRUIT 500 PREGNANT PEOPLE AND THEIR RESULTING OFFSPRING FROM MIDDLESEX COUNTY, NJ, ONE OF THE MOST DIVERSE COUNTIES IN THE U.S., INTO THE NATIONAL ECHO COHORT. OUR PROPOSED SCIENTIFIC FOCUS IS ON THE EARLY LIFE MICROBIOME AND EXPOSURE TO MICROBIOME-PERTURBING EXPOSURES (CESAREAN SECTION, INFANT FORMULA, AND MEDICATION USE) IN RELATION TO UPPER AND LOWER AIRWAY HEALTH. OUR SPECIFIC AIMS ARE TO: (1) CHARACTERIZE SOCIAL DETERMINANTS AND RACIAL/ETHNIC DISPARITIES IN COMMON MICROBIOME-PERTURBING EXPOSURES DURING CRITICAL EARLY LIFE PERIODS IN THE ECHO-WIDE COHORT AND EVALUATE ASSOCIATIONS WITH LONGITUDINAL MICROBIOME STRUCTURES IN MOTHERS AND CHILDREN; (2) ESTIMATE ASSOCIATIONS BETWEEN MICROBIOME-PERTURBING EXPOSURES AND CHILD OUTCOMES, WITH A FOCUS ON UPPER AND LOWER AIRWAY HEALTH; (3) RECRUIT 500 PREGNANT PARTICIPANTS REFLECTING THE UNIQUE DIVERSITY OF MIDDLESEX COUNTY, NJ; AND (4) (EXPLORATORY) EXAMINE THE EXTENT TO WHICH MATERNAL MICROBIOME PERTURBATION IN THE 12 MONTHS BEFORE CONCEPTION IS ASSOCIATED WITH ADVERSE UPPER AND LOWER AIRWAY OUTCOMES IN CHILDREN. THE ADDITION OF NJ CONTRIBUTES UNIQUE DIVERSITY TO THE ECHO CONSORTIUM. IN TURN, OUR TEAM'S ECHO-WIDE RESEARCH AT A NATIONAL SCALE WILL YIELD KNOWLEDGE THAT INFORMS CLINICAL AND PUBLIC HEALTH INTERVENTIONS THAT PROMOTE A “HEALTHY” MICROBIOME AND IMPROVE CHILD HEALTH.

GLUTAMINE SYNTHETASE IN CANCER CELL METABOLISM AND ONCOGENESIS

A PRECLINICAL PROGRAM FOR TARGETING MYCOBACTERIUM TUBERCULOSIS KASA - ABSTRACT WE PRESENT HEREIN A GRANT APPLICATION FOCUSED ON THE LATE-STAGE DEVELOPMENT OF PRECLINICAL CANDIDATE JSF-3285. PER OUR RECENTLY PUBLISHED RESEARCH, WE HAVE DISCLOSED THE GENESIS OF THIS PROGRAM THAT LED TO THE HIT COMPOUND DG167 AND IDENTIFICATION OF THE ESSENTIAL SS-KETO ACYL SYNTHASE KASA AS ITS TARGET. BUILDING ON THIS EFFORT, OUR PRELIMINARY DATA DETAIL THE OPTIMIZATION TO ARRIVE AT JSF-3285 WHICH IS EFFICACIOUS IN THE ACUTE AND CHRONIC MODELS OF M. TUBERCULOSIS INFECTION IN MICE AT DOSES AS LOW AS 5 MG/KG ONCE-DAILY ORAL. THIS PROPOSAL SEEKS TO BUILD ON THIS DATA BY CONDUCTING THE REQUISITE DRUG COMBINATION AND RELAPSE STUDIES TO ACHIEVE CLINICAL STATUS AND BEGIN IND-ENABLING STUDIES. IN ADDITION, WE PROPOSE A SECOND GENERATION PROGRAM BASED ON PRELIMINARY DATA CONSISTING OF A STRUCTURALLY DISTINCT AMIDE SERIES WITH PROMISING IN VITRO EFFICACY, MOUSE PK, AND X-RAY STRUCTURAL DATA. THE GRANT'S SECOND AIM WILL EVOLVE THIS SERIES, LEVERAGING OUR EXTENSIVE X-RAY STRUCTURAL DATA, SAR, AND MACHINE LEARNING MODELS, TO PRODUCE AT MINIMUM NOVEL EARLY LEAD COMPOUNDS IF NOT COMPOUNDS EQUAL TO OR SURPASSING JSF-3285. THE SUM TOTAL OF THE TWO AIMS, FEATURING JSF-3285 AND SECOND GENERATION CANDIDATE/S, WILL LEND A HIGH PROBABILITY TO A KASA INHIBITOR BECOMING CLINICALLY RELEVANT IN THE NEXT 5 YEARS.

VASCULAR CONTRIBUTION TO WHITE MATTER LESIONS AND MOTOR DYSFUNCTION IN AD AND ADRD - MOST ALZHEIMER’S DISEASE (AD) PATIENTS EXPERIENCE SEVERE MOTOR IMPAIRMENT AT THE LATER STAGE OF DISEASE AND 10 - 40% OF AD PATIENTS EXHIBIT SIGNS OF MOTOR DYSFUNCTION AT EVEN EARLIER STAGES OF AD. FURTHERMORE, CHANGES IN MOTOR FUNCTION OFTEN PRECEDE OTHER SYMPTOMS OF AD AS WELL AS CORRELATE WITH INCREASED SEVERITY AND MORTALITY. DESPITE THE FREQUENT OCCURRENCE OF MOTOR DYSFUNCTION IN AD PATIENTS, LITTLE IS KNOWN ABOUT THE MECHANISMS BY WHICH THIS BEHAVIOR IS ALTERED. IN SEVERAL OTHER NEUROLOGICAL DISEASES, SUCH AS STROKE AND VASCULAR PARKINSONISM (VP), CEREBROVASCULAR LESIONS UNDERLIE MOTOR DYSFUNCTION DURING THE PROGRESSION OF THESE DISEASES, ESPECIALLY IN THE BASAL GANGLIA. IN ADDITION, WHITE MATTER LESIONS (WMLS), WHICH ARE PRIMARILY CONSIDERED A SMALL VESSEL DISEASE AND CHARACTERIZED AS FOCAL ABNORMAL MYELINATION, ARE HIGHLY CORRELATED WITH MOTOR DEFICITS IN VP. MOREOVER, WMLS ARE STRONGLY ASSOCIATED WITH THE CLINICAL RISK OF AD AND MAY ACCELERATE THE CLINICAL MANIFESTATION OF THE DISEASE. FAMILIAL DANISH DEMENTIA (FDD) IS ANOTHER AD-LIKE FAMILIAL NEURODEGENERATIVE DISEASE ASSOCIATED WITH MOTOR DYSFUNCTION, WML, AND VASCULAR IMPAIRMENT. HOWEVER, IT IS UNCLEAR WHICH PATHOGENIC MECHANISMS PRODUCE VASCULAR IMPAIRMENT, WML, MOTOR DYSFUNCTION IN AD AND FDD. SINCE SEVERAL CLINICAL STUDIES SUGGEST A STRONG CONNECTION BETWEEN VASCULAR DEFICITS IN BASAL GANGLIA AND MOTOR DYSFUNCTION IN SEVERAL NEUROLOGICAL DISEASES, WE INVESTIGATED THESE PATHOLOGIC CORRELATIONS IN AD MOUSE MODEL. WE FOUND A SIGNIFICANT INCREASE IN FIBRIN DEPOSITS, DEMYELINATION, AND AXONAL DEGENERATION AS WELL AS A DECREASE IN BLOOD VESSEL DENSITY IN THE STRIATUM OF THE AGED AD MICE WHICH EXHIBITED MOTOR DEFICITS. FURTHERMORE, WE FOUND THE DEPLETION OR DESTABILIZATION OF FIBRIN IN AD MICE IMPROVED THEIR MOTOR PERFORMANCE. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT FIBRIN DEPOSITS AND VASCULAR DEGENERATION LEAD TO BLOOD BRAIN BARRIER (BBB) DAMAGE, AGGRAVATE INFLAMMATION AND DEMYELINATION, AS WELL AS CAUSE AXONAL DEGENERATION, FINALLY LEADING TO MOTOR DYSFUNCTION IN AD AND FDD. IN THIS PROPOSAL WE WILL ANALYZE POSTMORTEM BRAIN TISSUES OF AD PATIENTS WHO CLINICALLY EXHIBITED MOTOR DEFICITS IN THE EARLY DISEASE STATE AND INVESTIGATE THE PATHOGENIC MECHANISM OF MOTOR DYSFUNCTION IN RODENT MODELS OF AD AND FDD USING BIOCHEMICAL, HISTOLOGICAL, AND GENETIC METHODS (EXPERTISE BY MPI AHN). WE WILL ALSO INVESTIGATE HOW STRIATAL FIBRIN DEPOSITS CAUSE DEMYELINATION AND MOTOR DYSFUNCTION IN AD BY INDUCTION OF RESISTANT FIBRIN CLOTS OR DEPLETING THE COAGULATION FACTOR FXIII. FURTHERMORE, WE WILL EMPLOY ADVANCED MAGNETIC RESONANCE IMAGING (MRI) TECHNIQUES IN A MOUSE MODEL OF AD, FXIII DEFICIENT AD MICE AND A KNOCK-IN RAT MODEL OF FDD (EXPERTISE BY MPI DYKE). OUR TECHNIQUES WILL INTERROGATE THE PERMEABILITY OF THE BBB AND ASSESS CEREBRAL BLOOD FLOW, AND WMLS SEEN IN WHITE MATTER HYPERINTENSITIES AS WELL AS DEMYELINATION. OUR LONG-TERM OBJECTIVE IS TO TRANSLATE OUR FINDINGS IN THIS PROPOSAL FOR THE DIRECT CLINICAL MRI USE IN ASSESSING PERMEABILITY, DEMYELINATION AND NEURODEGENERATION IN HUMAN SUBJECTS AND DEVELOPING THERAPEUTICS FOR AD AND FDD.

EVOLUTION AND CLINICAL IMPACT OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL IN BREAST TUMOR MICROENVIRONMENT

T CELL REGULATION OF PATHOGENIC B CELL IN SYSTEMIC AUTOIMMUNITY

RETINOIC ACID INDUCED LYMPHANGIOGENESIS FOR POST-SURGICAL LYMPHEDEMA - LYMPHEDEMA IS AN INCURABLE CONDITION CHARACTERIZED BY LYMPHATIC OBSTRUCTION, TISSUE SWELLING, IMMUNE DYSFUNCTION, AND FIBROSIS AFTER LYMPHATIC INJURY. LYMPHEDEMA AFFECTS 5 MILLION AMERICANS AND IS ASSOCIATED WITH POOR QUALITY OF LIFE DUE TO EXTREMITY DISABILITY, DISFIGUREMENT, AND RISK FOR RECURRENT LIMB-THREATENING INFECTION. IN THE US, LYMPHEDEMA IS MOST COMMONLY A CONSEQUENCE OF LYMPH NODE DISSECTION FOR THE TREATMENT OF SOLID TUMORS SUCH AS BREAST OR PELVIC CANCER. DESPITE THE FACT THAT LYMPHEDEMA IS COMMON AND MORBID, THERE ARE CURRENTLY NO EFFECTIVE DRUG TREATMENTS. USING PRECLINICAL RODENT MODELS OF LYMPHEDEMA, WE HAVE SHOWN THAT 9-CIS RETINOIC ACID (RA) SIGNIFICANTLY ACCELERATES LYMPHATIC REGENERATION FOLLOWING INJURY, RESTORES FUNCTIONAL LYMPHATIC DRAINAGE, AND PREVENTS DEVELOPMENT OF LYMPHEDEMA. OUR OVERARCHING HYPOTHESIS IS THAT RA-MEDIATED LYMPHANGIOGENESIS IS A PROMISING THERAPY FOR SECONDARY LYMPHEDEMA. THE OBJECTIVE OF THIS PROPOSAL, WHICH IS THE FIRST LOGICAL STEP TOWARDS IMPLEMENTING THIS TREATMENT CLINICALLY, IS TO INCREASE OUR UNDERSTANDING OF THE MECHANISMS BY WHICH RAS REGULATE LYMPHANGIOGENESIS AND DEVELOP A TRANSLATIONAL FRAMEWORK FOR THE USE OF THESE COMPOUNDS. THE SPECIFIC AIMS OF THIS PROPOSAL INCLUDE AIM 1: DETERMINE HOW RA SELECTIVELY INDUCES LYMPHANGIOGENESIS; AIM 2: ELUCIDATE THE ROLES OF FGFR AND VEGFR SIGNALING IN RA-MEDIATED LYMPHANGIOGENESIS; AND AIM 3: USE EARLY BIOMARKERS OF LYMPHATIC INSUFFICIENCY TO DEVELOP A PREDICTIVE MODEL THAT CAN GUIDE INITIATION OF RA THERAPY. BASED ON THE CURRENT LACK OF EFFECTIVE THERAPY, IT IS CLEAR THAT THERE IS A NEED TO DEVELOP AN ETIOLOGY-FOCUSED TREATMENT FOR POST-SURGICAL LYMPHEDEMA. THE PROPOSED STUDIES WILL ADDRESS IMPORTANT MECHANISTIC QUESTIONS REGARDING RA MEDIATED LYMPHANGIOGENESIS AND ALSO DEVELOP AN EARLY BIOMARKER BASED PREDICTIVE MODEL THAT WILL GUIDE TREATMENT WINDOWS FOR RA THERAPY. THE PROPOSED WORK WILL SIGNIFICANTLY IMPROVE OUR UNDERSTANDING OF RA-MEDIATED LYMPHANGIOGENESIS AS WELL AS SUPPORT CLINICAL TRANSLATION OF A RA AS A PREVENTATIVE TREATMENT REGIMEN FOR POST-SURGICAL LYMPHEDEMA.

THE ROLE OF HOMELESSNESS AND SUPPORTIVE HOUSING IN HEALTHCARE DISPARITIES AMONG ADULTS IN MEDICAID - ABSTRACT THERE IS AMPLE EVIDENCE THAT HOMELESSNESS IS ASSOCIATED WITH INADEQUATE ACCESS TO ESSENTIAL HEALTH SERVICES AND THAT AFRICAN AMERICAN, HISPANIC/LATINX AND RURAL POPULATIONS ARE AT HIGH RISK FOR HOMELESSNESS AND/OR ITS CONSEQUENCES. HOWEVER, THERE IS INSUFFICIENT KNOWLEDGE ABOUT GAPS IN USE OF SPECIFIC TYPES OF HEALTHCARE AMONG HOMELESS ADULTS, WHETHER SUCH GAPS ARE GREATER AMONG MINORITY AND RURAL POPULATIONS, AND THE POTENTIAL OF PERMANENT SUPPORTIVE HOUSING (PSH) PROGRAMS TO MITIGATE THE GAPS. THIS STUDY AIMS TO: 1) QUANTIFY THE CONTRIBUTION OF HOMELESSNESS TO GAPS IN ESSENTIAL HEALTH SERVICES USE AMONG MEDICAID BENEFICIARIES BY RACE/ETHNICITY AND RURAL RESIDENTIAL STATUS; 2) EVALUATE THE EXTENT TO WHICH THE GAPS ARE MITIGATED BY PLACEMENT IN PSH PROGRAMS; AND 3) IDENTIFY MEDICAID AND PSH POLICY AND PROGRAMMATIC STRATEGIES FOR IMPROVING ACCESS TO ESSENTIAL HEALTH SERVICES AND REDUCING ASSOCIATED RACIAL/ETHNIC AND RURAL DISPARITIES. THIS STUDY WILL OVERCOME SHORTCOMINGS IN PRIOR RESEARCH BY USING NOVEL LARGE SCALE, POPULATION- BASED, LONG-TERM DATA, COMBINED WITH INTEGRATED QUANTITATIVE-QUALITATIVE RESEARCH METHODS. THE STUDY WILL ADDRESS THE FIRST TWO AIMS USING 10 YEARS (2011-2020) OF LINKED HOMELESS SERVICES AND MEDICAID ADMINISTRATIVE DATA FOR NEW JERSEY AND PENNSYLVANIA. THE CONTRIBUTION OF HOMELESSNESS TO HEALTHCARE GAPS AND DISPARITIES WILL BE MEASURED BY COMPARING UTILIZATION AND SPENDING FOR A BROAD SPECTRUM OF COMMUNITY-BASED AND HOSPITAL HEALTH SERVICES AMONG ADULTS EXPERIENCING HOMELESSNESS TO MATCHED MEDICAID BENEFICIARIES WHO HAVE NOT BEEN HOMELESS. PSH WILL BE EVALUATED BY COMPARING TRENDS IN HEALTHCARE USE AND DISPARITIES BY RACE/ETHNIC AND RURAL RESIDENTIAL STATUS AMONG THOSE RECEIVING HOUSING PLACEMENTS TO ADULTS IN SIMILAR CIRCUMSTANCES WHO DID NOT RECEIVE SUCH PLACEMENTS. SPECIFIC ACTIONABLE STRATEGIES FOR IMPROVING POLICY AND PRACTICE WILL BE IDENTIFIED IN FOCUS GROUPS WITH FRONT-LINE PSH PROFESSIONALS DURING WHICH QUANTITATIVE FINDINGS WILL BE SHARED AND DISCUSSED.

IMPACT OF MUTATION BURDEN ON CANCER GROWTH AND THE IMMUNE LANDSCAPE

BIOMARKER SIGNATURES OF TB INFECTION IN YOUNG CHILDREN WITH AND WITHOUT HIV - PER YEAR, GLOBALLY AN ESTIMATED ONE MILLION CHILDREN DEVELOP TUBERCULOSIS (TB) AND MORE THAN 15 MILLION CHILDREN ARE ESTIMATED TO BE EXPOSED TO MYCOBACTERIUM TUBERCULOSIS (MTB). THE CASE FATALITY RATE IS HIGH IN CHILDREN < 5 YEARS OF AGE. CURRENT APPROACHES TO DIAGNOSIS AND MANAGEMENT OF YOUNG CHILDREN THAT ARE CLOSE CONTACTS TO A TB CASE ARE INADEQUATE. THOSE THAT ARE SYMPTOMATIC MAY UNDERGO SPUTUM-BASED DIAGNOSTICS THAT ARE NOT WELL TOLERATED (EG GASTRIC ASPIRATES), REQUIRE ACCESS TO A REFERENCE LABORATORY, AND ARE NOT SENSITIVE BECAUSE TB MAY BE PAUCIBACILLARY OR EXTRAPULMONARY. FOR THAT REASON EMPIRICAL MULTIDRUG ANTI-TB TREATMENT PREDOMINATES IN MANY LOCALES. MANAGEMENT OF THE ASYMPTOMATICS IS SUB-OPTIMAL AS WELL. GIVEN THE POOR PERFORMANCE OF IGRAS AND TST IN THIS AGE GROUP, MOST ARE TREATED WITH ISONIAZID PREVENTIVE THERAPY (IPT). IN ADULTS, ASYMPTOMATIC (SUBCLINICAL TB) IS AT LEAST AS COMMON AS ACTIVE TB AND WILL NOT BE DETECTED BY CURRENT SYMPTOM-BASED SCREENING. WE DO NOT KNOW HOW OFTEN THIS IS THE CASE IN EXPOSED CHILDREN, HOWEVER, IPT, WOULD BE INADEQUATE IN THEM. FURTHER, ABOUT 19% OF CHILDREN IN THIS AGE GROUP WITH LATENT TB INFECTION (LTBI) WILL PROGRESS TO ACTIVE TB, USUALLY WITHIN THE NEXT 3-6 IN THE ABSENCE OF IPT (AND IPT IS ONLY 63% EFFECTIVE). THE NEED THEREFORE IS TO DISCOVER A BIOMARKER OR BIOMARKERS THAT IDENTIFY THOSE CHILDREN < 5 YEARS OF AGE WITH SUBCLINICAL TB (LIKELY TO PROGRESS DESPITE IPT); AND THOSE WITHOUT SUBCLINICAL TB THAT ARE LIKELY TO PROGRESS. THESE BIOMARKERS WOULD ALLOW APPROPRIATE TARGETING OF IPT AND ATT TO THOSE LIKELY TO BENEFIT. THIS CONSORTIUM OF INVESTIGATORS HAVE ON-GOING DIAGNOSTIC AND COHORT STUDIES OF CHILD (< 5 YEARS OF AGE) CLOSE CONTACTS OF TB CASES IN UGANDA THAT INCLUDE A RIGOROUS BACTERIOLOGIC REFERENCE STANDARD APPLIED TO ASYMPTOMATIC AS WELL AS SYMPTOMATICS AND EVALUATION OF NOVEL DIAGNOSTICS AND DISCOVERY OF NON-SPUTUM- BASED APPROACHES. WE PROPOSE NOW TO EVALUATE IN CHILDREN < 5YEARS OLD THAT ARE CLOSE CONTACTS OF A TB CASE A DIVERSE AND COMPLEMENTARY PANEL OF BACTERIAL, HOST-BASED AND IMAGING NON-SPUTUM BIOMARKERS THAT HAVE SHOWN PROMISE AS PREDICTORS OF PROGRESSION IN ADULTS. FURTHER, WE WILL DISCOVER RELEVANT BIOMARKERS IN THIS POPULATION THROUGH AN UNBIASED MULTI-OMICS APPROACH USING PROTEOMICS, SINGLE-CELL OMICS, T-CELL ACTIVATION MARKERS, ANTIGEN-SPECIFIC ANTIBODY PROFILING, MTB EXOSOMAL ASSAYS, COMPUTER-AIDED DETECTION (CAD) FOR CHEST X-RAY INTERPRETATION AND POINT-OF-CARE ULTRASOUND (POCUS). OUR GOAL IS TO CHARACTERIZE A BIOMARKER OR GROUP OF BIOMARKERS THAT MEET A MINIMAL TARGET PERFORMANCE PROFILE TO IDENTIFY CHILDREN WITH SUBCLINICAL TB AND/OR AT HIGH RISK OF PROGRESSION. WE WILL APPLY ADVANCED MACHINE LEARNING AND INTEGRATIVE MULTIOMICS TO IDENTIFY COMBINATIONS OF THESE BIOMARKER SIGNATURES ALONGSIDE TB RISK VARIABLES TO IMPROVE PRECISION OF PREDICTING PROGRESSION. THESE RESULTS WILL PROVIDE NOVEL APPROACHES TO RISK-STRATIFY CHILDREN <5 YEARS OF AGE FOR TARGETING THE ADMINISTRATION OF PREVENTIVE THERAPY AND ATT.

USING THE GENETIC ARCHITECTURE OF SUBSTANCE USE DISORDERS TO ADVANCE GENE IDENTIFICATION AND UNDERSTANDING OF PATHWAYS OF RISK

LOSS-OF-FUNCTION ANALYSES OF SETD1A IN HUMAN NEURAL MODELS - MODIFIED PROJECT SUMMARY/ABSTRACT SECTION RARE LOSS-OF-FUNCTION (LOF) MUTATIONS IN SETD1A ARE STRONGLY ASSOCIATED WITH SCHIZOPHRENIA (SZ), A DEBILITATING MENTAL DISORDER AFFECTING 1% OF THE POPULATION, AND OTHER SEVERE NEURODEVELOPMENTAL DISORDERS. SETD1A ENCODES A COMPONENT OF THE HISTONE METHYLTRANSFERASE COMPLEX PRODUCING MONO-, DI, AND TRIMETHYLATED HISTONE H3 AT LYSINE 4 (H3K4). H3K4 TRIMETHYLATION (H3K4ME3) AND H3K4ME1 ARE EPIGENOMIC MARKS OF ACTIVE GENE TRANSCRIPTIONAL PROMOTERS AND ENHANCERS, RESPECTIVELY. INTERESTINGLY, HISTONE METHYLATION HAS ALSO BEEN SUGGESTED AS ONE OF THE MOST ENRICHED GENE PATHWAYS IN COMMON VARIANT-BASED GENOME-WIDE ASSOCIATIONS STUDIES (GWAS) OF MAJOR PSYCHIATRIC DISORDERS. FURTHERMORE, A RECENT MOUSE MODEL WITH HETEROZYGOUS KNOCKOUT OF SETD1A EXHIBITED WORKING MEMORY DEFICITS AND SHOWED TRANSCRIPTIONAL CHANGES THAT OVERLAP WITH THOSE IMPLICATED IN NEURODEVELOPMENTAL DISORDERS, HOWEVER, SEEMINGLY INDEPENDENT FROM A H3K4ME3 MECHANISM. THEREFORE, IT REMAINS LARGELY UNCLEAR WHETHER AND HOW SETD1A CAUSES SZ-RELEVANT MOLECULAR AND CELLULAR CHANGES IN A HUMAN BRAIN. OUR CENTRAL HYPOTHESIS IS THAT HUMAN INDUCED PLURIPOTENT STEM CELL (HIPSC)-DERIVED NEURONAL CELLS AND CORTICAL ORGANOIDS RECAPITULATE KEY SZ-RELEVANT EPIGENETIC, MOLECULAR AND CELLULAR PROPERTIES OF SETD1A LOF IN THE HUMAN BRAIN. USING CRISPR/CAS9 GENE EDITING, WE HAVE GENERATED ISOGENIC HIPSC LINES CARRYING HETEROZYGOUS LOF MUTATIONS (IN EXON 4 AND EXON 16, ON DIFFERENT GENETIC BACKGROUNDS) OF SETD1A. PRELIMINARY RESULTS SHOWED THAT MUTANT LINES WERE DEFECTIVE IN CORTICAL ORGANOID DEVELOPMENT WITH PREMATURE NEURONAL DIFFERENTIATION AT EARLY DEVELOPMENTAL STAGES. FURTHERMORE, MORPHOLOGICAL, ELECTROPHYSIOLOGICAL AND TRANSCRIPTOMIC ANALYSES OF HIPSC NEURONS CARRYING SETD1A LOF MUTATION SHOWED DEFECTIVE SYNAPTIC NEUROTRANSMISSION. INTERESTINGLY, GENES SHOWING DIFFERENTIAL EXPRESSION IN BOTH 3D CORTICAL ORGANOIDS AND 2D CULTURES FROM MUTANT LINES ARE ENRICHED FOR COMMON GWAS RISK VARIANTS OF SZ AND OTHER NEUROPSYCHIATRIC DISORDERS/TRAITS, SUGGESTING POSSIBLE CONVERGENT PATHWAYS SHARED BY SETD1A LOF AND COMMON GWAS RISK VARIANTS OF MAJOR PSYCHIATRIC DISORDERS. LEVERAGING OUR RESPECTIVE EXPERTISE IN HIPSC MODELS AND NEUROGENESIS, SYNAPTIC PHYSIOLOGY AND FUNCTIONAL GENOMICS WITHIN OUR TEAM, WE PROPOSE TO CHARACTERIZE THE MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE DEFICITS ASSOCIATED WITH SZ-ASSOCIATED LOF MUTATIONS IN SETD1A IN HUMAN NEURAL SYSTEMS. WE WILL IDENTIFY THE CELL-TYPE-SPECIFIC AND DEVELOPMENTAL STAGE-SPECIFIC CELLULAR AND MOLECULAR PHENOTYPES ASSOCIATED WITH SETD1A LOF IN CORTICAL ORGANOIDS, AND THEN INVESTIGATE THE SYNAPTIC PHENOTYPE(S) OF SETD1A LOF MUTATIONS IN HUMAN NEURONS AND ASSOCIATED TRANSCRIPTOME CHANGES. THE PROPOSED STUDY WILL ENABLE US TO PERFORM A WELL-CONTROLLED ASSESSMENT OF THE IMPACT OF SETD1A LOF MUTATIONS ON THE MOLECULAR AND CELLULAR MECHANISMS UNDERLYING DEFICITS IN EARLY NEURODEVELOPMENT AND SYNAPTIC PROPERTIES.

OPTIMIZING VACCINE SCIENCE TO IMPROVE THE OUTCOME OF TUBERCULOSIS TREATMENT - PROJECT SUMMARY TUBERCULOSIS (TB), CAUSED BY PATHOGENIC BACTERIA MYCOBACTERIUM TUBERCULOSIS (MTB), IS CAUSING SIGNIFICANT MORBIDITY AND MORTALITY TO HUMANS ACROSS THE WORLD. LIVE, ATTENUATED M. BOVIS BACILLUS CALMETTE-GUERIN (BCG), IS THE ONLY TB VACCINE CURRENTLY LICENSED BY THE WORLD HEALTH ORGANIZATION FOR USE IN HUMANS. ALTHOUGH BCG PREVENTS SEVERE DISEASE IN CHILDREN WITH VARIABLE EFFICACY, IT FAILS TO PROTECT AGAINST PULMONARY TB IN ADULTS, WHO ARE THE PRIMARY SOURCE OF TRANSMISSION OF MTB IN THE COMMUNITY. MOREOVER, BCG MAY CAUSE DISEASE IN IMMUNE- COMPROMISED INDIVIDUALS, SUCH AS THOSE CO-INFECTED WITH HIV. TO CONTROL THE DEVELOPMENT OF ACTIVE DISEASE AND TO BREAK THE CHAIN OF MTB TRANSMISSION, A NEW, SAFER AND MORE EFFECTIVE VACCINATION APPROACH IS URGENTLY REQUIRED. THE DEVELOPMENT OF “PARADIGM-SHIFTING” PROTECTIVE MEASURES AGAINST TB WILL SIGNIFICANTLY BE AIDED BY THE OPTIMIZATION OF SAFE AND EFFECTIVE COMBINATORIAL PLATFORMS, SUCH AS INTEGRATING NOVEL VACCINES WITH ADJUNCT HOST-DIRECTED THERAPY (HDT) AND/OR ANTIMYCOBACTERIAL DRUGS. THIS STRATEGY IS AIMED AT INDUCING APPROPRIATE INNATE IMMUNITY ALONG WITH POTENT AND DURABLE T CELL RESPONSES, BOTH OF WHICH ARE NECESSARY FOR EFFECTIVE CONTROL OF TB. SUCH AN INTEGRATED APPROACH IS URGENTLY NEEDED TO CONTROL THE PATHOLOGY OF ACTIVE, CAVITARY TB CASES AND TRANSMISSION OF MTB, AS WELL AS TO PREVENT REACTIVATION OF LATENTLY INFECTED INDIVIDUALS, ESTIMATED TO BE ABOUT A QUARTER OF THE WORLD POPULATION, WHO ARE MTB-INFECTED AND MOSTLY ASYMPTOMATIC BUT CAN REACTIVATE THE DISEASE UPON IMMUNE SUPPRESSION. SELECTION AND USAGE OF A RELEVANT ANIMAL MODEL THAT RECAPITULATES THE PATHOPHYSIOLOGY OF CAVITARY TB, AS SEEN IN HUMANS IS VITAL TO SCREEN NOVEL AND BETTER INTERVENTION STRATEGIES TO COMBAT THE DISEASE, INCLUDING POTENT VACCINE AND DRUG CANDIDATES. WE HAVE ESTABLISHED A RABBIT MODEL OF AEROSOL MTB INFECTION THAT MIMICS THE RANGE OF HUMAN MANIFESTATIONS OF PULMONARY TB, FROM CAVITARY (TRANSMISSIBLE) DISEASE TO LATENT INFECTION. DR. SUBBIAN HAS ESTABLISHED A RABBIT MODEL OF CAVITARY TB AND THE SUB-AWARD PI, DR. KUPZ HAS DEVELOPED A TRACTABLE AND REPRODUCIBLE MOUSE MODEL TO STUDY THE REACTIVATION DYNAMICS OF LATENT MTB INFECTION FOLLOWING THE LOSS OF CD4+ T CELLS AS IT OCCURS IN HIV CO-INFECTED INDIVIDUALS. USING THESE TWO MODELS, WE PROPOSE TO DETERMINE THE ABILITY OF A NOVEL RECOMBINANT BCG STRAIN (BCG::ESAT- 6-PE25SS DEVELOPED IN DR. KUPZ LAB), IN COMBINATION WITH MTOR INHIBITOR (EVEROLIMUS) AND/OR TWO FIRST-LINE ANTIBIOTICS, ISONIAZID AND RIFAMPICIN, TO PROTECT AGAINST PROGRESSION TO CAVITARY TB (RABBIT) AND/OR INDUCE STERILIZING IMMUNITY IN LATENCY (MICE). TO COMPARE OUR APPROACH, WE WILL TEST INDIVIDUAL COMPONENTS IN THESE MODEL ANIMALS. WE WILL ALSO DEFINE MUCOSAL (LUNG) AND SYSTEMIC (BLOOD) IMMUNE PARAMETERS THAT PREDICT PROTECTION AGAINST MTB CHALLENGE IN OUR MODEL SYSTEM. THE RESULTS OF THESE STUDIES CAN CONTRIBUTE TOWARDS THE DEVELOPMENT OF NEW GENERATION VACCINE PLATFORMS FOR TARGETING OTHER INTRACELLULAR PATHOGENS, IN ADDITION TO MTB.

ADVERSE HEALTH OUTCOMES FROM EXTREME HEAT, AIR POLLUTION, AND MEDICATIONS IN LOW-INCOME PREGNANT WOMEN AND THEIR OFFSPRING - CLIMATE CHANGE CONSTITUTES “THE SINGLE BIGGEST HEALTH THREAT FACING HUMANITY”. CLIMATE CHANGE EXACERBATES HEAT-RELATED MORBIDITY AND MORTALITY DUE TO MORE FREQUENT, LONGER AND EXTREME HEAT EVENTS. IT ALSO INCREASES WILDFIRE OCCURRENCE AND WORSENS AIR POLLUTION, WHICH IS LINKED TO THROMBOEMBOLIC AND BLEEDING EVENTS. THE HEALTH IMPACTS OF EXTREME HEAT AND AIR POLLUTION WILL ONLY INTENSIFY AS A RESULT OF THE CHANGING CLIMATE. CERTAIN SUBGROUPS ARE DISPROPORTIONATELY AFFECTED, INCLUDING LOW-INCOME POPULATIONS. PREGNANT WOMEN AND THEIR CHILDREN, ESPECIALLY THOSE FROM LOW-INCOME COMMUNITIES, ARE PARTICULARLY VULNERABLE TO HARMS FROM EXTREME HEAT AND AIR POLLUTION, NOT ONLY DUE TO PHYSIOLOGIC CHANGES DURING PREGNANCY AND SOCIAL VULNERABILITY, BUT ALSO BECAUSE OF THE MEDICATIONS THAT ARE TAKEN IN PREGNANCY TO TREAT CHRONIC DISEASES, MENTAL HEALTH CONDITIONS, AND PREGNANCY COMPLICATIONS. NEARLY TWO-THIRDS OF PREGNANT WOMEN IN THE US TAKE AT LEAST ONE PRESCRIPTION DRUG OTHER THAN VITAMINS, AND MEDICATION USE IS LIKELY TO PLAY AN IMPORTANT ROLE IN MODIFYING THE HEALTH EFFECTS OF HEAT AND AIR POLLUTION AND/OR FURTHER INCREASING MORBIDITY IN VULNERABLE PREGNANT PATIENTS AND THEIR OFFSPRING. HOWEVER, THE CURRENT EVIDENCE ASSESSING ADVERSE PERINATAL OUTCOMES IN RELATION TO HEAT AND AIR POLLUTION LACKS ADEQUATE CONSIDERATION OF INDIVIDUAL-LEVEL FACTORS INCLUDING MEDICATION USE AND INTERACTIONS BETWEEN MEDICATIONS AND OTHER RISK FACTORS. WHILE THE CDC RECENTLY PUBLISHED GUIDANCE FOR HEAT AND MEDICATIONS RECOGNIZING THE SIGNIFICANCE OF ENVIRONMENT-MEDICATION INTERACTIONS, EVIDENCE IS STILL LIMITED, ESPECIALLY FOR PREGNANT WOMEN. IN THE PRESENT PROPOSAL, AN INTERDISCIPLINARY TEAM OF EXPERTS IN CLIMATOLOGY, ENVIRONMENTAL AND PHARMACOEPIDEMIOLOGY, OBSTETRICS, CONGENITAL ABNORMALITIES, DATA SCIENCE, AND BIOSTATISTICS WILL WORK CLOSELY TO DESIGN A SERIES OF OBSERVATIONAL EPIDEMIOLOGIC STUDIES. WE WILL LINK TEMPERATURE/HUMIDITY AND AIR POLLUTION DATA WITH NATIONAL MEDICAID DATA AS WELL AS BIRTH REGISTRY DATA FROM NEW JERSEY, MASSACHUSETTS AND CALIFORNIA AND ANALYZE THE LINKED DATA USING THE STATE-OF-THE ART STUDY DESIGNS AND ANALYTIC METHODS. OUR STUDY AIMS TO: (1) ASSESS THE INDEPENDENT AND SYNERGISTIC EFFECTS OF EXTREME HEAT AND PRESCRIPTION OPIOIDS AND OTHER HEAT-SENSITIZING MEDICATIONS ON HEAT-RELATED ADVERSE EVENTS IN LOW-INCOME PREGNANT WOMEN; (2) ASSESS THE INDEPENDENT AND SYNERGISTIC EFFECTS OF AIR POLLUTION, I.E., PARTICULATE MATTER (PM2.5), AND MEDICATIONS ASSOCIATED WITH THROMBOEMBOLIC AND BLEEDING EVENTS ON THESE OUTCOMES; AND (3) ASSESS THE INDEPENDENT AND SYNERGISTIC EFFECTS OF EXTREME HEAT/AIR POLLUTION AND POTENTIALLY TERATOGENIC MEDICATIONS ON THE INCIDENCE OF CONGENITAL ABNORMALITIES. THE RESULTS OF OUR STUDY WILL QUANTIFY THE EFFECTS OF EXTREME HEAT AND AIR POLLUTION EXPOSURE AND THEIR POTENTIAL INTERACTIONS WITH MEDICATION USE IN LOW-INCOME PREGNANT WOMEN WHILE ALSO SHEDDING LIGHT ON POTENTIAL MECHANISMS THAT CONFER INCREASED RISK TO CERTAIN INDIVIDUALS. THE EVIDENCE GENERATED FROM OUR STUDY WILL HAVE A DIRECT IMPACT IN SHAPING ADAPTATION STRATEGIES AND POLICIES FOR CLIMATE CHANGE TO PROTECT VULNERABLE POPULATIONS FROM THE EFFECTS OF EXTREME HEAT AND AIR POLLUTION.

A DIGITAL INTERVENTION TO IMPROVE SKIN SELF-EXAMINATION AMONG MELANOMA SURVIVORS - ABSTRACT WITH INCIDENCE RATES MORE THAN TRIPLING IN THE LAST 45 YEARS, THE POPULATION OF MELANOMA SURVIVORS IN THE US IS ESTIMATED AT MORE THAN A MILLION PERSONS. SURVIVORS ARE AT ELEVATED RISK FOR RECURRENCE AND NEW PRIMARY CANCERS. MOST RECURRENT MELANOMAS ARE FOUND BY SURVIVORS THEMSELVES, WHICH IS WHY PHYSICIANS EDUCATE SURVIVORS ABOUT THE IMPORTANCE OF REGULAR, THOROUGH SKIN SELF-EXAMS (SSE) AND WHY PROFESSIONAL GUIDELINES FOR FOLLOW-UP SURVEILLANCE RECOMMEND REGULAR, THOROUGH (SSE). MORE THAN TWO THIRDS OF MELANOMA SURVIVORS DO NOT PERFORM REGULAR, THOROUGH SSE. TO ADDRESS THIS SIGNIFICANT PROBLEM, OUR EXPERIENCED TEAM DEVELOPED A DIGITAL INTERVENTION, CALLED MYSMARTSKIN (MSS), AND TESTED IT IN AN RCT AGAINST USUAL CARE IN NEW JERSEY. MSS ILLUSTRATED PROMISING EFFECTS ON THOROUGH SSE. IN THIS APPLICATION, WE PROPOSE TO PREPARE MSS FOR LARGE-SCALE DISSEMINATION USING AN INNOVATIVE TYPE 1 HYBRID EFFECTIVENESS-IMPLEMENTATION TRIAL. A TYPE 1 HYBRID EFFECTIVENESS-IMPLEMENTATION DESIGN ALLOWS US TO ENGAGE MULTILEVEL STAKEHOLDERS THROUGHOUT THE RESEARCH PROCESS, EVALUATE THE EFFECTIVENESS OF THE ENHANCED MSS, AND IDENTIFY CRITICAL FACTORS FOR WIDE-SCALE IMPLEMENTATION. THE STUDY’S THREE AIMS ARE GUIDED BY IMPLEMENTATION FRAMEWORKS AND BEHAVIOR CHANGE THEORIES. IN AIM 1, WE WILL ENHANCE MSS USING MULTI-LEVEL STAKEHOLDER ENGAGEMENT BY COLLABORATING WITH KEY STAKEHOLDERS IN ENHANCING MSS THROUGH QUALITATIVE INTERVIEWS AND USABILITY TESTING OF POTENTIAL ENHANCEMENTS. POTENTIAL ENHANCEMENTS ARE BASED ON EMPIRICALLY-VALIDATED BEHAVIOR CHANGE TECHNIQUES (BCTS) AND FINDINGS FROM OUR PRIOR STUDY. WE WILL UTILIZE AN ITERATIVE PROCESS THAT INCLUDES KEY INFORMANT INTERVIEWS WITH SURVIVORS, PROVIDERS, AND RELEVANT PROFESSIONAL ORGANIZATIONS REGARDING PROPOSED ENHANCEMENTS, CONVERSION TO AN ENHANCED MOBILE-BASED INTERVENTION DELIVERY PLATFORM, USABILITY TESTING WITH SURVIVORS, AND ITERATIVE PROGRAM REFINEMENTS. AIM 2 COMPARES THE EFFECTS OF ENHANCED MSS VS. A NON-INTERACTIVE EDUCATIONAL WEBPAGE ON COMPREHENSIVE SSE IN AN RCT WITH SURVIVORS RECRUITED THROUGH TWO STATE CANCER REGISTRIES AND SOCIAL MEDIA (N=300). IN AIM 3, WE IDENTIFY FACTORS RELEVANT TO FUTURE SCALE-UP FOR WIDESPREAD DISSEMINATION AND IMPLEMENTATION USING MIXED METHODS TO ASSESS SELECTED IMPLEMENTATION OUTCOMES FROM THE RCT AND EXPLORE PERSPECTIVES FROM SURVIVORS, CARE PROVIDERS, AND PROFESSIONAL ORGANIZATIONS ABOUT HOW TO BEST DISSEMINATE AND IMPLEMENT MSS ON A BROAD SCALE. WE WILL ESTIMATE PROGRAM COSTS AND ASSESS COST-EFFECTIVENESS OF MSS. THIS PROJECT ADDRESSES A DOCUMENTED GAP IN CARE FOR MELANOMA SURVIVORS BY ENHANCING EFFECTS OF A PROMISING SURVIVOR-FACING INTERVENTION AND PROACTIVELY IDENTIFYING BARRIERS AND FACILITATORS TO FUTURE IMPLEMENTATION. WE INNOVATIVELY “DESIGN FOR DISSEMINATION” BY ENSURING THAT ENHANCEMENTS ARE DESIGNED WITH THE TARGET POPULATION OF POTENTIAL USERS. SERVING AS A MODEL FOR OPTIMIZING PROMISING FULLY-AUTOMATED ONLINE INTERVENTIONS FOR CANCER SURVIVORS FOR DISSEMINATION, THIS PROJECT WILL PROVIDE IMPORTANT INFORMATION ABOUT POTENTIALLY COST-EFFECTIVE WAYS TO REACH SURVIVORS AS WELL AS ABOUT HOW TO ADAPT SUCH AN INTERVENTION FOR DISSEMINATION.

TRAINED IMMUNITY AND THE REGULATION OF ANTI-FUNGAL DEFENSE - ABSTRACT: ALTHOUGH OFTEN OVERLOOKED AS A SIGNIFICANT HEALTH PROBLEM, PULMONARY INFECTIONS WITH FUNGAL PATHOGENS PRESENT A CLINICAL PROBLEM OF GROWING CONCERN. ASPERGILLUS FUMIGATUS (AF) AND CRYPTOCOCCUS NEOFORMANS (CN) ARE TWO CLINICALLY IMPORTANT FUNGAL PATHOGENS THAT AFFECT IMMUNOSUPPRESSED PATIENTS WORLDWIDE. BOTH INFECTIONS ARE DIFFICULT TO TREAT AND ARE ASSOCIATED WITH HIGH MORTALITY RATES. A BETTER UNDERSTANDING OF IMMUNE MECHANISMS OF HOST DEFENSE AGAINST FUNGI HOLD THE PROMISE OF PROVIDING THE BASIS FOR THE FUTURE DEVELOPMENT OF NOVEL, IMMUNE BASED INTERVENTIONS TO IMPROVE PATIENT OUTCOMES. PULMONARY MACROPHAGES ARE CRITICAL, FRONT-LINE MEDIATORS OF HOST PROTECTION AGAINST FUNGI AND OTHER PULMONARY PATHOGENS. DESPITE THE WELL-DEFINED ROLE OF LUNG MACROPHAGES AS CRUCIAL INITIATORS OF IMMUNITY TO DIVERSE SETS OF PATHOGENS, OUR UNDERSTANDING OF HOW PREVIOUS INFECTION HISTORY SHAPES SUBSEQUENT MACROPHAGE RESPONSES TO FUNGAL INFECTION IN THE LUNG REMAIN POORLY DEFINED. MOREOVER, AN EMERGING BODY OF LITERATURE HAS NOW REVEALED THAT MACROPHAGE POPULATIONS IN THE LUNG ARE MORE HETEROGENEOUS THAN ORIGINALLY APPRECIATED AND CAN UNDERGO INNATE TRAINING; AN ENHANCED RESPONSE TO DIVERSE SECONDARY CHALLENGES. IT IS NOW ALSO UNDERSTOOD THAT ALVEOLAR MACROPHAGES PRESENT IN THE LUNG CAN ORIGINATE FROM EMBRYONIC PRECURSORS (TISSUE-DERIVED ALVEOLAR MACROPHAGES-TD-AMS) OR FROM BLOOD MONOCYTES (MONOCYTE-DERIVED ALVEOLAR MACROPHAGES-MO-AMS). WHETHER TD-AM AND MO-AM ARE EQUALLY CAPABLE OF UNDERGOING INNATE TRAINING IS CURRENTLY UNCLEAR. IT IS ALSO UNKNOWN WHETHER INNATE TRAINING IS A CONSERVED RESPONSE TO ANY INFECTIOUS STIMULI OR REGULATED BY SPECIFIC PATHWAYS. IN PRELIMINARY STUDIES, WE UNCOVERED THAT PRIMING WITH AN IMMUNOGENIC STRAIN OF CN (HK-FBP1) COULD CONFER HETEROLOGOUS PROTECTION AGAINST INFECTION WITH AF EVEN IN THE CONTEXT OF DRUG-INDUCED IMMUNOSUPPRESSION AND IN A T CELL-INDEPENDENT MANNER. PRELIMINARY DATA GATHERED, SUGGEST THAT NEUTROPHILS AND STAT1-DEPENDENT SIGNALS ARE IMPORTANT REGULATORS OF ANTIFUNGAL MONOCYTES AND THEIR DIFFERENTIATION INTO MONOCYTE-DERIVED CELLS. BASED ON OUR AGGREGATE OBSERVATIONS, THE CENTRAL HYPOTHESIS OF THIS PROJECT IS THAT: CCR2+MO ARE CRITICAL MEDIATORS OF ANTIFUNGAL IMMUNITY AND CAN BE INSTRUCTED BY HK-FBP1 INTO TRAINED MO-AM VIA THE COORDINATED ACTIONS OF NEUTROPHILS AND AN INTERFERON (IFN) CASCADE. WE WILL ADDRESS TWO RELATED BUT INDEPENDENT AIMS: AIM 1: INVESTIGATE THE IMPACT OF HK-FBP1 IMMUNIZATION TO PULMONARY INNATE CELL PRIMING AND TRAINING TO PROMOTE ANTIFUNGAL IMMUNITY; AIM 2: DECIPHER THE CONTRIBUTIONS OF NEUTROPHILS IN THE REGULATION OF ANTIFUNGAL TRAINED IMMUNITY.

FEND-TB - AMONG THE ESTIMATED 10 MILLION PEOPLE WITH TUBERCULOSIS (TB) IN 2022, OVER 3 MILLION WERE NOT DIAGNOSED, UNDERSCORING THE NEED FOR NEW TOOLS AND DIAGNOSTIC STRATEGIES TO IMPROVE TB CASE DETECTION, INCLUDING IN DIFFICULT TO-DIAGNOSE POPULATIONS SUCH AS CHILDREN AND PEOPLE WITH EXTRAPULMONARY OR EARLY/SUBCLINICAL TB. AN EQUALLY URGENT NEED IS FOR DRUG SUSCEPTIBILITY TESTS (DST) THAT CAN RAPIDLY IDENTIFY TB DRUG RESISTANCE/SUSCEPTIBILITY, INCLUDING TO NEW DRUGS, TO CURE EACH PERSON WITH TB AND TO PROTECT THE EFFICACY OF NEWER DRUGS FOR THOSE WHO MAY BENEFIT FROM THEM IN THE FUTURE. PARTIALLY FUELED BY INNOVATIVE PLATFORMS DEVELOPED TO ADDRESS THE COVID-19 EPIDEMIC, THE LAST DECADE HAS SEEN A SURGE OF NEW TB DIAGNOSTIC PLATFORMS AND ASSAYS. THESE NEW TESTS, SOMETIMES DEVELOPED BY SMALL COMPANIES WITH LIMITED RESOURCES AND LITTLE OR NO EXPERIENCE WORKING WITH MYCOBACTERIUM TUBERCULOSIS (MTB) AND CLINICAL TB, REQUIRE RIGOROUS AND UNBIASED EVALUATIONS. FURTHERMORE, MANY DIAGNOSTIC DEVELOPERS DO NOT SUFFICIENTLY APPRECIATE THE CHALLENGES PRESENTED BY SAMPLE PROCESSING, THE (OFTEN) NEED FOR HIGH TEST SENSITIVITY, OR THE ACCEPTABLE TRADEOFFS BETWEEN SENSITIVITY/SPECIFIC VERSUS ASSAY COSTS, EASE OF USE AND RELEVANT TARGET POPULATIONS OR TB DISEASE STATES. THUS, THE UNMET NEEDS OF TB DIAGNOSTIC DEVELOPERS ARE SPECIFIC TO THE TYPE OF MANUFACTURER, DIAGNOSTIC TECHNOLOGY, ASSAY FORMAT, AND INTENDED USE. OUR PROPOSAL BRINGS TOGETHER A CONSORTIUM OF EXPERIENCED INVESTIGATORS AND A GLOBAL NETWORK OF CLINICAL RESEARCH SITES TO SUPPORT TB DIAGNOSTIC EVALUATIONS THROUGH A FAST-PACED AND FLEXIBLE PIPELINE THAT INCLUDES TECH SCOUTING, DEVELOPMENT MENTORING, AND CLINICAL TESTING OF EARLY-STAGE TB DIAGNOSTICS. WITH THE INCLUSION OF AN ANALYTIC LABORATORY CORE THAT CAN ASSESS AND HELP OPTIMIZE NEW TECHNOLOGIES PRIOR TO AND AFTER CLINICAL STUDIES OUR PROGRAM OFFERS A UNIQUE OPPORTUNITY TO ACCELERATE PROMISING TB DIAGNOSTICS THROUGH THEIR OPTIMAL DEVELOPMENT PIPELINE. CONSORTIUM MEMBERS HAVE ALMOST THREE DECADES OF LEADERSHIP EXPERIENCE IN DIAGNOSTIC TECH SCOUTING, RESEARCH, DEVELOPMENT, CLINICAL TRIALING, AND IMPLEMENTATION ACTIVITIES. FIELDING A BALANCE OF ESTABLISHED PLATFORMS, FAST FOLLOWERS, AND CUTTING- EDGE TECHNOLOGIES, WE WILL PERFORM THE FOLLOWING SPECIFIC AIMS: 1) IDENTIFY PROMISING EARLY-STAGE DIAGNOSTICS FOR EVALUATION AND DEVELOP FOR EACH A STEPWISE EVALUATION PLAN; 2) EVALUATE THE DIAGNOSTIC ACCURACY OF NOVEL RAPID POINT OF CARE/NEAR CARE TB DIAGNOSTICS AND DETERMINE THE IMPACT OF RELEVANT PATIENT CHARACTERISTICS ON TEST ACCURACY; AND 3) PROVIDE FEEDBACK TO DIAGNOSTIC DEVELOPERS, POLICYMAKERS, AND OTHER STAKEHOLDERS ON PERFORMANCE AND USABILITY OF NOVEL DIAGNOSTIC TESTS AND POTENTIAL STRATEGIES FOR USE IN TB ENDEMIC SETTINGS.

TRANSCRIPTOME AND PROTEOME REMODELING BY MYCOBACTERIUM TUBERCULOSIS MAZF TOXINS

ENHANCING SELF CARE AMONG ORAL CANCER SURVIVORS: THE EMPOWERED SURVIVOR TRIAL

COMMON SCHIZOPHRENIA VARIANTS FUNCTIONING IN DEVELOPMENTAL HUMAN CORTICAL INTERNEURONS - ABSTRACT SCHIZOPHRENIA (SCZ) IS A HIGHLY HERITABLE AND COMPLEX NEURODEVELOPMENTAL DISORDER. REMARKABLE ADVANCES HAVE BEEN MADE RECENTLY IN SCZ GENETIC STUDIES WITH AN INCREASING NUMBER OF RISK LOCI REACHING GENOME-WIDE SIGNIFICANCE; HOWEVER, GLEANING BIOLOGICAL INSIGHT FROM THESE LOCI HAS BEEN CHALLENGING. THE MAJORITY OF SCZ RISK LOCI ARE LOCATED IN NON-CODING REGIONS. AS SUCH, IT IS HYPOTHESIZED THAT THEY FUNCTION BY REGULATING DISTAL GENE EXPRESSION VIA 3D CHROMATIN INTERACTIONS. HOWEVER, IT HAS YET TO BE DETERMINED WHICH LOCI ARE OPERATIONAL IN WHICH CELLS, AT WHAT TIME POINTS, AND WITH WHAT IMPACT. RECENT GENOMIC ANALYSES SHOWED ENRICHED SCZ HERITABILITY IN HUMAN FETAL BRAINS RATHER THAN ADULT BRAINS, SUGGESTING THE ROLE OF SCZ RISK LOCI IN MODULATING FETAL DEVELOPMENT FOR INCREASED SCZ RISKS. THUS, UNRAVELING SCZ RISK LOCI FUNCTION DURING DEVELOPMENT WILL BE CRITICAL FOR UNDERSTANDING GENETIC INFLUENCES ON SCZ RISKS. GENETIC INFLUENCES ON GENE EXPRESSION (E.G. EXPRESSION QUANTITATIVE TRAIT LOCI (EQTLS)) ARE CELL-TYPE-SPECIFIC, AND SOMETIMES CONFER OPPOSING EFFECTS DEPENDING ON THE CELL TYPE, UNDERSCORING THE IMPORTANCE OF CELL-TYPE-SPECIFIC STUDIES USING HOMOGENEOUS CELL POPULATIONS FOR A CLEAR MECHANISTIC UNDERSTANDING. PARVALBUMIN (PV)- OR SOMATOSTATIN (SST)-EXPRESSING MEDIAL GANGLIONIC EMINENCE (MGE)-DERIVED CORTICAL INTERNEURONS (CINS) ARE CONSISTENTLY AFFECTED IN SCZ BRAINS. MORE IMPORTANTLY, SCZ HERITABILITY IS SHOWN TO BE ENRICHED IN MGE CELLS IN HUMAN FETAL BRAINS, NECESSITATING THE STUDY OF THESE CELLS TO UNDERSTAND THE MECHANISMS OF SCZ RISK LOCI. ALTHOUGH THERE ARE NO POSTMORTEM FETAL SCZ TISSUES FOR MECHANISTIC STUDY, IN VITRO DIFFERENTIATION OF IPSC—WHICH WELL RECAPITULATES EARLY EMBRYONIC DEVELOPMENT— PROVIDES DEVELOPMENTAL SCZ BRAIN CELLS WITH THE SAME GENETIC MAKEUP AS PATIENT BRAINS. WE ESTABLISHED METHODS FOR THE EFFICIENT GENERATION OF HOMOGENEOUS POPULATIONS OF MGE-DERIVED CINS FROM HEALTHY CONTROL (HC) AND SCZ IPSCS. WE ALSO EXTENSIVELY VALIDATED THEIR FUNCTIONALITY AND AUTHENTICITY BOTH IN VITRO AND IN VIVO, INCLUDING ROBUST MIGRATION AND SYNAPTIC INTEGRATION INTO HOST BRAINS THAT RESULTS IN EFFICIENT INHIBITORY REGULATION OF HOST CIRCUITRY IN TRANSPLANTED MICE. USING AN UNPRECEDENTEDLY LARGE NUMBER OF IPSCS TO PROVIDE HOMOGENEOUS POPULATIONS OF HC VS SCZ FETAL CINS FOR MECHANISTIC STUDIES, WE WILL ADDRESS OUR HYPOTHESIS THAT SCZ RISK LOCI ACTIVE IN DEVELOPMENTAL MGE-TYPE CINS REGULATE DISTAL GENE EXPRESSION VIA 3D CHROMATIN INTERACTIONS. EMPLOYING TRANSCRIPTOME ANALYSIS, PREDIXCAN ANALYSIS, AND MICRO-C ANALYSIS, WE WILL MAP SCZ RISK LOCI WITH UNKNOWN FUNCTIONS TO THE RISK GENES THEY REGULATE IN THESE VULNERABLE CELL POPULATIONS DURING DEVELOPMENT. DEVELOPMENTAL CIN-SPECIFIC GENETIC INFLUENCES ON GENE EXPRESSION, IDENTIFIED BASED ON MULTIPLE LINES OF CORROBORATING EVIDENCE, WILL BE FUNCTIONALLY VALIDATED USING CRISPRI/CRISPRA APPROACHES. THIS UNBIASED GENOME-WIDE COMPREHENSIVE DATA SET FROM DEVELOPMENTAL MGE-TYPE CINS WITH FUNCTIONAL VALIDATION WILL PROVIDE A ROAD MAP FOR UNRAVELLING THE GENETIC BASIS OF DEVELOPMENTAL SCZ RISKS AND HELP US IDENTIFY MECHANISM-BASED NOVEL THERAPEUTIC TARGETS.

A MULTI-LEVEL INVESTIGATION OF US INDOOR TANNING POLICYENACTMENT, IMPLEMENTATION, COMPLIANCE, IMPACT, AND ECONOMICS

NANOTECHNOLOGY-BASED PERSONALIZED TREATMENT OF METASTATIC OVARIAN CANCER - THIS IS AN APPLICATION FOR AN INTERDISCIPLINARY PROJECT TO DEVELOP A NOVEL APPROACH FOR PERSONALIZED CHEMOTHERAPY OF GYNECOLOGIC CANCERS. ESTIMATES FROM THE NATIONAL CANCER INSTITUTE INDICATE THAT MORE THAN 116,000 WOMEN IN THE UNITED STATES WILL BE DIAGNOSED WITH A GYNECOLOGIC CANCER AND ABOUT 34,000 DIE FROM THESE TYPES OF CANCER IN 2021. DESPITE ADVANCES IN SURGICAL AND RADIATION TREATMENTS, CHEMOTHERAPY CONTINUES TO BE AN IMPORTANT TREATMENT OPTION FOR GYNECOLOGIC MALIGNANCIES, ESPECIALLY FOR LOCALLY ADVANCED AND METASTATIC TUMORS. HOWEVER, THE EFFICACY OF CHEMOTHERAPY IS SUBSTANTIALLY LIMITED BY THE INTRINSIC AND ACQUIRED RESISTANCE OF CANCER CELLS TO CYTOTOXIC DRUGS. WE ARE PROPOSING TO DEVELOP AND VALIDATE A NANOTECHNOLOGY-BASED APPROACH OF PERSONALIZED TREATMENT OF OVARIAN CARCINOMA (MOST LETHAL TYPE OF GYNECOLOGICAL CANCERS) CONSTRUCTED ON THE INDIVIDUAL GENETIC PROFILE OF THE PATIENT’S TUMOR. BASED ON THE RESULTS OF THE PRESENT TRANSLATIONAL RESEARCH THE FOLLOWING TREATMENT PROTOCOL WILL BE PROPOSED FOR FUTURE CLINICAL TRIALS AFTER THE COMPLETION OF THE PRESENT PROJECT. SAMPLES OF A PATIENT’S TUMOR AND NORMAL SURROUNDING TISSUES WILL BE OBTAINED DURING THE TUMOR DEBULKING SURGERY AND TUMOR PROFILE DATA (THE EXPRESSION OF PREDEFINED GENES AND PROTEINS) WILL BE OBTAINED AND ANALYZED. BASED ON THIS ANALYSIS, SEVERAL MOLECULAR TARGETS AND THE MOST EFFECTIVE ANTICANCER DRUG(S) WILL BE SELECTED. FINALLY, A MIXTURE OF COMPLEX NANOCARRIER-BASED TARGETED DELIVERY SYSTEMS (TDS) CONTAINING DRUG(S)/SIRNA(S)/TARGETED PEPTIDE WILL BE SELECTED FROM THE PRE-SYNTHESIZED BANK AND THE PATIENT WILL BE TREATED WITH THE CHOSEN COCKTAIL OF TDS DESIGNED SPECIFICALLY FOR THEIR INDIVIDUAL TUMOR. THE SELECTED SYSTEMS WILL INCLUDE THE LIPID-BASED CARRIER, THE TUMOR TARGETING MOIETY, THE MOST EFFECTIVE DRUG(S) AND SIRNA(S) SELECTED FOR EACH INDIVIDUAL PATIENT BASED ON A GENETIC PROFILE OF THE PATIENT’S TUMOR. IT IS EXPECTED THAT SUCH PERSONALIZED THERAPY WILL EFFECTIVELY SUPPRESS DRUG RESISTANCE AND TUMOR GROWTH, INHIBIT THE DEVELOPMENT OF METASTASES AND LIMIT ADVERSE SIDE EFFECTS OF THERAPY IN THE PARTICULAR PATIENT. THE MAIN GOALS OF THE PROPOSED RESEARCH ARE TO IDENTIFY PROFILES OF GENE/PROTEIN EXPRESSION IN TISSUE SAMPLES ISOLATED FROM PATIENTS WITH OVARIAN CANCER THAT PREDICT TUMOR RESPONSE AND RESISTANCE TO ANTICANCER DRUGS WITH DIFFERENT MECHANISMS OF ACTION. WE ALSO WILL DEVELOP A SET OF TDSS CONTAINING ANTICANCER DRUG(S) OR SIRNA(S) TARGETED TO DIFFERENT MRNAS OVEREXPRESSED IN THE TUMOR OF THE PATIENT. FINALLY, A GENETIC PROFILE AND PROTEIN EXPRESSION PHENOTYPE WILL BE PERFORMED ON SAMPLES OF TUMOR TISSUES AND MALIGNANT ASCITES FROM PATIENTS WITH OVARIAN CARCINOMA. CANCER CELLS WILL BE ISOLATED FROM FRESH SAMPLES OBTAINED DURING SURGERY. BASED ON THE RESULTS OF THE GENETIC PROFILING, A MIXTURE OF TDS WILL BE CREATED AND TESTED IN VITRO (ON CELL CULTURE MODEL) AND IN VIVO (ON SUBCUTANEOUS MURINE CANCER MODEL) USING CANCER CELLS ISOLATED FROM EACH INDIVIDUAL PATIENT AND RECOMMENDATIONS FOR THE PERSONALIZED TREATMENT OF OVARIAN CANCER WILL BE DEVELOPED.

COVID-19 NETWORK OF NETWORKS EXPANDING CLINICAL AND TRANSLATIONAL APPROACHES TO PREDICT SEVERE ILLNESS IN CHILDREN (CONNECT TO PREDICT SICK CHILDREN) - THE SARS-COV-2 PANDEMIC HAS MANIFESTED IN CHILDREN WITH A WIDE SPECTRUM OF CLINICAL PRESENTATIONS RANGING FROM ASYMPTOMATIC INFECTION TO DEVASTATING ACUTE RESPIRATORY SYMPTOMS, APPENDICITIS (OFTEN WITH RUPTURE), AND MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS-C), A SERIOUS INFLAMMATORY CONDITION PRESENTING SEVERAL WEEKS AFTER EXPOSURE TO OR INFECTION WITH THE VIRUS. THESE PRESENTATIONS OVERLAP IN THEIR CLINICAL SEVERITY WHILE MAINTAINING DISTINCT CLINICAL PROFILES. PUBLIC HEALTH AND CLINICAL APPROACHES WILL BENEFIT FROM AN IMPROVED UNDERSTANDING OF THE SPECTRUM OF ILLNESS ASSOCIATED WITH SARS COV-2 AND FROM THE CAPACITY TO INTEGRATE DATA TO ACHIEVE TWO GOALS: (I) TO IDENTIFY THE CLINICAL, SOCIAL, AND BIOLOGICAL VARIABLES THAT PREDICT SEVERE COVID-19 AND MIS-C, AND (II) TO TARGET THOSE POPULATIONS AND INDIVIDUALS AT GREATEST RISK FOR HARM FROM THE VIRUS. WE PROPOSE THE COVID-19 NETWORK OF NETWORKS EXPANDING CLINICAL AND TRANSLATIONAL APPROACHES TO PREDICT SEVERE ILLNESS IN CHILDREN (CONNECT TO PREDICT SICK CHILDREN) COMPRISING EIGHT PARTNERS PROVIDING ACCESS TO DATA ON >15 MILLION CHILDREN. OUR NETWORK WILL SYSTEMATICALLY INTEGRATE SOCIAL, EPIDEMIOLOGICAL, GENETIC, IMMUNOLOGICAL, AND COMPUTATIONAL APPROACHES TO IDENTIFY BOTH POPULATION- AND INDIVIDUAL-LEVEL RISK FACTORS FOR SEVERE ILLNESS. OUR UNDERLYING HYPOTHESIS IS THAT A COMBINATION OF MULTIDIMENSIONAL DATA – CLINICAL, SOCIODEMOGRAPHIC, EPIDEMIOLOGIC, AND BIOLOGICAL -- CAN BE INTEGRATED TO PREDICT WHICH CHILDREN ARE AT GREATEST RISK TO HAVE SEVERE CONSEQUENCES FROM SARS-COV-2 INFECTION. TO TEST OUR HYPOTHESIS, WE WILL DEVELOP CONNECT TO PREDICT SICK CHILDREN, A NETWORK OF NETWORKS THAT LEVERAGES INPATIENT, OUTPATIENT, COMMUNITY, AND EPIDEMIOLOGICAL DATA RESOURCES TO SUPPORT THE ANALYSIS OF LARGE DATA USING MACHINE LEARNING AND MODEL-BASED ANALYSES. FOR THE R61 PHASE, WE WILL DEVELOP AND REFINE PREDICTIVE MODELS USING DATA FROM OUR NETWORK OF NETWORKS (AIM 1). WE WILL ALSO RECRUIT PARTICIPANTS PREVIOUSLY DIAGNOSED WITH EITHER COVID-19 OR MIS-C (ALONG WITH APPROPRIATE CONTROLS WHO HAVE HAD MILD OR ASYMPTOMATIC INFECTIONS WITH SARS-COV2), WHO WILL PROVIDE SURVEY DATA (INCLUDING SOCIAL DETERMINANTS) AND SALIVA AND BLOOD SAMPLES TO IDENTIFY PERSISTING BIOLOGICAL FACTORS ASSOCIATED WITH SEVERE DISEASE (AIM 2). WE WILL ITERATIVELY ASSESS OUR MODELS USING A KNOWLEDGE MANAGEMENT FRAMEWORK THAT CONSIDERS THE MARGINAL VALUE OF DATA FOR IMPROVING MODELS' PREDICTIVE CAPACITY OVER TIME. IN THE R33 PHASE, WE WILL VALIDATE AND FURTHER REFINE PREDICTIVE MODELS INCORPORATING DATA FROM ADDITIONAL PARTICIPANTS RECRUITED THROUGHOUT OUR NETWORK OF NETWORKS, INCLUDING NEWLY INFECTED CHILDREN WITH SEVERE COVID-19 OR MIS-C IDENTIFIED THROUGH REAL-TIME SURVEILLANCE (AIM 3). WE SEEK TO DEVELOP PREDICTIVE MODELS FOR CHILDREN AND ADOLESCENTS THAT ARE USEFUL, SENSITIVE TO COMMUNITY AND ENVIRONMENTAL CONTEXTS, AND INFORMED BY THE REASSURED FRAMEWORK SPECIFIED BY THE RFA. THE MODELS AND BIOMARKERS DEVELOPED THROUGH OUR NATIONWIDE NETWORK OF NETWORKS WILL PRODUCE GENERALIZABLE KNOWLEDGE THAT WILL IMPROVE OUR ABILITY TO PREDICT WHICH CHILDREN ARE AT GREATEST RISK FOR SEVERE COMPLICATIONS OF SARS-COV- 2 INFECTION. THIS KNOWLEDGE WILL FACILITATE INTERVENTIONS TO PREVENT AND TREAT SEVERE PEDIATRIC ILLNESS.

MOTIVATIONAL INTERVIEWING AND MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT FOR TOBACCO DEPENDENCE AND OTHER DRUG USE IN METHADONE TREATMENT - PROJECT SUMMARY POLYSUBSTANCE USE IS COMMON AMONG PEOPLE WITH AN OPIOID USE DISORDER (OUD), AND, AND ALTHOUGH APPROXIMATELY 80% OF PEOPLE WITH OUD SMOKE CIGARETTES, TOBACCO USE IS RARELY ADDRESSED IN OUD TREATMENT. SMOKING CESSATION INTERVENTIONS THAT ARE EFFECTIVE IN THE GENERAL POPULATION HAVE BEEN MINIMALLY EFFECTIVE AMONG PEOPLE WITH AN OUD. YET, SMOKING CESSATION IS RELATED TO REDUCED DRUG RELAPSE IN THIS POPULATION. PAIN AND DISTRESS, WHICH AFFECT MOST PEOPLE RECEIVING METHADONE TREATMENT (MT) FOR OUD, ARE THOUGHT TO CONTRIBUTE TO CONTINUED OPIOID, TOBACCO, AND OTHER DRUG USE. HOWEVER, TYPICALLY, MT PROGRAMS AND SMOKING CESSATION INTERVENTIONS FAIL TO ADDRESS THE PHYSICAL PAIN, EMOTION DYSREGULATION, AND REWARD PROCESSING DEFICITS THAT CO- OCCUR WITH SUBSTANCE USE. NOVEL BEHAVIORAL INTERVENTIONS ARE NEEDED TO ADDRESS THESE FACTORS AND TO SUPPORT OPIOID, TOBACCO, AND OTHER DRUG ABSTINENCE, SIMULTANEOUSLY, IN THIS POPULATION, TO SAVE AND IMPROVE LIVES. MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) IS A NOVEL BEHAVIORAL INTERVENTION THAT SHOWS PROMISE FOR ADDRESSING OPIOID, TOBACCO, AND OTHER SUBSTANCE USE, SEPARATELY, AND HAS NEVER BEEN EVALUATED TO ADDRESS POLYSUBSTANCE USE, SIMULTANEOUSLY. MORE INTEGRATES TRAINING IN MINDFULNESS, REAPPRAISAL, AND SAVORING SKILLS INTO AN 8-WEEK GROUP THERAPY DESIGNED TO REMEDIATE HEDONIC DYSREGULATION IN BRAIN REWARD SYSTEMS UNDERPINNING SUBSTANCE USE DISORDERS. ALSO, MOTIVATION AND SELF-EFFICACY FOR TOBACCO AND OTHER DRUG USE ABSTINENCE OFTEN DIFFERS FROM MOTIVATION AND SELF-EFFICACY FOR OPIOID USE ABSTINENCE AMONG PEOPLE IN MT; THEREFORE, WE WILL EXAMINE THE IMPACT OF MOTIVATIONAL-INTERVIEWING (MI) RELATIVE TO TREATMENT AS USUAL (I.E., “NO MI”), PRIOR TO MORE OR A SUPPORT GROUP (SG) CONTROL INTERVENTION, ON TREATMENT ENGAGEMENT AND OUTCOMES. WE WILL CONDUCT A 2 X 2 RANDOMIZED TRIAL OF MORE VS. A SG, WITH OR WITHOUT MI, TO ADDRESS OPIOID, TOBACCO, AND OTHER DRUG USE, SIMULTANEOUSLY, AMONG PEOPLE IN MT WHO SMOKE CIGARETTES. ALL PARTICIPANTS WILL RECEIVE COMBINATION NICOTINE REPLACEMENT THERAPY (C-NRT). EXPEDITED IMPLEMENTATION AND DISSEMINATION OF EFFECTIVE INTERVENTIONS IS NEEDED. HOWEVER, UPTAKE OF NOVEL INTERVENTIONS MAY BE SLOW IN MT BECAUSE TIME AND RESOURCES ARE OFTEN LIMITED. TO BEST ADDRESS POTENTIAL IMPLEMENTATION ISSUES AND TO OPTIMIZE FUTURE MI AND MORE IMPLEMENTATION AND DISSEMINATION, IN THIS STUDY, WE WILL UTILIZE A TYPE 2, HYBRID IMPLEMENTATION-EFFECTIVENESS STUDY DESIGN TO EVALUATE AN IMPLEMENTATION STRATEGY AND TO ASSESS BARRIERS AND FACILITATORS TO INTEGRATING MI AND MORE FOR POLYSUBSTANCE USE INTO MT. WE WILL: 1) DETERMINE MORE’S EFFECTIVENESS FOR DECREASING TOBACCO, OPIOID, AND OTHER DRUG USE, SIMULTANEOUSLY, AMONG PEOPLE IN MT WHO SMOKE (N=420), 2) DETERMINE THE EFFECTIVENESS OF AN MI SESSION, RELATIVE TO TREATMENT AS USUAL, FOR INCREASING TREATMENT ENGAGEMENT AND MOTIVATION FOR DECREASING OPIOID, TOBACCO, AND OTHER DRUG USE, AND 3) EXAMINE BARRIERS AND FACILITATORS TO IMPLEMENTING MI AND MORE FOR POLYSUBSTANCE USE AND EVALUATE STRATEGIES FOR OPTIMIZING TRAINING, FIDELITY, AND CLINIC UPTAKE.

STIGMA AND THE NON-COMMUNICABLE DISEASE SYNDEMIC IN AGING HIV POSITIVE AND HIV NEGATIVE MSM - ABSTRACT OVER THE NEXT DECADE, MORE THAN 70% OF PEOPLE LIVING WITH HIV (PWH) WILL BE OLDER THAN 50. THE INCREASING BURDEN OF THE NON-COMMUNICABLE DISEASES (NCDS) HYPERTENSION, DIABETES, AND DYSLIPIDEMIA HAS AL-READY BEGUN TO PRESENT KEY CHALLENGES TO EFFECTIVE HIV CARE AMONG AGING PLWH, INCLUDING SEXUAL MINORITY MEN (SMM). BECAUSE THESE NCDS OFTEN PRESENT TOGETHER AS COMORBID CONDITIONS, INTERACT WITH EACH OTHER ADVERSELY, AND ARE INFLECTED BY SOCIAL AND STRUCTURAL INEQUITIES, THEY MAY COMPRISE A SYNERGISTIC EPIDEMIC (SYNDEMIC). IN THE U.S., THERE ARE SUBSTANTIAL RACIAL, ETHNIC, AND SOCIOECONOMIC DISPARITIES IN THE PREVALENCE AND/OR CONTROL OF NCDS AND HIV. INTERSECTING STIGMAS, SUCH AS RACISM, CLASSISM, AND HOMOPHOBIA, MAY DRIVE THESE HEALTH DISPARITIES THROUGH DIRECT AND INDIRECT MECHANISMS. DIRECTLY, INTERSECTIONAL STIGMA IN HEALTHCARE SETTINGS MAY CONTRIBUTE TO HEALTHCARE AVOIDANCE, DECREASING SUCCESS RATES ALONG HIV AND NCD SYNDEMIC CONTINUA OF CARE DOMAINS OF RETENTION, TREATMENT, ADHERENCE, AND DISEASE CONTROL. INDIRECTLY, EXPERIENCING INTERSECTIONAL STIGMA MAY LEAD TO A PSYCHOSOCIAL SYNDEMIC OF STRESS, DEPRESSION, VIOLENCE, AND SUBSTANCE USE, THEREBY CONTRIBUTING TO HIV AND NCD INCIDENCE, PREVALENCE, AND POORER DISEASE CONTROL. VERY FEW IF ANY STUDIES HAVE PROSPECTIVELY ASSESSED THE CONTRIBUTION OF INTERSECTIONAL STIGMA TO SOCIAL DISPARITIES IN NCD SYNDEMIC INCIDENCE, PREVALENCE, AND CONTROL AMONG PWH; AND FEW IF ANY STUDIES HAVE RIGOROUSLY ASSESSED HOW THE PSYCHOSOCIAL SYNDEMIC MAY MEDIATE PATHWAYS BETWEEN SOCIAL POSITION AND SYNDEMIC NCD AND HIV OUTCOMES. COLLECTING DATA OVER A FOUR-YEAR PERIOD, WE WILL UTILIZE THE MACS/WIHS COMBINED COHORT STUDY, THE LONGEST-RUNNING COHORT STUDY OF HIV+ AND HIV- SMM IN THE U.S., TO ASSESS THE FOLLOWING SPECIFIC AIMS: 1) ASSESS RELATIONSHIPS BETWEEN SOCIAL POSITION, INTERSECTIONAL STIGMA, AND THE PSYCHOSOCIAL SYNDEMIC AMONG MIDDLE-AGED AND AGING HIV+ AND HIV- SMM; 2) ASSESS RELATIONSHIPS BETWEEN SOCIAL POSITION AND NCD SYNDEMIC INCIDENCE AND PREVALENCE; AND 3) ASSESS RELATIONSHIPS BETWEEN SOCIAL POSITION AND HIV AND NCD SYNDEMIC CONTINUA OF CARE OUTCOMES, MEDIATED BY INTERSECTIONAL STIGMA AND THE PSYCHOSOCIAL SYNDEMIC. OUR SCIENTIFIC PREMISE IS THAT MULTIPLY MARGINALIZED POPULATIONS EXPERIENCE DISPARITIES IN NCD SYNDEMIC INCIDENCE, PREVALENCE, AND CONTROL, WHICH ARE MEDIATED BY INTERSECTIONAL STIGMA AND THE PSYCHOSOCIAL SYNDEMIC. THE PROPOSED WORK WILL EXTEND INTERSECTIONAL STIGMA AND PSYCHOSOCIAL SYNDEMICS RESEARCH ON THE HIV CONTINUUM OF CARE TO THE NCD SYNDEMIC CONTINUUM OF CARE. THIS PROPOSAL ALIGNS WITH NIH HIGH PRIORITY AIDS RESEARCH AREAS OUTLINED IN NOT-OD-15-137 (“ADDRESSING THE IMPACT OF HIV-ASSOCIATED COMORBIDITIES”) AND WITH NHLBI RFA-HL-21-018, WHICH CALLS FOR MULTIFACTORIAL RESEARCH USING SYNDEMICS FRAMEWORKS TO CHARACTERIZE CLUSTERING OF HEART, LUNG, BLOOD, AND SLEEP CONDITIONS WITHIN PWH. THIS STUDY WILL PROVIDE CRITICAL DATA FOR INFORMING THE DEVELOPMENT OF INTEGRATED, MULTILEVEL INTERVENTIONS INTENDED TO REMEDIATE DISPARITIES IN NCD INCIDENCE, PREVALENCE, AND CONTROL AMONG MIDDLE-AGED AND AGING SMM, PARTICULARLY SMM OF COLOR AND PWH.

ADDRESSING DISPARITIES IN LANGUAGE AND SOCIAL-EMOTIONAL SKILL ACQUISITION THROUGH LITERACY PROMOTION IN PRIMARY CARE

ER-SHAPING PROTEINS OF PLASMODIUM - ABSTRACT THE ENDOPLASMIC RETICULUM (ER) OF EUKARYOTIC CELLS IS AN ESSENTIAL ORGANELLE WITH MANY CRITICAL FUNCTIONS INCLUDING, PROTEIN SECRETION. ITS FUNCTION IS CLOSELY TIED TO ITS MORPHOLOGY. WORK IN HIGHER EUKARYOTES HAS SHOWN THAT MUTATIONS IN KEY PROTEINS REQUIRED TO GENERATE THE ER TUBULAR NETWORK CAUSE SPECIFIC GROWTH AND DEVELOPMENTAL DEFECTS. IN CONTRAST TO HIGHER EUKARYOTES, LITTLE IS KNOWN OF HOW THE ER IS SHAPED IN EARLY EUKARYOTES SUCH AS PROTOZOA. ER STRUCTURE IN THE PROTOZOAN PARASITE, PLASMODIUM IS DYNAMIC AND STAGE-SPECIFIC BUT ITS MOLECULAR DETERMINANTS ARE UNKNOWN. TO UNDERSTAND HOW THE ER ACQUIRES ITS SHAPE IN DIFFERENT STAGES OF PLASMODIUM, WE IDENTIFIED HOMOLOGS OF KEY ER-SHAPING PROTEINS INCLUDING ONES THAT CONTAIN A RETICULON HOMOLOGY DOMAIN. ONE OF THESE PROTEIN INDUCES MEMBRANE CURVATURE IN VITRO. P. BERGHEI PARASITES LACKING THE PROTEIN HAVE DYSMORPHIC ER, AN ENLARGED DIGESTIVE VACUOLE, ARE SEVERELY ATTENUATED IN THE ASEXUAL CYCLE BUT INFECT HEPATOCYTES NORMALLY. WE HYPOTHESIZE THAT THE PUTATIVE PLASMODIUM ER-SHAPING PROTEINS WE IDENTIFIED HAVE STAGE-SPECIFIC ROLES IN MAINTAINING PROPER ER STRUCTURE/FUNCTION. THIS PROPOSAL WILL DETERMINE THE CONTRIBUTIONS OF THESE PROTEINS IN SHAPING THE ER OF ERYTHROCYTIC AND HEPATIC STAGES OF PLASMODIUM, USING MORPHOLOGICAL AND ULTRASTRUCTURAL STUDIES OF P. BERGHEI GENE-KNOCKOUTS. IT WILL DETERMINE THE EFFECT OF THEIR LOSS ON A KEY ER FUNCTION, PROTEIN TRAFFICKING IN THE PARASITE. OUR STUDY WILL PROVIDE THE FIRST CAUSAL LINK BETWEEN ER ARCHITECTURE, PROTEIN TRAFFICKING AND THE ABILITY OF THE MALARIA PARASITE TO RESIDE IN DIFFERENT HOST ENVIRONMENTS.

IMPROVING MOUD ACCESS, OPIOID-RELATED OUTCOMES AND EQUITY AMONG MEDICARE BENEFICIARIES WITH DISABILITY - PROJECT ABSTRACT MEDICATIONS FOR OPIOID USE DISORDER (MOUD) ARE A KEY TOOL IN REDUCING HARMS OF THE OPIOID EPIDEMIC. YET ONLY A MINORITY OF THOSE WITH OUD INITIATE TREATMENT, EARLY DISCONTINUATION IS TYPICAL, AND DISPARITIES ARE ENDEMIC. PEOPLE WITH DISABILITIES ARE AT ESPECIALLY HIGH RISK AND EPITOMIZE THE CHALLENGES OF OUD WITH MULTIMORBIDITY. PRELIMINARY ANALYSES IDENTIFIED 45,035 FATAL OPIOID OVERDOSES AMONG MEDICARE DISABILITY BENEFICIARIES (MDBS) FROM 2008-2016, AND CONTINUING UNDER-UTILIZATION AND DISPARITIES IN MOUD, INCLUDING AMONG OVERDOSE SURVIVORS. WITH ITS WIDE INFLUENCE IN THE HEALTH CARE SYSTEM, MEDICARE'S ROLE IS VITAL; IT IS ESSENTIAL TO EXAMINE THE MEDICARE SYSTEM'S SUCCESSES AND FAILURES IN ENGAGING AND RETAINING MDBS IN TREATMENT. SEVERAL RECENT POLICY CHANGES ARE PROMISING, WITH IMPORTANT IMPLICATIONS FOR OTHER PAYERS, BUT THEIR IMPACT ACROSS BENEFICIARY SUBGROUPS, TIME AND COMMUNITIES NEEDS TO BE BETTER UNDERSTOOD TO INFORM ACTION TO IMPROVE UPTAKE AND REDUCE DISPARITIES. THIS STUDY, RESPONDING TO RFA-DA-22-037, WILL USE NATIONAL MEDICARE DATA LINKED WITH THE NATIONAL DEATH INDEX, MEDICAID CLAIMS, COMMUNITY RESOURCES, PRESCRIPTION DRUG PLAN (PDP) FORMULARY POLICIES, AND OTHER DATA SOURCES TO ASSESS HOW POLICY, COMMUNITY, PROVIDER AND PATIENT FACTORS INTERACT TO SHAPE MOUD INITIATION AND RETENTION, AND IN TURN OVERDOSE AND OTHER CLINICAL OUTCOMES. WITH ANNUAL UPDATES THROUGH 2025, THE PROJECT WILL PROVIDE A POWERFUL FRAMEWORK FOR ASSESSING EVOLVING TREATMENT PATTERNS AND OUTCOMES IN A RAPIDLY EVOLVING ENVIRONMENT, AS WELL AS POTENTIAL CHANGES IN POLICY IMPACTS OVER TIME. WE WILL ASSESS THE DRIVERS OF RACIAL/ETHNIC AND OTHER DISPARITIES IN ACCESS; MOUD CHANGES FOLLOWING POLICY AND FORMULARY CHANGES BY MEDICARE AND ITS PDPS; AND HOW THESE POLICIES INTERACT WITH THE EVOLVING MOUD PROVIDER SYSTEM, COMMUNITY RESOURCES AND PATIENT CHARACTERISTICS. WE WILL ANALYZE TRENDS AND DISPARITIES IN MOUD TREATMENT AND OVERDOSES AMONG MDBS. IN COHORTS OF BENEFICIARIES WITH NEW OUD DIAGNOSES OR NON-FATAL OVERDOSES, WE WILL ASSESS FACTORS ASSOCIATED WITH TREATMENT INITIATION AND RETENTION, AND ASSOCIATION OF TREATMENT WITH CLINICAL OUTCOMES INCLUDING NON-FATAL AND FATAL OVERDOSE. WE WILL ASSESS MOUD UPTAKE ACROSS COMMUNITY, PROVIDER, AND PATIENT SUBGROUPS; CHANGES IN MOUD TREATMENT PATTERNS ASSOCIATED WITH THE SHIFT TO TELE-HEALTH; AND ASSOCIATED CHANGES IN THE MOUD TREATMENT NETWORK SERVING MDBS. WE WILL EXAMINE THE SEQUELAE OF CHANGES IN FORMULARY POLICIES ACROSS MEDICARE'S MORE THAN 6000 PDPS, INCLUDING PRIOR AUTHORIZATION REQUIREMENTS FOR MOUD, ACROSS BENEFICIARY SUBGROUPS. EXPANDED REIMBURSEMENT FOR TELE-MOUD AND ELIMINATION OF PRIOR AUTHORIZATION HAVE THE POTENTIAL TO SAVE MANY LIVES, BUT IT IS CRITICAL TO BETTER UNDERSTAND THEIR IMPACT ON ACCESS AND DISPARITIES. AN ACTIVE DISSEMINATION STRATEGY SUPPORTED BY A STAKEHOLDER ADVISORY BOARD, COMPLEMENTING PEER-REVIEWED PUBLICATION, WILL SUPPORT TRANSLATION INTO EVIDENCE-INFORMED POLICY. RESULTS OF THIS INNOVATIVE AND COMPREHENSIVE ASSESSMENT OF THE MULTI-LEVEL FACTORS SHAPING MOUD UPTAKE AND OUTCOMES AMONG MDBS WILL HAVE IMPORTANT IMPLICATIONS FOR POLICY AND PRACTICE ACROSS PATIENT SUBGROUPS, PAYERS AND HEALTH CARE SYSTEMS.

SINGLE-NUCLEI MULTIOMIC ANALYSIS OF DLB PROGRESSION - PROJECT SUMMARY DEMENTIA WITH LEWY BODY (DLB) HAS BEEN HISTORICALLY UNDER-INVESTIGATED RELATIVE TO ITS PREVALENCE AS MOST STUDIES OF SYNUCLEINOPATHIES FOCUS ON PD AND PDD. ACCUMULATING EVIDENCE INDICATES, HOWEVER, DLB IS A DISTINCT AGE-ASSOCIATED NEURODEGENERATIVE DEMENTIA. LIKE PD, VARIOUS TYPES OF CELLS INCLUDING NEURONS, MICROGLIA, ASTROCYTES, OLIGODENDROCYTES, ENDOTHELIAL CELLS, AND PERIPHERAL LYMPHOCYTES MIGHT CONTRIBUTE TO DLB PATHOGENESIS. TO UNDERSTAND COMPLEXITIES OF DLB PATHOGENESIS, MORE COMPREHENSIVE APPROACHES TO INVESTIGATING DIFFERENT CELL TYPES AND MULTIPLE BRAIN REGIONS OVER THE COURSE OF DISEASE PROGRESSION ARE NECESSARY. OUR LAB HAS PUT EXTENSIVE EFFORT INTO SINGLE-NUCLEI ANALYSIS OF POSTMORTEM BRAIN TISSUES USING A RECENTLY RELEASED CHROMIUM SINGLE-CELL MULTIOME ATAC PLUS GENE EXPRESSION PLATFORM (10X GENOMICS) AND SUCCESSFULLY ESTABLISHED ALL KEY TECHNIQUES AND A DATA ANALYSIS PIPELINE. TO TRACK THE PROGRESSION OF DISEASE USING BOTH RNA- AND ATAC-SEQ DATA IN THE SAME CELL, WE HAVE DEVELOPED A NOVEL STRATEGY: “CORRELATED PSEUDO-PATHOGENESIS (CPP)” TRAJECTORY ANALYSIS. WE ALSO ESTABLISHED “GENE-PEAK” ANALYSIS ALLOWING US TO ANALYZE RELATIONSHIPS BETWEEN GENE EXPRESSION AND CHROMATIN ACCESSIBILITY IN A SINGLE CELL. OUR TECHNICAL ADVANCEMENTS AND INNOVATIVE DATA ANALYSIS SKILLS WILL SATISFY THIS FOA REQUESTING “PROJECTS TO IDENTIFY CELLULAR CHANGES IN ADRD POST- MORTEM BRAIN TISSUE ACROSS DISEASE PROGRESSION.” TO ACHIEVE THE GOAL SET BY THE CURRENT FOA, WE WILL PURSUE THE FOLLOWING AIMS: AIM 1. NEUROPATHOLOGICAL STAGING OF DLB AND VALIDATION OF CONTROL POSTMORTEM SAMPLES. POSTMORTEM BRAIN TISSUES FROM THE HBTRC WILL BE FURTHER VALIDATED FOR NEUROPATHOLOGICAL STAGING BY H&E AND A- SYN IMMUNOHISTOCHEMICAL STAINING ACCORDING TO UNIFIED STAGING SYSTEM FOR LEWY BODY DISORDERS (USSLB). TO ELIMINATE INCIDENTAL LEWY BODY DISEASE (ILBD), CONTROL TISSUES WILL ALSO BE INVESTIGATED FOR A-SYN PATHOLOGY. AIM 2. ISOLATE NUCLEI FROM EACH SAMPLE AND PERFORM SNRNA-SEQ AND SNATAC-SEQ ANALYSIS. 4 BRAIN REGIONS FROM THREE GROUPS: 1) CONTROL; 2) STAGE II (LIMBIC OR BRAINSTEM PREDOMINANT)/III (BOTH LIMBIC AND BRAINSTEM); 3) AND STAGE IV (NEOCORTICAL), WILL BE SUBJECT TO SINGLE-NUCLEI MULTIOMIC ANALYSIS. AIM 3. SPATIAL TRANSCRIPTOMIC ANALYSIS FOR TOPOLOGICAL DOMAIN MAPPING. DIFFERENTIAL GENE EXPRESSION IN THE SPECIFIC MICRODOMAINS OF EACH BRAIN REGION AND RELATIONSHIP TO A-SYN PATHOLOGY WILL BE INVESTIGATED USING A SPATIALLY BARCODED GENE EXPRESSION PROFILING ARRAY.

DISEASE OUTCOMES IN OLDER ADULTS UNDER EXTREME HEAT, AIR POLLUTION AND MEDICATION USE (DO-NO-HARM)

RCT OF CONTROLLED BREATHING EFFECTS ON AMBULATORY BP

RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY, PROJECT ABSTRACT - FY 2023 THE NEW JERSEY AGRICULTURAL EXPERIMENT STATION (NJAES) AND RUTGERS COOPERATIVE EXTENSION (RCE) DEVELOP AND DELIVER PRACTICAL SCIENCE-BASED SOLUTIONS THAT CONTRIBUTE TO AGRICULTURAL SUSTAINABILITY, THE HEALTH AND WELLNESS OF OUR COMMUNITIES, AND THE ENVIRONMENT, THROUGH RESEARCH AND COMMUNITY OUTREACH. THE CRITICAL ISSUES THAT STAKEHOLDERS HAVE IDENTIFIED FALL INTO FIVE BROAD CATEGORIES AND FORM THE BASIS OF THE NJAES/RCE WORK PLAN: 1. BUILD SUSTAINABLE AND RESILIENT COMMUNITIES; 2. ENSURE HEALTHY OUTCOMES: FOOD, NUTRITION, HEALTH; 3. ENSURE POSITIVE OUTCOMES FOR OUR YOUTH; 4. MAINTAIN VIABLE AGRICULTURE AND AQUACULTURE; 5. PROTECT AND SUSTAIN OUR RESOURCES. NJAES AND RCE SUPPORT RESEARCH AND EXTENSION PROJECTS AND PROGRAMS WITH OUR FEDERAL APPROPRIATIONS THAT ARE FOCUSED ON COMBATING CLIMATE CHANGE, REDUCING RELIANCE ON NON-RENEWABLE ENERGY SOURCES, DEALING WITH THE EMERGENCE OF PESTICIDE-RESISTANT PESTS AND PATHOGENS, AND INCREASING FOOD SECURITY WHICH IS CONSISTENT WITH USDA-NIFA SCIENCE PRIORITY AREAS. NJAES AND RCE MAINTAIN THEIR COMMITMENT TO MAKING THEIR RESOURCES, EXPERTISE, AND PROGRAMS AVAILABLE TO ALL NJ RESIDENTS, BUSINESSES, AND COMMUNITIES. THIS IS MANIFESTED IN ACTIVE EFFORTS TO INCREASE EQUITABLE ACCESS TO ALL NJAES PROGRAMS AND RESOURCES. THROUGH OUR RESEARCH AND EXTENSION PROGRAMS, WE USE INNOVATIVE APPROACHES TO APPLY THE LAND-GRANT MODEL TO SUPPORT A SUSTAINABLE AGR ICULTURAL AND FOOD SYSTEM AT THE URBAN/SUBURBAN FRINGE; PROTECT THE STATE'S NATURAL RESOURCES; SUSTAINABLY DEVELOP NJ'S HUMAN AND COMMUNITY CAPITAL; AND ADDRESS NUTRITION, HEALTH, AND WELLNESS CONCERNS. RESEARCH DEVELOPMENT FINDINGS ARE DELIVERED VIA EDUCATIONAL PROGRAMS AND TRAINING, TECHNOLOGY TRANSFER, POLICY RECOMMENDATIONS, PUBLIC-ORIENTED PUBLICATIONS, PEER-REVIEWED PROFESSIONAL/SCIENTIFIC PUBLICATIONS, AND THE FORMATION OF SPIN-OFF COMPANIES. THIS IS ACHIEVED STATEWIDE THROUGH DOZENS OF CENTERS, INSTITUTES, OFF-CAMPUS RESEARCH STATIONS, AND COOPERATIVE EXTENSION OFFICES. NJAES-SUPPORTED SCHOOL OF ENVIRONMENTAL AND BIOLOGICAL SCIENCES (SEBS) FACULTY HAVE ACCESS TO STATE-OF-THE-ART RESEARCH METHODS AND TECHNOLOGIES. THESE INCLUDE LAND, SEA, AND AIR-BASED REMOTE SENSING ROBOTIC TECHNOLOGIES; EFFICIENT GENOMIC SEQUENCING METHODS AND EQUIPMENT FOR USE IN TECHNIQUES THAT INCLUDE ENVIRONMENTAL DNA SURVEILLANCE AND GENOTYPING THROUGH SEQUENCING FOR PLANT AND ANIMAL BREEDING; MASS SPECTROMETRY SYSTEMS FOR NATURAL PRODUCT ANALYSIS (INCLUDING GAS CHROMATOGRAPHY, LIQUID CHROMATOGRAPHY, AND ION TRAP SYSTEMS); HIGH-RESOLUTION MICROSCOPY SYSTEMS; FLOW CYTOMETRY; BIOMOLECULAR FRAGMENT ANALYSIS SYSTEMS; AND HIGH INPUT/OUTPUT COMPUTATIONAL TECHNOLOGIES TO GATHER AND ANALYZE DATA. IN ADDITION TO LABORATORY-BASED RESEARCH, OUR EXTENSION SPECIALISTS CONDUCT APPLIED RESEARCH STUDIES WITHIN NJ COMMUNITIES, AND AT A GRICULTURE AND AQUACULTURE FARMS AND LABORATORIES. THEY IDENTIFY AND ASSESS RELEVANT RESEARCH FINDINGS AND CONVEY THIS INFORMATION TO STAKEHOLDERS, EITHER DIRECTLY OR THROUGH RCE COUNTY AGENTS. THIS INTEGRATION OF RESEARCH AND EXTENSION DELIVERS SOUND SCIENCE-BASED INFORMATION AND EDUCATIONAL PROGRAMS THAT BENEFIT COMMUNITIES, INDIVIDUALS, AND INDUSTRIES. ADDITIONALLY, NJAES-SUPPORTED RESEARCHERS ALSO ACTIVELY COLLABORATE WITH THEIR PEERS AT OTHER LAND-GRANT INSTITUTIONS TO ADDRESS ISSUES THAT ARE REGIONAL OR NATIONAL IN SCOPE. RCE COUNTY AGENTS ARE FACULTY MEMBERS OF RUTGERS UNIVERSITY. THEY PROVIDE LOCAL EDUCATIONAL LEADERSHIP TO DELIVER SCIENCE-BASED PROGRAMS IN AGRICULTURE, RESOURCE MANAGEMENT, FAMILY AND COMMUNITY HEALTH SCIENCES, AND 4-H YOUTH DEVELOPMENT. COUNTY AGENTS ARE OFTEN INVOLVED IN APPLIED RESEARCH PROJECTS, WHOSE FINDINGS WILL BE DISSEMINATED THROUGH RCE EDUCATIONAL PROGRAMMING. NJAES AND RCE ARE DEEPLY COMMITTED TO REACHING UNDERSERVED AND UNDERREPRESENTED POPULATIONS IN NJ. ONE OF THE PRIMARY GOALS OF THIS EFFORT HAS BEEN EDUCATIONAL PROGRAMMING THAT IS CULTURALLY SENSITIVE TO THE NEEDS OF URBAN YOUTH AND FAMILIES. THE OFFICE OF URBAN EXTENSION AND ENGAGEMENT WAS ESTABLISHED TO INCREASE THE COORDINATION OF PROGRAMS AND FACILITATE COLLABORATIONS TO ADDRESS FOOD SECURITY, INDIVIDUAL AND COMMUNITY HEALTH, RESOURCE STEWARDSHIP, URBAN AGRICULTURE, FOOD CHAINS, ENVIRONMENTAL PLANNING AND DESIGN, AND OTHER CONCERNS FACING OUR STATE'S URBAN COMMUNITIES.

THE NEW JERSEY AGRICULTURAL EXPERIMENT STATION (NJAES) AND RUTGERS COOPERATIVE EXTENSION (RCE) DEVELOP AND DELIVER PRACTICAL SCIENCE-BASED SOLUTIONS THAT CONTRIBUTE TO AGRICULTURAL SUSTAINABILITY, THE HEALTH AND WELLNESS OF COMMUNITIES, AND THE ENVIRONMENT, THROUGH RESEARCH AND COMMUNITY OUTREACH. THE CRITICAL ISSUES THAT STAKEHOLDERS HAVE IDENTIFIED FALL INTO FIVE CATEGORIES AND FORM THE BASIS OF THE NJAES/RCE WORK PLAN: BUILD SUSTAINABLE AND RESILIENT COMMUNITIES; ENSURE HEALTHY OUTCOMES: FOOD, NUTRITION, AND HEALTH; ENSURE POSITIVE OUTCOMES FOR OUR YOUTH; MAINTAIN VIABLE AGRICULTURE AND AQUACULTURE; PROTECT AND SUSTAIN OUR RESOURCES. NJAES AND RCE SUPPORT RESEARCH AND EXTENSION PROJECTS AND PROGRAMS WITH OUR FEDERAL APPROPRIATIONS FOCUSED ON COMBATING CLIMATE CHANGE, REDUCING RELIANCE ON NON-RENEWABLE ENERGY SOURCES, DEALING WITH THE EMERGENCE OF PESTICIDE-RESISTANT PESTS AND PATHOGENS, AND INCREASING FOOD SECURITY WHICH IS CONSISTENT WITH USDA-NIFA SCIENCE PRIORITY AREAS. NJAES AND RCE ARE COMMITTED TO MAKING RESOURCES, EXPERTISE, AND PROGRAMS AVAILABLE TO ALL NJ RESIDENTS, BUSINESSES, AND COMMUNITIES. THIS IS MANIFESTED IN ACTIVE EFFORTS TO INCREASE EQUITABLE ACCESS TO ALL NJAES PROGRAMS AND RESOURCES. THROUGH OUR RESEARCH AND EXTENSION PROGRAMS, WE USE INNOVATIVE APPROACHES TO APPLY THE LAND-GRANT MODEL TO SUPPORT A SUSTAINABLE AGRICULTURAL AND FOOD SYSTEM AT THE URBAN/SUBURBAN FRINGE; PROTECT THE STATE'S NATURAL RESOURCES; SUSTAINABLY DEVELOP NJ'S HUMAN AND COMMUNITY CAPITAL; AND ADDRESS NUTRITION, HEALTH, AND WELLNESS CONCERNS. RESEARCH DEVELOPMENT FINDINGS ARE DELIVERED VIA EDUCATIONAL PROGRAMS AND TRAINING, TECHNOLOGY TRANSFER, POLICY RECOMMENDATIONS, PUBLIC-ORIENTED PUBLICATIONS, PEER-REVIEWED PROFESSIONAL/SCIENTIFIC PUBLICATIONS, AND THE FORMATION OF SPIN-OFF COMPANIES. THIS IS ACHIEVED STATEWIDE THROUGH OUR CENTERS, INSTITUTES, OFFCAMPUS RESEARCH STATIONS, AND COOPERATIVE EXTENSION OFFICES. NJAES-SUPPORTED SCHOOL OF ENVIRONMENTAL AND BIOLOGICAL SCIENCES (SEBS) FACULTY HAVE ACCESS TO STATE-OF-THE-ART RESEARCH METHODS AND TECHNOLOGIES. THESE INCLUDE LAND, SEA, AND AIR-BASED REMOTE SENSING ROBOTIC TECHNOLOGIES; EFFICIENT GENOMIC SEQUENCING METHODS AND EQUIPMENT FOR USE IN TECHNIQUES; MASS SPECTROMETRY SYSTEMS FOR NATURAL PRODUCT ANALYSIS (INCLUDING GAS CHROMATOGRAPHY, LIQUID CHROMATOGRAPHY, AND ION TRAP SYSTEMS; AND MORE TO GATHER AND ANALYZE DATA. EXTENSION SPECIALISTS CONDUCT APPLIED RESEARCH STUDIES WITHIN NJ COMMUNITIES, AND AT AGRICULTURE AND AQUACULTURE FARMS AND LABORATORIES. THEY IDENTIFY AND ASSESS RELEVANT RESEARCH FINDINGS AND CONVEY THIS INFORMATION DIRECTLY OR THROUGH RCE COUNTY AGENTS TO STAKEHOLDERS. THIS INTEGRATION OF RESEARCH AND EXTENSION DELIVERS SOUND SCIENCE-BASED INFORMATION AND EDUCATIONAL PROGRAMS THAT BENEFIT COMMUNITIES, INDIVIDUALS, AND INDUSTRIES. NJAES-SUPPORTED RESEARCHERS ALSO ACTIVELY COLLABORATE WITH THEIR PEERS AT OTHER LAND-GRANT INSTITUTIONS TO ADDRESS ISSUES THAT ARE REGIONAL OR NATIONAL IN SCOPE. RCE COUNTY AGENTS PROVIDE LOCAL EDUCATIONAL LEADERSHIP TO DELIVER SCIENCE-BASED PROGRAMS IN AGRICULTURE, RESOURCE MANAGEMENT, FAMILY AND COMMUNITY HEALTH SCIENCES, AND 4-H YOUTH DEVELOPMENT. COUNTY AGENTS ARE OFTEN INVOLVED IN APPLIED RESEARCH PROJECTS, WHOSE FINDINGS WILL BE DISSEMINATED THROUGH RCE EDUCATIONAL PROGRAMMING. NJAES AND RCE ARE DEEPLY COMMITTED TO REACHING UNDERSERVED AND UNDERREPRESENTED POPULATIONS IN NJ. ONE OF THE PRIMARY GOALS OF THIS EFFORT HAS BEEN EDUCATIONAL PROGRAMMING THAT IS CULTURALLY SENSITIVE TO THE NEEDS OF URBAN YOUTH AND FAMILIES. THE OFFICE OF URBAN EXTENSION AND ENGAGEMENT IS WORKING TO INCREASE THE COORDINATION OF PROGRAMS AND FACILITATE COLLABORATIONS TO ADDRESS FOOD SECURITY, INDIVIDUAL AND COMMUNITY HEALTH, RESOURCE STEWARDSHIP, URBAN AGRICULTURE, FOOD CHAINS, ENVIRONMENTAL PLANNING AND DESIGN, AND OTHER CONCERNS FACING OUR STATE'S URBAN COMMUNITIES.

THE NEW JERSEY AGRICULTURAL EXPERIMENT STATION (NJAES) AND RUTGERS COOPERATIVE EXTENSION (RCE) DEVELOP AND DELIVER PRACTICAL SCIENCE-BASED SOLUTIONS THAT CONTRIBUTE TO AGRICULTURAL SUSTAINABILITY, THE HEALTH AND WELLNESS OF COMMUNITIES, AND THE ENVIRONMENT, THROUGH RESEARCH AND COMMUNITY OUTREACH. THE CRITICAL ISSUES THAT STAKEHOLDERS HAVE IDENTIFIED FALL INTO FIVE CATEGORIES AND FORM THE BASIS OF THE NJAES/RCE WORK PLAN: BUILD SUSTAINABLE AND RESILIENT COMMUNITIES; ENSURE HEALTHY OUTCOMES: FOOD, NUTRITION, AND HEALTH; ENSURE POSITIVE OUTCOMES FOR OUR YOUTH; MAINTAIN VIABLE AGRICULTURE AND AQUACULTURE; PROTECT AND SUSTAIN OUR RESOURCES. NJAES AND RCE SUPPORT RESEARCH AND EXTENSION PROJECTS AND PROGRAMS WITH OUR FEDERAL APPROPRIATIONS FOCUSED ON COMBATING CLIMATE CHANGE, REDUCING RELIANCE ON NON-RENEWABLE ENERGY SOURCES, DEALING WITH THE EMERGENCE OF PESTICIDE-RESISTANT PESTS AND PATHOGENS, AND INCREASING FOOD SECURITY WHICH IS CONSISTENT WITH USDA-NIFA SCIENCE PRIORITY AREAS. NJAES AND RCE ARE COMMITTED TO MAKING RESOURCES, EXPERTISE, AND PROGRAMS AVAILABLE TO ALL NJ RESIDENTS, BUSINESSES, AND COMMUNITIES. THIS IS MANIFESTED IN ACTIVE EFFORTS TO INCREASE EQUITABLE ACCESS TO ALL NJAES PROGRAMS AND RESOURCES. THROUGH OUR RESEARCH AND EXTENSION PROGRAMS, WE USE INNOVATIVE APPROACHES TO APPLY THE LAND-GRANT MODEL TO SUPPORT A SUSTAINABLE AGRICULTURAL AND FOOD SYSTEM AT THE URBAN/SUBURBAN FRINGE; PROTECT THE STATE'S NATURAL RESOURCES; SUSTAINABLY DEVELOP NJ'S HUMAN AND COMMUNITY CAPITAL; AND ADDRESS NUTRITION, HEALTH, AND WELLNESS CONCERNS. RESEARCH DEVELOPMENT FINDINGS ARE DELIVERED VIA EDUCATIONAL PROGRAMS AND TRAINING, TECHNOLOGY TRANSFER, POLICY RECOMMENDATIONS, PUBLIC-ORIENTED PUBLICATIONS, PEER-REVIEWED PROFESSIONAL/SCIENTIFIC PUBLICATIONS, AND THE FORMATION OF SPIN-OFF COMPANIES. THIS IS ACHIEVED STATEWIDE THROUGH OUR CENTERS, INSTITUTES, OFF CAMPUS RESEARCH STATIONS, AND COOPERATIVE EXTENSION OFFICES. NJAES-SUPPORTED SCHOOL OF ENVIRONMENTAL AND BIOLOGICAL SCIENCES (SEBS) FACULTY HAVE ACCESS TO STATE-OF-THE-ART RESEARCH METHODS AND TECHNOLOGIES. THESE INCLUDE LAND, SEA, AND AIR-BASED REMOTE SENSING ROBOTIC TECHNOLOGIES; EFFICIENT GENOMIC SEQUENCING METHODS AND EQUIPMENT FOR USE IN TECHNIQUES; MASS SPECTROMETRY SYSTEMS FOR NATURAL PRODUCT ANALYSIS (INCLUDING GAS CHROMATOGRAPHY, LIQUID CHROMATOGRAPHY, AND ION TRAP SYSTEMS; AND MORE TO GATHER AND ANALYZE DATA. EXTENSION SPECIALISTS CONDUCT APPLIED RESEARCH STUDIES WITHIN NJ COMMUNITIES, AND AT AGRICULTURE AND AQUACULTURE FARMS AND LABORATORIES. THEY IDENTIFY AND ASSESS RELEVANT RESEARCH FINDINGS AND CONVEY THIS INFORMATION DIRECTLY OR THROUGH RCE COUNTY AGENTS TO STAKEHOLDERS. THIS INTEGRATION OF RESEARCH AND EXTENSION DELIVERS SOUND SCIENCE-BASED INFORMATION AND EDUCATIONAL PROGRAMS THAT BENEFIT COMMUNITIES, INDIVIDUALS, AND INDUSTRIES. NJAES-SUPPORTED RESEARCHERS ALSO ACTIVELY COLLABORATE WITH THEIR PEERS AT OTHER LAND-GRANT INSTITUTIONS TO ADDRESS ISSUES THAT ARE REGIONAL OR NATIONAL IN SCOPE. RCE COUNTY AGENTS PROVIDE LOCAL EDUCATIONAL LEADERSHIP TO DELIVER SCIENCE-BASED PROGRAMS IN AGRICULTURE, RESOURCE MANAGEMENT, FAMILY AND COMMUNITY HEALTH SCIENCES, AND 4-H YOUTH DEVELOPMENT. COUNTY AGENTS ARE OFTEN INVOLVED IN APPLIED RESEARCH PROJECTS, WHOSE FINDINGS WILL BE DISSEMINATED THROUGH RCE EDUCATIONAL PROGRAMMING. NJAES AND RCE ARE DEEPLY COMMITTED TO REACHING UNDERSERVED AND UNDERREPRESENTED POPULATIONS IN NJ. ONE OF THE PRIMARY GOALS OF THIS EFFORT HAS BEEN EDUCATIONAL PROGRAMMING THAT IS CULTURALLY SENSITIVE TO THE NEEDS OF URBAN YOUTH AND FAMILIES. THE OFFICE OF URBAN EXTENSION AND ENGAGEMENT CONTINUES ITS WORK TO INCREASE THE COORDINATION OF PROGRAMS AND FACILITATE COLLABORATIONS TO ADDRESS FOOD SECURITY, INDIVIDUAL AND COMMUNITY HEALTH, RESOURCE STEWARDSHIP, URBAN AGRICULTURE, FOOD CHAINS, ENVIRONMENTAL PLANNING AND DESIGN, AND OTHER CONCERNS FACING OUR STATE'S URBAN COMMUNITIES.

BIONANOTECHNOLOGY APPROACH FOR TREATMENT OF LUNG CANCER

THE NEW JERSEY AGRICULTURAL EXPERIMENT STATION (NJAES) AND RUTGERS COOPERATIVE EXTENSION (RCE) DEVELOP AND DELIVER PRACTICAL SCIENCE-BASED SOLUTIONS THAT CONTRIBUTE TO AGRICULTURAL SUSTAINABILITY, THE HEALTH AND WELLNESS OF COMMUNITIES, AND THE ENVIRONMENT, THROUGH RESEARCH AND COMMUNITY OUTREACH. THE CRITICAL ISSUES THAT STAKEHOLDERS HAVE IDENTIFIED FALL INTO FIVE CATEGORIES AND FORM THE BASIS OF THE NJAES/RCE WORK PLAN: BUILD SUSTAINABLE AND RESILIENT COMMUNITIES; ENSURE HEALTHY OUTCOMES: FOOD, NUTRITION, AND HEALTH; ENSURE POSITIVE OUTCOMES FOR OUR YOUTH; MAINTAIN VIABLE AGRICULTURE AND AQUACULTURE; PROTECT AND SUSTAIN OUR RESOURCES. NJAES AND RCE SUPPORT RESEARCH AND EXTENSION PROJECTS AND PROGRAMS WITH OUR FEDERAL APPROPRIATIONS FOCUSED ON COMBATING WEATHER VARIABILITY, REDUCING RELIANCE ON NON-RENEWABLE ENERGY SOURCES, DEALING WITH THE EMERGENCE OF PESTICIDE-RESISTANT PESTS AND PATHOGENS, AND INCREASING FOOD SECURITY WHICH IS CONSISTENT WITH USDA-NIFA SCIENCE PRIORITY AREAS. NJAES AND RCE ARE COMMITTED TO MAKING RESOURCES, EXPERTISE, AND PROGRAMS AVAILABLE TO ALL NJ RESIDENTS, BUSINESSES, AND COMMUNITIES. THIS IS MANIFESTED IN ACTIVE EFFORTS TO INCREASE ACCESS TO ALL NJAES PROGRAMS AND RESOURCES. THROUGH OUR RESEARCH AND EXTENSION PROGRAMS, WE USE INNOVATIVE APPROACHES TO APPLY THE LAND-GRANT MODEL TO SUPPORT A SUSTAINABLE AGRICULTURAL AND FOOD SYSTEM AT THE URBAN/SUBURBAN FRINGE; PROTECT THE STATE'S NATURAL RESOURCES; SUSTAINABLY DEVELOP NJ'S HUMAN AND COMMUNITY CAPITAL; AND ADDRESS NUTRITION, HEALTH, AND WELLNESS CONCERNS. RESEARCH DEVELOPMENT FINDINGS ARE DELIVERED VIA EDUCATIONAL PROGRAMS AND TRAINING, TECHNOLOGY TRANSFER, POLICY RECOMMENDATIONS, PUBLIC-ORIENTED PUBLICATIONS, PEER-REVIEWED PROFESSIONAL/SCIENTIFIC PUBLICATIONS, AND THE FORMATION OF SPIN-OFF COMPANIES. THIS IS ACHIEVED STATEWIDE THROUGH OUR CENTERS, INSTITUTES, OFFCAMPUS RESEARCH STATIONS, AND COOPERATIVE EXTENSION OFFICES. NJAES-SUPPORTED SCHOOL OF ENVIRONMENTAL AND BIOLOGICAL SCIENCES (SEBS) FACULTY HAVE ACCESS TO STATE-OF-THE-ART RESEARCH METHODS AND TECHNOLOGIES. THESE INCLUDE LAND, SEA, AND AIR-BASED REMOTE SENSING ROBOTIC TECHNOLOGIES; EFFICIENT GENOMIC SEQUENCING METHODS AND EQUIPMENT FOR USE IN TECHNIQUES; MASS SPECTROMETRY SYSTEMS FOR NATURAL PRODUCT ANALYSIS (INCLUDING GAS CHROMATOGRAPHY, LIQUID CHROMATOGRAPHY, AND ION TRAP SYSTEMS; AND MORE TO GATHER AND ANALYZE DATA. EXTENSION SPECIALISTS CONDUCT APPLIED RESEARCH STUDIES WITHIN NJ COMMUNITIES, AND AT AGRICULTURE AND AQUACULTURE FARMS AND LABORATORIES. THEY IDENTIFY AND ASSESS RELEVANT RESEARCH FINDINGS AND CONVEY THIS INFORMATION DIRECTLY OR THROUGH RCE COUNTY AGENTS TO STAKEHOLDERS. THIS INTEGRATION OF RESEARCH AND EXTENSION DELIVERS SOUND SCIENCE-BASED INFORMATION AND EDUCATIONAL PROGRAMS THAT BENEFIT COMMUNITIES, INDIVIDUALS, AND INDUSTRIES. NJAES-SUPPORTED RESEARCHERS ALSO ACTIVELY COLLABORATE WITH THEIR PEERS AT OTHER LAND-GRANT INSTITUTIONS TO ADDRESS ISSUES THAT ARE REGIONAL OR NATIONAL IN SCOPE. RCE COUNTY AGENTS PROVIDE LOCAL EDUCATIONAL LEADERSHIP TO DELIVER SCIENCE-BASED PROGRAMS IN AGRICULTURE, RESOURCE MANAGEMENT, FAMILY AND COMMUNITY HEALTH SCIENCES, AND 4-H YOUTH DEVELOPMENT. COUNTY AGENTS ARE OFTEN INVOLVED IN APPLIED RESEARCH PROJECTS, WHOSE FINDINGS WILL BE DISSEMINATED THROUGH RCE EDUCATIONAL PROGRAMMING. NJAES/RCE IS DEEPLY COMMITTED TO REACHING OUT AND ENGAGING WITH ALL OUR NJ COMMUNITIES. ONE OF THE PRIMARY GOALS OF THIS EFFORT IS EDUCATIONAL PROGRAMMING THAT UNDERSTANDS THE NEEDS OF YOUTH AND FAMILIES. THE OFFICE OF URBAN EXTENSION AND ENGAGEMENT WAS ESTABLISHED TO INCREASE THE COORDINATION OF PROGRAMS AND FACILITATE COLLABORATIONS TO ADDRESS FOOD SECURITY, INDIVIDUAL AND COMMUNITY HEALTH, RESOURCE STEWARDSHIP, URBAN AGRICULTURE AND FOOD CHAINS, ENVIRONMENTAL PLANNING AND DESIGN, AND OTHER CONCERNS FACING OUR STATE'S URBAN COMMUNITIES.

ROLE OF NEGATIVE ELONGATION FACTOR COMPLEX IN RNA POLYMERASE II PAUSING AND GENE TRANSCRIPTION IN HEART - PROJECT SUMMARY/ABSTRACT CONGESTIVE HEART FAILURE IS ONE OF THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN THE USA AND THE WORLD. HOWEVER, DESPITE THE MAJOR ADVANCEMENTS IN RESEARCH AND THERAPEUTIC DEVELOPMENTS, THERE HAS BEEN NO IMPROVEMENT IN DEATH RATES OVER THE YEARS. THIS NECESSITATES REINVESTIGATING THE BASIC MECHANISMS THAT GOVERN THE PROGRESSION HEART FAILURE. ADAPTATION OF GENE EXPRESSION IS THE EARLIEST FUNDAMENTAL RESPONSE DURING OVERLOAD. WE HAVE SHOWN THE WIDESPREAD REGULATORY INFLUENCE OF PROMOTER-PROXIMAL RNA POLYMERASE II (POL II) PAUSING ON GENE TRANSCRIPTION IN HEART. HOWEVER, THE UNDERLYING MECHANISMS THAT CONTROL AND SYNCHRONIZE THE RELEASE OF PAUSED POL II FOR ACTIVE TRANSCRIPTION ARE UNCLEAR AND CONFLICTING, AND ITS CONTRIBUTION TO DEVELOPMENT OF CARDIAC HYPERTROPHY AND FAILURE STILL UNKNOWN. NEGATIVE ELONGATION FACTORS (NELF), COMPRISING OF FIVE SUBUNITS (NELFA TO NELFE) HAS BEEN IMPLICATED IN POL II PAUSING, WITH NELFA SUBUNIT IDENTIFIED AS AN ESSENTIAL COMPONENT FOR PAUSING. OUR PRELIMINARY DATA SHOWS INCREASE IN NELFA EXPRESSION WITH CARDIAC HYPERTROPHY, WHICH IS REQUIRED FOR COMPENSATORY INCREASE IN GENE EXPRESSION IN THESE HEARTS. CONVERSELY, NELFA LEVELS DECLINE IN FAILING HEARTS, SUGGESTING DOWNREGULATION OF NELFA COULD BE CONTRIBUTING TO DECOMPENSATION AND PROGRESSION OF FAILURE. OUR GENOME-WIDE SEQUENCING DATA SHOWS WIDESPREAD NELFA OCCUPANCY ON ACTIVE PROMOTERS INCLUDING INDUCIBLE AND CONSTITUTIVELY EXPRESSED ESSENTIAL GENES. INTERESTINGLY, IMMUNOPRECIPITATION OF CHROMATIN BOUND NELFA SHOWS ASSOCIATION WITH CHROMATIN REMODELERS AND PRE-MRNA PROCESSING PROTEINS. IN THIS STUDY, WE INVESTIGATE THE ROLE OF NELFA IN POL II DYNAMICS, CHROMATIN REMODELING AND GENE EXPRESSION, AND ITS IMPACT ON PROGRESSION OF HEART FAILURE. WE HAVE HYPOTHESIZED THAT ADAPTATION OF GENE EXPRESSION DURING CARDIAC HYPERTROPHY IS ACHIEVED BY PHOSPHORYLATION DEPENDENT INCREASE IN THE RATE OF CLEARANCE OF PAUSED POL II FROM ESSENTIAL GENE PROMOTERS, AND DE NOVO RECRUITMENT OF NELFA AND ASSEMBLY OF PAUSED COMPLEX AT INDUCIBLE PROMOTERS. LOSS OF NELFA RESULTS IN DISRUPTED PAUSED COMPLEX, ALTERED CHROMATIN REMODELING, INEFFICIENT TRANSCRIPT PROCESSING AND INHIBITED GENE EXPRESSION THAT PRECIPITATES HEART FAILURE. WE HAVE PROPOSED TWO ROBUST SPECIFIC AIMS TO TEST OUR HYPOTHESIS – 1. TO EXAMINE THE MECHANISMS REGULATING NELFA -DEPENDENT POL II PAUSING IN GENE TRANSCRIPTION DURING CARDIAC HYPERTROPHY. 2. TO INVESTIGATE THE EFFECTS OF LOSS OF NELFA ON GENE EXPRESSION AND PROGRESSION OF HEART FAILURE IN CONDITIONAL NELFA-KO MODEL SUBJECTED TO PRESSURE OVERLOAD.

A NOVEL APPROACH TO EXAMINE WITHIN-CLASS THERAPEUTIC EXCHANGEABILITY OF MEDICATIONS

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION FY 2022

UNDERSTANDING THE IMMUNE RESPONSE CHANGES TO CLINICAL INTERVENTIONS FOR EPSTEIN-BARR VIRUS INFECTION PRIOR TO LYMPHOMA DEVELOPMENT IN CHILDREN AFTER ORGAN TRANSPLANTS (UNEARTH) - ABSTRACT/SUMMARY AMONG THE EPSTEIN-BARR VIRUS ASSOCIATED CANCERS IS POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD), A RARE BUT MAJOR COMPLICATION OF PEDIATRIC SOLID ORGAN TRANSPLANTS (SOT). MANY CHILDREN ARE EBV-SERONEGATIVE AT TIME OF SOT, LEADING TO PRIMARY EBV INFECTION FROM THE ALLOGRAFT UNDER INTENSE IMMUNOSUPPRESSION, AND A HIGHER CHANCE OF A CHRONIC HIGH VIRAL LOAD (CHVL) STATE OR PTLD. LONGITUDINAL PERIPHERAL BLOOD EBV DNA NUCLEIC ACID TESTING (NAT) HAS NOT IMPROVED THE INDIVIDUAL PREDICTION OF PTLD OCCURRENCE, LIKELY DUE TO VARIABLE SOT RECIPIENT IMMUNE RESPONSES. FURTHER, THESE PATIENTS RECEIVE CLINICAL INTERVENTIONS FOR EBV DNAEMIA, WITH INCOMPLETE RESPONSES FOR UNKNOWN REASONS. OUR TEAM OF SOT, INFECTIOUS DISEASE AND IMMUNOLOGY PROFESSIONALS WILL BRING NEW AND COMPLIMENTARY EXPERTISE TO CLOSE THESE KNOWLEDGE GAPS. WE WILL PERFORM LONGITUDINAL T AND NK CELL IMMUNE FUNCTION ASSAYS IN CONJUNCTION WITH LOCAL AND CENTRAL EBV AND ANELLOVIRUS NAT IN 1390 SAMPLES ACROSS 5 TIME POINTS IN THE FIRST YEAR AFTER 278 SOT (KIDNEY, LIVER, HEART, LUNG OR INTESTINE) AT 3 MAJOR CHILDREN'S HOSPITALS. WE WILL ACCOMPLISH THE FOLLOWING SPECIFIC AIMS, COMPARING THORACIC AND ABDOMINAL SOT RECIPIENTS WITH PRIMARY EBV INFECTION OR CHVL STATE: 1. ASSESS THE PROSPECTIVE PHENOTYPIC AND FUNCTIONAL FEATURES OF T CELL “EXHAUSTION” AND CORRELATE WITH EBV INFECTION OUTCOMES AND NK CELL PROFILE. HYPOTHESIS: SOT RECIPIENTS' THAT DEVELOP CHVL STATE DISPLAY DISTINCT PHENOTYPIC MEMORY DIFFERENTIATION AND EXHAUSTED CD8+ AND CD4+ T CELL PROFILES THAT ARE REGULATED BY DISTINCT INFLAMMATORY CIRCUITS. WE WILL ACCOMPLISH THIS AIM BY PERFORMING MULTI- SPECTRAL FLOW CYTOMETRY TO CHARACTERIZE T CELL PHENOTYPE AND FUNCTION, AS WELL AS MESO SCALE DISCOVERY PLATFORM TO ASSESS DISTINCT VIRAL CONTROL-RELEVANT PLASMA CYTOKINES/CHEMOKINES, DURING THE PHASES OF INITIAL REPLICATION, EXPANSION, PROGRESSION, CHVL OR RECOVERY STATES. 2. TO PROSPECTIVELY DEFINE THE NUMBER, PHENOTYPE, AND FUNCTIONAL STATUS OF NK CELLS, AND CORRELATE WITH EBV INFECTION OUTCOMES. HYPOTHESIS: NK CELL ACTIVATION WILL COINCIDE WITH PRIMARY INFECTION, AND WILL CORRELATE POSITIVELY WITH CLEARANCE VS. NEGATIVELY WITH PERSISTENT EBV REPLICATION. NK CELL DYSFUNCTION WILL DEVELOP IN PATIENTS WITH CHVL, WHO ARE AT HIGHEST RISK OF PTLD. WE WILL LEVERAGE OUR ESTABLISHED MULTI-SPECTRAL FLOW CYTOMETRY PANEL AND ANALYZE PATIENTS WITH PRIMARY EBV INFECTION AFTER SOT AND ANSWER QUESTIONS RELATED TO THE ACTIVATION STATUS, NK RECEPTOR REPERTOIRE, AND FUNCTIONAL CAPACITY. 3. DETERMINE THE ASSOCIATION OF PERIPHERAL BLOOD TORQUETENOVIRUS (TTV) DNA LOADS TO EBV OUTCOMES, T AND NK CELL PROFILES. HYPOTHESIS: TTV LOADS REDUCE WITH CLINICAL REDUCTIONS IN IMMUNOSUPPRESSION AND PREDICT EBV CLEARANCE. WE WILL ACCOMPLISH THIS AIM USING LONGITUDINAL WHOLE BLOOD NAT ASSAYS FOR BOTH VIRUSES AT COMMON TIME POINTS, PERFORMED CENTRALLY TO MINIMIZE LAB VARIABILITY. BY STUDY END, WE WILL KNOW THE T AND NK IMMUNE RESPONSES TO EBV ACROSS MULTIPLE CLINICAL SITUATIONS. WE EXPECT TO FIND KEY IMMUNE MECHANISMS THAT WILL PREDICT POOR OR DELAYED EBV CLEARANCE DESPITE CLINICAL INTERVENTIONS, WHICH MAY LEAD TO NEW TRANSLATIONAL IMMUNOTHERAPY APPROACHES TO PREVENT PTLD, OR INFORM EBV ONCOGENESIS IN OTHER POPULATIONS.

DEVELOPMENT OF DUAL INHIBITORS TARGETING THE VIRAL MAIN PROTEASE AND THE HOST CATHEPSIN L AS SARS-COV-2 ANTIVIRALS - PROJECT SUMMARY THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2), ALSO CALLED NOVEL CORONAVIRUS 2019 (NCOV-19), STARTED TO CIRCULATE AMONG HUMANS AROUND DECEMBER 2019, AND IT IS NOW WIDESPREAD AS A GLOBAL PANDEMIC. THERE IS NO VACCINE OR ANTIVIRAL AVAILABLE FOR SARS-COV-2. IN THIS GRANT, WE PROPOSE TO DEVELOP DUAL INHIBITORS TARGETING VIRAL MAIN PROTEASE AND CATHEPSIN L AS SARS-COV-2 ANTIVIRALS. USING THE FRET-BASED ENZYMATIC ASSAY, WE RECENTLY IDENTIFIED SEVERAL INHIBITORS INCLUDING BOCEPREVIR, GC-376, AND CALPAIN INHIBITORS II AND XII, THAT HAVE POTENT ACTIVITY WITH SINGLE-DIGIT TO SUBMICROMOLAR IC50 VALUES IN THE ENZYMATIC ASSAY. SIGNIFICANTLY, ALL FOUR COMPOUNDS INHIBIT INFECTIOUS SARS-COV-2 REPLICATION IN CELL CULTURE WITH EC50 VALUES RANGING FROM 0.5 TO 3.4 ΜM. OVERALL, THE COMPOUNDS IDENTIFIED PROVIDE PROMISING STARTING POINTS FOR THE FURTHER DEVELOPMENT OF SARS-COV-2 THERAPEUTICS. OUR DISCOVERY OF CALPAIN INHIBITOR II AS A POTENT INHIBITOR AGAINST SARS-COV-2 IS INNOVATIVE AS IT SUGGESTS IT MIGHT BE FEASIBLE TO DEVELOP SARS-COV-2 ANTIVIRALS BY SIMULTANEOUSLY TARGETING BOTH VIRAL MPRO AND HOST CATHEPSIN L, BOTH OF WHICH ARE ESSENTIAL FOR VIRAL REPLICATION. COMPARED TO RECENTLY REPORTED MPRO INHIBITORS, THE HITS IDENTIFIED FROM OUR STUDY REPRESENT THE MOST POTENT AND SELECTIVE DRUG CANDIDATES WITH A NOVEL MECHANISM OF ACTION, THEREFORE WARRANTING FURTHER DEVELOPMENT. GIVEN OUR ENCOURAGING PRELIMINARY DATA, WE PROPOSE TO OPTIMIZE DUAL INHIBITORS AS SARS-COV-2 ANTIVIRALS. THE OBJECTIVE OF THIS PROPOSAL IS TO DEVELOP DUAL INHIBITORS AS POTENT SARS-COV-2 ANTIVIRALS WITH HIGH POTENCY, SELECTIVITY, FAVORABLE PHARMACOKINETIC PROPERTIES, AS WELL AS BROAD-SPECTRUM ANTIVIRAL ACTIVITY AGAINST CLOSELY RELATED CORONAVIRUSES SUCH AS SARS AND MIDDLE EAST RESPIRATORY SYNDROME (MERS) CORONAVIRUSES. OUR GOALS OF THIS GRANT ARE TO IDENTIFY ADDITIONAL DUAL INHIBITORS THROUGH BOTH HIGH-THROUGHPUT SCREENING AND STRUCTURE-BASED LEAD OPTIMIZATION OF OUR RECENTLY IDENTIFIED DUAL INHIBITORS. BY TARGETING THE SARS-COV-2 MPRO, THE EXPECTED OUTCOMES OF THE PROPOSED RESEARCH ARE BROAD-ACTING CORONAVIRUS ANTIVIRALS WITH A CONFIRMED MECHANISM OF ACTION, A HIGH SELECTIVITY INDEX, AND FAVORABLE IN VITRO PHARMACOKINETIC PROPERTIES THAT ARE READY FOR IN VIVO ANTIVIRAL EFFICACY TESTING IN RELEVANT ANIMAL MODELS. OVERALL, THIS GRANT IS BASED ON STRONG PRELIMINARY DATA AND OUR EXPERTISE IN DEVELOPING ANTIVIRALS TARGETING CYSTEINE PROTEASES.

STRENGTHENING THE EVIDENCE-BASE FOR DRUG-DISEASE INTERACTIONS IN OLDER ADULTS

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTIUTION - FY 2019

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION - FY 2020

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION FY2021

DECISION NEUROSCIENCE OF CRAVING - PROJECT SUMMARY/ABSTRACT THE CURRENT OPIOID EPIDEMIC IS A PRESSING PUBLIC HEALTH CRISIS. A KEY PRECIPITATING FACTOR OF REUSE AND RELAPSE AMONG PEOPLE WITH OPIOID USE DISORDERS (OUD) IS CRAVING, OR THE INTENSE, SPECIFIC DESIRE FOR THE DRUG. WHILE CRAVING HAS BEEN EXTENSIVELY STUDIED, AND IS KNOWN TO PREDICT DRUG USE, WE STILL LACK AN EXPLANATORY AND ALGORITHMICALLY-PRECISE MODEL THAT CAN DIRECTLY LINK CRAVING NEUROBIOLOGY TO ITS OBSERVED CONSEQUENCES: THE DECISION TO PURSUE DRUGS OVER OTHER VALUABLE ALTERNATIVES. GIVEN THAT TYPICAL TREATMENTS FOR OUD DO NOT ADEQUATELY ADDRESS CRAVING AND FAIL TO PREVENT REUSE IN MANY PATIENTS, CLARIFYING THE PRECISE, DECISION-RELEVANT, MECHANISM OF CRAVING MAY CRITICALLY INFORM MORE TARGETED WAYS TO TREAT CRAVING AND IMPROVE CLINICAL OUTCOME. TO ADDRESS THESE IMPORTANT QUESTIONS, WE DEVELOPED AN EXPERIMENTAL PARADIGM TO STUDY CRAVING BASED ON METHODS WIDELY USED IN DECISION NEUROSCIENCE TO ASSESS VALUE-BASED DECISION-MAKING. DECISION NEUROSCIENCE (OR NEUROECONOMICS) INTEGRATES CONCEPTS AND METHODS FROM PSYCHOLOGY, ECONOMICS, AND NEUROSCIENCE TO UNDERSTAND THE NEURAL ARCHITECTURE FOR DECISION-MAKING, AND HAS BEEN INCREASINGLY APPLIED IN MECHANISTIC STUDIES OF PSYCHIATRIC DISORDERS INCLUDING ADDICTION. OUR PARADIGM CONSTITUTES A NOVEL APPLICATION OF THIS FRAMEWORK BY QUANTIFYING A SUBJECT’S IN-THE-MOMENT (I.E., STATE-DEPENDENT) DECISION PROCESS DURING CRAVING15. IN PILOT BEHAVIORAL STUDIES IN HEALTHY AND OPIOID ADDICTED SUBJECTS, WE FIND THAT THIS PARADIGM CAPTURES 1) HOW VALUE—THE KEY DETERMINANT OF THE DECISION TO PURSUE A PARTICULAR OPTION VERSUS ANOTHER—CHANGES UNDER CRAVING, AND 2) THE SELECTIVITY OF THIS EFFECT TO THE OBJECT OF CRAVING. IT ALSO 3) PROVIDES AN ALGORITHMICALLY-SPECIFIC PROCESS (A MATHEMATICAL DESCRIPTION) OF THIS CHANGE THAT CAN BE USED TO TIE BEHAVIOR TO ITS NEURAL SUBSTRATE. IN THE PRESENT STUDY WE AIM TO ELUCIDATE THIS NEURAL SUBSTRATE BY IDENTIFYING THE SPECIFIC NEURAL COMPUTATIONS THROUGH WHICH CRAVING MODULATES THE VALUE OF DRUG AND NONDRUG ALTERNATIVES AND THEREBY DRUG USE DECISIONS IN HUMAN OUD. WE PROPOSE TO IDENTIFY THE NEURAL SUBSTRATE OF OPIOID CRAVING IN N=89 OUD PATIENTS WHO WILL COMPLETE OUR PARADIGM DURING FMRI IN A WITHIN-SUBJECTS CROSS-OVER DESIGN FOLLOWING A BRIEF CRAVING INDUCTION OR A CONTROL MANIPULATION16. BECAUSE DECISION CIRCUITS ENCODE VALUE IN A REWARD-IDENTITY SPECIFIC MANNER, OUR DESIGN WILL ENABLE US TO ISOLATE THE COMPUTATIONS ASSOCIATED WITH DRUG-RELATED VALUE FROM THOSE OF NONDRUG VALUE. OUR STUDY WILL FOR THE FIRST TIME DETERMINE WHETHER AND HOW EXPERIMENTALLY-INDUCED CRAVING DYNAMICALLY SHIFTS SUCH “IDENTITY-SPECIFIC” NEURAL ENCODING OF DRUG-RELATED VALUE (AIM 1), AND THE PARTS OF A PUTATIVE ‘CRAVING CIRCUIT’ INVOLVED IN THIS SHIFT (AIM 2). TO TEST WHETHER THIS MECHANISM IS UNIQUE AND REWARD-IDENTITY SPECIFIC, WE WILL ALSO MEASURE BRAIN ACTIVITY ASSOCIATED WITH EXPERIMENTALLY-INDUCED FOOD CRAVING AND SPECIFIC FOOD-VALUE IN THE SAME PATIENTS AND N=89 HEALTHY CONTROLS (AIM 3). IF SUCCESSFUL, THIS INTEGRATIVE APPROACH WILL UNCOVER PRECISE TARGETS FOR SELECTIVELY MITIGATING CRAVING-INDUCED INCREASES IN DRUG-VALUE THAT PROMOTE OPIOID REUSE, LAYING THE GROUNDWORK FOR PRECISION INTERVENTIONS TO TREAT CRAVING IN TREATMENT UNRESPONSIVE INDIVIDUALS.

FUNCTION AND REGULATION OF MUCOSAL ASSOCIATED INVARIANT T CELLS IN THE LUNG - PROJECT SUMMARY/ABSTRACT ASTHMA REMAINS A SERIOUS PUBLIC HEALTH THREAT WITH UNMET THERAPEUTIC NEEDS. THE DEVELOPMENT OF SUCCESSFUL THERAPIES RELIES A MORE IN-DEPTH UNDERSTANDING OF THE IMMUNE SUBSETS AND PATHWAYS INVOLVED. MAIT CELLS ARE INNATE-LIKE T CELLS THAT RECOGNIZE MICROBIAL RIBOFLAVIN METABOLITES PRESENTED BY MR1 AND CAN FUNCTION THROUGH BOTH TCR DEPENDENT AND INDEPENDENT PATHWAYS. INTERESTINGLY, PREVIOUS STUDIES INDICATED AN INVERSE ASSOCIATION BETWEEN MAIT CELLS AND HUMAN ASTHMA. THE PRECISE ROLE OF MAIT CELLS IN ASTHMA DEVELOPMENT AND EXACERBATION, HOWEVER, REMAINS UNKNOWN. WE HYPOTHESIZE THAT A DEFICIENCY OF MAIT CELLS IN ASTHMA PATIENTS CONTRIBUTES TO EXACERBATED AIRWAY INFLAMMATORY RESPONSES TO ALLERGEN AND OTHER STIMULUS, AND THAT INCREASING MAIT CELL NUMBERS MAY HELP PREVENT ASTHMA DEVELOPMENT AND EXACERBATION. USING FRESH LUNG SAMPLES FROM DECEASED ORGAN DONORS, WE WILL EXAMINE THE ABUNDANCE, HETEROGENEITY AND FUNCTION OF LUNG-RESIDENT MAIT CELLS IN SEVERE ASTHMA PATIENTS AND CONTROL INDIVIDUALS WITHOUT LUNG DISEASES. WE WILL USE MAIT CELL DEFICIENT MICE AND ADOPTIVE TRANSFER STRATEGIES TO INTERROGATE THE SPECIFIC ROLES OF MAIT CELLS IN ALLERGEN AND AIR POLLUTANT- INDUCED AIRWAY INFLAMMATION. FINALLY, WE WILL TEST WHETHER BOOSTING THE NUMBER OF MAIT CELLS BY AN ENGINEERED PROBIOTIC STRAIN CAN HELP PREVENT SEVERE ASTHMA DEVELOPMENT AND EXACERBATION.

CARDIOVASCULAR HEALTH AFTER PLACENTAL ABRUPTION (CHAP)

MYCOESTROGENS AND MATERNAL-CHILD HEALTH IN THE TIDES COHORT - THE ACCUMULATION OF MYCOTOXINS, CHEMICAL BY-PRODUCTS OF FUNGAL GROWTH, IS AN EMERGING ISSUE IN PUBLIC HEALTH DUE TO THEIR WIDESPREAD PRESENCE IN FOOD SYSTEMS. MYCOTOXINS CONTAMINATE CROPS WORLDWIDE AND THEIR PREVALENCE WILL INCREASE AS ECOSYSTEMS BECOME WARMER AND WETTER. ONE OF THE MOST COMMON MYCOTOXINS, ZEARALENONE (ZEN), DERIVES FROM FUSARIUM SPECIES AND IS WIDELY DETECTED IN CEREAL GRAINS, GRAIN-BASED PRODUCTS, MEAT, MILK, WINE, BEER, DRIED FRUIT, AND SPICES. ZEN AND ITS METABOLITES BIND TO ESTROGEN RECEPTORS EARNING THEIR DESIGNATION AS ‘MYCOESTROGENS’. IN LIVESTOCK AND EXPERIMENTAL MODELS, ZEN EXPOSURE DYSREGULATES MATERNAL AND OFFSPRING HORMONE SIGNALING, ALTERS GESTATIONAL WEIGHT GAIN, AND DISRUPTS OFFSPRING GROWTH AND PUBERTAL TRAJECTORIES. DESPITE THE LARGE AND COMPELLING TOXICOLOGICAL LITERATURE AND THE NEAR UBIQUITOUS HUMAN EXPOSURE, ALARMINGLY LITTLE IS KNOWN ABOUT ZEN’S IMPACTS ON HUMAN HEALTH. IN THE FIRST EPIDEMIOLOGICAL STUDY OF ITS KIND, WE RECENTLY OBSERVED THAT HIGHER URINARY ZEN CONCENTRATIONS IN U.S. PREGNANT WOMEN WERE ASSOCIATED WITH SEXDEPENDENT DIFFERENCES IN CIRCULATING ESTROGENS IN PREGNANCY, GREATER GESTATIONAL WEIGHT GAIN, AND ALTERED INFANT SIZE. THESE FINDINGS HAVE LED US TO THE OVERARCHING HYPOTHESIS THAT DEVELOPMENTAL MYCOESTROGEN EXPOSURE DISRUPTS STEROIDOGENIC AND METABOLIC ACTIVITY IN HUMANS, LEADING TO SEX-SPECIFIC ALTERATIONS IN CHILD GROWTH. WHAT IS NOW URGENTLY NEEDED ARE STUDIES THAT MORE EXTENSIVELY CHARACTERIZE BOTH PRENATAL AND CHILDHOOD EXPOSURES TO ZEN IN LARGE, DIVERSE SAMPLES WITH FURTHER EXPLORATION OF MECHANISTIC PATHWAYS AND EXTENDED FOLLOW-UP INTO ADOLESCENCE. HERE, WE FILL THOSE GAPS AND ADVANCE THE LIMITED EPIDEMIOLOGICAL RESEARCH ON ZEN BY LEVERAGING EXISTING DATA AND BIOSPECIMENS FROM TIDES (THE INFANT DEVELOPMENT AND THE ENVIRONMENT STUDY), A DEEPLY-PHENOTYPED, MULTI-SITE U.S. COHORT THAT RECRUITED PREGNANT WOMEN FROM 2010-2012. USING EXISTING DATA AND BIOSPECIMENS FROM THE FULL TIDES COHORT (494 MOTHER-CHILD DYADS), WE WILL EXAMINE PRENATAL AND CHILDHOOD EXPOSURES TO ZEN AND ITS METABOLITES IN RELATION TO (A) STEROIDOGENESIS AND METABOLOMICS IN PREGNANCY; AND (B) CHILD GROWTH FROM BIRTH THROUGH ADOLESCENCE. THIS WILL BE THE FIRST STUDY TO EXAMINE THE POTENTIAL HEALTH IMPACTS OF PRENATAL AND CHILDHOOD EXPOSURE TO MYCOESTROGENS IN U.S. MOTHERS AND CHILDREN. LEVERAGING THE UNIQUELY SUITED TIDES COHORT, WE ADDRESS NATIONAL MANDATES TO EXAMINE VARIATION BY SEX AND PROVIDE SORELY NEEDED INFORMATION ON EMERGING MYCOESTROGEN EXPOSURES. WE ANTICIPATE THAT RESULTS MAY HELP IDENTIFY HARMS AND INFORM MITIGATION STRATEGIES TO REDUCE EXPOSURES AS WELL AS EFFORTS TO REGULATE MYCOESTROGENS IN THE FOOD SUPPLY IN THE U.S. AND BEYOND.

COMPUTATIONAL PSYCHIATRY INVESTIGATION OF THE ROLE OF UNREALISTIC OPTIMISM IN OPIOID USE DISORDER AND RELAPSE - PROJECT SUMMARY/ABSTRACT THE CURRENT OPIOID EPIDEMIC IS A MAJOR HEALTH CRISIS THAT HAS CONTRIBUTED TO DECREASED LIFE EXPECTANCY IN THE U.S. A MAIN CAUSE OF MORBIDLY AND MORTALITY IS OPIOID REUSE AND RELAPSE IN CHRONIC CASES. UNDERSTANDING THE NEUROCOGNITIVE MECHANISMS AND FACTORS UNDERLYING REUSE VULNERABILITY IS THUS A PRESSING NEED. LEVERAGING A NOVEL COMBINATION OF NEUROCOGNITIVE TOOLS AND A MULTI-SESSION LONGITUDINAL DESIGN, OUR RECENT WORK IN OPIOID USE DISORDER (OUD) HAS BEGUN TO DELINEATE A PRECISE DECISION MAKING MECHANISM FOR OPIOID REUSE BY SHOWING THAT TREATMENT-ENGAGED PATIENTS ARE AT HIGHER RISK FOR REUSE WHEN THEY EXHIBIT INCREASED TOLERANCE OF UNKNOWN PROBABILISTIC OUTCOMES (AMBIGUITY TOLERANCE) IN A FINANCIAL CHOICE TASK (KONOVA ET AL., 2019 JAMA PSYCHIATRY). BUT WHY PATIENTS BECOME MORE TOLERANT OF AMBIGUOUS UNCERTAINTY IN PERIODS PRECEDING REUSE REMAINS UNKNOWN. ONE POTENTIAL EXPLANATION CONSISTENT WITH DECISION THEORY IS THAT, IN THESE PERIODS, THEY BECOME OVEROPTIMISTIC ABOUT AMBIGUOUS OUTCOMES, WHICH LEADS THEM TO OVERESTIMATE THE PROBABILITY OF GOOD OUTCOMES (OR UNDERESTIMATE BAD OUTCOMES) WHEN FACED WITH A DECISION TO REUSE, AND THEREFORE MORE LIKELY TO DO SO. HERE, WE PROPOSE A MULTI-LEVEL, CONVERGENT TEST OF THIS FRAMEWORK BY USING WELL-DEFINED, QUANTITATIVE MEASURES OF THIS PRESUMED “OPTIMISM BIAS”, ALONGSIDE QUANTITATIVE MEASURES OF UNCERTAINTY TOLERANCE, WHICH WE PROPOSE TO COLLECT WITH CONCURRENT HIGH-RESOLUTION FMRI RECORDINGS, AND YOKED TO LONGITUDINAL CLINICAL ASSESSMENTS. IN AIM 1, WE AIM TO ESTABLISH THE RELATIONSHIP BETWEEN UNCERTAINTY TOLERANCE AND OPTIMISM BIAS IN PATIENTS WITH OUD AND MATCHED CONTROLS BY STUDYING THESE BEHAVIORS ACROSS A SET OF CHOICE AND ESTIMATION TASKS (THE LATTER DESIGNED TO CAPTURE OPTIMISM ABOUT SIMPLE FINANCIAL AND MORE COMPLEX OUTCOMES, TAPPING INTO DRUG-CHOICE-RELEVANT DOMAINS SUCH AS HEALTH OUTCOMES). WE ALSO EXAMINE FOR POTENTIAL MODERATION BY VARIOUS PSYCHOPATHOLOGICAL DIMENSIONS IN A LARGE, UNSELECTED POPULATION OF ONLINE (MTURK) SUBJECTS. IN AIM 2, WE COLLECT FMRI DATA DURING THE SAME CHOICE AND ESTIMATION TASKS TO DELINEATE THE MECHANISM BY WHICH OPTIMISTIC NEURAL REPRESENTATIONS OF UNCERTAINTY MIGHT DRIVE BEHAVIORAL TOLERANCE OF THIS UNCERTAINTY, AND REUSE, IN OUD. IN AIM 3, WE USE A MULTI- SESSION LONGITUDINAL DESIGN TO UNDERSTAND THE INTERACTION BETWEEN OPTIMISM BIAS AND UNCERTAINTY TOLERANCE AS THEY RELATE TO OPIOID REUSE, SESSION-TO-SESSION, ALLOWING US TO ELUCIDATE THE SPECIFIC TIMESCALE AND NATURE OF THIS INTERACTION. WITH THIS PROJECT WE AIM TO PROVIDE AN ANSWER TO WHY PATIENTS BECOME MORE UNCERTAINTY TOLERANT IN PERIODS PRECEDING REUSE AND, IN DOING SO, HOPE TO UNCOVER AN UPSTREAM MECHANISM (CENTERED ON OPTIMISM BIAS) OF THIS VULNERABILITY, INCLUDING ITS NEURAL IMPLEMENTATION. IN ADDITION TO THIS CONCEPTUAL ADVANCE, THIS WORK WILL PROVIDE A NOVEL SET OF COGNITIVE TOOLS TO PRECISELY AND OBJECTIVELY MEASURE THESE PROCESSES WITH POTENTIAL TO PREDICT POOR OUTCOMES SUCH AS REUSE, IN A WAY THAT CAN BE EASILY IMPLEMENTED IN CLINICAL SETTINGS. FINALLY, THE FINDINGS FROM THIS WORK WILL INFORM NOVEL THERAPEUTIC INTERVENTIONS BY PROVIDING PRECISE NEUROCOGNITIVE TARGETS, AS WELL AS THEIR IDEAL TIMING, WITH THE GOAL OF MITIGATING REUSE RISK AND IMPROVING LONG-TERM PATIENT OUTCOME.

A NATIONAL STUDY ON THE EFFECTS OF AIR POLLUTION AND TEMPERATURE ON CHILDREN'S NEURODEVELOPMENTAL OUTCOMES - PROJECT SUMMARY/ABSTRACT EVIDENCE SUGGESTS THAT THE PREVALENCE OF CERTAIN DEVELOPMENTAL DISORDERS, SPECIFICALLY AUTISM SPECTRUM DISORDERS (ASD) AND ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), HAS INCREASED SHARPLY IN RECENT DECADES. RECENT STUDIES HAVE SHOWN A MODERATE HERITABILITY FOR NEURODEVELOPMENTAL DELAYS (NDDS), SUGGESTING A NONGENETIC COMPONENT CONTRIBUTING TO ITS ETIOLOGY. THE ESTIMATED ANNUAL COST OF ENVIRONMENTALLY MEDIATED NDDS IN US CHILDREN IS $18.3 BILLION. EPIDEMIOLOGIC STUDIES EXAMINED PRENATAL AND EARLY CHILDHOOD EXPOSURE TO AIR POLLUTANTS AND NDDS, WITH NON-CONCLUSIVE EVIDENCE ON THE EFFECTS OF DIFFERENT POLLUTANTS, INTERACTIONS, SENSITIVE WINDOWS OF EXPOSURE AND CHEMICAL COMPONENTS OF PM2.5. IN ADDITION, THE ROLE OF SOCIOECONOMIC STATUS (SES) IN THESE ASSOCIATIONS IS COMPLEX. OUR OVERARCHING GOAL IS TO COMPREHENSIVELY INVESTIGATE THE INDEPENDENT AND JOINT PRENATAL AND EARLY CHILDHOOD EXPOSURE TO PM2.5, NO2 AND O3, PM2.5 CHEMICAL COMPONENTS AND INTERACTIONS WITH TEMPERATURE ON NDDS AS WELL AS EFFECT MODIFICATION BY SES. THE SPECIFIC AIMS OF THIS APPLICATION ARE: 1) QUANTIFY THE ASSOCIATION PRENATAL AND EARLY CHILDHOOD EXPOSURE TO PM2.5, NO2, O3, TEMPERATURE AND NDDS, 2) EXAMINE THE ASSOCIATION BETWEEN PRENATAL AND EARLY CHILDHOOD EXPOSURE TO PM2.5 CHEMICAL SPECIATION AND NDDS, AND 3) EXAMINE PATHWAYS AND SYNERGISTIC EFFECTS, AMONG ENVIRONMENTAL EXPOSURES AND SES ON NDDS. WE HAVE ESTABLISHED A BIRTH COHORT OF MORE THAN 4 MILLION PREGNANCIES FROM TWO POPULATION-BASED DATABASES—THE MEDICAID ANALYTIC EXTRACT AND IBM MARKETSCAN—THAT INCLUDE RICH INFORMATION ON LOCATION AND INDIVIDUAL-LEVEL CHARACTERISTICS. BY 8 YEARS OF AGE, 23.9% OF PUBLICLY INSURED CHILDREN AND 11.0% OF PRIVATELY INSURED CHILDREN RECEIVED A DIAGNOSIS OF 1 OR MORE NDDS. FOR ALL POLLUTANTS, PM2.5 CHEMICAL COMPONENTS AND TEMPERATURE, WE HAVE VALIDATED HIGHLY RESOLVED DAILY PREDICTIONS FOR THE ENTIRE CONTINENTAL US. THE UNIQUE COMPOSITION OF THESE TWO COHORTS, ALLOWS US TO DETERMINE THE EXTENT TO WHICH SES MODIFIES THESE ASSOCIATIONS. FOR OUR ANALYSES, WE WILL ADJUST FOR A WIDE RANGE OF INDIVIDUAL-LEVEL CHARACTERISTICS AND SPATIOTEMPORAL COVARIATES. WE WILL ESTIMATE HAZARD RATIOS AND THEIR 95% CONFIDENCE INTERVALS USING COX REGRESSION, DISTRIBUTED-LINEAR/NON-LINEAR LAG MODELS, AND WE WILL EXAMINE EFFECT MODIFICATION BY INFANT SEX. WE WILL USE ADVANCED STATISTICAL METHODS TO ESTIMATE THE EFFECTS OF MIXTURES. OUR PRIOR WORK AND DATA SUPPORT BOTH THE HYPOTHESIS FOR AND THE FEASIBILITY OF THE PROPOSED STUDY. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT WILL BE THE FIRST STUDY TO: 1) INVESTIGATE ASSOCIATIONS BETWEEN AIR POLLUTANTS, TEMPERATURE AND NDDS ON A NATIONAL SCALE; 2) USE STATE-OF-THE-ART SPATIOTEMPORAL MODELS TO ASSESS INDIVIDUAL EXPOSURES TO PM2.5, NO2, O3 AND TEMPERATURE; 3) EMPLOY INNOVATIVE RESOURCES OF CLINICAL DATA BY LEVERAGING TWO LARGE PREGNANCY COHORTS. THE PROPOSED RESEARCH IS OF GREAT SIGNIFICANCE BECAUSE IT WILL GUIDE DECISIONS AND POLLUTANT REGULATIONS TO PROTECT THE HEALTH OF PREGNANT WOMEN AND CHILDREN, INFORM HEAT WAVE WARNING SYSTEMS, POTENTIALLY REDUCING RATES OF NDDS AND SUBSEQUENT SOCIAL, FINANCIAL, AND PUBLIC HEALTH BURDEN.

HARNESSING INFLAMMATORY MACROPHAGES TO THWART LUNG DISEASE CAUSED BY CHRONIC OZONE EXPOSURE - ABSTRACT UNCONTROLLED INFLAMMATION IS CENTRAL TO THE PATHOPHYSIOLOGY OF ASTHMA AND COPD WHICH CAN DEVELOP FOLLOWING CHRONIC EXPOSURE TO OZONE. EVIDENCE SUGGESTS THAT THESE PATHOLOGIES ARE DUE TO AN INABILITY TO ADEQUATELY RESOLVE THE ACUTE INFLAMMATORY RESPONSE TO LUNG INJURY. THIS SUGGESTS THAT PROMOTING THE RESOLUTION OF INFLAMMATION WILL BE MORE BENEFICIAL THAN SUPPRESSING PERSISTENT UNRESTRAINED INFLAMMATION. OUR STUDIES ARE FOCUSED ON MACROPHAGES WHICH PLAY A KEY ROLE IN BOTH INITIATING AND RESOLVING INFLAMMATORY RESPONSES TO TISSUE INJURY. THIS ACTIVITY IS MEDIATED BY DISTINCT SUBSETS BROADLY CLASSIFIED AS PROINFLAMMATORY M1 AND PRORESOLUTION M2 MACROPHAGES. EFFECTIVE RESOLUTION OF INFLAMMATION DEPENDS ON METABOLIC REPROGRAMMING OF MACROPHAGES FROM AN M1 PHENOTYPE TO AN M2 PHENOTYPE, WHICH INVOLVES A SWITCH FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION AS A SOURCE OF ENERGY. WE DISCOVERED THAT THIS REPROGRAMMING IS SUPPRESSED FOLLOWING CHRONIC OZONE EXPOSURE. THE GOAL OF OUR STUDIES IS TO ANALYZE MECHANISMS UNDERLYING SUPPRESSION OF MACROPHAGE REPROGRAMMING. IN RECENT STUDIES WE IDENTIFIED FARNESOID-X RECEPTOR (FXR), A NUCLEAR RECEPTOR IMPORTANT IN BILE ACID METABOLISM, WITH ANTI-INFLAMMATORY ACTIVITY, AS IMPORTANT IN PROMOTING M1 TO M2 MACROPHAGE REPROGRAMMING IN THE LUNG. FOLLOWING OZONE EXPOSURE, MACROPHAGE FXR ACTIVITY IS DOWNREGULATED. THIS IS ASSOCIATED WITH INCREASED ACTIVITY OF PROINFLAMMATORY M1 MACROPHAGES AND REDUCED ACTIVITY OF PRORESOLVING M2 MACROPHAGES. WE ALSO FOUND THAT MICRORNAS THAT REGULATE THE PROINFLAMMATORY TRANSCRIPTION FACTOR NFB ARE DYSREGULATED IN MACROPHAGES AFTER OZONE EXPOSURE. AS A CONSEQUENCE, THERE IS PROTRACTED ACTIVATION OF NFB SIGNALING RESULTING IN INCREASED PRODUCTION OF TNF, IL-1, AND CYTOTOXIC REACTIVE NITROGEN SPECIES. WE HYPOTHESIZE THAT THESE MEDIATORS SUPPRESS FXR ACTIVITY WHICH PREVENTS ACTIVATION OF THE NUCLEAR RECEPTOR NR4A1, A KEY INDUCER OF MACROPHAGE M1 TO M2 METABOLIC REPROGRAMMING. TO TEST THIS HYPOTHESIS, WE WILL (1) DETERMINE IF PERSISTENT INFLAMMATION FOLLOWING CHRONIC OZONE EXPOSURE AND THE DEVELOPMENT OF LUNG DISEASE IS DUE TO DEFECTIVE DEVELOPMENT OF PRORESOLUTION M2 MACROPHAGES, AND ASSESS WHETHER THIS IS CAUSED BY PROTRACTED ACTIVATION OF NFB IN M1 MACROPHAGES; (2) ANALYZE THE ROLE OF FXR AND ITS TARGET NR4A1, IN THE DEVELOPMENT OF PRORESOLUTION M2 MACROPHAGES IN THE LUNG FOLLOWING CHRONIC OZONE EXPOSURE; AND (3) DETERMINE IF PROTRACTED ACTIVATION OF NFB IS DUE TO OZONE-INDUCED ALTERATIONS IN MICRORNAS REGULATING NFB. RESULTS OF THESE STUDIES WILL PROVIDE NEW MECHANISTIC INSIGHTS INTO CHRONIC OZONE TOXICITY AND MAY LEAD TO THE DEVELOPMENT OF NEW APPROACHES FOR THWARTING THE DEVELOPMENT OF CHRONIC LUNG DISEASE.

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION- FY2017

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION - FY 2018

EVALUATING THE ROLE OF MULTIMORBIDITY IN MODULATION MEDICATION EFFECTS IN OLDER ADULTS - MULTIMORBIDITY, DEFINED AS THE CO-OCCURRENCE OF TWO OR MORE MEDICAL CONDITIONS, IMPACTS TWO-THIRDS OF OLDER INDIVIDUALS OVER 65 – CORRESPONDING TO 36 MILLION U.S. ADULTS, AND IS A MAJOR DRIVER OF HEALTHCARE SPENDING, POLYPHARMACY, AND MORTALITY. HOWEVER, THE ROUTINE EXCLUSION OF OLDER AND MORE MULTIMORBID PATIENTS FROM CLINICAL TRIALS HAS RESULTED IN THE PAUCITY OF DATA REGARDING THE RISKS AND BENEFITS OF MEDICATIONS IN THIS POPULATION, OR AN UNDERSTANDING OF HOW MULTIMORBIDITY ALTERS TREATMENT EFFECTS. TO ADDRESS THIS UNMET NEED, THIS PROPOSAL WILL EVALUATE THE ROLE OF MULTIMORBIDITY IN MODULATING MEDICATION EFFECTS AND IDENTIFY THE OPTIMAL APPROACH THAT BEST QUANTIFIES ITS IMPACT ON MEDICATION OUTCOMES. OUR CENTRAL HYPOTHESIS IS THAT (A) BY ATTENUATING DRUG-RELATED BENEFITS AND AMPLIFYING DRUG-RELATED HARMS, MULTIMORBIDITY SHOULD BE A KEY CONSIDERATION WHEN MAKING TREATMENT DECISIONS, AND THAT (B) APPROACHES THAT INCORPORATE THE CUMULATIVE BURDEN OF ILLNESS – ESPECIALLY THE MULTI- MORBIDITY WEIGHTED INDEX [MWI] – CAN BETTER CHARACTERIZE THESE ALTERATIONS IN MEDICATION EFFECTS (PRELIMINARY ANALYSIS). THE PROPOSAL WILL USE MEDICARE FEE-FOR-SERVICE DATA FROM >23 MILLION PATIENTS AND REPLICATE FINDINGS IN TWO LARGE EXTERNAL DATABASES. WE WILL FOCUS ON CARDIOMETABOLIC THERAPIES AS: OLDER ADULTS HAVE THE HIGHEST BURDEN OF THESE CONDITIONS, AND SINCE 2010, MORE THAN 20 NEW CARDIOMETABOLIC THERAPIES HAVE BEEN APPROVED, HIGHLIGHTING THE IMMENSE NEED TO STUDY THESE MEDICATIONS. WE WILL IDENTIFY PATIENTS WITH: (A) TYPE 2 DIABETES INITIATING SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS VS ESTABLISHED ANTIDIABETIC THERAPIES; (B) ATRIAL FIBRILLATION INITIATING DIRECT ORAL ANTICOAGULANTS VS WARFARIN; AND (C) ATHEROSCLEROTIC CARDIOVASCULAR DISEASE [CVD] INITIATING NEWER ANTIPLATELET DRUGS (E.G. TICAGRELOR) VS CLOPIDOGREL. AIM 1 WILL EVALUATE HOW CLINICAL (E.G. COGNITIVE IMPAIRMENT) AND NON-CLINICAL (E.G. SOCIAL DEPRIVATION) FACTORS INTERACT WITH MULTIMORBIDITY TO INFLUENCE MEDICATION PRESCRIBING OF CARDIOMETABOLIC THERAPIES IN THE REAL WORLD. AIM 2 WILL ELUCIDATE THE ROLE OF MULTIMORBIDITY IN MODULATING THE RISKS AND BENEFITS FOR NEWER COMPARED TO ESTABLISHED CARDIOMETABOLIC MEDICATIONS BY ESTIMATING THE ADJUSTED RATES OF DISEASE SPECIFIC BENEFITS (I.E. REDUCTION IN CVD EVENTS), HARMS (E.G. MAJOR BLEEDING) AND UNIVERSAL OUTCOME MEASURES (E.G. HOME-TIME, LOSS OF FUNCTIONAL INDEPENDENCE) BY LEVELS OF MULTIMORBIDITY. WE WILL ALSO VALIDATE MULTIMORBIDITY MEASURES (E.G. MWI, ELIXHAUSER INDEX) AND FRAMEWORKS (E.G. DISEASE DYADS) AGAINST MEDICATION OUTCOMES. THE IMPACT OF THIS PROPOSAL IS SIGNIFICANT AS IT WILL ESTABLISH A RIGOROUS AND READILY SCALABLE FRAMEWORK TO STUDY THE EFFECTS OF MULTIMORBIDITY ON DRUG OUTCOMES IN OLDER ADULTS. IT WILL ALSO REPRESENT THE FIRST EFFORT TO SYSTEMATICALLY EVALUATE AND VALIDATE MULTIMORBIDITY INDICES AND APPROACHES AGAINST MEDICATION OUTCOMES, BEGINNING A NEW AND EXCITING LINE OF RESEARCH THAT HAS POTENTIAL TO EXPAND TO OTHER POPULATIONS (E.G. MIDDLE-AGED ADULTS) AND CLINICAL AREAS. GIVEN THE PAUCITY OF DATA FROM CLINICAL TRIALS, STUDY FINDINGS WILL SERVE AS THE PRIMARY SOURCE OF INFORMATION FOR PATIENTS, CAREGIVERS, AND CLINICIANS TO MAKE INDIVIDUALIZED EVIDENCE-BASED DECISIONS.

IMPLEMENTATION AND EFFECTIVENESS OF MINDFULNESS ORIENTED RECOVERY ENHANCEMENT AS AN ADJUNCT TO METHADONE TREATMENT FOR OPIOID USE DISORDER - PROJECT SUMMARY THE UNITED STATES IS EXPERIENCING AN OPIOID USE AND OVERDOSE CRISIS. TO ADDRESS THIS CRISIS, PROGRAMS THAT PROVIDE MEDICATION FOR OPIOID USE DISORDER (MOUD) ARE BEING EXPANDED AND ENHANCED. MOUD IS THE MOST EFFECTIVE INTERVENTION FOR AN OUD, AND METHADONE TREATMENT (MT) IS THE MOST COMMONLY PRESCRIBED MOUD; HOWEVER, APPROXIMATELY HALF OF PEOPLE WHO BEGIN MT DISCONTINUE WITHIN A YEAR, AND HALF OF PEOPLE RETAINED IN MT USE OPIOIDS WITHIN SIX MONTHS. PHYSICAL PAIN, EMOTION DYSREGULATION, AND REWARD PROCESSING DEFICITS, AFFECTING MOST PEOPLE ON MT, COULD BE CONTRIBUTING TO THEIR ONGOING OPIOID USE. NOVEL BEHAVIORAL INTERVENTIONS THAT ADDRESS PHYSICAL PAIN, EMOTION DYSREGULATION, REWARD PROCESSING DEFICITS AND OPIOID USE AMONG PEOPLE ON MOUD ARE NEEDED. MINDFULNESS-ORIENTED RECOVERY ENHANCEMENT (MORE) INTEGRATES TRAINING IN MINDFULNESS, REAPPRAISAL, AND SAVORING SKILLS INTO AN 8-WEEK GROUP THERAPY DESIGNED TO REMEDIATE HEDONIC DYSREGULATION IN BRAIN REWARD SYSTEMS UNDERPINNING OUD. ACROSS MULTIPLE TRIALS, MORE HAS DEMONSTRATED EFFICACY FOR REDUCING OPIOID USE, CRAVING, EMOTIONAL DISTRESS, AND PAIN IN OTHER HEALTHCARE SETTINGS. OUR R21 PILOT RANDOMIZED CONTROLLED TRIAL OF MORE WAS THE FIRST TO DEMONSTRATE MORE’S FEASIBILITY AND ACCEPTABILITY AS DELIVERED IN MT CLINICS, WITH INDICATIONS OF PRELIMINARY EFFICACY FOR DECREASING DRUG USE, CRAVING, DEPRESSION, ANXIETY, AND PAIN FOR PEOPLE WITH OUD. FURTHER, EXPEDITED IMPLEMENTATION AND DISSEMINATION OF EFFECTIVE INTERVENTIONS IS NEEDED. HOWEVER, UPTAKE OF NOVEL INTERVENTIONS MAY BE SLOW IN MT BECAUSE TIME AND RESOURCES ARE OFTEN LIMITED. THEREFORE, TO BEST ADDRESS POTENTIAL IMPLEMENTATION ISSUES AND TO OPTIMIZE FUTURE MORE IMPLEMENTATION AND DISSEMINATION, IN THIS STUDY, WE WILL UTILIZE A TYPE 2, HYBRID IMPLEMENTATION-EFFECTIVENESS STUDY DESIGN. WE WILL NOT ONLY EVALUATE MORE’S EFFECTIVENESS BUT ALSO ASSESS BARRIERS AND FACILITATORS TO INTEGRATING MORE INTO MT AND EVALUATE THE IMPACT OF A SUSTAINABLE TRAIN-THE-TRAINER MODEL ON PROVIDER BURDEN, INTERVENTION FIDELITY AND ENGAGEMENT, AND PATIENT OUTCOMES. WE WILL RANDOMIZE MT CLINICIANS TO RECEIVE TRAINING IN 1) A HIGHER INTENSITY MORE IMPLEMENTATION STRATEGY CONSISTING OF A TRAIN-THE- TRAINER MODEL WITH TRAINING IN THE FULL MORE TREATMENT MANUAL PLUS SUPERVISION AND FEEDBACK OR 2) A MINIMAL INTENSITY IMPLEMENTATION STRATEGY CONSISTING OF A SIMPLE, SCRIPTED MINDFULNESS PRACTICE (SMP) EXTRACTED FROM THE MORE TREATMENT MANUAL WITH MINIMAL TRAINING, NO SUPERVISION, AND MINIMAL FEEDBACK. SPECIFICALLY, WE AIM TO: 1) USING A RE-AIM (REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION, AND MAINTENANCE) FRAMEWORK, EXAMINE BARRIERS AND FACILITATORS TO IMPLEMENTATION OF MORE AND SMP IN MT AND EVALUATE STRATEGIES FOR OPTIMIZING TRAINING, FIDELITY, AND ENGAGEMENT, 2) OPTIMIZE EXISTING MORE AND SMP TRAINING AND IMPLEMENTATION TOOLKITS, INCLUDING ADAPTABLE RESOURCES THAT CAN ACCELERATE THE TRANSLATION OF EVIDENCE INTO PRACTICE, AND 3) EVALUATE EFFECTIVENESS AND TREATMENT FIDELITY OF A HIGHER INTENSITY MORE IMPLEMENTATION STRATEGY VERSUS A LOWER INTENSITY SMP IMPLEMENTATION STRATEGY AS AN ADJUNCT TO MT (N=420).

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTION - FY2014

PQ#12; TARGETING NAMPT-MEDIATED NAD+ METABOLISM IN CHEMOBRAIN

EVALUATING CIGARETTE RELIGHTING BEHAVIOR: PREVALENCE, CORRELATES, TOXICANT EXPOSURE, AND IMPLICATIONS FOR CESSATION - ALTHOUGH SMOKING PREVALENCE HAS DECREASED, MORE THAN 34 MILLION AMERICANS CONTINUE TO SMOKE. DISENFRANCHISED GROUPS INCREASINGLY COMPRISE THE REMAINING SMOKING POPULATION, AND CIGARETTE RELIGHTERS MAY BE SOME OF THE MOST DISENFRANCHISED (E.G., LOW SOCIOECONOMIC STATUS). RELIGHTING REFERS TO EXTINGUISHING, SAVING, AND LATER RELIGHTING UNFINISHED CIGARETTES. RESEARCH SUGGESTS THIS IS A PREVALENT BEHAVIOR ENGAGED IN BY 44-73% OF SMOKERS, WITH 17-21% OF SMOKERS REPORTING THEY RELIGHT ‘USUALLY’ OR ‘FREQUENTLY’, THUS IMPACTING MILLIONS OF AMERICANS. APPARENT REASONS FOR RELIGHTING INCLUDE COST, PERCEIVED BENEFITS FOR HEALTH AND CESSATION, AND SMOKING BANS. THIS BEHAVIOR MAY INCREASE HARMS TO SMOKERS SUCH AS LUNG CANCER AND CHRONIC BRONCHITIS. FOR EXAMPLE, RELIGHTING COULD CONTRIBUTE TO WORSE CESSATION AND HEALTH OUTCOMES IF RELIGHTERS (WHO TEND TO BE HIGHLY NICOTINE-DEPENDENT) HAVE LOWER MOTIVATION TOWARD TOTAL ABSTINENCE BECAUSE THEY BELIEVE THEY ARE MINIMIZING THE AMOUNT THEY SMOKE. THEY MAY ALSO BE INADEQUATELY TREATED AND ADVISED BY CLINICIANS BECAUSE THEY APPEAR TO BE LESS DEPENDENT OR SMOKE FEWER NUMBERS OF CIGARETTES PER DAY (CPD) COMPARED TO NON-RELIGHTERS, DESPITE A GREATER NUMBER OF SMOKING SESSIONS PER DAY AND EXPOSURE TO TOXICANTS. THIS COULD LEAD TO UNDER-DOSING OF PHARMACOTHERAPY. GIVEN THAT REASONS FOR RELIGHTING INCLUDE THE INCREASING COST OF CIGARETTES, PREVALENCE OF RELIGHTING MAY GROW IN THE FUTURE (ESPECIALLY DURING THIS ECONOMIC CRISIS) AND MAY CONTINUE TO IMPACT DISPROPORTIONATELY THOSE WITH GREATER EXISTING TOBACCO-RELATED DISPARITIES. MORE RESEARCH IS NEEDED TO ADDRESS THESE CHALLENGES BY INVESTIGATING WHO RELIGHTS AND WHY, AND POTENTIAL EFFECTS OF RELIGHTING ON TOBACCO DEPENDENCE, CESSATION, AND HEALTH. UNDERSTANDING RELIGHTING IS CRITICAL BECAUSE: 1) CURRENT ASSESSMENTS (I.E., CPD) MAY UNDERESTIMATE TOXICANT EXPOSURE AND NICOTINE DEPENDENCE AMONG RELIGHTERS AND 2) IF RELIGHTING CONTINUES TO BE LARGELY IGNORED BY PROVIDERS, A HIGH PROPORTION OF SMOKERS MAY BE UNDERTREATED. SPECIFIC AIMS OF THIS FOUR-YEAR PROJECT ARE TO: 1) ESTABLISH CRITERIA AND REASONS FOR, AS WELL AS PREVALENCE, FREQUENCY, AND CORRELATES OF RELIGHTING IN A NATIONAL SURVEY; 2) EVALUATE POTENTIAL TOXIC EFFECTS OF RELIGHTING USING TOPOGRAPHY AND TOXICANT ANALYSES; 3) INVESTIGATE THE POTENTIAL IMPACT OF RELIGHTING BY OBSERVING TOBACCO TREATMENT AND OUTCOMES OF RELIGHTERS IN A STATE-WIDE TOBACCO TREATMENT PROGRAM. PRELIMINARY STUDIES NEED TO BE REPLICATED AND EXTENDED TO BE MORE RIGOROUS, COMPREHENSIVE, AND ON A LARGER SCALE TO ADDRESS NUMEROUS REMAINING QUESTIONS THAT WOULD LAY THE GROUNDWORK FOR UNDERSTANDING THE INDIVIDUAL AND PUBLIC HEALTH IMPACT OF RELIGHTING. THIS STUDY WILL PROVIDE IMPORTANT INFORMATION ABOUT THE EXTENT, FREQUENCY, CONTEXTUAL FACTORS, AND POTENTIAL DANGERS OF THIS UNDERSTUDIED BEHAVIOR. THE STUDY HAS IMPLICATIONS FOR BOTH SURVEILLANCE AND TREATMENT SUCH AS NEW MEASURES TO SCREEN FOR RELIGHTING CLINICALLY AND IN POPULATION SURVEYS AS WELL AS POTENTIALLY INFORMING CLINICIANS IN PRESCRIBING APPROPRIATE-INTENSITY TREATMENTS FOR RELIGHTERS. TOGETHER, DATA FROM THE PROPOSED SPECIFIC AIMS WILL PROVIDE A CLEARER PICTURE OF THE EXTENT AND IMPACT OF CIGARETTE RELIGHTING.

MULTILEVEL FACTORS ASSOCIATED WITH DISPARITIES IN THE USE OF TARGETED CANCER THERAPIES IN MEDICARE - ABSTRACT THIS APPLICATION IS BEING SUBMITTED IN RESPONSE TO THE NOTICE OF SPECIAL INTEREST (NOSI) IDENTIFIED AS NOT-CA- 23-044. IDENTIFICATION OF PATIENTS WITH PATHOGENIC VARIANTS IS CRUCIAL TO ENABLE THE USE OF TREATMENT AND GUIDE PREVENTION. YET, THERE ARE IMPORTANT RACIAL DISPARITIES IN GENOMIC CANCER MEDICINE: FOR EXAMPLE, BLACK PERSONS EXPERIENCE SIGNIFICANT DISPARITIES IN ACCESS TO GERMLINE CANCER GENOMIC SERVICES AND BEAR THE LARGEST CANCER MORTALITY BURDEN OF ANY RACIAL/ETHNIC GROUP. PRELIMINARY EVIDENCE SUGGESTS THAT THERE MAY ALSO BE DISPARITIES IN THE USE OF GENOMICALLY-TARGETED THERAPIES. WHILE THE PARENT R01 FOCUSES ON WELL-KNOWN DISPARITIES IN GERMLINE CANCER GENOMIC RISK TESTING, CONSIDERABLY LESS IS KNOWN ABOUT WHETHER THERE ARE DISPARITIES IN THE USE OF GENOMICALLY-TARGETED CANCER THERAPIES. WE WILL ASSESS THESE DISPARITIES AND THE POTENTIALLY IMPORTANT ROLE OF HEALTH POLICY FACTORS AS THEY RELATE TO DISPARITIES AMONG CANCER CASES AGES IN MEDICARE. IN MARCH 2018, TO IMPROVE MEDICARE BENEFICIARIES’ ACCESS TO TARGETED GENOMIC CANCER THERAPIES, CMS ISSUED A NATIONAL COVERAGE DETERMINATION (NCD) PAYING FOR NEXT GENERATION SEQUENCING (NGS) BASED TUMOR GENOMIC TESTS FOR PATIENTS WITH ADVANCED OR METASTATIC CANCER AND NO PREVIOUS NGS TESTING. IMPLEMENTING THE NEW PAYMENT POLICY BY MEDICARE IS INTENDED TO INCREASE THE USE OF GENOMICALLY-TARGETED CANCER TREATMENTS. HOWEVER, LITTLE IS KNOWN ABOUT HOW THE IMPLEMENTATION OF THE NATIONAL POLICY FOR NGS TESTING HAS INFLUENCED DISPARITIES IN THE USE OF GENOMICALLY-TARGETED THERAPIES. TO INFORM FUTURE HEALTHCARE COVERAGE POLICIES AROUND GENOMIC CANCER MEDICINE, IT IS IMPORTANT TO ASSESS WHETHER THE COVERAGE POLICY EQUITABLY ADDRESSES ACCESS TO EFFECTIVE TREATMENT, GIVEN THE DISPARITIES OBSERVED IN BOTH GENETIC TESTING AND TARGETED TREATMENTS. THIS STUDY WILL ADDRESS THIS GAP. USING THE MOST RECENT FIVE YEARS OF SEER-MEDICARE PART D DATA, WE WILL FIRST DOCUMENT WHETHER THE IMPLEMENTATION OF NCD FOR NGS TESTING HAS INCREASED THE USE OF GENOMICALLY-TARGETED THERAPIES. THEN, WE WILL EXAMINE WHETHER THERE ARE RACIAL AND SOCIO-ECONOMIC DISPARITIES IN THE USE OF THESE THERAPIES, ACCOUNTING FOR THE 2018 NCD FOR NGS TESTING. THE USE OF SELECTED GENOMICALLY-TARGETED ORAL ANTICANCER DRUGS BEFORE VS. AFTER THE NCD WILL BE THE PRIMARY OUTCOME OF INTEREST. POLICY-LEVEL VARIABLES WILL INCLUDE HEALTH INSURANCE FACTORS SUCH AS PATIENTS’ MEDICARE ADVANTAGE ENROLLMENT, LOW-INCOME SUBSIDY STATUS, AND PATIENTS WITH COORDINATION OF BENEFITS FROM THIRD PARTIES. THE SPECIFIC AIMS OF THE PROPOSED STUDY ARE TO 1) COMPARE THE USE OF ORALLY ADMINISTERED GENOMICALLY-TARGETED CANCER AGENTS AMONG MEDICARE BENEFICIARIES BEFORE AND AFTER THE IMPLEMENTATION OF THE 2018 NCD POLICY FOR NGS TESTING; 2) EXAMINE RACIAL-ETHNIC AND SOCIOECONOMIC DISPARITIES IN THE USE OF ORAL GENOMICALLY-TARGETED CANCER DRUGS ASSOCIATED WITH INSURANCE BENEFIT DESIGNS. FINDINGS FROM THIS STUDY CAN BE USED TO INFORM POLICY DECISIONS FOR ADVANCING CANCER HEALTH EQUITY AND IMPROVING ACCESS TO GENOMICALLY-TARGETED CANCER THERAPIES. THIS APPROACH COULD BE APPLIED TO OTHER DRUGS AND GENOMIC MEDICATIONS, AS WELL AS VALUE-BASED HEALTHCARE INITIATIVES.

THE REGULATION OF THE HISTONE CODE DURING CARDIAC HYPERTROPHY - ABSTRACT OUR GOAL IS TO INVESTIGATE THE IMPACT OF DIET AND PRESSURE OVERLOAD ON THE HISTONE CODE, AND HOW THIS INFLUENCES CHANGES IN GENE EXPRESSION IN THE HEALTHY AND HYPERTROPHIED/FAILING HEARTS AND, IN TURN, HOW IT IMPACTS PROGRESSION OF THE DISEASE. DECIPHERING THE HISTONE CODE AND HOW DIET CAN MODIFY IT, PROVIDES US AN EDUCATED MEANS TO EXPLOIT IT TO OUR ADVANTAGE, ESPECIALLY DURING PATHOLOGICAL CONDITIONS. ACETYLATION AND METHYLATION OF HISTONE LYSINE (K) RESIDUES WERE THE FIRST HISTONE MODIFICATIONS DISCOVERED AND ARE, THEREFORE, THE MOST WIDELY STUDIED AND UNDERSTOOD. HOWEVER, TO-DATE, THERE ARE 11 CONFIRMED MODIFIERS OF HISTONE LYSINE RESIDUES, INCLUDING THE ACYL GROUPS BUTYRYL (BU), CROTONYL (CR), AND B-HYDROXYBUTYRATE (BHB) 1, WHOSE SOURCE, GENOMIC DISTRIBUTION, AND FUNCTIONAL RELEVANCE, REMAIN LARGELY UNKNOWN IN THE HEART, AND ARE THE FOCUS OF OUR STUDY. OUR RECENT FINDINGS UNIQUELY SHOW THAT DIETARY FAT IS A MAJOR REGULATOR OF HISTONE BUTYRYLATION, INCLUDING H3K9-BUTYRYL (H3K9BU). USING GENOME-WIDE CHROMATIN IMMUNOPRECIPITATION-SEQUENCING (CHIP-SEQ), WE SHOW THAT H3K9BU IS ABUNDANT AT ALL TRANSCRIPTIONALLY ACTIVE PROMOTERS. BOTH A HIGH-FAT DIET AND STRESS ACCELERATED THE CONVERSION OF BUTYRYL-COA TO CROTONYL-COA VIA ACYL-COA DEHYDROGENASE SHORT CHAIN (ACADS), RESULTING IN A SUBSTANTIAL REDUCTION IN GLOBAL PROMOTER-H3K9BU. A DELETION OF ACADS BOTH IN THE MOUSE HEART AND IN HUMAN CELLS REVERSED THIS EFFECT AND INCREASED PROMOTER AND GENE-BODY H3K9BU. PARADOXICALLY, THOUGH, A FAT-FREE DIET HAD THE HIGHEST LEVELS OF H3K9BU. DELETION OF FATTY ACID SYNTHETASE (FASN), ABOLISHED H3K9BU IN CELLS MAINTAINED IN A GLUCOSE-RICH, FATTY ACID-FREE, BUT NOT IN A FATTY ACID-RICH, MEDIUM, PROVING THAT FATTY ACID SYNTHESIS FROM CARBOHYDRATES SUBSTITUTES FOR DIETARY FAT AS A SOURCE BUTYRYL-COA. IN CONTRAST TO H3K9BU, THERE WERE MINIMAL DIETARY-INDUCED CHANGES IN H3K9-ACETYL (H3K9AC) LEVELS. IMPORTANTLY, RNA-SEQUENCING (RNA-SEQ) REVEALED THAT DIET-INDUCED CHANGES IN H3K9BU ABUNDANCE IN THE MOUSE HEART WAS ASSOCIATED WITH DIFFERENTIAL CHANGES IN GENE EXPRESSION, BUT ONLY WHEN STRESSED BY PRESSURE OVERLOAD. MOREOVER, PROMOTER-H3K9BU LEVELS INVERSELY CORRELATED WITH THE EXTENT OF CHANGES IN GENE EXPRESSION LEVELS, AS EVIDENCED BY THE MORE ROBUST CHANGES SEEN IN THE HEARTS OF MICE ON A, SHORT-TERM, HIGH-FAT VS A FAT-FREE DIET, AS WELL AS, AFTER DELETION OF THE ACADS. INTERESTINGLY, H3K9BU ABUNDANCE INVERSELY CORRELATED WITH H3K9-CROTONYL (H3K9CR) AND CDK9. IN SUM, OUR DATA UNIQUELY SHOW THAT H3K9BU IS ENRICHED AT ACTIVE PROMOTERS, IS NEGATIVELY REGULATED BY HIGH-FAT AND STRESS IN AN ACADS-DEPENDENT FASHION, AND ITS ABUNDANCE INVERSELY CORRELATES WITH STRESS-INDUCED CHANGES IN GENE EXPRESSION. WE ARE PROPOSING THAT HISTONE H3K9BU, H3K9CR, AND H3K9-B-HYDROXYBUTYRYL (H3K9BHB), ARE PRODUCTS OF THE B-OXIDATION INTERMEDIATES, BUTYRYL-COA, CROTONYL-COA, AND B-HYDROXYBUTYRYL-COA, OR THE KETONE BODY, B-HYDROXYBUTYRATE, WHICH SERVE AS SUBSTRATES FOR HISTONES MODIFICATIONS. THESE MARKS ARE LABILE AND DIFFERENTIALLY INFLUENCE PRESSURE OVERLOAD-INDUCED GENE EXPRESSION, BUT NOT BASELINE EXPRESSION. SPECIFICALLY, AS H3K9BU DECREASES IT IS REPLACED BY H3K9CR DURING A HIGH-FAT DIET. THIS EXCHANGE EXAGGERATES GENE EXPRESSION AND WORSENS THE OUTCOME OF CARDIAC FAILURE. CONVERSELY, H3K9BHB THAT INCREASES DURING A KETOGENIC DIET HAS THE OPPOSITE EFFECT, AS IT IS REPORTED TO HAVE BENEFICIAL EFFECTS ON HEALTH AND AGING. THIS DIFFERENTIAL INFLUENCE OF THE HISTONE MARKS ON GENE EXPRESSION IS MEDIATED BY REGULATING THE RECRUITMENT OF CDK9 TO GENE PROMOTERS. WE HYPOTHESIZE THAT 1) A HIGH-FAT DIET (60 KCAL% FAT, 20 KCAL% CARB), OR PRESSURE OVERLOAD, ACCELERATES THE CONVERSION OF NUCLEAR BUTYRYL- COA TO CROTONYL-COA IN AN ACADS-DEPENDENT MANNER, THUS, REDUCING H3K9BU AND INCREASING H3K9CR, WHICH IS RESPONSIBLE FOR EXAGGERATING STRESS-INDUCED GENE EXPRESSION AND WORSENING THE OUTCOME OF HEART FAILURE (HF).

CD103 ENGAGEMENT REGULATES INTESTINAL IEL EFFECTOR FUNCTION - PROJECT SUMMARY. MUCOSAL SURVEILLANCE OF THE INTESTINAL BARRIER BY TISSUE-RESIDENT LYMPHOCYTES IS CRITICAL FOR PREVENTING THE INVASION OF ENTERIC PATHOGENS AND A NECESSARY COMPONENT OF PROTECTIVE IMMUNITY. A SINGLE LAYER OF EPITHELIAL CELLS LINES THE INTESTINAL TRACT AND PROVIDES A PHYSICAL BARRIER BETWEEN MICROBES, DIETARY ANTIGENS, TOXINS AND THE REST OF THE TISSUE. THEREFORE, THE REACTIVATION OF LYMPHOCYTES AT THE INTESTINAL BARRIER MUST BE TIGHTLY REGULATED, AS TOO ROBUST OF A RESPONSE COULD RESULT IN DESTRUCTION OF THE EPITHELIUM LEADING TO MICROBIAL TRANSLOCATION AND EVENTUAL AUTOIMMUNITY, AS OBSERVED IN INFLAMMATORY BOWEL DISEASE AND CELIAC DISEASE. TISSUE-RESIDENT INTRAEPITHELIAL LYMPHOCYTES (IELS) IN THE INTESTINE PROVIDE A FIRST LINE OF DEFENSE AGAINST INVADING MICROORGANISMS AND THE INTESTINAL IEL COMPARTMENT IS COMPOSED OF WHAT HAS BEEN TERMED INDUCED AND NATURAL IELS. INDUCED IELS ARE CD8AB+ TCRAB+ TISSUE RESIDENT MEMORY (TRM IELS) CELLS THAT ARE RECRUITED TO THE EPITHELIAL COMPARTMENT FOLLOWING ANTIGEN EXPOSURE. IN CONTRAST, NATURAL IELS ARE NOT MHC-RESTRICTED AND INCLUDE CD8AA+ IELS EXPRESSING TCRGD (GD IELS). GD AND TRM IELS REPRESENT THE MAJORITY OF THE LYMPHOCYTES IN THE INTESTINAL EPITHELIUM AND COULD SERVE BOTH PROTECTIVE AND PATHOGENIC ROLES, YET MECHANISMS REGULATING THEIR ACTIVATION DURING INFECTION IN VIVO REMAIN LARGELY UNEXPLORED. CD103 (AEB7 INTEGRIN) IS EXPRESSED BY THE MAJORITY OF GD AND TRM IELS LOCATED IN THE INTESTINE AND AT OTHER BARRIER SITES. CD103 BINDS TO EPITHELIAL E-CADHERIN AND PLAYS AN IMPORTANT ROLE IN THE RECRUITMENT AND MAINTENANCE OF TISSUE LYMPHOCYTES. HOWEVER, THE CONTRIBUTION OF CD103 TO IEL FUNCTIONALITY WITHIN THE INTESTINE DURING INFECTION HAS NOT BEEN ADDRESSED. SUCCESSFUL COMPLETION OF THE PROPOSED AIMS WILL PROVIDE FUNDAMENTAL INSIGHT INTO THE MOLECULAR MECHANISMS BY WHICH CD103 LIGATION TO E-CADHERIN PROMOTES (1) THE MOTILITY AND ACTIVATION OF TRM AND (2) GD IELS AND THE ROLE OF CD103 IN PROMOTING PROTECTIVE RESPONSES TO ENTERIC INFECTION. THESE STUDIES WILL UNCOVER NOVEL MECHANISMS BY WHICH DIRECT INTERACTION BETWEEN IELS AND EPITHELIAL CELLS CONTRIBUTE TO HOST IMMUNITY AND FURTHER DEFINE THE MOLECULAR CUES REGULATING SENTINEL LYMPHOCYTE POPULATIONS IN MUCOSAL HOMEOSTASIS AND INFECTION.

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTIONS - FY2012

THE ROLE OF THE HOST UBIQUITIN SYSTEM IN PROMOTING SARS-COV-2 REPLICATION AND PATHOGENESIS - THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (COV-2) BELONGS TO A FAMILY OF PATHOGENIC ENVELOPED RNA VIRUSES OF THE FAMILY CORONAVIRIDAE. THE ONGOING PANDEMIC HAS CAUSED A PUBLIC HEALTH EMERGENCY WORLDWIDE, ACCOMPANIED BY DIRE HEALTH AND ECONOMIC CONSEQUENCES. THERE IS EVIDENCE SUGGESTING THAT COV-2 MAY HAVE RELATIVELY HIGHER INFECTION RATES COMPARED TO PREVIOUS EPIDEMIC STRAINS OF SARS AND HIGHER AFFINITY TO THE RECEPTOR ACE2 THAN SARS-1. IN ADDITION, NEW COV-2 VARIANTS HAVE APPEARED RECENTLY WITH MUTATIONS THAT CORRELATE WITH HIGHER INFECTION RATES AND THE ABILITY TO ESCAPE SPECIFIC IMMUNITY, CAUSING MAJOR CONCERNS. A MAJOR GAP IN KNOWLEDGE REMAINS AS TO HOW COV-2 MAY HAVE ACQUIRED THE ABILITY TO SPREAD MORE EFFICIENTLY, AND HOW NEW MUTATIONS MAY AFFECT VIRUS INFECTIVITY. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS THAT REGULATE COV-2 CELL ENTRY AND REPLICATION, AND HOW THE APPEARANCE OF NEW VARIANTS COULD LEAD TO IMMUNE ESCAPE. WE WILL FOCUS ON THE ROLE OF THE HOST UBIQUITIN (UB) SYSTEM IN PROMOTING COV-2 INFECTION. THIS INFORMATION COULD HELP PREDICT APPEARANCE OF MORE TRANSMISSIBLE VARIANTS OF CORONAVIRUSES, AND TO DEVELOP ANTIVIRAL APPROACHES BY TARGETING SPECIFIC STEPS OF THE UBIQUITINATION PROCESS. OUR DATA RECENTLY PUBLISHED IN NATURE, SHOW THAT THE ENVELOPE PROTEIN OF FLAVIVIRUSES IS K63-LINKED POLYUBIQUITINATED, WHICH ENHANCES VIRUS ATTACHMENT TO HOST CELL RECEPTORS. THEREFORE, WE ASKED WHETHER A SIMILAR MECHANISM APPLIES TO SARS-COV-2. OUR PRELIMINARY DATA INDICATE THAT COV-2 STRUCTURAL PROTEINS ARE UBIQUITINATED ON MULTIPLE LYSINE RESIDUE, SOME OF WHICH ARE NOT CONSERVED IN THE ORIGINAL EPIDEMIC COV STRAIN. IN ADDITION, NEW VARIANTS OF COV-2 HAVE APPEARED WITH MUTATIONS ON THESE UBIQUITINATION SITES. OUR DATA ALSO SUGGEST THAT UBIQUITINATION OF SPIKE (S) PROTEIN MAY PLAY A ROLE IN STABILIZING THE COV-2 S-ACE2 INTERACTION, POTENTIALLY LEADING TO ENHANCED ENTRY AND PATHOGENESIS. IT IS CURRENTLY UNKNOWN WHETHER ANY MEMBER OF THE CORONAVIRIDAE FAMILY, INCLUDING SARS-COV-2, UTILIZE UBIQUITINATION OF VIRAL STRUCTURAL PROTEINS AS A MECHANISM OF VIRUS ATTACHMENT AND ENTRY. WE HAVE ALSO IDENTIFIED E3-UB LIGASES OF THE TRIPARTITE MOTIF (TRIM) FAMILY OF PROTEINS, WHICH UBIQUITINATES VIRAL STRUCTURAL PROTEINS. OUR GENERAL HYPOTHESIS IS THAT THE VARIANTS OF COV-2 THAT HAVE GAINED SPECIFIC LYSINE RESIDUES PROVIDE NEW UB ACCEPTOR SITES ON STRUCTURAL PROTEINS, WHICH CAN ENHANCE VIRUS REPLICATION AND IMMUNE ESCAPE. BY USING IN VITRO BIOCHEMICAL APPROACHES, NOVEL RECOMBINANT MUTANT VIRUSES, AND IN VIVO MODELS, WE WILL ASSESS HOW UBIQUITINATION OF STRUCTURAL COV-2 PROTEINS CONTRIBUTE TO COV-2 INFECTIVITY. IN AIM 1 WE WILL DETERMINE THE MECHANISTIC ROLE OF UBIQUITINATION OF THE COV-2 S PROTEIN IN VIRUS REPLICATION AND ANTIBODY ESCAPE, AND IN AIM 2 WE WILL DETERMINE THE MECHANISTIC ROLE OF UBIQUITINATION OF THE COV-2 MEMBRANE PROTEIN IN VIRUS REPLICATION AND IFN ANTAGONISM. THE OUTCOME OF THESE STUDIES MAY HELP EXPLAIN HOW NEW MORE INFECTIOUS VIRUSES MAY APPEAR BY GAINING UBIQUITINATION SITES AND WILL PROVIDE THE BASIS FOR THE DEVELOPMENT OF AN ANTIVIRAL APPROACH THAT COULD BE APPLIED TO A BROAD RANGE OF ENVELOPED VIRUSES.

THE UNVARNISHED TRUTH: PURSUING HEALTH EQUITY BY CORRECTING DISINFORMATION TARGETING AFRICAN AMERICANS ABOUT THE FDA'S PROPOSED BAN ON MENTHOL CIGARETTES AND FLAVORED CIGARS - PROJECT ABSTRACT IN APRIL 2022, THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) ANNOUNCED A PROPOSED BAN ON MENTHOL CIGARETTES AND ALL CHARACTERIZING FLAVORS IN CIGARS. AFRICAN AMERICANS HAVE HIGH RATES OF MENTHOL CIGARETTE AND FLAVORED CIGAR USE, WHICH LIKELY CONTRIBUTES TO THEIR DISPROPORTIONATE EXPERIENCE OF TOBACCO-RELATED HEALTH CONDITIONS. IN RESPONSE TO THE FDA’S ANNOUNCEMENT, THE TOBACCO INDUSTRY AND ITS SOURCES PROMULGATED DISINFORMATION IN AFRICAN AMERICAN COMMUNITIES ABOUT THE INCREASED CRIMINALIZATION AND POLICE DISCRIMINATION FOR USING TOBACCO PRODUCTS WHEN THE RULES ARE ENFORCED. ALTHOUGH THE FDA HAS STATED THAT IT CANNOT AND WILL NOT ENFORCE ACTIONS AGAINST INDIVIDUAL CONSUMERS FOR POSSESSING OR USING MENTHOL CIGARETTES OR FLAVORED CIGARS, DISINFORMATION ABOUT THE FLAVOR BAN AND ITS HARMFUL IMPACTS CONTINUES SPREADING AMONG AFRICAN AMERICAN COMMUNITIES. THE PROPOSED STUDY SEEKS TO DEVELOP AND EVALUATE THE EFFECTIVENESS OF MULTI-LEVEL, ANTI-DISINFORMATION MESSAGES (ADM) TO DISRUPT THE SPREAD AND MITIGATE THE DETRIMENTAL EFFECTS OF DISINFORMATION ABOUT THE FDA’S PROPOSED BAN ON MENTHOL CIGARETTES AND FLAVORED CIGARS. IN AIM 1, WE WILL EMPLOY COMMUNITY-BASED PARTICIPATORY RESEARCH METHODS TO DEVELOP AND ENGAGE WITH AN EXPERT ADVISORY BOARD (EAB) THAT WILL ENGAGE IN SHARED DECISION-MAKING AND PROVIDE THEIR PERSPECTIVES ON ALL STUDY ACTIVITIES. IN AIM 2, WE WILL CONDUCT FORMATIVE RESEARCH TO A) CHARACTERIZE THE TOBACCO INDUSTRY AND ITS OPERATIVES’ RHETORIC ABOUT THE CONSEQUENCES OF THE ANTICIPATED FLAVOR BAN AND B) ELICIT AA/BS’ KNOWLEDGE AND PERCEPTIONS ABOUT THE ANTICIPATED FLAVOR BAN. AIM 2 DATA WILL INFORM THE DEVELOPMENT OF THE INTERVENTION MAPPING (IM) LOGIC MODELS THAT DEPICT THE BEHAVIORAL AND ENVIRONMENTAL RISK FACTORS AND DETERMINANTS OF RESPONDENTS’ FLAVOR BAN RECEPTIVITY. IN AIM 3, WE WILL USE OF IM PROCESS TO DEVELOP, PRE-TEST, AND REFINE THE INDIVIDUAL AND COMMUNITY-LEVEL ADM AND CREATIVE CONCEPTS AMONG AA/B PARTICIPANTS. FINALLY, IN AIM 4, WE WILL CONDUCT A RANDOMIZED TREATMENT AND CONTROL EVALUATION DESIGN TO TEST THE EFFECTIVENESS OF OUR INDIVIDUAL AND COMMUNITY-BASED ADM CAMPAIGN ON AA/BS’ RECEPTIVITY TO THE FLAVOR BAN AND COUNTER- INDUSTRY BELIEFS. KNOWLEDGE GAINED FROM THIS STUDY WILL INFORM THE FDA’S CENTER FOR TOBACCO PRODUCTS COMMUNICATION OFFICE AND STATE AND LOCAL PUBLIC HEALTH DEPARTMENTS REGARDING SALIENT MESSAGES TO COMMUNICATE ABOUT THE FLAVOR BAN TO AA/B AND OTHER VULNERABLE POPULATIONS.

UNDERSTANDING ADOLESCENT IN-VIVO EXPOSURE TO ALCOHOL CONTENT IN THE MEDIA

INVESTIGATING THE ROLE OF LIQUID-LIQUID PHASE SEPARATION IN THE INTERACTION BETWEEN MYCOBACTERIUM TUBERCULOSIS AND MACROPHAGES - PROJECT SUMMARY THERE IS A FUNDAMENTAL GAP IN OUR UNDERSTANDING OF THE COMPLEX PROCESSES THAT GOVERN THE INTERACTIONS BETWEEN MTB AND MACROPHAGES. THE OVERALL OBJECTIVE OF THIS APPLICATION IS TO INVESTIGATE HOW THE NOVEL BIOPHYSICAL PHENOMENON OF PHASE SEPARATION IMPACTS BIOLOGICAL PROCESSES, SPECIFICALLY IN THE CONTEXT OF MTB INFECTION. A DETAILED KNOWLEDGE OF THE MOLECULES THAT RECOGNIZE AND RESPOND TO PATHOGENS IS REQUIRED TO REVEAL HOW CELLS FIGHT INFECTION; THEREFORE, THERE IS A CRITICAL NEED TO UNDERSTAND HOW PHASE SEPARATION MAY INFLUENCE OR CONTROL INNATE IMMUNE RESPONSES. MYCOBACTERIUM TUBERCULOSIS (MTB) IS AN INCREDIBLY SUCCESSFUL AND DEADLY HUMAN PATHOGEN THAT INFECTS ONE-QUARTER OF THE WORLD'S POPULATION. WHILE INTERACTION OF MTB BACILLI AND MACROPHAGES ACTIVATES NUMEROUS INNATE IMMUNE PATHWAYS, WE HAVE A LIMITED UNDERSTANDING OF HOW THESE COMPLEX NETWORKS OF HOST SENSING MOLECULES ARE REGULATED TO WORK COOPERATIVELY. FURTHERMORE, ONLY A SMALL SUBSET OF THE MANY SECRETED EFFECTORS USED BY M. TUBERCULOSIS HAVE WELL-CHARACTERIZED FUNCTIONS. RECENT STUDIES HAVE ILLUMINATED THE BIOLOGICAL AND CELLULAR IMPORTANCE OF LIQUID-LIQUID PHASE SEPARATION, A PROCESS BY WHICH PROTEINS CONDENSE INTO DISCRETE DROPLETS TO ALTER THEIR LOCALIZATION AND FUNCTION IN A CELL. SEVERAL PROTEINS INVOLVED IN THE HOST RESPONSE TO M. TUBERCULOSIS INFECTION, LIKE CGAS, TBK1, P62, AND LC3, HAVE BEEN FOUND TO PHASE SEPARATE IN VITRO, BUT HOW IN VIVO PHASE SEPARATION IMPACTS HOST RESPONSES TO INFECTION IS UNKNOWN. PRELIMINARY STUDIES HAVE FOUND THAT THESE AND OTHER INNATE IMMUNE PROTEINS FORM CIRCULAR PUNCTA IN M. TUBERCULOSIS-INFECTED CELLS THAT RESEMBLE PHASE SEPARATED DROPLETS. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT UPON INFECTION, PATHOGEN- SENSING AND POST-TRANSLATIONAL MODIFICATIONS INDUCE PHASE SEPARATION OF HOST PROTEINS AND THAT MTB MODULATES THESE CONDENSATION EVENTS WITH ITS OWN PHASE-SEPARATING PE/PPE PROTEINS. HERE, A COMBINATION OF NOVEL OPTOGENETICS TOOLS, LIVE CELL FLUORESCENT IMAGING, AND HOST AND BACTERIAL GENETICS WILL BE EMPLOYED TO PROBE THE BIOLOGICAL CONSEQUENCES OF PHASE SEPARATION OF HOST PROTEINS (AIM 1) AND MTB PROTEINS (AIM 2). IN ADDITION, DIRECTED AND UNBIASED GENETICS APPROACHES WILL BE USED TO PROBE HOW POST-TRANSLATIONAL MODIFICATIONS, AND ESPECIALLY UBIQUITINATION IN PARTICULAR, CONTRIBUTES TO PHASE SEPARATION DURING MTB INFECTION (AIM 3). THIS APPROACH IS INNOVATIVE IN THAT IT USES NOVEL TOOLS TO SPECIFICALLY AND PRECISELY MODULATE PHASE SEPARATION IN ORDER TO LINK THIS BIOPHYSICAL PROCESS WITH MEANINGFUL CELLULAR PHENOTYPES. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL GREATLY EXPAND OUR UNDERSTANDING OF HOW MACROPHAGES DESTROY MTB AND ADVANCE EFFORTS TO COMBAT MTB INFECTION VIA ENHANCING HOST RESPONSES.

ROLE OF DORSAL ROOT GANGLION FTO, A RNA DEMETHYLASE, IN NEUROPATHIC PAIN

TRANSCRIPTIONAL MECHANISMS IN CARDIAC HYPERTROPHY

BRAIN-REGION-SPECIFIC HUMANIZED CORTICAL INTERNEURON MICE - ABSTRACT GABAERGIC CORTICAL INTERNEURONS (CINS) PLAY CRITICAL ROLES IN BALANCING, SYNCHRONIZING, AND GATING BRAIN ACTIVITY BY INHIBITING OTHER NEURONS. THEIR MALFUNCTION, ESPECIALLY THOSE OF MEDIAL GANGLIONIC EMINENCE (MGE)-DERIVED CINS, HAS BEEN ASSOCIATED WITH VARIOUS NEURODEVELOPMENTAL BRAIN DISORDERS, SUCH AS SCHIZOPHRENIA (SCZ) AND AUTISM SPECTRUM DISORDERS (ASD). CONSIDERING THE FACT THAT THE DIVERGENCE BETWEEN HUMAN BRAINS AND RODENT BRAINS HAS RESULTED IN THE FAILURE OF MANY CENTRAL NERVOUS SYSTEM (CNS) THERAPEUTICS VALIDATED IN RODENT MODELS, IT IS CRITICAL TO STUDY HUMAN NEURONS TO BETTER UNDERSTAND THE MECHANISMS OF THESE CIN-ASSOCIATED BRAIN DISORDERS. HUMAN FETAL BRAIN TISSUES ARE NOT ACCESSIBLE FOR MECHANISTIC STUDIES, BUT WE HAVE DEVELOPED A METHOD TO EFFICIENTLY GENERATE HOMOGENEOUS POPULATIONS OF MGE-TYPE HUMAN CINS FROM PLURIPOTENT STEM CELLS (PSCS) OF HEALTHY OR DISEASED SUBJECTS. WE HAVE EXTENSIVELY CHARACTERIZED THEM AND DEMONSTRATED THEIR AUTHENTICITY AND FUNCTIONALITY, MAKING IT POSSIBLE TO STUDY THE CONVERGING FUNCTIONAL CONSEQUENCES OF COMPLEX GENETICS IN REAL PATIENT NEURONS, WHICH CANNOT BE STUDIED IN MOUSE NEURONS DUE TO A LACK OF CONSERVATION OF NON-CODING REGIONS, WHERE MOST OF RISK LOCI ARE PRESENT. HOWEVER, IN VITRO CULTURED NEURONS LACK OTHER CRITICAL COMPONENTS OF THE BRAIN ENVIRONMENT, SUCH AS ASTROCYTES, OLIGODENDROCYTES, MICROGLIA AND BLOOD VESSELS, WHICH CAN SIGNIFICANTLY IMPACT THEIR FUNCTION. THERE HAVE BEEN EFFORTS TO OPTIMIZE IN VITRO CULTURE SYSTEMS TO BETTER RECAPITULATE IN VIVO PHYSIOLOGICAL ENVIRONMENTS BY ADDING OTHER BRAIN CELLULAR COMPONENTS, BUT THERE ARE STILL LIMITATIONS AS TO HOW CLOSELY THEY CAN SIMULATE IN VIVO SITUATIONS. TO RESOLVE THIS ISSUE, IN OUR PREVIOUS STUDY, WE PIONEERED HUMAN NEURON-MOUSE BRAIN CHIMERAS TO STUDY THE FUNCTION OF HUMAN SCZ NEURONS IN PHYSIOLOGICAL ENVIRONMENTS. ALTHOUGH WE WERE ABLE TO SUCCESSFULLY IDENTIFY SCZ CIN-INTRINSIC CONNECTIVITY DEFICITS IN MOUSE BRAINS, WE WERE NOT ABLE TO ANALYZE THE IMPACTS OF GRAFTED NEURONS ON BRAIN CIRCUITS AND BEHAVIORS DUE TO THE PRESENCE OF HEALTHY MOUSE NEURONS IN THE GRAFTED MICE. THUS, IN THIS PROPOSED STUDY, WE WILL PERFORM BRAIN-REGION-SPECIFIC CIN-ABLATION IN NODSCID GAMMA (NSG) MICE, FOLLOWED BY THE REPLACEMENT OF ABLATED HOST CINS WITH HUMAN CINS TO GENERATE REGION-SPECIFIC HUMANIZED CIN CHIMERAS. BASED ON PREVIOUS STUDIES, INCLUDING OURS, THAT SHOW SUCCESSFUL RESTORATION OF COMPROMISED MOUSE INHIBITION BY GRAFTED HUMAN CINS, THESE MICE WILL ALLOW US TO ANALYZE THE FUNCTIONAL IMPACTS OF GRAFTED HUMAN CINS ON THE BRAIN CIRCUITS AND BEHAVIORS IN PHYSIOLOGICAL IN VIVO ENVIRONMENTS. THIS NOVEL PHYSIOLOGICAL MODEL SYSTEM WILL HELP US TEASE APART CELL-TYPE- AND BRAIN-REGION-SPECIFIC DISEASE MECHANISMS FOR COMPLEX BRAIN DISORDERS, AND AID IN DEVELOPING NOVEL THERAPEUTICS.

AMBIENT AIR POLLUTION, WEATHER, AND PLACENTAL ABRUPTION (APWA) - ABSTRACT PLACENTAL ABRUPTION RESULTS IN HEMORRHAGE, ISCHEMIA, AND FETAL HYPOXIA, PLACING A TREMENDOUS HEALTH BURDEN ON BOTH THE MOTHER AND THE NEWBORN. EFFORTS TO UNDERSTAND THE ETIOLOGY OF THIS DEVASTATING OBSTETRICAL COMPLICATION HAVE BEEN DISAP- POINTING. THIS PROJECT WILL DELINEATE ENVIRONMENTALLY-ASSOCIATED PATHWAYS TO ABRUPTION AND DETERMINE THE IMPACT OF POL- LUTANT TRIGGERS THAT ARE IMPLICATED IN ACUTE VERSUS CHRONIC PLACENTAL ABRUPTION. GIVEN THAT ONE-FOURTH OF ALL ABRUPTION CASES HAVE AN ACUTE ETIOLOGY AND 15% OF ABRUPTIONS MAY RECUR IN FUTURE PREGNANCIES, THE ROLE OF ENVIRONMENTAL TRIGGERS IS A CRITICALLY IMPORTANT, YET UNEXPLORED, OPPORTUNITY TO UNDERSTAND THE PATHOPHYSIOLOGY OF THIS ENIGMATIC OBSTETRICAL COMPLI- CATION. THE PROJECT WILL CAPITALIZE ON HIGH RESOLUTION EXPOSURE AND HEALTH OUTCOME DATA AS IT AIMS TO DEVELOP A BIRTH LINKAGE DATABASE THAT WILL INCLUDE HOSPITAL DISCHARGES LINKED TO BOTH STILLBIRTHS AND LIVE BIRTHS-INFANT DEATHS TO RESIDENT WOMEN IN CALIFORNIA, FLORIDA, MASSACHUSETTS, MICHIGAN, AND SOUTH CAROLINA (ESTIMATED 16 MILLION BIRTHS, INCLUDING 155,000 ABRUPTION CASES) BETWEEN 2000–2016. FOR EACH PREGNANCY WE WILL ASSIGN AVERAGE DAILY AMBIENT EXPOSURE TO FINE PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER =2.5 ΜM (PM2.5), ITS CONSTITUENTS (ELEMENTAL CARBON AND ORGANIC CARBON, SULFATE, NITRATE, AND AMMONIUM), AS WELL AS GASEOUS POLLUTANTS (NITROGEN DIOXIDE AND OZONE), USING SPATIOTEMPORALLY RESOLVED MODELS THAT PREDICT EXPOSURE FOR EACH RESIDENTIAL LOCATION. WE WILL ALSO ASSIGN EVERY RESIDENCE WITH AVERAGE DAILY TEMPERATURE, HUMID- ITY, DEW POINT, HEAT WAVES, AND ATMOSPHERIC AIR PRESSURE. THE PROJECT WILL FOCUS ON DISENTANGLING THE RELATIVE CONTRIBUTIONS OF AMBIENT AIR POLLUTION AND WEATHER-RELATED CONDITIONS ON ACUTE ABRUPTION THROUGH A BI-DIRECTIONAL, TIME-STRATIFIED CASE- CROSSOVER DESIGN, AND THOSE OF ABRUPTIONS WITH CHRONIC UNDERPINNINGS USING A COHORT DESIGN. WE WILL APPLY DISTRIBUTED LAG LINEAR AND NON-LINEAR MODELS TO IDENTIFY CRITICAL WINDOWS OF EXPOSURE, BAYESIAN KERNEL MACHINE REGRESSION TO CHARACTERIZE ASSOCIATIONS BASED ON MULTI-POLLUTANT EXPOSURES, AND CAUSAL INTERACTION-MEDIATION DECOMPOSITION ANALYSES THROUGH ISCHEMIC PLACENTAL DISEASE (PREECLAMPSIA, FETAL GROWTH DISTURBANCES). WE WILL CONSIDER INDIVIDUAL– AND NEIGHBORHOOD–LEVEL CON- FOUNDERS DERIVED FROM RESIDENTIAL CENSUS TRACTS. ALL ASSOCIATIONS WILL BE CORRECTED FOR SIMULTANEOUS EXPOSURE AND OUTCOME MISCLASSIFICATION, AS WELL AS FOR EXPOSURE MEASUREMENT ERROR OWING TO MATERNAL RESIDENTIAL MOBILITY THROUGH A REGRESSION CALIBRATION APPROACH. THE UBIQUITOUS NATURE OF AIR POLLUTION AND WEATHER EXPOSURES AND THEIR POTENTIAL IMPACT ON ADVERSE PERINATAL OUTCOMES, AS WELL AS THE PRELIMINARY DATA SUPPORTING THE ASSOCIATIONS, PRESENTS UNPRECEDENTED OPPORTUNITIES TO ADDRESS IMPLICATIONS OF THE ADVERSE IMPACT OF AIR POLLUTION AND WEATHER-RELATED EXPOSURES ON PLACENTAL ABRUPTION AND RELATED OBSTETRICAL COMPLICATIONS. THIS PROJECT ALIGNS WITH 2 MAJOR CRITICAL AREAS OF RESEARCH–CO-EXPOSURES, AND DATA SCI- ENCE AND BIG DATA–OUTLINED IN THE 2018-2023 STRATEGIC GOALS OF NIH-NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES.

THE ROLE OF TRIM6 AND UBIQUITIN IN INFLUENZA VIRUS-INDUCED PATHOLOGY - ABSTRACT. INFLUENZA A VIRUS (IAV) CAUSES ANNUAL EPIDEMICS AND DANGEROUS PANDEMICS INVOLVING MILLIONS OF CASES OF ILLNESS AND DEATHS WORLDWIDE. THE MAIN CAUSE OF PATHOLOGY FROM IAV IS EXCESSIVE INFLAMMATION, THEREFORE, THE OVERARCHING GOAL OF THIS PROPOSAL IS TO LEARN HOW MECHANISMS OF INFLAMMATION CAN BE MANIPULATED TO PROMOTE DISEASE TOLERANCE TO VIRUS INFECTION. CYTOKINE PRODUCTION, A CHIEF CONTRIBUTOR OF INFLAMMATION, IS REGULATED AT THE POST-TRANSLATIONAL LEVEL TO BALANCE BETWEEN EFFICIENT ANTIVIRAL RESPONSES AND DAMAGING INFLAMMATION. A MAJOR MOLECULAR REGULATORY MECHANISM INVOLVES UBIQUITINATION OF SIGNALING COMPONENTS. THE SPECIFIC GOAL OF THIS PROPOSAL IS TO IDENTIFY MECHANISMS OF REGULATION OF INFLAMMATION BY THE UBIQUITIN (UB) SYSTEM DURING IAV INFECTION IN VIVO. WE RECENTLY REPORTED THAT THE E3-UB LIGASE, TRIM6, CATALYZES THE SYNTHESIS OF UNANCHORED POLY-UB CHAINS, WHICH PROMOTE ANTIVIRAL IFN-I RESPONSES. HOWEVER, THE ROLE OF TRIM6 IN REGULATING OTHER INFLAMMATORY CYTOKINES IS NOT KNOWN. WE GENERATED TRIM6 KNOCKOUT MICE (TRIM6-/-), WHICH PROVIDES A UNIQUE TOOL TO IDENTIFY NOVEL IMMUNE PATHWAYS REGULATED BY TRIM6 AND UNANCHORED UB IN VIVO. OUR PRELIMINARY DATA SHOW THAT TRIM6-/- MICE HAVE FEWER SIGNS OF PATHOLOGY EVEN THOUGH THERE ARE INCREASED IAV TITERS AT EARLY TIME POINTS POST-INFECTION. WE ALSO FOUND REDUCED EXPRESSION LEVELS OF CXCL1, A WELL-KNOWN NEUTROPHIL CHEMO-ATTRACTANT, WHICH CORRELATED WITH REDUCED NEUTROPHIL INFILTRATION TO THE LUNGS OF IAV-INFECTED TRIM6-/- MICE. WE FOUND THAT TRIM6 AND UNANCHORED UB FORM A COMPLEX WITH PI3K/AKT SIGNALING COMPONENTS, AND THEIR PHOSPHORYLATION IS IMPAIRED IN TRIM6-/- CELLS. OUR DATA ALSO SUGGEST THAT TNFA PRODUCED BY INFECTED CELLS INDUCES PATHOGENIC CXCL1 IN BYSTANDER CELLS TO RECRUIT NEUTROPHILS. NEUTROPHILS ARE KNOWN TO BE RECRUITED TO THE LUNG DURING IAV INFECTION AND CAN PLAY BOTH PROTECTIVE AND DETRIMENTAL ROLES. HOWEVER, WHAT FACTORS DRIVE NEUTROPHILS TO CAUSE TISSUE DAMAGE DURING INFECTION ARE NOT WELL-UNDERSTOOD. THEREFORE, THERE IS A GAP IN KNOWLEDGE ON THE MECHANISMS OF REGULATION OF NEUTROPHIL RECRUITMENT AND THEIR ROLES IN THE BALANCE BETWEEN PROTECTIVE RESPONSES AND PATHOGENIC INFLAMMATION. OUR HYPOTHESIS IS THAT TRIM6 IS ACTIVATED BY TNFA SIGNALING AND PROMOTES EARLY CXCL1-MEDIATED PATHOGENIC INFLAMMATION, THEREBY INHIBITING DISEASE TOLERANCE. IN AIM 1, WE WILL DETERMINE THE CELLULAR SOURCE OF TRIM6-INDUCED CXCL1, AND ITS ROLE IN NEUTROPHIL RECRUITMENT TO THE LUNGS, DURING IAV INFECTION. WE WILL DEMONSTRATE THE ROLE OF EARLY CXCL1 PRODUCTION IN PATHOLOGY AND WHETHER TNFA IS INVOLVED IN INDUCING TRIM6-MEDIATED CXCL1. IN AIM 2, WE WILL DETERMINE THE MECHANISM BY WHICH TRIM6 AND UB MODULATE THE ACTIVATION OF PI3K-AKT FOR DOWNSTREAM SIGNALING AND HOW TRIM6 IS ACTIVATED DURING INFECTION. THE OUTCOMES INCLUDE THE IDENTIFICATION OF THE CELLULAR SOURCE OF PATHOGENIC CXCL1, AND THE MECHANISM BY WHICH TRIM6 IS ACTIVATED FOR SIGNALING. THIS INFORMATION WILL GUIDE THE DEVELOPMENT OF THERAPEUTIC APPROACHES BY TARGETING TRIM6 AND CXCL1-PRODUCING CELLS TO REDUCE INFLAMMATORY DISEASES.

COHORT AND BIOMARKERS FOR COVID-19 SEVERITY, NATURAL HISTORY, AND REINFECTION - SUMMARY AS THE COVID-19 PANDEMIC CONTINUES, THERE IS AN URGENT NEED TO BETTER UNDERSTAND THE ILLNESS AND HOST RESPONSES. IN SPRING 2020, WE ESTABLISHED TWO COHORTS OF U.S. HEALTHCARE WORKERS (HCW), A PARTICULARLY HARD- HIT FRONTLINE COMMUNITY, TO UNDERSTAND THE CHARACTERISTICS OF THE ILLNESS AND TO IDENTIFY PREDICTORS OF POOR OUTCOMES, AS WELL AS OF LONG-TERM SEQUELAE. WITH THE CURRENT STUDY PHASE ENDING, EXTENDING FOLLOW-UP ACTIVITIES IN THESE WELL-CHARACTERIZED COHORTS IS CRITICAL TO MONITOR THE EVOLUTION OF THE INFECTION AND ITS SEQUELAE IN A RAPIDLY EVOLVING SITUATION, WHICH NOW INCLUDES VACCINATION AND EMERGENCE OF VIRUS VARIANTS. IN THIS TIME- SENSITIVE PROPOSAL, WE EXTEND THE FOLLOW-UP PERIOD FOR AN ADDITIONAL 3 YEARS, ALLOWING US TO ANSWER IMPORTANT EPIDEMIOLOGICAL AND MECHANISTIC QUESTIONS ABOUT INFECTION, SYMPTOMS, LONG-TERM OUTCOMES, AND PROTECTIVE IMMUNITY. IN AIM 1, WE WILL DEFINE BIOMARKERS OF SARS- COV-2 SYMPTOM ONSET AND SEVERITY, CAPITALIZING ON SERIAL BIOSPECIMENS COLLECTED FROM COHORT SUBJECTS PRIOR TO AND DURING EARLY STAGES OF INFECTION. WE WILL TEST THE HYPOTHESIS THAT SYMPTOM ONSET AND SEVERITY CORRESPOND TO BASELINE DIFFERENCES IN PRE-EXISTING FACTORS, INCLUDING ORAL VIROME CHARACTERISTICS AND PERIPHERAL BLOOD TRANSCRIPTOME. WE ALSO WILL TEST WHETHER, AMONG SARS-COV-2+ INDIVIDUALS, PROGRESSION OF ILLNESS SEVERITY CAN BE PREDICTED BY ANALYSIS OF EARLY BIOMARKERS AT THE TIME OF DIAGNOSIS, INCLUDING INFLAMMATORY BIOMARKERS, IMMUNE CELL POPULATIONS, AND ORGAN-SPECIFIC BIOMARKERS OF DYSFUNCTION, SUCH AS CARDIAC ENZYMES AND COAGULATION FACTORS. IN AIM 2, WE WILL EXAMINE LONG- TERM SEQUELAE OF ASYMPTOMATIC AND SYMPTOMATIC COVID-19 INFECTIONS. WE WILL ASSESS EVIDENCE OF SUSTAINED PHYSIOLOGICAL DYSREGULATION UP TO 3 YEARS FOLLOWING SARS-COV-2 INFECTIONS OF VARYING SEVERITY (INCLUDING ASYMPTOMATIC), FOCUSING ON LONGITUDINAL BIOMARKERS AND PULMONARY FUNCTION. WE WILL EXAMINE WHETHER SOME INFECTED INDIVIDUALS HAVE PERSISTENT ABNORMALITIES IN IMMUNOLOGIC, VIROLOGIC, AND END-ORGAN BIOMARKERS AND PULMONARY FUNCTION, COMPARED TO PRE-INFECTION BIOMARKER AND UNINFECTED COMPARISON SUBJECTS. WE ALSO WILL ASSESS WHETHER PERSISTENT ABNORMALITIES IN BIOMARKERS ARE ASSOCIATED WITH PROLONGED CONVALESCENCE AND REDUCED PULMONARY FUNCTION. IN AIM 3, WE WILL IDENTIFY SERUM MARKERS PERSISTING AFTER ACUTE INFECTION THAT MAY CONFER PROTECTIVE IMMUNITY. USING SERA FROM SARS-COV-2+ INDIVIDUALS, WE WILL CHARACTERIZE THE SPECTRUM AND FUNCTIONS OF ANTI-SARS-COV-2 ANTIBODIES AND THEIR RELATION TO IMMUNE PROTECTION IN THE COHORT AS WELL AS IN AN INNOVATIVE EX VIVO LUNG SLICE MODEL. WE WILL SPECIFICALLY EXAMINE VARIATION IN MAGNITUDE, DURATION, FUNCTION, AND SPECTRUM OF ANTIBODY RESPONSES IN RELATION TO SEVERITY OF INITIAL CLINICAL INFECTION. WE WILL TEST THE HYPOTHESIS THAT ANTI-SARS-COV-2 ANTIBODY CONCENTRATIONS AND PROTECTIVE FUNCTIONS ARE ASSOCIATED WITH LOWER RATES OF SUBSEQUENT RE-INFECTION IN COHORT PARTICIPANTS, AS AFFECTED BY VACCINATION STATUS. THE BIOSPECIMENS (CURRENTLY >40,000) FROM THESE COHORTS WILL BE AVAILABLE FOR COLLABORATIVE STUDIES.

THE C'RILLOS PROJECT: IMPACT OF TOBACCO REGULATORY POLICY ON DYNAMIC USE OF EXCLUSIVE, DUAL OR POLY CIGAR AND OTHER TOBACCO PRODUCT USE AMONG YOUNG ADULTS - PROJECT SUMMARY AFRICAN-AMERICANS/BLACKS (AA/B) AND HISPANICS/LATINOS (H/L) ARE VASTLY UNDERREPRESENTED IN TOBACCO REGULATORY SCIENCES RESEARCH. YET AS THEIR SMOKING PERSISTS, THESE GROUPS BEAR THE MOST SIGNIFICANT BURDEN OF TOBACCO-RELATED HEALTH DISEASES, INCLUDING CANCER. THESE DISPARITIES ARE DUE, IN PART, TO THE USE OF FLAVORED TOBACCO PRODUCTS, LIKE LITTLE FILTERED CIGARS AND CIGARILLOS (LCCS), AND THE TOBACCO INDUSTRY’S AGGRESSIVE PROMOTION OF LCCS TO AA/B AND H/L COMMUNITIES. AN INTENDED CONSEQUENCE OF THE ANTICIPATED FLAVOR BAN IS THE SMOKING REDUCTION OF FLAVORED LCCS. HOWEVER, THE TOBACCO INDUSTRY’S REPACKAGING OF THEIR FLAVORED TOBACCO PRODUCTS AND THEIR RHETORIC ABOUT OVER-POLICING AND DISCRIMINATION AGAINST AA/B SMOKERS THREATENS TO DISRUPT THE HEALTH EQUITY IMPACTS OF THE IMPENDING FLAVOR BAN. CRITICAL GAPS IN THE SCIENTIFIC EVIDENCE EXIST ABOUT THE EFFECTS OF EXPOSURE AND RECEPTIVITY TO CIGAR PRODUCT REPACKAGING AND SOCIO-POLITICAL RHETORIC ON AA/B AND H/L YOUNG ADULTS’ (YA) SMOKING BEHAVIOR. OUR PROPOSED PROJECT SEEKS TO ADDRESS GAPS AND PROVIDE EVIDENCE TO THE FDA’S IMPACT, MARKETING, AND BEHAVIORAL DOMAINS BY ANSWERING: “DO CIGAR PRODUCT REPACKAGING AND RHETORIC ABOUT OVER-POLICING AND ILLICIT CIGAR TRADE INFLUENCE AA/B AND H/L YA’S FLAVOR BAN PERCEPTIONS AND PREDICT FUTURE LCC SMOKING BEHAVIORS AMONG NON-USERS AND CURRENT USERS?

COOPERATIVE EXTENSION PROGRAM AT 1862 LAND-GRANT INSTITUTIONS - FY2013

HEALTH EQUITY IN EMERGENCY TRAUMA CARE: ANALYSIS OF DISPARITIES IN THE PRE-HOSPITAL EMERGENCY TRAUMA CARE SYSTEM - PROJECT SUMMARY/ABSTRACT TRAUMA IS THE LEADING CAUSE OF DEATH FOR CHILDREN AND ADULTS 46 YEARS AND YOUNGER, KILLING MORE AMERICANS THAN AIDS AND STROKE COMBINED. AFRICAN AMERICANS (OR 1.2, P<0.001), PEOPLE LIVING IN HIGH POVERTY NEIGHBORHOODS (OR 1.01, P<0.001), AND THOSE ENROLLED IN PUBLIC HEALTH INSURANCE PROGRAMS (OR 1.53, P<0.001) HAVE INCREASED MORTALITY AFTER TRAUMA WHEN COMPARED TO THEIR INJURED COUNTERPARTS. QUANTIFYING THE EQUITY IN ACCESS TO EMERGENCY MEDICAL SERVICES (EMS) AND DESIGNATED/VERIFIED TRAUMA CENTERS (TCS), AS WELL AS THE EXTENT TO WHICH TIMELY ACCESS TO CARE IMPROVES HEALTH OUTCOMES ARE CRITICAL FIRST STEPS TO ADDRESS THIS ALARMING DISCREPANCY. EQUITABLE AVAILABILITY TO EMS HAS YET TO BE EVALUATED AND EQUITABLE ACCESS TO TCS IS UNDERSTUDIED. IN FACT, NO ONE HAS EXPLORED THE IMPORTANCE OF EXPEDITIOUS AVAILABILITY TO EMERGENCY HEALTH CARE SERVICES SUCH AS EMS AND TIMELY ACCESS TO EMERGENT TRAUMA CARE AS KEY SOCIAL DETERMINANTS OF HEALTH (SDOH). MODELS TO EVALUATE THE ROLE OF SDOH AS MAJOR PREDICTORS OF THESE DISPARITIES REMAIN UNTESTED. RAPID TRANSPORT TO A TC IS ASSOCIATED WITH A 25% REDUCTION IN MORTALITY; HOWEVER, NEARLY 45 MILLION AMERICANS LACK TIMELY ACCESS TO A VERIFIED TC. WHEN COMPARED TO WHITE POPULATIONS, RECENT DATA SHOW RACIAL/ETHNIC MINORITY POPULATIONS HAVE SIGNIFICANTLY LESS ACCESS TO TC AND WORSE OUTCOMES FOLLOWING TRAUMA. UNDERSTANDING THE FACTORS THAT DETERMINE TRAUMA-RELATED SOCIO-SPATIAL DISPARITIES CAN INFORM INTERVENTIONS AT BOTH THE POLICY AND SYSTEM LEVELS TO MITIGATE THE DISPROPORTIONATELY LARGE NUMBERS OF DEATHS EXPERIENCED BY MINORITIZED POPULATIONS. THUS, THERE IS A COMPELLING NEED FOR RESEARCH IN THESE AREAS TO FACILITATE TARGETED INTERVENTIONS TO ELIMINATE SOCIO-SPATIAL DISPARITIES WITHIN THE PRE-HOSPITAL PHASE OF THE EMERGENCY TRAUMA CARE SYSTEM TO IMPROVE PATIENT OUTCOMES. TO EVALUATE SOCIO-SPATIAL DISPARITIES IN AVAILABILITY AND ACCESS TO BOTH EMS AND TO TCS AMONG CRITICALLY INJURED TRAUMA PATIENTS, WE WILL APPLY THE HEALTH EQUITY MEASURABLE FRAMEWORK (HEMF) TO THE PRE-HOSPITAL PHASE OF THE EMERGENCY TRAUMA CARE SYSTEM (AVAILABILITY TO EMS, EMS RESPONSE TIME, EMS SCENE TIME, EMS TRANSPORTATION TIME, EMS DECISION TO TRANSPORT TO TCS VS. NON-TCS, AND EMS TOTAL PREHOSPITAL TIME) AND USE LARGE NATIONAL DATABASES TO DEVELOP SPATIOTEMPORAL MODELS TO ASSESS DRIVERS OF DISPARITIES IN TRAUMATIC INJURIES. HEMF WILL BE PARTICULARLY WELL SUITED FOR OUR PROPOSED STUDY BECAUSE IT IS DESIGNED TO DESCRIBE SDOH IN A CAUSAL FRAMEWORK TO GUIDE THE QUANTITATIVE ANALYSIS OF HEALTH EQUITY FOR ONGOING PRE-HOSPITAL TRAUMA CARE SURVEILLANCE OF THE CRITICALLY INJURED AND SUBSEQUENT POLICY DEVELOPMENT. OUR INTERDISCIPLINARY TEAM WILL USE DATA SCIENCE METHODS AND NOVEL ANALYTICS TO ADDRESS THIS CRITICAL PUBLIC HEALTH NEED BY IDENTIFYING HEALTH DISPARITIES AT THE LEVEL OF THE PRE-HOSPITAL EMERGENCY TRAUMA CARE SYSTEM.

THE ROLE OF NEUROFIBROMIN 2 IN HEART FAILURE - PROJECT SUMMARY THE HEART IS A METABOLICALLY DEMANDING ORGAN, AND DERANGEMENTS IN METABOLIC PROCESSES LEAD TO ENERGETIC DEFICITS, GENERATION OF TOXIC METABOLITES, AND REDOX IMBALANCE, WHICH DRIVE PATHOGENESIS TO HEART FAILURE. HOWEVER, CURRENT THERAPIES FOR HEART FAILURE DO NOT ADDRESS THIS FUNDAMENTAL ISSUE, AND THERE REMAINS AN UNMET CLINICAL NEED FOR EFFECTIVE MECHANISM-BASED TREATMENTS. ALTERED TRANSCRIPTIONAL PROGRAMS ARE THOUGHT TO CONTRIBUTE SIGNIFICANTLY TO IMPAIRED MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION AND INSUFFICIENT ENERGY PRODUCTION IN HEART FAILURE. THE ESTROGEN-RELATED RECEPTORS (ERRA, B, AND G) ARE KEY REGULATORS OF MITOCHONDRIAL RESPIRATION THAT ARE DOWNREGULATED IN THE FAILING HEART, YET THE MOLECULAR MECHANISMS REGULATING THEIR EXPRESSION AND ACTIVITY REMAIN LARGELY UNKNOWN. IN PRELIMINARY STUDIES WE HAVE IDENTIFIED A NOVEL MOLECULAR PATHWAY THAT PROMOTES THE EXPRESSION OF ERRB, AND ERRG IN CARDIOMYOCYTES, AND DEFINE A NEW HEART FAILURE PATHWAY LINKING CHRONIC STRESS TO IMPAIRMENT OF MITOCHONDRIAL OXIDATIVE RESPIRATION. OUR UNEXPECTED RESULTS DEMONSTRATE THAT THE TUMOR SUPPRESSOR PROTEIN NEUROFIBROMIN 2 (NF2) PROMOTES PROPER METABOLIC FUNCTION, AND THAT CARDIAC DELETION OF NF2 PREDISPOSES THE HEART TO PATHOLOGICAL REMODELING AND FAILURE IN RESPONSE TO LV PRESSURE OVERLOAD STRESS. TRANSCRIPTOME PROFILING OF CARDIAC DEFICIENT NF2 CKO HEARTS INDICATED DOWNREGULATION OF METABOLIC PATHWAYS AND DECREASED EXPRESSION/ACTIVITY OF ERRB AND ERRG. USING A PROTEOMICS-BASED APPROACH, WE IDENTIFIED THE TRANSCRIPTION FACTOR ZSCAN21 AS AN INTERACTING PARTNER OF NF2 AND A NOVEL POSITIVE REGULATOR OF METABOLIC GENE EXPRESSION AND MITOCHONDRIAL OXIDATIVE RESPIRATION IN CARDIOMYOCYTES. THEREFORE, WE HYPOTHESIZE THAT ENDOGENOUS NF2 ENGAGES THE TRANSCRIPTION FACTOR ZSCAN21 TO POSITIVELY REGULATE EXPRESSION OF ERRB AND ERRG AND PROMOTE ENERGY PRODUCTION DURING PRESSURE OVERLOAD STRESS IN THE HEART. THE OBJECTIVES OF THE CURRENT APPLICATION ARE TO FURTHER DEFINE THE CLINICAL ROLE OF THIS PATHWAY, AND TO ELUCIDATE THE MOLECULAR MECHANISMS BY WHICH NF2 REGULATES EXPRESSION OF MYOCARDIAL ERRB AND ERRG AND PREVENTS ENERGY DEFICIT. THESE OBJECTIVES WILL BE ACCOMPLISHED IN 3 AIMS. IN AIM1, WE WILL ESTABLISH EVIDENCE OF NF2 AS AN IMPORTANT AND NOVEL MEDIATOR OF CARDIAC METABOLIC COUPLING AND ENERGY PRODUCTION DURING THE INITIAL AND LATE PHASES OF PRESSURE OVERLOAD STRESS. IN AIM2, WE WILL INVESTIGATE IN DETAIL THE MOLECULAR INTERACTION BETWEEN NF2 AND ZSCAN21 AND DETERMINE THE ABILITY OF ZSCAN21 TO REGULATE EXPRESSION OF ERRB AND ERRG, MITOCHONDRIAL OXIDATIVE RESPIRATION, AND ENERGY PRODUCTION IN CARDIOMYOCYTES. IN AIM3, WE WILL DETERMINE THE THERAPEUTIC POTENTIAL OF NORMALIZING CARDIAC NF2 FOR TREATMENT IN THE PRESSURE OVERLOAD MODEL OF HFREF. THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO DEFINE MECHANISTIC EVENTS THAT MEDIATE MITOCHONDRIAL METABOLIC DYSFUNCTION IN HEART FAILURE AND IDENTIFY POTENTIAL CANDIDATES FOR NEW THERAPEUTIC STRATEGIES TARGETING EARLY STAGES OF HEART FAILURE.

IDENTIFICATION OF A NOVEL DRG-SPECIFIC LONG NONCODING RNA AND ITS ROLE IN NEUROPATHIC PAIN - PROJECT ABSTRACT LONG NONCODING RNAS (LNCRNAS) REGULATE GENE EXPRESSION. PERIPHERAL NERVE INJURY DYSREGULATED THEIR EXPRESSION IN THE PAIN-RELATED REGIONS INCLUDING DORSAL ROOT GANGLION (DRG). HOWEVER, THE ROLE OF MOST IDENTIFIED LNCRNAS IN NEUROPATHIC PAIN IS STILL UNCERTAIN. IDENTIFYING NOVEL LNCRNAS AND EXPLORING THEIR CONTRIBUTION TO NEUROPATHIC PAIN MAY PROVIDE NOVEL STRATEGIES FOR MANAGEMENT OF THIS DISORDER. WE RECENTLY USED A NEXT GENERATION RNA SEQUENCING APPROACH AND IDENTIFIED A LARGE, NATIVE, FULL-LENGTH NON-CODING RNA IN MICE AND HUMAN. BECAUSE IT IS EXPRESSED HIGHLY IN THE DRG, WE NAMED IT AS DRG SPECIFIC LONG NONCODING RNA (DS-LNCRNA). OUR PRELIMINARY DATA REVEALED THAT PERIPHERAL NERVE INJURY DOWNREGULATED DS-LNCRNA LIKELY DUE TO A DECREASE IN THE EXPRESSION OF A TRANSCRIPTIONAL ACTIVATOR POU4F3 IN THE INJURED DRG. RESCUING THIS DOWNREGULATION ATTENUATED THE NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY, LIKELY THROUGH BLOCKADE OF THE INCREASED INTERACTION BETWEEN RALY (A TRANSCRIPTION CO-FACTOR) AND THE RNA POLYMERASE II (RNA II) AND CONSEQUENT SILENCE OF THE RALY/RNA II-TRIGGERED EXPRESSION OF EHMT2 MRNA AND ITS CODING PROTEIN G9A (A KEY PLAYER IN NEUROPATHIC PAIN) IN THE INJURED DRG. GIVEN THAT DS-LNCRNA CAN DIRECTLY BIND TO RALY, OUR PRELIMINARY RESULTS INDICATE THAT DRG DS-LNCRNA DOWNREGULATION IS REQUIRED FOR NEUROPATHIC PAIN LIKELY THROUGH NEGATIVE REGULATION OF DRG RALY/RNA II-TRIGGERED G9A EXPRESSION. THIS PROPOSAL WILL FURTHER EXAMINE WHETHER AND HOW DS-LNCRNA CONTRIBUTES TO NEUROPATHIC PAIN. IN SPECIFIC AIM 1, WE WILL FIRST INVESTIGATE WHETHER RESCUING DOWNREGULATION OF DS-LNCRNA IN THE INJURED DRG ATTENUATES NEUROPATHIC PAIN DEVELOPMENT AND MAINTENANCE. WE WILL THEN EXAMINE WHETHER MIMICKING NERVE INJURY-INDUCED DOWNREGULATION OF DRG DS-LNCRNA LEADS TO NEUROPATHIC PAIN SYMPTOMS IN THE ABSENCE OF NERVE INJURY. IN SPECIFIC AIM 2, WE WILL EXAMINE WHETHER PERIPHERAL NERVE INJURY RESULTS IN TIME-DEPENDENT DOWNREGULATION OF DS-LNCRNA AND ITS TRANSCRIPTION FACTOR POU4F3 IN THE DRG. WE WILL ALSO EXAMINE WHETHER DS-LNCRNA DOWNREGULATION IS ATTRIBUTED TO A DECREASE OF POU4F3 EXPRESSION IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. IN SPECIFIC AIM 3, WE WILL TEST THE EFFECT OF DS-LNCRNA ON THE EXPRESSION OF EHMT2 MRNA, G9A AND THEIR DOWNSTREAM PAIN-RELATED GENES IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. WE WILL ALSO DETERMINE WHETHER DS-LNCRNA DOWNREGULATION ENHANCES THE BINDING OF RALY TO RNA II LEADING TO RALY/RNA II-TRIGGERED EHMT2/G9A INCREASE AND G9A-CONTROLLED PAIN-RELATED GENE DECREASE IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. OUR STUDY WILL LIKELY IDENTIFY A PREVIOUSLY UNKNOWN REGULATORY MECHANISM FOR NEUROPATHIC PAIN. GIVEN THAT VIRUS- MEDIATED GENE THERAPY HAS BEEN USED IN CLINICAL TRIAL, THE PRESENT STUDY WILL HAVE A POTENTIAL CLINICAL APPLICATION IN NEUROPATHIC PAIN MANAGEMENT.

SYNAPTIC AND CIRCUIT MECHANISMS OF CENTRAL GLP-1 SIGNALING IN ENERGY BALANCE - PROJECT SUMMARY/ABSTRACT CENTRAL NERVOUS SYSTEM (CNS) CONTROL OF METABOLISM PLAYS A PIVOTAL ROLE IN MAINTAINING ENERGY HOMEOSTASIS. GLUCAGON-LIKE PEPTIDE 1 (GLP-1, ENCODED BY GCG), SECRETED BY A DISTINCT POPULATION OF NEURONS LOCATED WITHIN THE NUCLEUS TRACTUS SOLITARIUS, SUPPRESSES FEEDING. CENTRAL AND PERIPHERAL GLP-1 WORK INDEPENDENTLY TO SUPPRESS FEEDING . HOWEVER, THE CELLULAR AND CIRCUIT MECHANISMS MEDIATING ENDOGENOUS GLP-1 ACTION IN THE CNS ARE STILL POORLY UNDERSTOOD. THIS IS MAINLY DUE TO THE PRESENCE OF DIVERSE NEURONAL SUBTYPES, COMPLEX CENTRAL NEURONAL CONNECTIVITY, AND THE LACK OF MOLECULAR TOOLS THAT CAN DIRECTLY DETECT GLP-1 RELEASE IN THE BRAIN. ADDRESSING THE CNS MECHANISM OF GLP-1 WILL HELP DEVELOP MORE TAILORED TREATMENT FOR INTERVENTION OF OBESITY. OUR OVERARCHING GOAL IS TO GAIN A MECHANISTIC UNDERSTANDING OF ENDOGENOUS GLP-1 RELEASE AND ITS FUNCTIONS IN THE CNS IN A CELL TYPE- AND CIRCUIT-DEFINED MANNER. IN A PREVIOUS STUDY, WE FOUND THAT NTS GLP-1 PROJECTION TO THE PARAVENTRICULAR HYPOTHALAMIC NUCLEUS (PVN) ENHANCES GLUTAMATERGIC SYNAPTIC TRANSMISSION, WHICH IS SUFFICIENT TO SUPPRESS FOOD INTAKE, AND ABLATION OF PVN GLP-1R CAUSES OVEREATING AND OBESITY. THESE RESULTS HIGHLIGHT THE POTENTIAL ROLE OF CENTRAL GLP-1 IN REGULATING ENERGY HOMEOSTASIS. HOWEVER, GLP-1 SIGNALING IS COMPLEX DUE TO THE HETEROGENEITY OF PVN REGION GLP-1R NEURONS WHICH FORM SYNAPSES WITH THE DORSAL MOTOR NUCLEUS OF THE VAGUS NERVE (DMV) NEURONS AND RELEASE GLUTAMATE, WHILE ALSO RELEASING G-AMINOBUTYRIC-ACID IN THE BED NUCLEUS OF STRIA TERMINALIS (BNST). DMV AND BNST MAY MEDIATE FOOD INTAKE BEHAVIOR DIFFERENTIALLY, I.E. HOMEOSTATIC VS. HEDONIC FEEDINGS, BUT THE ROLES THAT THE PVN GLP-1R NEURONS-TO-DMV AND BNST PROJECTIONS PLAY REMAINS UNEXPLORED. MOREOVER, USING OUR RECENTLY DEVELOPED OPTICAL SENSORS FOR GLP-1, TERMED REPORTER FOR TRANSMISSION MEDIATED BY G PROTEIN-COUPLED RECEPTOR, WE FOUND THE TIMING OF GLP-1 RELEASE INTO THE PVN IS INVERSELY RELATED TO EATING BOUTS. WE THUS HYPOTHESIZE THAT CIRCUIT AND NEURONAL SUBTYPE-DEPENDENT ENDOGENOUS GLP-1 SIGNALING IN THE PVN REGULATES EATING PATTERNS (E.G. MEAL TIMING AND SIZES), ENERGY EXPENDITURE, AND FOOD REWARDS. TO TEST THIS HYPOTHESIS, WE WILL DETERMINE THE TEMPORAL DYNAMICS OF GLP-1 RELEASE AND NEURONAL ACTIVITY IN THE PVN DURING FEEDING EPISODES; AND WE WILL TEST THE HYPOTHESIS THAT GLP-1 SIGNALING REGULATES HOMEOSTATIC AND MOTIVATIONAL FEEDING VIA DIFFERENT NEURONAL PATHWAYS. THE RESULTS OF THIS STUDY WILL ADVANCE OUR CONCEPTUAL UNDERSTANDING OF THE REGULATORY EFFECTS OF ENDOGENOUS GLP-1, FACILITATING THE DEVELOPMENT OF NEUROPEPTIDE-TARGETING CLINICAL INTERVENTIONS FOR EATING DISORDERS AND OBESITY.

TARGETING A PHOSPHATIDYLSERINE/TAM RECEPTOR/PD-L1 AXIS AS A VULNERABILITY IN CANCER - PROJECT SUMMARY: TYRO3, AXL, AND MERTK (ABBREVIATED TAM RECEPTORS) ARE A FAMILY OF HOMOLOGOUS TYPE I RECEPTOR TYROSINE KINASES (RTKS) THAT HAVE HOMEOSTATIC FUNCTIONS UNDER PHYSIOLOGICAL CONDITIONS TO DAMPEN INFLAMMATION AND MAINTAIN TISSUE TOLERANCE IN MULTI-CELLULAR ORGANISMS. THE LIGANDS FOR TAMS ARE TWO VITAMIN K- MODIFIED PROTEINS, GROWTH ARREST SPECIFIC FACTOR 6 (GAS6) AND PROTEIN S (PROS1) THAT BIND PHOSPHATIDYLSERINE (PS) ON APOPTOTIC CELLS, AND IN DOING SO, ACT AS BRIDGING MOLECULES TO FACILITATE THE CLEARANCE OF APOPTOTIC CELLS (EFFEROCYTOSIS). WHILE PS-MEDIATED EFFEROCYTOSIS, MOST EMBLEMATICALLY VIA MERTK EXPRESSED ON MACROPHAGES, HAVE IMPORTANT HOMEOSTATIC FUNCTIONS TO PREVENT CHRONIC INFLAMMATION AND AUTOIMMUNITY, THE CONSTITUTIVELY EXTERNALIZED PS THAT OCCURS IN THE TUMOR MICROENVIRONMENT (TME) OF SOLID CANCERS, IN COMBINATION WITH THE EXPRESSION OF MERTK ON INFILTRATING MACROPHAGES, PATHO-PHYSIOLOGICALLY SUBVERT PS- MEDIATED TOLEROGENIC FUNCTIONS TO SUPPRESS HOST ANTI- TUMOR IMMUNE RESPONSES. THE CENTRAL HYPOTHESIS IN THIS APPLICATION IS THAT CONSTITUTIVELY DYS- REGULATED PS EXTERNALIZATION OBSERVED IN THE TME, IN COMBINATION WITH THE INFILTRATION OF MERTK-EXPRESSING MACROPHAGES, ACT AS AN IMPORTANT IMMUNE INHIBITORY AXIS TO SUPPRESS HOST ANTI- TUMOR IMMUNITY. THIS AXIS IS LIKELY TO BE ACTIVATED IN A WIDE RANGE OF SOLID CANCERS FOR IMMUNE ESCAPE, BUT ALSO MAY REPRESENT VULNERABILITY IN CANCER IF EFFECTIVELY TARGETED BY THERAPEUTICS. IN THIS APPLICATION, WE OUTLINE MECHANISTIC EXPERIMENTS TO IDENTIFY HOW EXTERNALIZED PS IS DYSREGULATED IN THE TME (AIM #1) AS WELL AS DETERMINE THE MECHANISMS BY WHICH MERTK ACTS AS AN INHIBITORY RECEPTOR ON MACROPHAGES TO SUPPRESS HOST ANTI-TUMOR IMMUNITY AND TOLERANCE (AIM #2). IN AIM #3, WE PROPOSE A SERIES OF PRE-CLINICAL THERAPEUTIC MOUSE STUDIES TO TEST COMBINATIONS OF A FIRST- IN-CLASS ANTI-MERTK NEUTRALIZING MAB IN COMBINATION WITH ANTI-PD1 MAB, AS WELL AS EXPLORE AND VALIDATE THE BIOLOGY OF MERTK AS AN INHIBITORY RECEPTOR USING HUMAN MODELS. COLLECTIVELY, OUR STUDIES AIM TO OPEN UP NEW AVENUES TO INTERROGATE A NOVEL TYPE OF CHECKPOINT INHIBITORY NETWORK IN IMMUNO-ONCOLOGY.

FERROPTOSIS IN THE HEART: IRON CALCIUM CROSSTALK AND COMPARTMENTALIZATION - SUMMARY APPROXIMATELY ONE PERSON DIES FROM HEART DISEASE EVERY 30 SECONDS IN THE UNITED STATES. ABOUT 1.5 MILLION AMERICANS DIE FROM MYOCARDIAL INFARCTION EACH YEAR. CLINICALLY, GENETIC DISORDERS (E.G. HEREDITARY HEMOCHROMATOSIS) AND REPEATED BLOOD TRANSFUSIONS (AS REQUIRED FOR SICKLE CELL ANEMIA AND BETA THALASSEMIA) ARE KNOWN TO CAUSE FE ACCUMULATION IN THE HEART WITH IRON OVERLOAD CARDIOMYOPATHY BEING A MAJOR CAUSE OF DEATH. IT HAS BEEN RECENTLY REPORTED THAT DILATED CARDIOMYOPATHY OCCURS IN UP TO 95% OF PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY AND THAT IRON LEVELS ARE ELEVATED IN MOUSE MODELS. FURTHERMORE, IRON LEVELS ARE KNOWN TO BE ELEVATED IN THE HEART AFTER ISCHEMIA FOLLOWED BY REPERFUSION. NEVERTHELESS, THE UNDERLYING MECHANISM(S) INVOLVED IN FE ASSOCIATED CARDIOTOXICITY REMAIN UNCLEAR. CALCIUM AND IRON ARE BOTH KNOWN TO PLAY VITAL CELLULAR ROLES IN THE HEART. CELLS EXHIBIT A REMARKABLE DEPENDENCE ON KEEN REGULATION OF CALCIUM AND IRON CONCENTRATIONS. CELLULAR DYSREGULATION OF EITHER ION CAN RESULT IN SYSTOLIC AND DIASTOLIC DYSFUNCTION AND ULTIMATELY CARDIOMYOPATHY. LOSS OR DISRUPTION OF NORMAL HOMEOSTASIS OF CELLULAR CALCIUM AND/OR CELLULAR IRON CONCENTRATIONS CAN NOT ONLY CAUSE DIRECT MYOCARDIAL CARDIOTOXICITY, BUT CAN ALSO RESULT IN LOSS OF MYOCARDIAL EXCITABILITY AND ABNORMAL EXCITATION CONTRACTION COUPLING. WE PROPOSE THAT A CROSS TALK BETWEEN CALCIUM AND IRON COMBINED RESULTS IN A HIGHLY CARDIOTOXIC CELLULAR ENVIRONMENT. WE POSIT THAT THE PRESENCE OF IRON CAN RESULT IN CELL DEATH VIA AN UNDERAPPRECIATED PATHWAY, I.E. FERROPTOSIS IN THE HEART RESULTING IN CARDIOMYOPATHY AS WELL AS ISCHEMIA REPERFUSION INJURY. FURTHERMORE, WE PROPOSE A SIMILAR LINK BETWEEN MYOCARDIAL STUNNING SEEN AFTER BRIEF PERIODS OF ISCHEMIA REPERFUSION TO BE IN PART DUE TO THE SAME CROSS TALK RESULTING IN A PARTIALLY REVERSIBLE REDUCTION IN MYOCARDIAL SYSTOLIC FUNCTION. LINKING THE TRANSPORT OF CALCIUM AND IRON SIGNALING IS THE MITOCHONDRIA CA UNIPORTER (MCU) AND THE ACTIVATION OF TRANSIENT RECEPTOR POTENTIAL CANONICAL CHANNELS. WE SHOW THAT IRON CAN REGULATE TRPC ION CHANNEL FUNCTION. OUR PRELIMINARY DATA HAVE SHOWN THAT TRPC CHANNELS ARE DIRECTLY ACTIVATED BY IRON. IMPORTANTLY, ACTIVATION OF TRPCS HAS BEEN IMPLICATED IN CALCIUM PARADOX INJURY AND POST- MYOCARDIAL INFARCTION REMODELING. WE AIM TO DEMONSTRATE THAT NEITHER CALCIUM NOR IRON ARE SIMPLY PASSIVE PARTICIPANTS IN CELLULAR PROCESSES, BUT WHEN FORCES ARE JOINED RESULT IN SYSTOLIC AND DIASTOLIC FAILURE OF THE HEART, CARDIOTOXCITY, AND TOGETHER ARE PREDICTIVE OF A REDUCED LIFESPAN IN HUMANS. WE WILL DEMONSTRATE THAT IT IS CELLULAR DIASTOLIC CALCIUM AND MITOCHONDRIAL CALCIUM THAT DEFINES CELL DEATH AND MYOCARDIAL FUNCTION WITH IRON LOADING. WE HYPOTHESIZE THAT MCU ACCOUNTS FOR MITOCHONDRIAL IRON OVERLOAD AND THAT AN INTERACTION (OR CROSSTALK) BETWEEN ELEVATED DIASTOLIC CALCIUM AND INCREASED MITOCHONDRIAL IRON RESULTS IN A HIGHLY VOLATILE AND CARDIOTOXIC ENVIRONMENT THAT CAUSES CARDIAC CELL DEATH VIA FERROPTOSIS RESULTING IN CARDIOMYOPATHY AND ISCHEMIA REPERFUSION INJURY. THE FIELD OF FERROPTOSIS IS NASCENT IN MANY REGARDS WHEN IT COMES TO THE HEART. THE KEY DRIVERS AND PATHWAYS OF FERROPTOSIS IN THE HEART DIFFER DEPENDING ON BIOLOGICAL CONTEXT. IN SUMMARY, THERE IS A WEALTH OF FORESEEABLE OPPORTUNITIES TO ELUCIDATE BOTH THE TRIGGER(S) AND PATHWAYS ACTIVATED THAT CAN RESULT IN FERROPTOSIS AND ITS ROLE IN VARIOUS FORMS OF CARDIAC CARDIOMYOPATHY AND ISCHEMIA-REPERFUSION INJURY. OUR PRELIMINARY STUDIES HAVE DEMONSTRATED FERROPTOSIS IN IRON INDUCED CARDIOMYOPATHY AND DUCHENNE MUSCULAR DYSTROPHY CARDIOMYOPATHY. WE WILL USE WOODCHUCKS THAT HAVE BEEN SHOWN BY US TO BE PROTECTED FROM ISCHEMIA REPERFUSION INJURY AS A TOOL TO IDENTIFY NOVEL ANTI-FERROPTOSIS PATHWAYS THAT CAN BE TARGETED FOR TREATMENT AND/OR PREVENTATIVE THERAPIES. WE WILL PURSUE THE FOLLOWING AIMS. AIM 1: DETERMINE THE ROLE OF MCU AND TRPCS IN FE INDUCED C

THE LANDSCAPE OF TUMOR INTRINSIC GENETIC RESISTANCE TO T CELL THERAPY - PROJECT SUMMARY/ABSTRACT EPITHELIAL CANCERS ARE COMMON MALIGNANCIES THAT ACCOUNT FOR 80 TO 90 PERCENT OF HUMAN CANCERS. DESPITE BREAKTHROUGHS IN CHEMOTHERAPY, TARGETED THERAPY, AND IMMUNOTHERAPY, THEY GENERALLY ARE INCURABLE IN ADVANCED STAGES. CELL THERAPY HAS SHOWN REMARKABLE EFFICACY IN CERTAIN ADVANCED STAGE HEMATOLOGIC CANCERS, BUT APPLICATION OF THE APPROACH TO EPITHELIAL CANCERS HAS BEEN MORE DIFFICULT. THE SHORT-TERM GOAL OF THIS PROJECT IS TO ELUCIDATE PRINCIPLES OF CELL THERAPY IN EPITHELIAL CANCERS USING HUMAN PAPILLOMAVIRUS (HPV)-ASSOCIATED CANCERS AS A DISEASE MODEL. THE LONG-TERM GOAL OF THIS PROJECT IS TO DISCOVER AND DEVELOP CELLULAR THERAPY FOR HPV-ASSOCIATED CANCERS AND OTHER COMMON MALIGNANCIES. RESEARCH IN THE SI2 PHASE DEMONSTRATED THAT TUMOR- INFILTRATING LYMPHOCYTES CAN CAUSE DURABLE, COMPLETE TUMOR RESPONSES IN HPV-ASSOCIATED CANCERS; GENETICALLY ENGINEERED T CELLS TARGETING AN HPV ONCOPROTEIN CAN INDUCE ROBUST TUMOR REGRESSION IN HPV-ASSOCIATED CANCERS – INCLUDING IMMUNE CHECKPOINT BLOCKADE RESISTANT TUMORS; AND TUMOR-INTRINSIC GENETIC DEFECTS IN ANTIGEN PROCESSING MACHINERY (APM) AND INTERFERON (IFN) RESPONSE PATHWAYS CONTROL RESISTANCE TO ENGINEERED TCR-T CELL THERAPY. RESEARCH IN THE R00 PHASE WILL BUILD ON THE SI2 FINDINGS WITH THE GOALS TO 1) ELUCIDATE IN HPV- ASSOCIATED CANCERS A MULTIDIMENSIONAL PICTURE OF TUMOR-INTRINSIC IMMUNE RELATED GENETIC RESISTANCE (IRGR) AND 2) INVESTIGATE THE IMPACT OF CELL THERAPY AND IMMUNE PRESSURE ON IRGR AND OF IRGR ON TUMOR RESPONSE TO CELL THERAPY. HPV-ASSOCIATED CANCERS WILL BE PROFILED FOR ALTERATIONS IN GENES WITH DEFINED FUNCTION IN TUMOR RECOGNITION AND KILLING BY T CELLS. IN ADDITION, EXPLORATORY ANALYSES WILL BE CONDUCTED TO IDENTIFY CANDIDATE IMMUNE EVASION GENES THAT ARE ALTERED AT FREQUENCIES GREATER THAN EXPECTED OR THAT DRIVE CLONAL EVOLUTION BASED ON SPATIAL CLONAL ARCHITECTURE MAPPING. THE IMPACT OF CELL THERAPY ON IRGR AND VICE VERSA WILL BE INVESTIGATED BY STUDY OF HPV-ASSOCIATED CANCERS FROM PATIENTS TREATED WITH TUMOR-INFILTRATING LYMPHOCYTE THERAPY AND ENGINEERED TCR-T CELL THERAPY. THE LONGITUDINAL IMPACT OF IMMUNE PRESSURE ON IRGR WILL BE INVESTIGATED BY COMPARING PRIMARY VERSUS METASTATIC TUMORS AND BY ANALYZING SERIAL INTRA-PATIENT, METACHRONOUS TUMOR RESECTIONS. THIS RESEARCH WILL PROVIDE AN INTEGRATED UNDERSTANDING OF THE RECIPROCAL EFFECTS OF IMMUNE RESPONSE AND IRGR IN HPV-ASSOCIATED CANCERS. THE WORK IS CRITICAL TO UNDERSTANDING IMMUNE EDITING AND TUMOR RESISTANCE IN THE CONTEXT OF CELL THERAPY AND IS NECESSARY TO GUIDE THE DISCOVERY OF PREDICTIVE BIOMARKERS AND THE RATIONAL DESIGN OF NEXT- GENERATION TREATMENT STRATEGIES.

EXAMINING A MULTICOMPONENT INTERVENTION TO IMPROVE HIV HEALTH AMONG BLACK MEN IN SOUTHERN ENDING THE HIV EPIDEMIC IN THE U.S. JURISDICTIONS - PROJECT SUMMARY/ABSTRACT BLACK MEN WHO HAVE SEX WITH MEN (BMSM) IN THE U.S. CONTINUE TO EXPERIENCE A VASTLY INEQUITABLE HIV BURDEN, PARTICULARLY IN SOUTHERN ENDING THE HIV EPIDEMIC IN THE U.S. (EHE) JURISDICTIONS. TO COMBAT THIS ALARMING TREND, THERE IS A NEED FOR INNOVATIVE, ACCESSIBLE, AND COMMUNITY-DEVELOPED INTERVENTIONS TO PROMOTE HIV HEALTH AMONG BMSM IN THESE AREAS. GIVEN RESEARCH THAT DAILY AND MULTILEVEL INTERSECTIONAL STIGMA CONTRIBUTES TO HIV INEQUITIES AMONG BMSM, A MULTICOMPONENT INTERVENTION THAT ADDRESSES MULTILEVEL BARRIERS TO HIV HEALTH AND COMBATS INTERSECTIONAL STIGMA IS ESSENTIAL. IN COLLABORATION WITH THRIVE SS, A LEADING BMSM- LED COMMUNITY-BASED ORGANIZATION SERVING BMSM LIVING WITH HIV IN THE ATLANTA AREA, WE DEVELOPED THRIVE365, AN EVIDENCE-BASED MULTICOMPONENT HIV INTERVENTION THAT PROVIDES INDIVIDUAL-LEVEL HEALTH EDUCATION AND MOTIVATION, BUILDS SOCIAL SUPPORT AMONG BMSM, FACILITATES ACCESS TO CULTURALLY-AFFIRMATIVE HEALTHCARE, AND COMBATS BARRIERS TO HOUSING AND ECONOMIC EMPOWERMENT IN LINE WITH THE INFORMATION- MOTIVATION-BEHAVIORAL SKILLS, SOCIAL CAPITAL, AND SOCIOECOLOGICAL MODELS OF HEALTH. PILOT EVIDENCE INDICATES THRIVE365 IS FEASIBLE, ACCEPTABLE, AND EFFICACIOUS IN PROMOTING DAILY ANTIRETROVIRAL TREATMENT (ART) ADHERENCE AND REDUCING DAILY DEPRESSIVE SYMPTOMS, ANXIETY SYMPTOMS, AND EMOTION REGULATION DIFFICULTIES AMONG BMSM LIVING WITH HIV. THRIVE365 IS READY FOR A FULL-SCALE EVALUATION GUIDED BY THE RE-AIM FRAMEWORK THAT INCLUDES A ROBUST EXAMINATION OF ITS EFFECTIVENESS FOR HIV-RELATED BEHAVIORAL AND PSYCHOLOGICAL OUTCOMES, ITS MODERATION EFFECTS ON INTERSECTIONAL STIGMA, AND ITS MAINTENANCE AND REACH OVER TIME. WE WILL DO SO WITH A FULLY-POWERED HYBRID TYPE 2 IMPLEMENTATION-EFFECTIVENESS TRIAL USING DAILY DIARY METHODS, SELF-REPORT FOLLOW-UPS OVER 6 MONTHS, AND PARADATA TO EXAMINE DAILY AND LONGER-TERM INTERVENTION ENGAGEMENT, EFFECTS, AND ADAPTATIONS. THE OVERARCHING AIMS OF THIS RESEARCH ARE TO: 1) TEST THE EFFECTIVENESS OF THRIVE365 IN IMPROVING DAILY AND LONGER-TERM HIV-RELATED BEHAVIORAL HEALTH (PRIMARY OUTCOME: ART ADHERENCE) AND PSYCHOLOGICAL HEALTH (E.G., SECONDARY OUTCOMES: LOWER DEPRESSIVE AND ANXIETY SYMPTOMS) IN A 6-MONTH WAITLIST RANDOMIZED CONTROLLED TRIAL WITH 350 BMSM LIVING WITH HIV IN THE FOUR ATLANTA-AREA EHE JURISDICTIONS; 2) EXAMINE THE MODERATING EFFECT OF THRIVE365 ON ASSOCIATIONS BETWEEN INTERSECTIONAL STIGMA AND OUR PRIMARY AND SECONDARY HIV OUTCOMES; 3) EVALUATE THRIVE365 MAINTENANCE AND REACH AT THE USER-LEVEL (E.G., WITHIN-USER CHANGES IN ENGAGEMENT AND DAILY EFFECTS) AND SETTING-LEVEL (E.G., INTERVENTION ADAPTATIONS, BMSM COMMUNITY UPTAKE). TOGETHER, THESE RESULTS WILL ESTABLISH THE EFFECTIVENESS OF THRIVE365, A COMMUNITY-LED, MULTICOMPONENT INTERVENTION, FOR IMPROVING HIV-RELATED BEHAVIORAL AND PSYCHOLOGICAL HEALTH AMONG BMSM LIVING WITH HIV IN FOUR OF THE EHE JURISDICTIONS WITH THE GREATEST HIV BURDEN. THRIVE365 WAS DESIGNED FOR IMPLEMENTATION AND IS POISED TO OFFER A MODEL FOR EFFECTIVE HIV CARE AMONG BMSM IN HIGH-STIGMA, LOW-RESOURCE AREAS OF THE U.S. SOUTH AND BEYOND.

POINT OF CARE DETECTION OF FLUROQUINOLONE, BEDAQUILINE AND LINEZOLID RESISTANT MYCOBACTERIUM TUBERCULOSIS FOR RAPID TREATMENT DECISIONS. - ABSTRACT RAPID AND SENSITIVE POINT OF CARE TESTS THAT CAN DETECT ALL FORMS OF DRUG RESISTANCE ARE URGENTLY NEEDED TO ENABLE APPROPRIATE TREATMENT FOR TB. MOLECULAR DRUG SUSCEPTIBILITY TESTS (MDSTS) WHICH USE NUCLEIC ACID AMPLIFICATION TECHNIQUES TO DETECT MUTATIONS ASSOCIATED WITH RESISTANCE TO THE PRIMARY TUBERCULOSIS (TB) DRUGS ISONIAZID (INH), AND RIFAMPIN (RIF), AND IN A FEW RARE CASES FLUOROQUINOLONES (FQS) HAVE DEMONSTRATED THE POTENTIAL OF THIS SUSCEPTIBILITY TESTING APPROACH. HOWEVER, CURRENT MDSTS ARE UNABLE TO DETECT THE LARGE NUMBERS OF MUTATIONS WHICH ENCODE FOR RESISTANCE TO THE CRITICAL NEW ANTI-TUBERCULAR DRUG, BEDAQUILINE (BDQ), AND LINEZOLID (LZD). THESE NEW DRUGS ALONG WITH FQS AND ANOTHER NEW DRUG PRETOMINID (PA) COMPRISE THE BACKBONE OF THE MOST PROMISING TB TREATMENTS OF THE FUTURE. YET, WITHOUT THE AVAILABILITY OF COMPANION MDSTS, THE WORLD RISKS LOSING THESE NEW DRUGS TO DRUG RESISTANCE WITHIN A FEW YEARS OF DEPLOYMENT. WE PROPOSE TO USE INNOVATIVE NEW FLUIDIC AND ASSAY DESIGNS TO ENABLE DETECTION OF HUNDREDS OF DIFFERENT MUTATIONS ENCODING FQ, LZD, AND BDQ RESISTANCE USING THE STANDARD CEPHEID ASSAY CARTRIDGE. THIS NEW TEST WOULD RETAIN ALL THE ADVANTAGES OF CURRENT CEPHEID TB ASSAYS, A ROBUST MANUFACTURING AND INSTRUMENT PLACEMENT BASE ENABLED BY THE HIGH VOLUME OF ASSAYS CURRENTLY PRODUCED. THIS RESEARCH PROGRAM WILL INCLUDE 4 AIMS. AIM 1. DEVELOP MIS-MATCH TOLERANT OR “SLOPPY” MOLECULAR BEACONS (SMBS) THAT IDENTIFY MUTATIONS ASSOCIATED WITH FQ AND LZD RESISTANCE THAT ARE OPTIMIZED FOR ULTIMATE USE IN THE NEW THREE-PHASE HIGHLY MULTIPLEX SYSTEM TO BE DEVELOPED IN THIS GRANT. AIM 2. BDQ ASSAY DEVELOPMENT DETECTING MUTATIONS IN ATPE AND A NEW SMB TILING APPROACH THAT QUERIES THE ENTIRE MTB RV0678 GENE TO IDENTIFY MUTATIONS CAUSAL OF BDQ RESISTANCE. AIM 3 OPTIMIZE THREE-PHASE CARTRIDGE FLUIDICS FOR HIGHLY MULTIPLEX MUTATION DETECTION. AIM 4. PERFORM AN INITIAL LABORATORY AND CLINICAL VALIDATION STUDY OF THE FINAL AIM 1-3 ASSAYS USING STORED CLINICAL SAMPLES.

SEX STEROIDS, KISSPEPTIN AND REGULATION OF GNRH

R01 UPSTREAM APPROACHES TO IMPROVE LATE LIFE CARE FOR PEOPLE LIVING WITH DEMENTIA

ONE-CARBON METABOLISM AND IMMUNE CELL FUNCTION IN TUBERCULOSIS - ABSTRACT THE IMMUNOMETABOLISM OF TUBERCULOSIS (TB) OFFERS NEW OPPORTUNITIES FOR CONTROLLING THIS DEADLY INFECTIOUS DISEASE. WE AND OTHERS HAVE CHARACTERIZED THE IMMUNOMETABOLIC CHANGES IN MULTIPLE ANIMAL MODELS OF TB AND FOUND THAT METABOLIC REMODELING TO THE HIF-1-MEDIATED WARBURG EFFECT IS A GENERAL RESPONSE TO INFECTION BY MYCOBACTERIUM TUBERCULOSIS, THE CAUSATIVE AGENT OF TB. RECENTLY, USING MULTIPLE APPROACHES THAT INCLUDE METABOLOMICS AND TRANSCRIPTOMIC PROFILING, WE IDENTIFIED NOVEL CORE METABOLIC PATHWAYS THAT ARE FOUND IN BOTH MTB-INFECTED M1-LIKE MACROPHAGES AND IN MOUSE LUNGS. THESE INCLUDE GLUTAMINOLYSIS AND ONE-CARBON METABOLISM. ONE-CARBON METABOLISM CATABOLIZES THE TRANSFER OF SERINE-DERIVED ONE-CARBON (1C) UNITS TO GENERATE METHYL-TETRAHYDROFOLATE (THF) INTERMEDIATES THAT ARE THEN UTILIZED FOR NUCLEOTIDE SYNTHESIS AND FOR METHYLATION REACTIONS THROUGH THE METHIONINE CYCLE. ONE-CARBON METABOLISM IS ALSO INVOLVED IN REDOX BALANCING THROUGH THE GENERATION OF NADH/NADPH AND OF GLYCINE AND CYSTEINE FOR GLUTATHIONE (GSH) SYNTHESIS. WE ALSO FOUND THAT INHIBITION OF METHYLENETETRAHYDROFOLATE DEHYDROGENASE 2 (MTHFD2) LEADS TO DIMINISHED M1-LIKE POLARIZATION THAT INCLUDES DYSREGULATED MITOCHONDRIAL FUNCTION AND DAMPENED MTORC1/ATF4 SIGNALING IN M1- LIKE MACROPHAGES. MTHFD2 IS A KEY MITOCHONDRIAL ENZYME OF ONE-CARBON METABOLISM THAT IS ENCODED BY MTHFD2, WHICH IS HIGHLY INDUCED IN MTB INFECTED M-LIKE MACROPHAGES AND MOUSE LUNGS. BASED ON THESE OBSERVATIONS, WE HYPOTHESIZE THAT MITOCHONDRIAL MTHFD2-MEDIATED, ONE-CARBON METABOLISM CONTRIBUTES TO METABOLIC REMODELING PROGRAMS OF ACTIVATING IMMUNE CELLS BY GENERATING 1C UNITS FOR NUCLEOTIDE SYNTHESIS AND METHYLATION REACTIONS, AS WELL AS REDUCING EQUIVALENTS AND GSH FOR REDOX HOMEOSTASIS. SINCE TB IS OFTEN ASSOCIATED WITH A DEFICIENCY OF FOLIC ACID, THE PRECURSOR OF THE 1C CARRIER THF, WE ALSO HYPOTHESIZE THAT FOLIC ACID DEFICIENCY DURING MTB INFECTION DAMPENS ONE-CARBON METABOLISM, LEADING TO DIMINISHED ACTIVATION, DIFFERENTIATION, AND EFFECTOR FUNCTION OF HOST IMMUNE CELLS. MOREOVER, SINCE ELEVATED MTHFD2 IN VIVO IS ASSOCIATED WITH INFLAMMATORY DISEASE SEVERITY, WE FURTHER HYPOTHESIZE THAT PROLONGED AND ELEVATED EXPRESSION OF ONE-CARBON METABOLISM CONTRIBUTES TO LUNG PATHOLOGY AT THE CHRONIC STAGE OF MTB INFECTION. TO TEST OUR HYPOTHESIS, IN AIM 1, WE WILL DELINEATE HOW MTHFD2- MEDIATED, ONE-CARBON METABOLISM REGULATES IMMUNOMETABOLIC PROPERTIES OF M1-LIKE MACROPHAGES, MITOCHONDRIAL BIOLOGY, SERINE METABOLIC PATHWAYS, AND THE MECHANISM OF MTHFD2 UPREGULATION. IN AIM 2, WE WILL GENERATE CONDITIONAL KO MOUSE STRAINS LACKING MTHFD2 IN MYELOID CELLS AND T CELL LINEAGE TO DELINEATE THE IMPACT OF MTHFD2 DEFICIENCY ON DISEASE PROGRESSION AND IMMUNOMETABOLIC PROPERTIES OF IMMUNE CELLS AND/OR SUBSETS. WITH AIM 3, WE WILL USE A SUSCEPTIBLE MOUSE MODEL OF TB TO EVALUATE THE EFFECTS OF FOLIC ACID DIETARY INTAKE ON THE EXPRESSION OF HOST IMMUNITY TO CONTROL MTB INFECTION. WE WILL ALSO DEFINE THE THERAPEUTIC ROLE OF INHIBITORS TARGETING ONE-CARBON METABOLISM DURING ANTI-TB TREATMENT AT CHRONIC STAGES OF THE INFECTION. OUR STUDY IS EXPECTED TO ADVANCE THE DEVELOPMENT OF URGENTLY NEEDED HOST-DIRECTED THERAPIES (HDTS) TO ENHANCE THE ABILITY OF IMMUNE CELLS TO CLEAR MTB INFECTION AND/OR TO PREVENT THE DEVELOPMENT OF PATHOLOGY.

THE ROLE OF PATHOGEN-EXPERIENCED MACROPHAGE SUBSETS IN MEDIATING LUNG IMMUNITY AND HETEROLOGOUS PROTECTION - ABSTRACT: INFECTIONS OF THE LUNG SIGNIFICANTLY IMPACT HEALTH WORLDWIDE, WITH NON-TUBERCULOSIS LOWER RESPIRATORY INFECTIONS CAUSING 2.7 MILLION DEATHS ANNUALLY AND CHRONIC INFECTIONS SIGNIFICANTLY CONTRIBUTING TO IMPAIRED LUNG FUNCTION AND MORBIDITY. PULMONARY MACROPHAGES ARE CRITICAL, FRONT-LINE MEDIATORS OF HOST PROTECTION AGAINST HELMINTH PARASITES, FUNGI, AND VIRUSES. DESPITE THE WELL-DEFINED ROLE OF LUNG MACROPHAGES AS CRUCIAL INITIATORS OF IMMUNITY TO DIVERSE SETS OF PATHOGENS, OUR UNDERSTANDING OF THE CELLULAR AND MOLECULAR EVENTS THAT REGULATE MACROPHAGE RESPONSES IN THE LUNG REMAIN POORLY DEFINED. FOR EXAMPLE, THE PRECISE MECHANISMS THAT ALLOW PULMONARY MACROPHAGES TO ELIMINATE BOTH INTRACELLULAR AND EXTRACELLULAR PATHOGENS WHILE SIMULTANEOUSLY MITIGATING TISSUE INJURY AND PRESERVING LUNG FUNCTION REMAIN ELUSIVE. FURTHER, AN EMERGING BODY OF LITERATURE HAS NOW REVEALED THAT MACROPHAGE POPULATIONS IN THE LUNG ARE MORE HETEROGENEOUS THAN ORIGINALLY APPRECIATED. SPECIFICALLY, IT IS NOW UNDERSTOOD THAT ALVEOLAR MACROPHAGES PRESENT IN THE LUNG CAN ORIGINATE FROM EMBRYONIC PRECURSORS (TISSUE- DERIVED ALVEOLAR MACROPHAGES-TD-AMS) OR FROM BLOOD MONOCYTES (MONOCYTE-DERIVED ALVEOLAR MACROPHAGES- MO-AMS). DESPITE THIS IMPORTANT ADVANCE, IT IS CURRENTLY UNCLEAR WHETHER THESE ONTOLOGICALLY DISTINCT PULMONARY MACROPHAGE POPULATIONS PERFORM COMPARABLE OR DISTINCT FUNCTIONS IN MEDIATING PROTECTION (REDUCTION IN PATHOGEN BURDENS AND/OR MAINTENANCE OF TISSUE INTEGRITY). ALSO, WHETHER THESE DISTINCT MACROPHAGE POPULATIONS INITIATE SIMILAR OR UNIQUE EFFECTOR FUNCTIONS IN THE CONTEXT OF HELMINTH, FUNGAL, OR VIRAL CHALLENGES REMAINS UNKNOWN. FINALLY, OUR UNDERSTANDING OF HOW A PREVIOUS EXPOSURE TO ONE PULMONARY PATHOGEN ALTERS THE RESPONSIVENESS OF LUNG MACROPHAGES TO A SUBSEQUENT CHALLENGE WITH A DISTINCT PATHOGEN IS POORLY UNDERSTOOD. THIS IMPORTANT GAP IN KNOWLEDGE HAS BECOME EXTREMELY EVIDENT DURING THE COVID-19 PANDEMIC WHERE INDIVIDUAL OUTCOMES VARY DRAMATICALLY AND WE HAVE A POOR UNDERSTANDING OF HOW ONE’S INFECTIOUS PAST MAY CONTRIBUTE TO THESE DIFFERENCES. THE LEADERS OF THIS PROJECT WILL EMPLOY THEIR COMBINED EXPERTISE TO ADDRESS THESE CRITICAL QUESTIONS. THE CENTRAL HYPOTHESIS OF THIS APPLICATION IS THAT INFECTION WITH DIVERSE PATHOGENS PROGRAM TD-AMS AND MO-AMS TO PERFORM DISTINCT FUNCTIONS AGAINST HETEROLOGOUS PATHOGENS WHILE MITIGATING TISSUE INJURY. WE FURTHER HYPOTHESIZE THAT THE PATHOGEN-INDUCED RESPONSE OF TD-AMS AND MO-AMS IS CRITICALLY SHAPED BY NEUTROPHIL-DERIVED SIGNALS AND TYPE I AND III INTERFERONS. IN THREE DISTINCT AND COMPLEMENTARY AIMS WE WILL USE A COMBINATION OF DISCOVERY-BASED STUDIES COMBINED WITH TARGETED IN VITRO AND IN VIVO APPROACHES TO DEFINE THE OVERLAPPING AND UNIQUE CONTRIBUTIONS OF TISSUE-DERIVED MACROPHAGES AND RECRUITED MONOCYTE-DERIVED CELLS TO HOST PROTECTIVE RESPONSES FOLLOWING HELMINTH, FUNGAL OR VIRAL INFECTIONS. THIS THOROUGH AND COMPREHENSIVE APPROACH WILL ALLOW US TO GAIN AN UNPRECEDENTED UNDERSTANDING OF FUNDAMENTAL INNATE IMMUNE FUNCTIONS. THIS NOVEL INSIGHT MAY INFORM THERAPEUTIC STRATEGIES TO TARGET LUNG MACROPHAGE POPULATIONS IN A MANNER THAT WILL ALLOW FOR THE FINE TUNING OF INFLAMMATION AND PULMONARY INFECTION OUTCOMES.

IMMUNE REGULATION OF TISSUE IRON IN HEALTH AND DISEASE - PROJECT ABSTRACT ANEMIA AND INFLAMMATION OFTEN CO-OCCUR IN CHRONIC DISEASES INCLUDING INFLAMMATORY BOWEL DISEASE (IBD), INFECTION, AND CANCER. ANEMIA IS OFTEN REFRACTORY TO TREATMENT IN THESE DISEASES, AND THE IMPACT OF ANEMIA AND ANEMIA THERAPIES ON DISEASE OUTCOME IS POORLY DEFINED. ACCORDINGLY, THERE IS A SIGNIFICANT MEDICAL NEED TO BETTER UNDERSTAND THE CAUSAL LINKS BETWEEN ANEMIA AND INFLAMMATORY DISEASES. ONE OF THE BEST DEFINED LINKS BETWEEN ANEMIA AND INFLAMMATION IS A PEPTIDE HORMONE CALLED HEPCIDIN, WHICH CRITICALLY INHIBITS IRON RELEASE FROM INTRACELLULAR STORES. HEPCIDIN LEVELS TYPICALLY INCREASE DRAMATICALLY DURING INFLAMMATION, AND CAN CAUSE ONE FORM OF ANEMIA TERMED ANEMIA OF INFLAMMATION (AI). CONVERSELY, INFLAMMATORY DISEASES ASSOCIATED WITH HEAVY BLEEDING CAUSE A DISTINCT FORM OF ANEMIA KNOWN AS IRON DEFICIENCY ANEMIA (IDA), IN WHICH HEPCIDIN LEVELS ARE SUPPRESSED. THE FUNDAMENTAL FOCUS OF THIS RESEARCH PROPOSAL IS TO: I.) INVESTIGATE THE IMPACT OF HEPCIDIN ON INFLAMMATORY DISEASE, II.) IDENTIFY CELLULAR POPULATIONS EXPRESSING HEPCIDIN AND ITS PARTNER FERROPORTIN DURING INFLAMMATION, AND III.) DETERMINE THE IMPACT OF IRON MODULATION BY DISTINCT CELLULAR POPULATION ON THE RESOLUTION OF INFLAMMATORY DISEASES. I WILL EMPLOY INNOVATIVE TECHNICAL APPROACHES AND DEVELOP NEW TOOLS TO DEFINE THE ROLE OF HEPCIDIN AND FERROPORTIN DURING CHEMICALLY-INDUCED INTESTINAL DAMAGE, INTESTINAL INFECTION, AND IN INFLAMMATION-INDUCED CANCER. COLLECTIVELY, RESULTS FROM THESE STUDIES WILL DEFINE THE REGULATION AND FUNCTIONAL SIGNIFICANCE OF NOVEL CELLULAR MEDIATORS OF IRON WITHIN THE INTESTINE. THESE FINDINGS WILL CRITICALLY INFORM ONGOING EFFORTS TO DEVELOP THERAPIES TARGETING TISSUE REPAIR AND ANEMIA IN THE CONTEXT OF INFLAMMATORY DISEASES.

ROLE OF PHOSPHOLIPIDS IN ANTIFUNGAL DRUG RESISTANCE IN CRYPTOCOCCUS NEOFORMANS - ABSTRACT CRYPTOCOCCUS NEOFORMANS AND ITS SIBLING SPECIES C. GATTII CAUSE CRYPTOCOCCOSIS, A DEADLY FUNGAL DISEASE THAT ACCOUNTS FOR OVER 15% OF HIV/AIDS RELATED DEATHS. TREATMENT OPTIONS FOR CRYPTOCOCCOSIS REMAIN LIMITED TO TWO DRUG CLASSES THAT ARE EITHER HIGHLY TOXIC (POLYENES) OR EXERT A FUNGISTATIC EFFECT (TRIAZOLES) THAT NECESSITATE LONG TREATMENT REGIMENS AND CAN INDUCE DRUG RESISTANCE. THE THIRD ANTIFUNGAL DRUG CLASS, ECHINOCANDINS, SHOWS LOW TOXICITY AND IS FUNGICIDAL AGAINST SOME PREVALENT FUNGAL PATHOGENS. HOWEVER, CRYPTOCOCCUS SPECIES ARE RESISTANT TO ECHINOCANDINS THROUGH AN UNKNOWN RESISTANCE MECHANISM. WE FOUND THAT LOSS OF CDC50, THE REGULATORY SUBUNIT OF LIPID FLIPPASE, AN ENZYME THAT MAINTAINS ASYMMETRY OF THE MEMBRANE LIPID BILAYERS AND REGULATES INTRACELLULAR VESICLE TRAFFICKING, SENSITIZES C. NEOFORMANS TO THE ECHINOCANDIN DRUG CASPOFUNGIN AND SEVERAL TRIAZOLES. WE FURTHER SHOWED THAT THE CDC50 MUTANT ABOLISHES LIPID FLIPPASE ACTIVITY. WE ALSO FOUND THAT THIS CDC50-MEDIATED ECHINOCANDIN RESISTANCE REQUIRES A MECHANOSENSITIVE CALCIUM CHANNEL PROTEIN, CRM1, WHICH MODULATES INTRACELLULAR CALCIUM HOMEOSTASIS. STRIKINGLY, WE DISCOVERED THAT LIPID FLIPPASE FUNCTION IS ESSENTIAL FOR VIRULENCE IN A MURINE MODEL OF CRYPTOCOCCOSIS, SUGGESTING THAT LIPID FLIPPASE MAY BE A NOVEL ANTIFUNGAL DRUG TARGET. IN THIS PROJECT, OUR GOALS ARE TO DETERMINE HOW LIPID FLIPPASE MEDIATES CRYPTOCOCCAL ECHINOCANDIN RESISTANCE, AND TO CONDUCT PROOF-OF-PRINCIPLE STUDIES OF ANTIBODY-BASED INHIBITORS TARGETING FLIPPASE FUNCTION AS NOVEL THERAPEUTICS FOR CRYPTOCOCCUS INFECTIONS. WE HYPOTHESIZE THAT C. NEOFORMANS HAS A UNIQUE PLASMA MEMBRANE STRUCTURE AND THAT LOSS OF LIPID FLIPPASE ALTERS THAT STRUCTURE TO PROMOTE THE INTERACTION OF CASPOFUNGIN WITH ITS TARGET AND COMPROMISES FUNGAL DRUG RESISTANCE MECHANISMS. WE PROPOSE THREE AIMS TO TEST OUR HYPOTHESIS. IN AIM 1, WE WILL ELUCIDATE HOW LOSS OF CDC50 CHANGES MEMBRANE STRUCTURE TO PROMOTE THE INTERACTION OF CASPOFUNGIN WITH ITS MEMBRANE TARGET SS-1,3-D-GLUCAN SYNTHASE (FKS1). AIM 2 WILL IDENTIFY THE DOWNSTREAM DRUG RESISTANCE PATHWAYS THAT ARE COMPROMISED BY THE ABSENCE OF CDC50, WHICH DISRUPTS INTRACELLULAR CALCIUM HOMEOSTASIS AND PROMOTES CELL DEATH. IN AIM 3, WE WILL DEVELOP AN ANTIBODY FAB FRAGMENT AND A STABLE PEPTIDE AGAINST THE EXOPLASMIC LOOP OF CDC50, WHICH IS ESSENTIAL FOR FLIPPASE FUNCTION. WE WILL VALIDATE HOW INHIBITORS SENSITIZE C. NEOFORMANS TO ANTIFUNGAL DRUGS AND MACROPHAGE KILLING IN VITRO AND IN VIVO IN ANIMAL MODELS. THE REGION OF CDC50 TARGETED BY THIS ANTIBODY-BASED APPROACH HAS LOW SEQUENCE HOMOLOGY TO ITS HUMAN COUNTERPART, AND OUR PRELIMINARY STUDIES SHOWED THAT AN ANTIBODY RAISED AGAINST THIS REGION IS FUNGAL- SPECIFIC, REDUCING THE CHANCE OF OFF-TARGET EFFECTS. THE IMPACT OF THIS STUDY TO ELUCIDATE THE MECHANISMS UNDERLYING LIPID FLIPPASE MEDIATED DRUG RESISTANCE IN C. NEOFORMANS WILL BE DEVELOPING STRATEGIES FOR EXPLOITING ECHINOCANDIN DRUGS TO EFFECTIVELY TREAT CRYPTOCOCCI AND OTHER RESISTANT FUNGAL PATHOGENS. OUR SUCCESSFUL DEVELOPMENT OF ANTIBODY-BASED INHIBITORS WILL ESTABLISH A NEW AVENUE OF RESEARCH AND DRUG DEVELOPMENT AGAINST OTHER MEMBRANE PROTEINS IN FUNGI AND BACTERIA.

DEVELOPMENT OF 2C INHIBITORS AS BROAD-SPECTRUM ENTEROVIRUS ANTIVIRALS - PROJECT SUMMARY NON-POLIO ENTEROVIRUSES (NPEVS) ARE ETIOLOGICAL AGENTS FOR SEVERAL HUMAN DISEASES INCLUDING RESPIRATORY INFECTIONS, HAND-FOOT-AND-MOUTH DISEASE (HFMD), ASEPTIC MENINGITIS, ENCEPHALITIS, NEONATAL SEPSIS, MYOCARDITIS, CONJUNCTIVITIS, AND ACUTE FLACCID PARALYSIS. AMONG THE MORE THAN 100 SEROTYPES OF NPEVS, SOME OF THE MOST SIGNIFICANT PATHOGENS ARE ENTEROVIRUS D68 (EV-D68), ENTEROVIRUS A71 (EV-A71) AND COXSACKIEVIRUS B3 (CV-B3). ACCORDING TO CDC, THESE NPEVS COMBINED HAVE CAUSED 10 TO 15 MILLION INFECTIONS AND TENS OF THOUSANDS OF HOSPITALIZATIONS IN THE U.S. CLEARLY, NPEVS ARE A PUBLIC CONCERN FOR BOTH U.S. AND THE WORLD. NO VACCINES ARE AVAILABLE IN THE U.S. FOR THE NPEVS SUCH AS EV-D68, EV-A71, AND CV-B3. THREE INACTIVATED EV-A71 VACCINES ARE AVAILABLE IN CHINA. HOWEVER, THERE ARE NOT BROADLY PROTECTIVE, AND THE EFFICACY IS LIMITED TO CERTAIN STRAINS. THERE IS NO FDA-APPROVED ANTIVIRAL FOR ANY OF THESE NPEVS. THUS, THERE IS A PRESSING NEED TO DEVELOP ORALLY BIOAVAILABLE PAN-ENTEROVIRUS ANTIVIRALS. THIS PROPOSAL FOCUSES ON TARGETING THE ENTEROVIRUS NONSTRUCTURAL 2C PROTEIN FOR THE DEVELOPMENT OF ORALLY BIOAVAILABLE BROAD-SPECTRUM NPEV ANTIVIRALS. SPECIFICALLY, IN AIM 1, WE WILL OPTIMIZE THE ANTIVIRAL ACTIVITY AND PHARMACOKINETIC PROPERTIES OF THREE SERIES OF 2C INHIBITORS. IN AIM 2, WE WILL DETERMINE THE HIGH-RESOLUTION X- RAY CRYSTAL STRUCTURES OF EV-A71, EV-D68, AND CV-B3 2C PROTEINS WITH STRUCTURALLY DISPARATE 2C INHIBITORS. IN AIM 3, WE WILL EVALUATE THE IN VIVO ANTIVIRAL EFFICACY OF 2C INHIBITORS IN EV-D68 AND EV-A71 INFECTION MOUSE MODELS. SUCCESSFUL IMPLEMENTATION OF THIS PROPOSAL WILL PROVIDE ORALLY BIOAVAILABLE BROAD-SPECTRUM NPEV DRUG CANDIDATES FOR FURTHER DEVELOPMENT.

DIELDRIN-INDUCED DIFFERENTIAL GENE METHYLATION AND PARKINSONIAN TOXICITY - PROJECT SUMMARY THE MAJORITY OF PARKINSON’S DISEASE (PD) CASES ARE NOT CAUSED BY AN INHERITED MONOGENIC MUTATION AND DISEASE ETIOLOGY INVOLVES A COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS. EPIDEMIOLOGICAL STUDIES SHOW THAT PESTICIDE EXPOSURE, PARTICULARLY TO ORGANOCHLORINE PESTICIDES SUCH AS DIELDRIN, INCREASES RISK OF SPORADIC PD. IN A MODEL OF INCREASED PD SUSCEPTIBILITY, MICE EXPOSED TO DIELDRIN DURING DEVELOPMENT SHOW MALE-SPECIFIC INCREASED SUSCEPTIBILITY TO ADULT EXPOSURE TO THE DOPAMINERGIC TOXICANT MPTP AND, IN NEW DATA FROM OUR NIEHS-FUNDED R21, A-SYNUCLEIN (A-SYN) PREFORMED FIBRILS (PFFS). THE EPIGENOME IS A POTENTIAL MEDIATOR OF THIS RELATIONSHIP BETWEEN DEVELOPMENTAL EXPOSURES, INCREASED NEURONAL VULNERABILITY, AND ADULT DISEASE. IN LINE WITH THIS IDEA, WE RECENTLY IDENTIFIED SEX-SPECIFIC DIFFERENTIAL METHYLATION PATTERNS IN RESPONSE TO DEVELOPMENTAL DIELDRIN EXPOSURE. WE HYPOTHESIZE THAT DIELDRIN-INDUCED EPIGENETIC MODIFICATIONS DURING DEVELOPMENT CAUSE CHANGES IN GENE EXPRESSION AND PHENOTYPE THAT PERSIST INTO ADULTHOOD, ALTERING THE SENSITIVITY TO PARKINSONIAN INSULTS AND CONTRIBUTING TO THE DEVELOPMENT OF PD. TO TEST THIS HYPOTHESIS, WE WILL DETERMINE CELL-TYPE SPECIFIC DNA MODIFICATIONS AND EXPRESSION PROFILES OF PREVIOUSLY IDENTIFIED CANDIDATE GENES IN THE DIELDRIN MODEL (AIM 1); ANALYZE THE FUNCTION OF SYNAPTIC TERMINALS IN OUR NOVEL DIELDRIN/PFF TWO-HIT MODEL (AIM 2); AND DETERMINE IF DIELDRIN OR ALTERED EXPRESSION OF CANDIDATE GENES AFFECTS SUSCEPTIBILITY TO A-SYN PFFS IN A DOPAMINERGIC NEURON CELL CULTURE MODEL (AIM 3). THE LONG-TERM GOAL OF THESE EXPERIMENTS IS TO DETERMINE WHETHER DIELDRIN-ASSOCIATED DIFFERENTIALLY METHYLATED GENES PLAY A FUNCTIONAL ROLE IN THE BIOLOGICAL RESPONSE TO PARKINSONIAN TOXICITY. COMPLETION OF THESE AIMS WILL FURTHER THE MISSION OF NIEHS TO INCREASE OUR UNDERSTANDING OF HOW THE ENVIRONMENT AFFECTS PEOPLE IN ORDER TO PROMOTE HEALTHIER LIVES, WITH A SPECIFIC PROJECT GOAL OF CONNECTING EXPOSURES WITH FUNCTIONAL CHANGES IN GENE EXPRESSION, NEURONAL PHENOTYPE, AND PD SUSCEPTIBILITY. THE EXPERIMENTS PROPOSED HERE WILL HELP TO ESTABLISH A BIOLOGICAL MECHANISM LINKING DEVELOPMENTAL EXPOSURE TO LATE LIFE DISEASE. THIS PROJECT WILL ALSO EXPAND OUR REPERTOIRE OF TOOLS FOR INTERROGATING THE FUNCTION OF EPIGENETIC CHANGES BY ESTABLISHING AN IN VITRO EXPERIMENTAL PARADIGM TO CONNECT SPECIFIC EPIGENETIC MECHANISMS WITH PARKINSONIAN TOXICITY. WITH OUR IN VIVO MODEL THAT COMBINES DEVELOPMENTAL EXPOSURE WITH ADULT PFF INJECTIONS, WE WILL HAVE A SET OF EXPERIMENTAL SYSTEMS IN PLACE THAT WILL ALLOW US TO TEST A WIDE VARIETY OF EXPOSURES, AS WELL AS COMBINATIONS OF EXPOSURES, BOTH IN VIVO AND IN VITRO. TOGETHER, THIS SUITE OF TOOLS WILL ENABLE US TO EXPLORE THE MECHANISMS BY WHICH PD- RELATED EXPOSURES ALTER NEURONAL VULNERABILITY IN PD, FURTHERING THE GOAL OF NIEHS TO UNDERSTAND HOW COMBINED EXPOSURES AFFECT DISEASE PATHOGENESIS AND INDIVIDUAL SUSCEPTIBILITY.

ENHANCING PUBLIC HEALTH SURVEILLANCE OF AUTISM SPECTRUM DISORDER THROUGH THE AUTISM AND DEVELOPMENTAL DISABILITIES MONITORING (ADDM) NETWORK - THE PURPOSE OF THIS PROJECT, ENHANCING PUBLIC HEALTH SURVEILLANCE OF AUTISM SPECTRUM DISORDER THROUGH THE AUTISM AND DEVELOPMENTAL DISABILITIES MONITORING (ADDM) NETWORK, IS TO INCREASE THE CAPACITY OF THE NEW JERSEY AUTISM STUDY (NJAS), TO CONDUCT AUTISM SPECTRUM DISORDER (ASD) PREVALENCE MONITORING IN METROPOLITAN NEW JERSEY (NJ). TOWARD THIS END, THE INVESTIGATORS WILL CONDUCT TWO CYCLES OF ASD MONITORING, FOCUSING ON 4, 8, AND 16-YEAR-OLDS RESIDING IN ESSEX AND UNION COUNTIES (COMPONENT A & B). THE INVESTIGATORS WILL HAVE ACCESS TO HEALTH, EDUCATION AND EARLY INTERVENTION PROGRAM (EIP) DATA AND USE THE ACTIVE, MULTIPLE-SOURCE, ADDM ASCERTAINMENT METHOD. MULTIPLE STRATEGIES AND ACTIVITIES WILL BE UNDERTAKEN SYSTEMATICALLY TO ACHIEVE SPECIFIC SHORT-TERM OBJECTIVES, LEADING TO BETTER UNDERSTANDING OF ASD (INCLUDING THE TRAJECTORIES OF ASD FROM CHILDHOOD THROUGH ADOLESCENCE), DECREASED DISPARITIES IN ASD DETECTION, DECREASED AGE OF DETECTION AND IMPROVED PRACTICES TO ADVANCE THE CARE OF INDIVIDUALS WITH ASD. THE PROPOSED FOLLOW-UP AT AGE 16 WILL PROVIDE UNIQUE, POPULATION-BASED, INFORMATION ABOUT THE EXPRESSION OF ASD, INCLUDING: ASSOCIATED FEATURES, CONCURRENT DISORDERS, TREATMENTS AND SERVICES AND TRANSITION PLANNING. ENHANCED SURVEILLANCE BY THE INVESTIGATORS WILL BE CHRONICLED AND MEASURED THROUGH MONITORING OF KEY EVALUATION AND PERFORMANCE PARAMETERS WHICH WILL MAKE THIS AND FUTURE ADDM NETWORK INVESTIGATIONS MORE EFFICIENT AND ROBUST. ASD IS A DYNAMIC CONDITION, POTENTIALLY AFFECTED MY MULTIPLE TYPES OF FACTORS AND INTERVENTIONS. THROUGH THIS PROJECT, INVESTIGATORS WILL ADD TO THE DEVELOPMENT OF WELL-CHARACTERIZED, POPULATION-BASED SET OF INFORMATION DESCRIBING THE EXPRESSION OF ASD, OVER TIME. SUCH INFORMATION MAY YIELD INSIGHTS INTO EFFECTIVE TREATMENTS FOR ASD AND THE ESTABLISHMENT OF BETTER OR MORE PERSONALIZED INTERVENTIONS FOR ASD, IN THE FUTURE.

COOPERATIVE AGREEMENT FOR IMPLEMENTING USAID/PARAGUAY'S NEW DRG PROJECT FOR STRENGTHENING HIGHER EDUCATION INSTITUTIONS' CAPACITY TO SUPPORT THE RULE OF LAW.

MTORC2 SIGNALING IN METABOLISM AND CELL FATE

GAIN-OF-FUNCTION MUTANT P53 AND METABOLIC REPROGRAMMING IN COLORECTAL CANCER - TUMOR SUPPRESSOR P53 PLAYS A CENTRAL ROLE IN TUMOR PREVENTION. P53 IS FREQUENTLY MUTATED IN HUMAN CANCER, INCLUDING COLORECTAL CANCER (CRC). MANY MUTANT P53 (MUTP53) PROTEINS NOT ONLY LOSE TUMOR SUPPRESSIVE FUNCTION OF WILD-TYPE P53, BUT ALSO GAIN NEW ONCOGENIC ACTIVITIES TO PROMOTE TUMORIGENESIS, WHICH IS DEFINED AS MUTP53 GAIN-OF-FUNCTION (GOF). MAINTAINING METABOLIC HOMEOSTASIS IS A NOVEL AND CRITICAL MECHANISM OF P53 IN TUMOR SUPPRESSION. CANCER CELLS OFTEN DISPLAY LIPID METABOLIC REPROGRAMMING, WHICH CONTRIBUTES GREATLY TO CANCER PROGRESSION. CURRENTLY, THE ROLE AND MECHANISM OF MUTP53 IN CANCER METABOLIC REPROGRAMMING ARE POORLY DEFINED. OUR PRELIMINARY STUDIES SUGGEST THAT MUTP53 DRIVES LIPID METABOLIC REPROGRAMMING AS A CRITICAL GOF IN CRC CELLS, AND TARGETING LIPID METABOLIC REPROGRAMMING COMPROMISES MUTP53 GOF IN COLORECTAL TUMORIGENESIS. BASED ON OUR PRELIMINARY RESULTS, WE HYPOTHESIZE THAT GOF MUTP53 DRIVES LIPID METABOLIC REPROGRAMMING AS A CRITICAL MECHANISM TO PROMOTE COLORECTAL TUMORIGENESIS, WHICH CAN BE TARGETED FOR THERAPY IN CRC CARRYING MUTP53. IN THIS PROPOSED STUDY, WE WILL DETERMINE THE ROLE (AIM 1) AND MECHANISM (AIM 2) OF GOF MUTP53 IN DRIVING LIPID METABOLIC REPROGRAMMING IN CRC. WE WILL FURTHER ASSESS TARGETING MUTP53-DRIVEN LIPID METABOLIC REPROGRAMMING AS A POTENTIAL THERAPEUTIC STRATEGY FOR CRC CARRYING MUTP53 (AIM 3). THE GOAL OF THIS STUDY IS TO DETERMINE THE MECHANISM OF GOF MUTP53 IN CRC TO PROVIDE EFFECTIVE TARGETS AND STRATEGIES FOR CRC THERAPY. METABOLIC REPROGRAMMING AND P53 MUTATIONS ARE COMMON EVENTS IN CANCER, AND HAVE BECOME EXTREMELY ATTRACTIVE TARGETS FOR CANCER THERAPY. WE EXPECT THAT THE RESULTS FROM THIS PROPOSED STUDY WILL DEEPEN OUR UNDERSTANDING OF THE ROLE AND MECHANISM OF MUTP53 IN METABOLIC REPROGRAMMING AND TUMORIGENESIS, AND PROVIDE THE RATIONALE AND BASE FOR THE DEVELOPMENT OF NEW THERAPEUTIC TARGETS AND STRATEGIES FOR CANCERS CARRYING MUTP53.

NEUROLOGICAL AND DIGITAL CORRELATES OF COGNITION IN OLDER MANDARIN-SPEAKING ADULTS - ABSTRACT ASIAN AMERICANS ARE THE FASTEST GROWING DEMOGRAPHIC GROUP IN THE US, WITH CHINESE NOW REPRESENTING THE THIRD MOST COMMON LANGUAGE SPOKEN AFTER ENGLISH AND SPANISH. DIAGNOSIS-BASED STUDIES HAVE SHOWN REDUCED DEMENTIA RISKS AMONG OLDER CHINESE ADULTS IN THE US AND CHINA, BUT ASSESSMENT-BASED STUDIES HAVE SUGGESTED SIGNIFICANT UNDER-DIAGNOSIS BY 50% OR MORE. A MAJOR PROBLEM IN DIAGNOSIS IS THE LACK OF RELIABLE TOOLS TO DIAGNOSE MILD COGNITIVE IMPAIRMENT (MCI) OR DEMENTIA (INCLUDING ALZHEIMER’S DISEASE [AD]) AMONG CHINESE ADULTS IN THE US: ABOUT HALF OF CHINESE NEUROPSYCHOLOGICAL TESTS WERE CREATED THROUGH CONTENT- ONLY TRANSLATION WITHOUT ADJUSTMENT FOR CULTURAL, LINGUISTIC, OR NEUROLOGICAL FACTORS, WHILE THE REMAINING ONLY HAVE TRANSLATED INSTRUCTIONS. BECAUSE LANGUAGE-INDEPENDENT NEUROPSYCHOLOGICAL TESTS ARE LIMITED IN SCOPE AND RESOLUTION, DETECTION OF MCI/AD IN OLDER US CHINESE ADULTS IS OFTEN DELAYED FOR EARLY INTERVENTION, CLINICAL TRIAL ENROLLMENT, AND INITIATION OF DISEASE-MODIFYING THERAPIES. BUILDING ON THE UNPARALLELED BILINGUAL NEUROCOGNITIVE EXPERTISE AT RUTGERS AND STANFORD, WE HAVE DEVELOPED NEW MANDARIN-BASED NEUROPSYCHOLOGICAL TESTS ACCOUNTING FOR COGNITION-RELATED DIFFERENCES BETWEEN MANDARIN AND ENGLISH TO MIRROR THE NATIONAL ALZHEIMER’S COORDINATING CENTER ASSESSMENTS. THESE INCLUDE: ARTICULATION-NORMALIZED FORWARD DIGIT SPAN; ARTICULATION- AND LEXEME-ADJUSTED CRAFT STORY 21; LEXEME- AND FREQUENCY-ADJUSTED WORD LIST RECALL; MANDARIN-SPECIFIC WORD GENERATION TASKS GUIDED BY CHARACTER, PHONEME/PINYIN, AND HOMONYM (ONE CHARACTER SOUND CORRESPONDING TO MULTIPLE CHARACTERS); AND EXPOSURE-BASED TRAIL MAKING TEST B. WE LEVERAGED OUR EXISTING COMMUNITY RELATIONSHIPS TO DEMONSTRATE THE FEASIBILITY AND RELIABILITY OF USING THESE TOOLS IN OLDER MANDARIN SPEAKERS, AND WE WILL FURTHER EXPAND THEIR RELIABILITY AND RELATIONSHIP TO PERFORMANCE USING ENGLISH INSTRUMENTS BY BILINGUAL OLDER ADULTS (AIM 1); DETERMINE CONSTRUCT AND DIAGNOSTIC VALIDITY ANALYSIS ACCOUNTING FOR IMAGING AND PLASMA BIOMARKERS OF NEURODEGENERATION (AIM 2); AND DETERMINE IF BILINGUALISM MEDIATES THE EFFECTS OF NEURODEGENERATION (AIM 3). WE WILL ADDITIONALLY TRANSFER THESE TESTS ONTO A DIGITAL PLATFORM WHICH CAN THEN BE USED BY CENTERS WITHOUT MANDARIN-SPEAKING CLINICIANS, AND EXPLORE THE FEASIBILITY OF LONGITUDINAL NEUROPSYCHOLOGICAL, BLOOD, AND MRI ANALYSIS IN A SUBSET OF THE OLDER CHINESE ADULTS. THROUGH THIS EFFORT, WE WILL PROVIDE THE FIRST LINGUISTICALLY, CULTURALLY, AND NEUROANATOMICALLY APPROPRIATE COGNITIVE TESTS FOR MANDARIN SPEAKERS TO ENHANCE CLINICAL DETECTION OF MCI/AD, ENABLE EQUITABLE ENROLLMENT INTO CLINICAL TRIALS, REDUCE LANGUAGE-ASSOCIATED HEALTH DISPARITIES, AND DETERMINE IF BILINGUALISM IS NEUROPROTECTIVE AMONG MANDARIN SPEAKERS.

TRAINING OF UGANDANS IN BASIC RESEARCH ON TB AND EMERGING INFECTIOUS DISEASES

PPAR? INDUCES IL-6 TO TRIGGER DIABETIC CARDIOMYOPATHY