Albert Einstein College Of Medicine

CORE SUPPORT FOR CANCER CENTER

EINSTEIN AGING STUDY

PROVIDENT: PREPOSITIONING OPTIMIZED STRATEGIES FOR VACCINES AND IMMUNOTHERAPEUTICS AGAINST DIVERSE EMERGING INFECTIOUS THREATS - THE OVERARCHING GOAL OF PROVIDENT (PREPOSITIONING OPTIMIZED STRATEGIES FOR VACCINES AND IMMUNOTHERAPEU- TICS AGAINST DIVERSE EMERGING INFECTIOUS THREATS) IS TO DELIVER “PLUG-AND-PLAY” VACCINE AND THERAPEUTIC AN- TIBODY BLUEPRINTS FOR EMERGING ENVELOPED RNA VIRUSES BELONGING TO THREE FAMILIES—NAIROVIRIDAE, HAN- TAVIRIDAE, AND PARAMYXOVIRIDAE. PROVIDENT IS A HIGHLY INTERWOVEN PARTNERSHIP AMONG 13 INSTITUTIONAL TEAMS FROM ACADEMIA, GOVERNMENT, AND INDUSTRY. CENTRAL TO PROVIDENT IS ITS FOCUS ON PLATFORM STRATEGIES THAT CAN RAPIDLY ADVANCE MANUFACTURABLE PRODUCTS WITH PATHWAYS TO REGULATORY APPROVAL AND PLANS FOR THEIR COMMERCIALIZATION THROUGH INDUSTRY PARTNERS WHO ARE INTEGRAL TO OUR CONSORTIUM. PROVIDENT WILL ACCOMPLISH ITS GOALS BY SYNTHESIZING THE ACTIVITIES OF FOUR RESEARCH PROJECTS, SUPPORTED BY THREE RESEARCH CORES AND A DATA MANAGEMENT CORE, AND OVERSEEN BY THE ADMINISTRATIVE CORE. USING A PROTOTYPE VIRUS STRATEGY IN PHASE I, WE WILL: (I) DISCOVER AND DISSECT HOST FACTORS AND PATHWAYS CRITICAL FOR VIRAL INFECTION AND PATHOGENESIS AND DE- LIVER TOOLS TO OTHER PROVIDENT COMPONENTS TO FACILITATE VACCINE AND IMMUNOTHERAPEUTIC DEVELOPMENT; (II) USE ADVANCED ANTIGEN ENGINEERING TO REFINE VACCINE DESIGN STRATEGIES THROUGH ITERATIVE ASSESSMENTS OF IMMUNO- GENICITY AND PROTECTIVE EFFICACY TO GENERATE OPTIMIZED VACCINE IMMUNOGENS; (III) DEVELOP RNA VACCINES AND EVALUATE TWO PLATFORMS TO OPTIMIZE IMMUNOGENICITY, PROTECTIVE EFFICACY, AND SAFETY AND (IV) GENERATE AN ADAP- TIVE ANTIBODY DEVELOPMENT PIPELINE THAT WILL COMPLEMENT AND INFORM VACCINE DESIGN STRATEGIES. IN PHASE II, WE WILL EVALUATE OUR PROTOTYPE-OPTIMIZED VACCINE PLATFORMS AGAINST OUR DIVERGENT OUTGROUP VIRUSES IN A SERIES OF TIMED EXERCISES WE TERM “SPRINTS,” WHICH SEEK TO GENERATE A VACCINE PRODUCT READY TO IMMUNIZE ANIMALS IN 10 DAYS. IN DOING SO, WE WILL PERFORM CROSS-FAMILY VALIDATIONS OF OUR VACCINE PLATFORMS FOR NAIROVIRUSES, HAN- TAVIRUSES, AND PARAMYXOVIRUSES AS A RIGOROUS CHALLENGE TO THE GENERALIZABILITY OF THE PHASE I BLUEPRINT DELIVER- ABLE, AND EITHER VALIDATE THE BLUEPRINT OR IDENTIFY WEAKNESSES FOR FURTHER REFINEMENT.

WOMEN'S INTERAGENCY HIV STUDY (WIHS) IV

DNA REPAIR, MUTATIONS AND CELLULAR AGING

FUNCTIONAL CONSEQUENCES OF IMPAIRED AUTOPHAGY IN AGING

CENTRAL AFRICA IEDEA

CLINICAL RESEARCH SITES FOR THE MACS/WIHS COMBINED COHORT STUDY (MACS/WIHS-CCS)

EINSTEIN-ROCKEFELLER-CUNY CENTER FOR AIDS RESEARCH

EINSTEIN-MOUNT SINAI DIABETES RESEARCH CENTER

CLINICAL AND TRANSLATIONAL SCIENCE AWARD

MEDICAL SCIENTIST TRAINING PROGRAM

GENETIC VARIANT-BASED DRUG DISCOVERY TARGETING CONSERVED PATHWAYS OF AGING

PROMETHEUS: A PLATFORM FOR RAPID DEVELOPMENT OF HUMAN ANTIBODY-BASED THERAPEUTICS AND PROPHYLACTICS AGAINST EMERGING VIRAL THREATS

MOTILITY AND INVASION

PROTEIN DYNAMICS IN ENZYMATIC CATALYSIS

DYNAMIC COGNITIVE PHENOTYPES FOR PREDICTION OF MENTAL HEALTH OUTCOMES IN SERIOUS MENTAL ILLNESS - PROJECT SUMMARY THE PROPOSED WORK WILL ENHANCE CLINICAL PREDICTION FOR INDIVIDUALS WITH SERIOUS MENTAL ILLNESS (SMI), ACROSS DIAGNOSES, BY INCORPORATION OF NOVEL, SCALABLE COGNITIVE MEASURES THAT CAN BE DELIVERED IN ACUTE INPATIENT SETTINGS (FOR CLINICAL SCREENING), OUTPATIENT SETTINGS (FOR IDENTIFYING TIME PERIODS OF RELATIVE RISK), AND IN ETHNORACIALLY DIVERSE POPULATIONS. OUR OVERALL GOAL IS TO IMPROVE PREDICTION OF MENTAL HEALTH OUTCOMES AND CLINICAL DECISION-MAKING THROUGH THE VALIDATION AND INTEGRATION OF DYNAMIC COGNITIVE PHENOTYPES (NOVEL AND INNOVATIVE MEASURES THAT CAPTURE FLUCTUATIONS IN COGNITION AND BEHAVIOR OVER TIME) IN CLINICAL CARE. FOR AIM 1, WE WILL RECRUIT 1500 PARTICIPANTS ACROSS FIVE INPATIENT PSYCHIATRY UNITS (FOUR ADULT, ONE NONDEMENTIA GERIATRIC) AT MCLEAN HOSPITAL THAT PROVIDE CARE TO INDIVIDUALS WITH THE HIGHEST LEVELS OF CLINICAL SEVERITY. IN THIS GROUP, WE WILL USE A COMBINATION OF BRIEF COGNITIVE ECOLOGICAL MOMENTARY ASSESSMENT (OVER 3 DAYS), ACTIGRAPHY, AND CLINICAL RECORDS TO PROSPECTIVELY PREDICT CLINICAL HEALTH OUTCOMES, INCLUDING CHANGE IN TRANSDIAGNOSTIC SYMPTOMS, CHANGE IN SUICIDALITY, LENGTH OF STAY, AND 12-MONTH HOSPITALIZATION (FROM ELECTRONIC HEALTH RECORDS). DYNAMIC COGNITIVE PHENOTYPES DERIVED FROM TIME SERIES DATA (INCLUDING SLOPE OF COGNITIVE CHANGE, DIURNAL CYCLE, VOLATILITY, COGNITION/SYMPTOM COUPLING) WILL BE USED TO IMPROVE PREDICTION. FOR AIM 2, 250 PARTICIPANTS WILL BE FOLLOWED POST-DISCHARGE TO COLLECT LONGITUDINAL COGNITIVE ECOLOGICAL MOMENTARY ASSESSMENT (EMA) DATA AND BUILD PERSONALIZED MODELS OF CLINICAL RISK. IN AIM 3, WE WILL EVALUATE GENERALIZABILITY AND TRANSFER LEARNING OF CLINICAL PREDICTION MODELS FROM AIMS 1-2, APPLIED TO 250 ETHNORACIALLY DIVERSE PARTICIPANTS WITH ELEVATED PSYCHIATRIC SYMPTOMS RECRUITED FROM BRONX COUNTY, NEW YORK WHO ARE PATIENTS IN THE MONTEFIORE HEALTH SYSTEM. FINALLY, IN AIM 4, WE WILL ADAPT COGNITIVE ASSESSMENT TO ENSURE BROAD USABILITY AMONG CULTURALLY- DIVERSE PARTICIPANTS INCLUDING THOSE WITH LOW ENGLISH LITERACY THROUGH PARTICIPATORY DESIGN SESSIONS AND LARGE- SCALE ONLINE DATA COLLECTION. ACROSS AIMS, THE PROJECT WILL INCORPORATE STRUCTURED AND ETHICAL RETURN OF INDIVIDUAL RESULTS TO PATIENTS, CLINICIANS, AND VOLUNTEERS TO ENHANCE THE POTENTIAL FOR CLINICAL INTEGRATION AND SUPPORT ENGAGEMENT AND TRUST AMONG DIVERSE PERSPECTIVES. THIS PROJECT IS SIGNIFICANT AS IT WILL IMPROVE RISK STRATIFICATION, ALLOWING RESOURCES TO BE DIRECTED TO THOSE MOST IN NEED AND DURING RISK PERIODS WHEN TIMELY INTERVENTION CAN MOST IMPROVE CLINICAL OUTCOMES. SUCCESSFUL COMPLETION OF THE AIMS WILL CREATE LOW-COST AND SCALABLE COGNITIVE PREDICTION TOOLS THAT CAN BE WIDELY DISSEMINATED (AS PART OF EXISTING DISSEMINATION INFRASTRUCTURE) FOR SCREENING AND PERSONALIZED PREDICTION ACROSS CLINICAL SETTINGS AND IN DIVERSE POPULATIONS.

EINSTEIN-MONTEFIORE CLINICAL AND TRANSLATIONAL SCIENCE AWARD HUB - THE HAROLD AND MURIEL BLOCK INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH (ICTR) AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND MONTEFIORE MEDICAL CENTER SERVES AS THE HOME OF OUR CTSA PROGRAM. THE VISION OF THE ICTR IS TO IMPROVE THE HEALTH OF THE BRONX, AND OTHER COMMUNITIES THAT DISPROPORTIONATELY AND UNJUSTLY SUFFER FROM POOR HEATH AND PREMATURE DEATH, BY ACCELERATING THE TRANSLATION OF BIOMEDICAL DISCOVERIES INTO EFFECTIVE AND SUSTAINABLE DISEASE PREVENTION AND TREATMENT STRATEGIES. CREATED IN 2007, THE ICTR HAS TRANSFORMED CLINICAL AND TRANSLATIONAL RESEARCH (CTR) THROUGHOUT EINSTEIN AND MONTEFIORE BY CREATING A ROBUST RESEARCH ENVIRONMENT; RE- ENGINEERING CTR PROCESSES; INTEGRATING RESEARCH AND HEALTHCARE; AND DEVELOPING STRONG COMMUNITY RELATIONSHIPS. THE ICTR THEME OF “BUILDING BRIDGES IN THE BRONX AND BEYOND” UNDERSCORES THE IMPORTANCE OF BRIDGING GAPS BETWEEN OUR RESEARCHERS, HEALTH SYSTEM LEADERS, CLINICIANS, PATIENTS, COMMUNITIES, AND CTSA PARTNERS TO ADVANCE TRANSLATIONAL SCIENCE AND HEALTH EQUITY. THE SPECIFIC AIMS OF THE ICTR ARE TO: (1) CATALYZE INNOVATIONS THAT WILL ENHANCE THE EFFICIENCY AND EFFECTIVENESS OF TRANSLATIONAL RESEARCH. WE WILL SUPPORT AND FUND STUDIES WITH HIGH POTENTIAL TO OVERCOME MAJOR CTR ROADBLOCKS AND HEALTH INEQUITIES; CREATE METHODOLOGICAL AND INFORMATICS TRANSLATIONAL SCIENCE INNOVATIONS; IMPROVE CTR OPERATIONS, AND ENHANCE DISSEMINATION AND IMPLEMENTATION STRATEGIES. (2) ENGAGE COMMUNITIES, PATIENTS, AND OTHER PARTNERS EARLY AND THROUGHOUT THE TRANSLATIONAL PROCESS. OUR NEW COMMUNITY AND STAKEHOLDER ENGAGEMENT RESEARCH MODULE WILL TRANSFORM OUR LEARNING HEALTH SYSTEM INTO A “LEARNING HEALTH RESEARCH COMMUNITY”; PROMOTE ACTIVE AND CONTINUOUS BIDIRECTIONAL COMMUNICATION WITH COMMUNITIES, PATIENTS AND OTHER PARTNERS; FACILITATE RESEARCH TO IDENTIFY AND MITIGATE SOCIAL DETERMINANTS OF HEALTH, AND ENHANCE UPTAKE OF EVIDENCE-BASED PROGRAMS BY TARGET POPULATIONS. (3) DEVELOP AND IMPLEMENT STATE-OF-THE-ART CLINICAL RESEARCH AND INFORMATICS RESOURCES AND SERVICES TO IMPROVE THE RIGOR, SAFETY, EFFICIENCY, EFFECTIVENESS, AND GENERALIZABILITY OF CTR. (4) TRAIN, DEVELOP, AND MAINTAIN A SKILLED, MULTIDISCIPLINARY, AND DIVERSE TRANSLATIONAL WORKFORCE TO SUPPORT AND LEAD HIGH QUALITY RESEARCH WITH NEW TRAINING AND PATHWAY PROGRAMS TO ENSURE MEMBERS OF HISTORICALLY EXCLUDED GROUPS ENGAGE IN CTR AND BECOME RESEARCH LEADERS. (5) PARTNER WITH OTHER CTSA HUBS AND THE CTSA CONSORTIUM TO ACCELERATE CTR AND RAPIDLY RESPOND TO URGENT PUBLIC HEALTH NEEDS. OUR AIMS ARE ALIGNED WITH THE NEW CTSA PROGRAM GOALS AND WILL ENABLE THE ICTR TO MAXIMALLY CONTRIBUTE TO THE COLLECTIVE EFFORTS OF THE NATIONAL COLLABORATIVE CTSA CONSORTIUM TO DELIVER MORE TREATMENTS TO MORE PATIENTS MORE QUICKLY IN THE BRONX AND BEYOND.

DEVELOPMENTAL IMPACT OF NICU EXPOSURES (DINE)

GENETIC BASIS OF SYNDROMIC AND NON-SYNDROMIC CONGENTIAL HEART DEFECTS

LIVER PATHOBIOLOGY AND GENE THERAPY RESEARCH CORE CENTER

INTEGRATED CARE FOR CHRONIC PAIN AND OPIOID USE DISORDER: THE IMPOWR RESEARCH CENTER AT MONTEFIORE/EINSTEIN (IMPOWR-ME) - ABSTRACT CHRONIC PAIN (CP) AND OPIOID USE DISORDER (OUD) ARE LEADING CAUSES OF MORBIDITY AND MORTALITY IN THE UNITED STATES. DESPITE BEING COMMONLY COMORBID, THERE IS A STRIKING LACK OF INTEGRATED TREATMENTS ACCESSIBLE TO PEOPLE IN NEED. THIS IS PARTICULARLY TRUE FOR BLACK AND HISPANIC INDIVIDUALS LIVING AND SEEKING CARE IN UNDER-RESOURCED SETTINGS LIKE THE BRONX, NY, ONE OF THE POOREST AND MOST RACIALLY DIVERSE COUNTIES IN THE U.S. SUBMITTED IN RESPONSE TO THE HEAL INITIATIVE: INTEGRATIVE MANAGEMENT OF CHRONIC PAIN AND OUD FOR WHOLE RECOVERY (IMPOWR) RFA-DA-21-030, THE OVERALL GOAL OF THIS PROPOSAL IS TO CREATE THE IMPOWR RESEARCH CENTER AT MONTEFIORE/EINSTEIN (“IMPOWR-ME”), IN THE HIGH-IMPACT COUNTY OF THE BRONX NY. IMPOWR-ME IS A SYNERGISTIC MULTIDISCIPLINARY RESEARCH CENTER THAT LEVERAGES EXCEPTIONAL RESEARCH INFRASTRUCTURE IN CP AND OUD AND EXISTING RELATIONSHIPS WITH PEOPLE LIVING WITH CP AND OUD, ADVOCATES, POLICYMAKERS AND PAYERS, AND HEALTH SYSTEM STAKEHOLDERS. THE AIMS OF IMPOWR-ME ARE TO: 1) CREATE A ROBUST AND SUSTAINABLE RESEARCH INFRASTRUCTURE TO RIGOROUSLY TEST AND DISSEMINATE INTEGRATED AND COST-EFFECTIVE EVIDENCE-BASED PRACTICES FOR PEOPLE WITH CP AND OUD; 2) PARTNER WITH PEOPLE WITH LIVED EXPERIENCE WITH CP, OUD, OR BOTH, AND DIVERSE STAKEHOLDERS IN ALL STAGES OF THE RESEARCH; AND 3) PROVIDE OPPORTUNITIES FOR MULTIDISCIPLINARY EARLY STAGE INVESTIGATORS TO BECOME INDEPENDENT RESEARCHERS FOCUSING ON CP AND OUD. THREE INNOVATIVE HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION TRIALS ARE PROPOSED TO RIGOROUSLY EXAMINE MULTI-MODAL EVIDENCE-BASED PRACTICES IN DIVERSE HEALTH CARE SETTINGS AND POPULATIONS OF PEOPLE WITH COMORBID CP AND OUD. SPECIFICALLY, WE PROPOSE: 1) A THREE-ARM TRIAL OF YOGA AND PHYSICAL THERAPY ONSITE AT METHADONE OPIOID TREATMENT PROGRAMS, 2) A 2X2 FACTORIAL TRIAL TO TEST ACCEPTANCE AND COMMITMENT THERAPY AND A CARE MANAGEMENT SMARTPHONE APP FOR INDIVIDUALS IN PRIMARY-CARE BASED BUPRENORPHINE TREATMENT, AND 3) A TWO-ARM TRIAL TO TEST MICRODOSING VS. STANDARD INDUCTION OF BUPRENORPHINE FOR HOSPITALIZED PATIENTS. PARTICIPANTS IN ALL PROJECTS HAVE BOTH CP AND OUD OR OPIOID MISUSE, AND SPECIFIC AIMS FOR EACH PROJECT WILL EXAMINE CP, OUD, IMPLEMENTATION, AND COST-EFFECTIVENESS OUTCOMES; ADDITIONAL PATIENT-CENTERED OUTCOMES WILL BE DRIVEN BY PEOPLE WITH LIVED EXPERIENCE. ALL THREE PROJECTS IMPROVE ACCESS TO CARE FOR BLACK AND HISPANIC INDIVIDUALS IN UNDER-RESOURCED SETTINGS BY BRINGING INTEGRATED TREATMENT OF CP AND OUD TO THEM, AND THE INTERVENTIONS HAVE HIGH POTENTIAL FOR DISSEMINATION AND SUSTAINABILITY. AN INNOVATIVE PROGRAM FOR PILOT STUDIES ACHIEVES A DUAL AIM OF CATALYZING STAKEHOLDER-DRIVEN RESEARCH AND TRAINING EARLY STAGE AND NEW INVESTIGATORS. AN EXCEPTIONAL TEAM OF INVESTIGATORS AND CLINICAL EXPERTS FOCUSED ON CP AND OUD, A LONGSTANDING HISTORY OF COLLABORATION WITH STAKEHOLDERS AND PEOPLE WITH LIVED EXPERIENCE, AND A HIGH-IMPACT POPULATION MAKE MONTEFIORE-EINSTEIN AN IDEAL SITE FOR AN IMPOWR RESEARCH CENTER.

DRUG AT THE RIGHT PLACE & CONCENTRATION: OPTIMIZING COMBINATION VAGINAL RING PR*

TRANSLATIONAL PLATFORM FOR EPILEPSY THERAPY AND BIOMARKER DISCOVERY - PROJECT SUMMARY THERE IS CURRENTLY NO VALIDATED TREATMENT TO PREVENT THE DEVELOPMENT OF ACQUIRED EPILEPSIES, SUCH AS POST- TRAUMATIC EPILEPSY. THE AVAILABILITY OF BIOMARKER THAT PREDICTS, AT AN EARLY STAGE, PEOPLE AT RISK TO DEVELOP EPILEPSY AND BENEFIT FROM TREATMENT INTERVENTIONS WOULD SIGNIFICANTLY ACCELERATE AND DE-RISK THE PROCESS OF IDENTIFYING AN ANTIEPILEPTOGENIC THERAPY. IN THIS STUDY, THAT IS BASED ON COLLABORATIONS AND PRELIMINARY DATA DERIVED FROM EPIBIOS4RX, AN NINDS FUNDED CENTER WITHOUT WALLS, WE AIM TO CREATE A RIGOROUS AND EFFECTIVE PRECLINICAL MODEL TO SCREEN A NEW CANDIDATE TREATMENT TO PREVENT POSTTRAUMATIC EPILEPSY IN THE LATERAL FLUID PERCUSSION INJURY MODEL AS WELL AS IDENTIFY BIOMARKERS TO GUIDE TREATMENT IMPLEMENTATION. WE WILL FOLLOW A MULTICENTER, DOUBLE-BLINDED, VEHICLE-CONTROLLED, RANDOMIZED PRECLINICAL ANTIEPILEPTOGENESIS STUDY FOLLOWING THE HIGH STANDARDS OF RIGOR ADVOCATED BY NINDS, THE AES/ILAE TRANSLATIONAL RESEARCH TASK FORCE AND THE ARRIVE GUIDELINES. WE HAVE FORMED A COLLABORATIVE GROUP OF FOUR INTERNATIONAL PRECLINICAL TESTING CENTERS (ALBERT EINSTEIN COLLEGE OF MEDICINE, UNIVERSITY OF MELBOURNE, TWO UCLA SITES), SUPPORTED BY EXPERTS IN PHARMACOKINETIC MODELING (UNIVERSITY OF MINNESOTA), PROTEIN BIOMARKER RESEARCH (UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SERVICES) AND BIOINFORMATICS (UNIVERSITY OF SOUTHERN CALIFORNIA). WE PLAN TO TEST A COMPOUND THAT REMOVES PATHOLOGICAL IRON STORES FROM THE BRAIN AND TEST WHETHER IT CAN MODIFY EARLY BIOMARKERS OF EPILEPTOGENESIS AND INJURY. WE AIM TO IDENTIFY (A) AT LEAST ONE PANEL OF MULTIMODAL BIOMARKERS THAT CAN PREDICT EARLY ON TREATMENT RESPONSE TO THE IRON CHELATOR, INCLUDING THE DEVELOPMENT OF POST-TRAUMATIC EPILEPTOGENESIS, (B) AT LEAST ONE BIOMARKER OF EPILEPTOGENESIS, (C) AND DETERMINE WHETHER IRON CHELATOR TREATMENT CAN PREVENT POST-TRAUMATIC EPILEPSY DEVELOPMENT.

EINSTEIN'S NATHAN SHOCK CENTER OF EXCELLENCE IN BASIC BIOLOGY OF AGING

TRAINING PROGRAM IN CELLULAR AND MOLECULAR BIOLOGY AND GENETICS

TRANSITION STATE ANALYSIS OF ENZYMATIC REACTIONS

THE BIOLOGY OF LUNG METASTASIS IN BREAST CANCER - METASTASIS IS THE MAJOR CAUSE OF MORTALITY IN HUMAN BREAST CANCER. THE MECHANISMS BY WHICH THE PRIMARY TUMOR MICROENVIRONMENT PROMOTES THE INVASION AND INTRAVASATION OF TUMOR CELLS HAS BEEN EXTENSIVELY STUDIED. IN CONTRAST, THE MECHANISMS REGULATING EXTRAVASATION OF BLOOD-BORNE TUMOR CELLS AT DISTAL SITES, THEIR SURVIVAL AND PROLIFERATION IN THEIR NEW MICROENVIRONMENT, AND THEIR RE-DISSEMINATION TO ADDITIONAL SITES, ARE LESS STUDIED AND NOT WELL UNDERSTOOD. THEREFORE, THE INVESTIGATION OF THE MECHANISMS THAT REGULATE BREAST CANCER CELLS AT THE METASTATIC SITE ARE AN AREA OF INTENSE SCIENTIFIC INTEREST WITH IMPORTANT CLINICAL APPLICATIONS. CTCS EFFICIENTLY DISSEMINATE THROUGHOUT THE BODY BUT FORM METASTASES WITH LOW FREQUENCY. THE CTCS THAT SUCCESSFULLY EXTRAVASATE, SURVIVE AND GROW AT DISTAL SITES HAVE ACQUIRED STEM-LIKE CHARACTERISTICS THAT PROMOTE THESE PROCESSES. THE ACQUISITION OF STEM-LIKE PROPERTIES IS CLOSELY LINKED TO THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). THUS, THE TRANSCRIPTIONAL CONTROL OF STEMNESS AND EMT IS AN IMPORTANT REGULATOR OF METASTATIC EFFICIENCY. STEMNESS AND/OR EMT IS INDUCED BY METABOLIC, HYPOXIC AND REDOX STRESS, AS WELL AS BY INTERACTIONS WITH MACROPHAGES AND PLATELETS. UNDERSTANDING THE REGULATION OF TUMOR CELL STEMNESS BY STROMAL CELLS COULD LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF METASTATIC DISEASE. PREVIOUS STUDIES ON THE ROLE OF STEMNESS IN METASTASIS TO DISTAL SITES HAS BEEN SIGNIFICANTLY LIMITED BY THE ANALYTIC METHODS USED. WE HAVE DEVELOPED GROUND-BREAKING NEW TECHNIQUES THAT ALLOW US TO DIRECTLY INTERROGATE THE RELATIONSHIP BETWEEN STEMNESS AND THE EFFICIENCY OF EXTRAVASATION, SURVIVAL AND GROWTH IN VIVO. OUR NOVEL IMAGING METHODS COMBINE THE USE OF A PERMANENT LUNG IMAGING WINDOW COMPATIBLE WITH MULTIPHOTON MICROSCOPY, NOVEL COMPUTATIONAL RECONSTRUCTIONS OF LARGE FIELDS OF VIEW, AND NEWLY DEVELOPED BIOSENSORS THAT REPORT ON THE INDUCTION OF STEMNESS, HYPOXIA AND ROS. THESE TOOLS ALLOW THE VISUALIZATION AND ANALYSIS OF BREAST CANCER CELLS AS THEY EXTRAVASATE AND FORM METASTATIC COLONIES IN THE LUNG. IN CONTRAST, TRADITIONAL END-POINT ANALYSES OF FIXED TISSUES CANNOT PROVIDE INFORMATION ON THE ROLE OF STEMNESS DURING EXTRAVASATION AND METASTATIC GROWTH. THIS PROGRAM PROJECT IS ORGANIZED AROUND THREE MAJOR QUESTIONS. FIRST, WE WILL DEFINE THE SIGNALING PATHWAYS THAT REGULATE BREAST CANCER CELLS IN THE LUNG METASTATIC NICHE. SECOND, WE WILL EXPLORE THE INDUCTION OF STEM-LIKE PROPERTIES IN TUMOR CELLS BY INTERACTIONS WITH STROMAL CELLS, AS A CRITICAL REGULATOR OF EXTRAVASATION AND SUBSEQUENT METASTATIC GROWTH IN THE LUNG. THIRD, WE WILL PURSUE NOVEL PRELIMINARY DATA ON THE EFFECTS OF CHEMOTHERAPY IN THE METASTATIC SITE. TAKING ADVANTAGE OF IMPORTANT SYNERGIES BETWEEN THE PROJECTS AND INNOVATIVE METHODOLOGICAL ADVANCES BY THE CORES, THIS PPG IS WELL-POSITIONED TO MAKE GROUND-BREAKING CONTRIBUTIONS TO OUR UNDERSTANDING OF CTC EXTRAVASATION AND GROW IN THE LUNG, AS WELL AS THEIR RE-DISSEMINATE TO TERTIARY SITES. THESE STUDIES WILL PROVIDE PARADIGM-SHIFTING INSIGHTS INTO THE BIOLOGY OF METASTASIS, WITH IMPORTANT IMPLICATIONS FOR THE CLINICAL TREATMENT OF SYSTEMIC METASTATIC DISEASE IN BREAST CANCER.

PAX6 AS A KEY REGULATOR OF LENS DEVELOPMENT

CONSEQUENCES OF PROLONGED FEBRILE SEIZURES IN CHILDHOOD

CENTER FOR CAENORHABDITIS ELEGANS ANATOMY

DNA REPLICATION INITIATION SITES IN MAMMALIAN CELLS

HEALTHY START INITIATIVE-ELIMINATING RACIAL/ETHNIC DISPARITIES

TRANSCRIPTIONAL CONTROL OF THE MOUSE AA-CRYSTALLIN LOCUS

BRONX EINSTEIN TRAINING IN TEACHING AND RESEARCH (BETTR)

TRANSITIONING EARLY CAREER NEUROSURGEONS TO SCIENTIFIC INDEPENDENCE

MECHANISM OF ACTIN MRNA LOCALIZATION AND LOCALIZED TRANSLATION IN NEURONS

MOLECULAR ANALYSIS OF ALPHAVIRUS MEMBRANE FUSION PROTEIN

PAUL CALABRESIS CAREER DEVELOPMENT AWARD FOR CLINICAL ONCOLOGY

VALIDATION OF THE REMOTE COGNITIVE AGING AND ALZHEIMER?S DISEASE RESEARCH (R-CARE) TOOLBOX FOR DIVERSE POPULATIONS - ABSTRACT IN-PERSON ADMINISTRATION IS THE CURRENT “GOLD-STANDARD” FOR ASSESSMENT OF COGNITION AND FUNCTION IN STUDIES OF ALZHEIMER’S DISEASE AND OTHER DEMENTIA (ADRD). REMOTE NEUROPSYCHOLOGICAL ASSESSMENT HAS BEEN ADVOCATED TO OVERCOME VARIOUS ACCESS BARRIERS AND DECREASE COSTS OF NEUROPSYCHOLOGICAL SERVICES. MOREOVER, DUE TO THE PRESSING CHALLENGES AND SAFETY CONCERNS IMPOSED BY THE COVID-19 PANDEMIC, THERE IS AN URGENT NEED FOR ROBUST METHODS FOR ASSESSING AND MONITORING COGNITIVE AND FUNCTIONAL STATUS THROUGH REMOTE ASSESSMENTS. THE OVERALL GOAL OF THE CURRENT PROJECT IS TO VALIDATE, REFINE, AND CALIBRATE THE REMOTE COGNITIVE AGING AND ALZHEIMER’S DISEASE RESEARCH (R-CARE) TOOLBOX FOR THE ASSESSMENT AND MONITORING OF COGNITION AND FUNCTION IN A DIVERSE SAMPLE OF INITIALLY DEMENTIA-FREE OLDER ADULTS. THE TOOLBOX WILL INCLUDE MEASURES FROM THE UNIFORM DATA SET, NEUROPSYCHOLOGICAL BATTERY (UDSNB-3.0), COMPLEMENTED BY FREQUENTLY USED TESTS IN PRECLINICAL AD TRIALS. IN-PERSON TESTS THAT POSE CHALLENGES FOR REMOTE ADMINISTRATION WILL BE REPLACED WITH TABLET-BASED COMPUTERIZED TASKS. WE WILL RECRUIT 600 DEMENTIA-FREE, RACIALLY/ETHNICALLY DIVERSE (~ 1/3 NON-HISPANIC BLACK, 1/3 HISPANIC, AND 1/3 NON- HISPANIC WHITE), COMMUNITY-RESIDING PARTICIPANTS AGED =65 YEARS. A RANDOMIZED, COUNTERBALANCED DESIGN WILL BE USED TO ADMINISTER A COMPREHENSIVE CLINICAL AND COGNITIVE BATTERY ACROSS BOTH ASSESSMENT MODES (IN-PERSON VS. REMOTE) SEPARATED BY 2-6 WEEKS AT BASELINE, WITH FOLLOW UP VISITS AT 18 AND 36 MONTHS. DIGITAL BIOMARKERS (COMPUTERIZED TESTS AND SPEECH-BASED) AND ADRD BLOOD-BASED BIOMARKERS WILL BE COLLECTED. AIM 1: TO EVALUATE THE PSYCHOMETRIC PROPERTIES OF REMOTE COGNITIVE TESTS AND ASSESS THEIR VALIDITY AGAINST STANDARD IN-PERSON TESTS. AIM 2: TO EVALUATE COMPARABILITY OF LONGITUDINAL CHANGE IN GLOBAL COGNITION AND WITHIN COGNITIVE DOMAINS ACROSS MODES OF ASSESSMENT (IN-PERSON VS REMOTE) FOR THE WHOLE SAMPLE AS WELL AS SUBGROUPS DEFINED BY SEX AND RACE/ETHNICITY. AIM 3 (EXPLORATORY): TO IDENTIFY NOVEL DIGITAL BIOMARKERS THAT PROVIDE INCREMENTAL VALIDITY FOR DIFFERENTIATING CLINICAL AND PATHOLOGICAL DISEASE STAGES, AND FOR MEASURING AND PREDICTING COGNITIVE AND FUNCTIONAL DECLINE. COLLECTIVELY, THIS STUDY WILL VALIDATE REMOTELY ADMINISTERED TESTS ACROSS DIFFERENT COGNITIVE DOMAINS, PROVIDE EVIDENCE FOR CROSS-SECTIONAL AND LONGITUDINAL VALIDITY, AND PROVIDE NORMATIVE DATA FOR REMOTE TESTS IN DIVERSE POPULATIONS. OUR LONG-TERM GOAL IS TO DEVELOP AN OPEN-SOURCE, RELIABLE AND VALID TOOLBOX THAT WOULD ENABLE AD-RESEARCHERS AND CLINICIANS TO EVALUATE OLDER ADULTS FROM DIVERSE BACKGROUNDS REGARDLESS OF ABILITY TO ATTEND IN-PERSON VISITS. 1

CHEMOKINES IN HEALING MYOCARDIAL INFARCTS

PROTEIN RNA REARRANGEMENTS IN THE SPLICEOSOME

RESOLUTION OF INFLAMMATION IN HEALING MYOCARDIAL INFARCTS

PASOS: PERIPHERAL ARTERY DISEASE STUDY OF SOL. AN ANCILLARY STUDY OF THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS

MECHANISMS OF METHYLMERCURY INDUCED NEURONAL TOXICITY

MECHANISMS OF STRESS-ENHANCED AVERSIVE CONDITIONING

ADHESION MECHANISMS MEDIATING SICKLE CELL VASOOCCLUSION IN VIVO

NEW YORK REGIONAL CENTER FOR DIABETES TRANSLATION RESEARCH

LSDS:A PILOT NBS AND EXAMINATION OF THE ASSOCIATED ETHICAL LEGAL & SOCIAL ISSUES

MEDICAL SCIENTIST TRAINING PROGRAM - PROJECT SUMMARY THE MISSION OF THE ALBERT EINSTEIN COLLEGE OF MEDICINE MEDICAL SCIENTIST TRAINING PROGRAM (MSTP) IS TO TRAIN PHYSICIAN-SCIENTISTS WHO WILL BECOME LEADERS IN BIOMEDICAL RESEARCH TO UNDERSTAND, DETECT, TREAT, AND PREVENT HUMAN DISEASE. TO ACCOMPLISH THIS MISSION, WE HAVE THREE GOALS, 1) TO RECRUIT A DIVERSE GROUP OF STUDENTS WITH OUTSTANDING POTENTIAL TO BECOME RESEARCH-ACTIVE PHYSICIAN-SCIENTISTS, 2) TO PROVIDE TRAINING IN AN INCLUSIVE, SAFE, AND STIMULATING LEARNING ENVIRONMENT WHERE STUDENTS CAN ACQUIRE THE FOUNDATIONAL KNOWLEDGE AND THE TECHNICAL, OPERATIONAL, AND PROFESSIONAL SKILLS NECESSARY TO PURSUE A CAREER AS A RESEARCH-ACTIVE PHYSICIAN- SCIENTIST AND A LEADER IN ACADEMIC MEDICINE AND/OR BIOMEDICAL RESEARCH, AND 3) TO SUPPORT/FACILITATE THEIR PROFESSIONAL DEVELOPMENT TO TRANSITION TO THE NEXT STAGE IN THE TRAINING CONTINUUM. THROUGH A HOLISTIC ADMISSIONS PROCESS, WE SEEK TO IDENTIFY INDIVIDUALS WITH THE INTELLIGENCE, CURIOSITY, CREATIVITY, RESILIENCE, PERSEVERENCE, AND ENTHUSIAM FOR SCIENCE THAT IS ESSENTIAL FOR A SUCCESSFUL RESEARCH CAREER. WE GUIDE THE STUDENTS THROUGH A PROGRAM TAILORED TO MEET THEIR INDIVIDUAL NEEDS AND INTERESTS. THE PROGRAM PROVIDES RIGOROUS, INTEGRATED MEDICAL AND RESEARCH TRAINING THROUGH A FLEXIBLE, CONTINOUSLY EVOLVING CURRICULUM THAT INCLUDES 1) SPECIALIZED MSTP COURSES, AND 2) INTEGRATION OF GRADUATE AND MEDICAL SCHOOL CURRICULUM IN THE FIRST 2 YEARS AND THROUGHOUT THE PROGRAM. THE TRAINING PROGRAM HAS 3 PHASES. IN THE FIRST 2 YEARS STUDENTS TAKE A COMBINATION OF MEDICAL, GRADUATE, AND MSTP-SPECIFIC COURSES TO GAIN THE DIDACTIC FOUNDATION FOR THEIR RESEACH AND CLINICAL TRAINING. RESEARCH ROTATIONS AND GUIDANCE FROM PROGRAM LEADERSHIP ASSIST THEM IN THESIS LAB SELECTION. IN THE PROGRAM’S 2ND PHASE, STUDENTS PERFORM INDEPENDENT, ORIGINAL RESEARCH UNDER THEIR MENTOR’S GUIDANCE. THEY PUBLISH THEIR DISCOVERIES IN HIGH QUALITY, PEER-REVIEWED PAPERS, AND PREPARE AND DEFEND A PHD THESIS. PARTICIPATION IN A PHD PHASE MSTP-RUN, OUTPATIENT CLINIC BUILDS CLINICAL SKILLS. IN THE FINAL PHASE, THEY COMPLETE THEIR CLINICAL TRAINING. A MULTIFACETED APPROACH TRAINS STUDENTS TO PERFORM RIGOROUS AND REPRODUCIBLE RESEARCH IN A RESPONSIBLE, ETHICAL MANNER. CURRENTLY, THE PROGRAM HAS 113 TRAINEES, 41% WOMAN, 28% FROM GROUPS UNDERREPRESENTED IN MEDICINE (TWICE PERCENTAGE IN THE APPLICANT POOL), AND 11% WITH DISABILITIES. WE WILL EXPAND TO ~120-130 TRAINEES BY INCREASING THE ENTERING CLASS SIZE TO 16. SINCE ITS INCEPTION IN 1964, AS ONE OF THE FIRST THREE NIH-FUNDED MSTPS, 484 TRAINEES HAVE GRADUATED. 413 HAVE COMPLETED POSTGRADUATE TRAINING AND PUBLISHED OVER 19,000 PAPERS, AN AVERAGE OF ~47 PAPERS/GRADUATE. 74% HAVE JOBS AT ACADEMIC MEDICAL CENTERS, RESEARCH INSTITUTES, NIH OR PHARMACEUTICAL COMPANIES. BY VARIOUS MEASURES, THE GRADUATES HAVE ACHIEVED OUTSTANDING SUCCESS AND ADVANCED BIOMEDICAL RESEARCH AND ACADEMIC MEDICINE. WE PROPOSE TO FURTHER INTEGRATE GRADUATE AND MEDICAL TRAINING, AND INCREASE OPPORTUNITIES FOR INVOLVEMENT IN CLINICAL AND TRANSLATIONAL RESEARCH TO PREPARE A FUTURE GENERATION OF PHYSICIAN-SCIENTISTS WHO WILL BE AT THE LEADING EDGE OF BIOMEDICAL RESEARCH WITH THE ULTIMATE GOAL OF IMPROVING HUMAN HEALTH AND REDUCING THE BURDEN OF DISEASE.

EFFECT OF BUPRENORPHINE ON MONOCYTES IN THE CONTEXT OF NEUROAIDS AND OPIOID ABUSE

NUCLEUS ACCUMBENS PROCESSING OF REWARD-PREDICTIVE CUES

FUNCTIONAL DETERMINANTS OF METASTATIC DORMANCY

TRAINING IN AGING RESEARCH

NOVEL REPORTER PHAGES TO DETECT COMPLEX TB DRUG RESISTANCE AND PERSISTENCE

PLASTICITY OF ELECTRICAL SYNAPSES

EINSTEIN BSL3 LABORATORY RENOVATION TO ADVANCE BIOMEDICAL RESEARCH ON RNA VIRUSES OF PANDEMIC POTENTIAL - ABSTRACT WE PROPOSE TO RENOVATE EXISTING LABORATORY SPACE IN THE CHANIN BUILDING AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE (EINSTEIN) WHICH WILL EXPAND AND IMPROVE AVAILABLE BSL-3 AND ABSL-3 FACILITIES TO SERVE THE GROWING NEEDS OF OUR EINSTEIN INVESTIGATORS WHO CONDUCT RESEARCH ON EMERGING RNA VIRUSES WITH THE ULTIMATE GOAL OF VACCINE AND THERAPEUTICS DEVELOPMENT. OUR CURRENT SMALL VIROLOGY BSL-3 FACILITY LACKS THE SPACE TO MEET CURRENT AND PROJECTED INVESTIGATOR DEMAND AND TO HOUSE THE EQUIPMENT NEEDED TO CONDUCT CUTTING-EDGE IN VITRO AND CELL-BASED STUDIES AND WORK WITH ANIMALS. IN ADDITION TO RENOVATION THAT INCLUDES EXPANDED BSL-3 AND ABSL-3 SPACE (1497 SQ FT SPECIFICALLY FOR RNA VIRUS RESEARCH), OUR PLAN INCLUDES MODERNIZATION OF BUILDING SYSTEMS AND INVESTMENTS IN FIXED EQUIPMENT AND NOVEL NONFIXED SCIENTIFIC EQUIPMENT TO ENHANCE AND STREAMLINE LABORATORY OPERATIONS. FURTHER, THE EXISTING BSL-3 SPACE IN CHANIN HAS TEMPERATURE CONTROL SYSTEMS WHICH ARE INADEQUATE AND SORELY IN NEED OF UPDATING; THIS WILL BE ALLEVIATED BY NEW AND INDEPENDENT SYSTEM FOR TEMPERATURE, HUMIDITY AND EXHAUST (DEDICATED AND REDUNDANT). WE THEREFORE REQUEST SUPPORT FOR THE FOLLOWING AIMS, WHICH ARE INTENDED TO EXPAND AND UPGRADE OUR EXISTING FACILITY, WITH NEW TECHNOLOGIES FOR LABORATORY SUPPORT, ANIMAL HOLDING, AND ENERGY EFFICIENCY. IN THE FOLLOWING SECTIONS, WE DESCRIBE AN OVERSIGHT PROCESS THAT WILL FACILITATE ALL ASPECTS OF THE RENOVATION PROCESS. AIM 1. MODERNIZE AND EXPAND OVERALL BSL-3 SPACE IN THE CHANIN BUILDING FOR EMERGING RNA VIRUS RESEARCH. AIM 2. CREATE INFRASTRUCTURE FOR ANIMAL VIRUS STUDIES AT THE BSL-3 LEVEL. AIM 3. FURNISH THE RENOVATED LABORATORY SPACE WITH FIXED EQUIPMENT AND NOVEL NONFIXED SCIENTIFIC EQUIPMENT TO RESULT IN A FULLY EQUIPPED EMERGING RNA VIRUS BSL-3 LABORATORY SPACE. THIS PROPOSAL INCLUDES INSTITUTIONAL SUPPORT TO SIGNIFICANTLY SUPPLEMENT LAB EQUIPMENT FOR THIS PROJECT, ENSURE ONGOING MAINTENANCE OF ALL EQUIPMENT AND INFRASTRUCTURE IMPROVEMENTS, AND PROVIDE NEEDED PERSONNEL SUPPORT. FINALLY, EINSTEIN IS COMMITTING PILOT FUNDING TO ENABLE MORE INVESTIGATORS TO UTILIZE THE NEW FACILITY AND OBTAIN DATA TO SUPPORT GRANT APPLICATIONS TO FUND STUDIES ON RNA VIRUSES WITH PANDEMIC POTENTIAL.

BINDING AND PRESENTATION OF LIPID ANTIGENS BY CD1

ROLE OF HEPATIC FAT METABOLISM IN GLUCOSE EFFECTIVENESS

ROLE OF CELLULAR FACTORS IN RETROVIRAL UNCOATING AND SYNTHESIS OF VIRAL DNA

MECHANISMS MEDIATING STEM/PROGENITOR CELL MOBILIZATION FROM BONE MARROW

NEUROTROPIC HERPESVIRUS ENVELOPMENT AND MICROTUBULE-MEDIATED TRANSPORT

CLINICAL GRADE CULTURED RARE RED BLOOD CELLS AS REAGENTS AND FUTURE TRANSFUSION SUPPORT

POST-DPP FOLLOW-UP STUDY

MOLECULAR MARKERS OF RISK OF SUBSEQUENT INVASIVE BREAST CANCER IN WOMEN WTH DUCTAL CARCINOMA IN SITU

INTERDISCIPLINARY LEADERSHIP TRAINING IN NEURODEV AND RELATED DISABILITIES

CODING OF AUDITORY SPACE IN THE AVIAN BRAIN

ROLE OF HYPOTHALAMIC IKK-BETA/NF-KAPPAB IN NUTRITIONAL CONTROL OF AGING

RESILIENCE TO ALZHEIMER'S DISEASE IN HUMANS WITH EXCEPTIONAL LONGEVITY

SUPPORT FOR THE ROSE F KENNEDY IDDRC P50 - PROJECT SUMMARY/ABSTRACT (OVERALL) THE OVERARCHING PURPOSE OF THE ROSE F. KENNEDY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER (RFK IDDRC) IS TO IMPROVE THE LIVES OF CHILDREN WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES (IDDS). FIFTY- PLUS YEARS OF DISTINGUISHED PROGRESS IN BASIC, TRANSLATIONAL AND CLINICAL RESEARCH AS ONE OF NICHD’S FLAGSHIP IDDRCS, COUPLED WITH IMPORTANT RECENT FACULTY RECRUITMENTS AND AN HISTORIC MERGER BETWEEN THE ALBERT EINSTEIN COLLEGE OF MEDICINE AND ITS UNIVERSITY-AFFILIATED HOSPITAL, MONTEFIORE MEDICAL CENTER, OFFER A SOLID PLATFORM FOR CONTINUING EXCELLENCE IN OUR COMMITMENT TO IDD RESEARCH. THE CENTER’S 4 HIGHLY INTEGRATED SCIENTIFIC CORES CONSIST OF: 1) OUR CLINICAL TRANSLATIONAL CORE KNOWN AS THE HUMAN CLINICAL PHENOTYPING (CORE B, HCP), WHICH SERVES TO FACILITATE BOTH ACCESS TO AND CHARACTERIZATION OF PARTICIPANTS FOR IDD RELEVANT RESEARCH; 2) A NEUROGENOMICS FACILITY (CORE C, NGEN) THAT PROVIDES CUTTING EDGE EPIGENETIC AND GENOMIC PROCESSING AND ANALYSES ON BOTH HUMAN AND ANIMAL TISSUES; 3) A NEURAL CELL ENGINEERING AND IMAGING FACILITY (CORE D, NCEI) THAT PROVIDES STATE-OF-THE-ART APPROACHES TO BRAIN CELL MANIPULATION AND VISUALIZATION; AND 4) AN ANIMAL PHENOTYPING FACILITY (CORE E, AP) FOR EVALUATION OF ANIMAL BEHAVIOR, METABOLISM AND IMAGING IN A MANNER WITH STRONG PARALLELS TO APPROACHES TAKEN IN PATIENTS ACCESSED THROUGH HCP. EACH OF OUR SCIENTIFIC CORES IS CAREFULLY OVERSEEN AND MONITORED BY THE ADMINISTRATIVE CORE (CORE A, ADM), WHICH ALSO SERVES AS THE HEAD GANGLION OF THE ENTIRE IDDRC IN ITS SUBSTANTIAL OUTREACH PROGRAMS TO EINSTEIN/MONTEFIORE, THE BRONX COMMUNITY AS WELL AS NATIONALLY. EACH SCIENTIFIC CORE HAS AN ESSENTIAL CONNECTION TO OUR SIGNATURE RESEARCH PROJECT WHICH BRINGS TOGETHER A MULTIDISCIPLINARY TEAM OF INVESTIGATORS FOCUSED ON MECHANISMS OF IDD IN CHILDREN WITH MUTATIONS IN THE TRANSCRIPTIONAL REGULATOR LYSINE DEMETHYLASE 5C GENE, KDM5C. A CENTRAL FUNCTION OF THE RFK IDDRC IS TO PROMOTE THE SUBSTANTIVE LINKS BETWEEN EINSTEIN RESEARCH LABORATORIES AND CLINICS AT THE CHILDREN'S EVALUATION AND REHABILITATION CENTER (CERC) AND THE CHILDREN’S HOSPITAL AT MONTEFIORE (CHAM). TOGETHER, OUR CORES AND RESEARCH PROJECT FORM A DYNAMIC NETWORK – A COMMUNITY – OF IDD-FOCUSED PROGRAMS AND PRACTICES THAT INTERLINK 18 DIFFERENT ACADEMIC DEPARTMENTS, >100 IDDRC MEMBERS AND 20-PLUS IDD-RELEVANT CLINICS AT EINSTEIN AND MONTEFIORE. THE LATTER INCLUDE 22Q11.2DS, RETT AND WILLIAMS SYNDROMES, TUBEROUS SCLEROSIS, NEUROFIBROMATOSIS, WEST SYNDROME AND INFANTILE SPASMS, AUTISM SPECTRUM DISORDERS, AND A WIDE RANGE OF NEUROMETABOLIC DISORDERS. NEW INITIATIVES MOVING FORWARD AT THIS TIME INCLUDE OUR UNIQUE PRECISION MEDICINE/COMMUNITY OUTREACH PROGRAM WE CALL OPERATION IDD GENE TEAM, OUR GOAL TO FORTIFY TIES WITH OUR EINSTEIN CLINICAL PARTNER (CERC AND ITS AFFILIATED UCEDD AND LEND PROGRAMS) UNDER THE UMBRELLA OF THE ROSE F. KENNEDY CENTER AND A HEIGHTENED FOCUS ON TRAINING THROUGH OUR NEWLY ESTABLISHED T32 FOR IDD POSTDOCTORAL FELLOWS.

A "TROJAN HORSE" BISPECIFIC ANTIBODY STRATEGY FOR BROAD FILOVIRUS THERAPEUTICS

MOLECULAR GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS

SUPPORT FOR THE ROSE F. KENNEDY IDDRC

THE MEDIATOR COMPLEX IN THE COORDINATE REGULATION OF LIPOGENIC GENE EXPRESSION

CORTICO-HIPPOCAMPAL MECHANISMS OF CONTEXT MEMORY

ENDOSOMAL-LYSOSOMAL FUNCTION IN NEURONAL STORAGE DISEASE

BACTERIAL N-ACETYLTRANSFERASES: RESISTANCE TO REGULATION

GENETIC ANALYSIS OF THE P13K/AKT PATHWAY IN THYROID BENIGN AND MALIGNANT DISEASE

PERSISTENT HPV IN WOMEN AT RISK FOR CERVIX CANCER

MOLECULAR GENETIC ANALYSIS OF MYCOBACTERIUM TUBERCULOSIS

GENERATION OF A COMPLETE SET OF PRECISE NULL BAR-CODED DELETION MUTANTS OF MYCOBACTERIUM TUBERCULOSIS

CONTROL OF VESICULAR TRAFFICKING IN THE HEPATOCYTE.

MECHANISM OF MICROTUBULE DYNAMICS REGULATION BY KINESINS

ROLE OF EXCEPTIONAL LONGEVITY GENOTYPES IN PROTECTION AGAINST FRAILTY IN AGING

MULTIPLEX IMAGING OF SIGNALING PATHWAYS IN CELL MOTILITY

EPIDEMIOLOGIC DETERMINANT OF CARDIAC STRUCTURE AND FUNCTION AMONG HISPANICS

ENHANCING PATHOGEN-SPECIFIC MEMORY CD8+ T CELL RESPONSES IN VIVO

VASCULAR DETERMINANTS OF STAGE B HF AMONG HISPANICS: THE ROLE OF THE HEART-VASCULAR INTERACTION - PROJECT SUMMARY AORTIC STIFFNESS INCREASES MARKEDLY WITH AGE AND IS ASSOCIATED WITH HYPERTENSION, HEART FAILURE (HF) AND ACCELERATED BRAIN AGING. ABNORMAL HEMODYNAMIC COUPLING BETWEEN LEFT VENTRICLE AND AORTA CONTRIBUTES TO PATHOGENESIS OF TARGET ORGAN DAMAGE, PARTICULARLY HF. HISPANICS/LATINOS HAVE A HIGHER INCIDENCE OF HF COMPARED TO NON-HISPANIC WHITES AND PRESENT YOUNGER WITH HF WITH MORE CO-MORBIDITIES AND A LOWER LEFT VENTRICULAR (LV) EJECTION FRACTION. FURTHERMORE, THE COMMUNITY-BASED ECHOCARDIOGRAPHIC STUDY OF LATINOS (ECHO-SOL [ES]; R01 PI: RODRIGUEZ) HAS FOUND THAT COMPARED TO PUBLISHED ESTIMATES IN NON-HISPANIC WHITES, HISPANICS HAVE A HIGHER HF RISK FACTOR BURDEN, WORSE DIASTOLIC FUNCTION AND LV STIFFNESS THUS SIGNALING HISPANICS AT HIGH RISK FOR HF WITH PRESERVED EF (HFPEF). ECHO-SOL 2 (ES2) (PI: RODRIGUEZ) OBTAINED SERIAL ECHOS SHOWING SIGNIFICANTLY WORSENING OF ECHO PARAMETERS OVER AN AVERAGE OF 4.3 YEARS OF FOLLOW-UP. MECHANISM(S) FOR THE SUSCEPTIBILITY OF HISPANICS TO HF ARE NOT WELL-ACCOUNTED FOR BY STANDARD HF RISK FACTORS. WE HYPOTHESIZE THAT VASCULAR FUNCTION AND VENTRICULAR-ARTERIAL COUPLING SIGNIFICANTLY CONTRIBUTES TO HF PATHOGENESIS AND HF RISK IN HISPANICS. BECAUSE THE HEART AND VASCULATURE ARE INTIMATELY COUPLED, LV STROKE VOLUME DEPENDS ON THE IMPORTANT INTERACTION OF MYOCARDIAL CONTRACTILITY WITH LOADING CONDITIONS FROM ARTERIAL SYSTEM COMPLIANCE. THERE HAS BEEN NO STUDY OF COMPREHENSIVE VASCULAR FUNCTION AND VENTRICULAR- ARTERIAL COUPLING ASSESSMENT CONCOMITANT WITH A DETAILED ECHOCARDIOGRAPHIC EXAM IN HISPANICS. THUS, WE PROPOSE LEVERAGING THE RESOURCES OF HCHS/SOL, ES AND ES2 WITH LONGITUDINAL DATA ON CARDIAC PHENOTYPING AS WELL AS CLINICAL, SOCIOCULTURAL, AND PSYCHOSOCIAL RISK FACTORS TO COMPREHENSIVELY CHARACTERIZE VASCULAR FUNCTION IN ES PARTICIPANTS FOCUSING ON KEY PRIMARY PRESSURE-FLOW PHENOTYPES: CAROTID-FEMORAL PULSE WAVE VELOCITY, CENTRAL PULSE PRESSURE, CHARACTERISTIC IMPEDANCE AND ENDOTHELIAL FUNCTION [FLOW MEDIATED DILATATION / HYPEREMIC BRACHIAL FLOW VELOCITIES] CONCOMITANT WITH A DETAILED ECHOCARDIOGRAPHIC ASSESSMENT INCLUDING 2D, COLOR, SPECTRAL / TISSUE DOPPLER AND SPECKLE TRACKING. OUR APPLICATION IS FOCUSED ON VASCULAR DYSFUNCTION AND ITS INTERACTION / EFFECTS ON THE HEART. IMPAIRED MECHANICAL COUPLING CONTRIBUTES TO COMBINATION OF RIGHT AND LEFT HEART ABNORMALITIES LIMITS CARDIAC OUTPUT AND CONTRIBUTES TO THE STAGE B HF (NOW TERMED PRE-HF) TO SYMPTOMATIC HF, PARTICULARLY HFPEF. OUR GOAL IS TO COMPREHENSIVELY DESCRIBE VASCULAR FUNCTION PRESSURE-FLOW RELATIONS AND ITS DETERMINANTS IN HISPANICS/LATINOS. (AIM 1) THEN, DETERMINE HOW VASCULAR FUNCTION RELATES TO CARDIAC STRUCTURAL AND FUNCTIONAL ABNORMALITIES (INCLUDING MYOCARDIAL STRAIN) TO TEST THE HYPOTHESIS THAT AORTIC STIFFNESS IMPAIRS MECHANICAL COUPLING. (AIM 2) BECAUSE OBTAINING AN ECHO EXAM IS A NATURAL COMPONENT OF OUR PRIMARY FOCUS, WE WILL HAVE THE BENEFIT OF LEVERAGING ~12 YEARS OF EXISTING ES AND ES2 LONGITUDINAL DATA TO IDENTIFY CARDIAC TRAJECTORIES, ASSESS THE DETERMINANTS OF EACH TRAJECTORIES AND THE INDEPENDENT ASSOCIATION WITH OUTCOMES SUCH AS VASCULAR PHENOTYPES OVERALL MORTALITY AND HF. (AIM 3) LASTLY, WE WILL LINK OUR DATASET WITH OTHER NIH-FUNDED COHORTS WITH EXISTING VASCULAR FUNCTION DATA TO PERFORM POOLED COHORT ANALYSES OF VASCULAR FUNCTION OF HISPANICS/LATINOS WITH NON-HISPANIC WHITES AND BLACKS FROM THE FRAMINGHAM HEART STUDY AND JACKSON HEART STUDY RESPECTIVELY, TO IDENTIFY AND ADDRESS VASCULAR DISPARITIES AMONG RACIAL-ETHNIC MINORITIES. (AIM 4) OUR LARGE-SCALE STUDY REPRESENTS AN INNOVATIVE AND COST-EFFECTIVE (LEVERAGING EXISTING RESOURCES) APPROACH TO ADVANCING OUR UNDERSTANDING OF THE VENTRICULAR-VASCULAR INTERACTION ON HF PROGRESSION IN AN UNDERREPRESENTED AND VULNERABLE POPULATION. IDENTIFICATION OF HISPANICS WITH PRE-HF AND ABNORMAL VASCULAR FUNCTION MAY HELP TO DIFFERENTIATE THOSE WHO ARE AT THE HIGHE

THE ROLES OF LIPID METABOLISM IN THE MAINTENANCE OF HEMATOPOIETIC STEM CELLS

EINSTEIN/RWANDA/DRC CONSORTIUM FOR RESEARCH IN HIV/HPV/MALIGNANCIES

THE B7X PATHWAY IN THE TUMOR MICROENVIRONMENT

MOLECULAR MECHANISM OF THE CYTOPLAMIC DYNEIN-DYNACTIN MOTOR COMPLEX

CARRIER MEDIATED ANTIFOLATE TRANSPORT AND RESISTANCE

GEOGRAPHIC MEDICINE AND EMERGING INFECTIONS

BIOCHEMISTRY AND GENETICS OF CHROMATIN ASSEMBLY FACTORS IN DROSOPHILA

INTRACELLULAR SIGNALING BY THE INSULIN RECEPTOR KINASE

KERALA-EINSTEIN STUDY: HEALTHY LIFESTYLE, VASCULAR DISEASE, AND COGNITIVE DECLINE

MECHANISMS UNDERLYING THE HIV-HSV-2 SYNDEMIC

MAPPING AUTOIMMUNE DIABETES AND THYROIDITIS GENES

MULTICULTURAL HEALTHY DIET TO REDUCE COGNITIVE DECLINE & ALZHEIMER DISEASE RISK

REST-ACTIVATED PROGRAM OF GENE EXPRESSION IN ISCHEMIA

HEPATIC ORGANIC ANION UPTAKE TRANSPORT

MOLECULAR AND CELLULAR REGULATION OF PRE-LEUKEMIC STEM CELLS AND THEIR THERAPEUTIC TARGETING - ABSTRACT CLINICAL OUTCOME IN MDS AND AML HAS NOT SIGNIFICANTLY IMPROVED OVER THE PAST 50 YEARS AND CURE RATES REMAIN BELOW 15% IN THE MAJORITY OF PATIENTS (~85%) WHICH ARE >55 YEARS OF AGE. FUNDAMENTALLY NOVEL APPROACHES ARE URGENTLY NEEDED TO IMPROVE OUR UNDERSTANDING OF DISEASE PATHOGENESIS AND TO ENABLE MORE EFFECTIVE THERAPEUTIC INTERVENTION. EVIDENCE OVER THE PAST 10 YEARS HAS SHOWN THAT MDS AND AML ARISE FROM PRELEUKEMIC STEM CELLS (PREL-SC), PRECEDING THE FORMATION OF FULLY TRANSFORMED LEUKEMIA STEM CELLS (LSC). RECENT WORK HAS UNCOVERED CONSIDERABLE SUBCLONAL HETEROGENEITY OF PREL-SC IN MDS AND AML AND HAS INDICATED THAT STEM CELL SUBCLONAL COMPLEXITY PLAYS A KEY ROLE IN PATHOGENESIS, PROGRESSION, AND THERAPEUTIC RESISTANCE. HOWEVER, THE MOLECULAR AND CELLULAR MECHANISMS GOVERNING THESE PROCESSES ARE STILL LARGELY UNKNOWN. TRANSCRIPTION FACTORS (TF) HAVE LONG BEEN RECOGNIZED AS CRITICAL REGULATORS OF NORMAL AND MALIGNANT HEMATOPOIESIS. SPECIFICALLY, IN MDS AND AML TRANSCRIPTIONAL DYSREGULATION IS KEY TO CONFER THE PATHOGNOMONIC FEATURES OF CELLULAR DYSPLASIA AND A MYELOID DIFFERENTIATION BLOCK. CELL FATE AND DIFFERENTIATION DECISIONS AS WELL AS THE INDUCTION OF A MYELOID BIAS AT THE STEM CELL AND MULTIPOTENT PROGENITOR LEVEL, WHICH IS ONE OF THE EARLIEST CELLULAR PROPERTIES DETECTED IN PREL-SC, ARE GOVERNED BY TRANSCRIPTION FACTORS. IN ADDITION, OUR RECENT WORK HAS DISCOVERED AN UNEXPECTED DEGREE OF TRANSCRIPTION DYNAMICS AND PLASTICITY IN HEMATOPOIETIC STEM AND PROGENITORS, AND THAT BOTH TRANSCRIPTIONAL PLASTICITY AND TRANSCRIPTIONAL MEMORY ARE DYSREGULATED IN PREL-SC AND LSC. OUR MAJOR RESEARCH QUESTIONS/GOALS ARE TO UNDERSTAND STEM CELL SUBCLONAL DYNAMICS AND THEIR REGULATION IN THE INITIATION AND PROGRESSION OF MDS AND AML, TO IDENTIFY AND STUDY MECHANISMS OF TRANSCRIPTIONAL COOPERATIVITY IN PRE-LEUKEMIC STEM CELLS AND THEIR THERAPEUTIC TARGETING, AND TO STUDY TRANSCRIPTION DYNAMICS AND PRE-LSC FATE DYSREGULATION AT A SINGLE-CELL AND SINGLE-MOLECULE RESOLUTION. TO ACCOMPLISH THESE GOALS WE WILL UTILIZE NOVEL TOOLS FOR STEM CELL SUBCLONAL ANALYSIS IN PATIENTS, AS WELL AS NEWLY DEVELOPED LONGITUDINAL MOUSE GENETIC MODELS OF PREL-SC PROGRESSION TO MDS AND AML. IN ADDITION, WE WILL LEVERAGE RECENT ADVANCES IN OUR ABILITY TO DIRECTLY TARGET KEY TRANSCRIPTION FACTORS BY NOVEL FIRST-IN-CLASS PHARMACOLOGICAL INHIBITORS, AS WELL AS NOVEL EXPERIMENTAL TOOLS FOR THE STUDY OF TRANSCRIPTION DYNAMICS AT A SINGLE-MOLECULE LEVEL IN PRIMARY STEM/PROGENITOR CELLS FROM MURINE MODELS AND PATIENTS. OVERALL, OUR RESEARCH WILL DELINEATE THE MOLECULAR REGULATION OF PRE-CANCEROUS CELL STATES IN MDS AND AML PATHOGENESIS. THIS WILL ENABLE THEIR THERAPEUTIC TARGETING, IN ADDITION TO THE ELIMINATION OF THE FULLY-TRANSFORMED LEUKEMIC CLONES. SUCH AN APPROACH HOLDS THE PROMISE OF ACHIEVING LASTING REMISSIONS AND POTENTIALLY CURE OF MDS AND AML. OUR LONG-TERM VISION IS THAT, ONCE WE UNDERSTAND THE EARLY TRANSFORMATION-INITIATING MECHANISMS IN PRE-CANCEROUS STEM CELLS, IT MAY EVEN BE POSSIBLE TO TARGET SUCH PRE-CANCEROUS STATES BEFORE THE ONSET OF OVERT LEUKEMIA AND THUS PREVENT TRANSFORMATION.

CHARACTERIZATION OF BRAIN DYSFUNCTION DURING DEVELOPMENT IN SURVIVORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

MOLECULAR MECHANISMS OF ALPHAVIRUS ENTRY AND EXIT

UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING

HIV AIDS AND OPPORTUNISTIC INFECTIONS

AMPLIFYING AND REDIRECTING CMV-SPECIFIC CD8 T CELLS TO PROVIDE SUSTAINED CONTROL OF HIV INFECTION - THE IMMUNE SYSTEM OF HIV-INFECTED INDIVIDUALS IS UNABLE TO ELIMINATE LATENTLY INFECTED CELLS FOLLOWING REACTIVATION, RESULTING IN THE RECURRENCE OF VIREMIA AFTER STOPPING ANTIRETROVIRAL THERAPY, PREVENTING FUNCTIONAL CURE. THIS NECESSITATES LIFELONG ART FOR PEOPLE WITH HIV (PWH). NEW STRATEGIES ARE NEEDED TO MOBILIZE THE IMMUNE SYSTEM TO PREVENT THE EMERGENCE OF HIV FROM THE HIV RESERVOIR AFTER ART CESSATION. WE RECENTLY DEVELOPED SYNTACS, INFUSIBLE IMMUNOSTIMULATORY BIOLOGICS CONSISTING OF DIMERIC FC-DOMAIN SCAFFOLDS LINKING MHC MOLECULES AND VIRUS-DERIVED PEPTIDES (C-PMHC) CAPABLE OF DELIVERING ANTIGEN-SPECIFIC TCR-SIGNALS AND LIGANDS THAT SUPPLY DEFINED COSTIMULATORY SIGNALS. WE DEMONSTRATED THAT SYNTACS BEARING CMV-DERIVED PEPTIDES, AND ANTI-CD28 SCFV OR 4-1BBL SIGNALING MODULES, STIMULATED VIGOROUS AND SELECTIVE EX VIVO AND IN VIVO EXPANSION OF HIGHLY POLYFUNCTIONAL CMV-SPECIFIC CD8+ T CELLS IN PWH PBMC, WHICH DISPLAYED POTENT IN VIVO ANTI-CMV ACTIVITIES. WE ALSO RECENTLY DESCRIBED THE POTENT IN VITRO AND IN VIVO ANTI-HIV ACTIVITY OF CAR-T CELLS THAT USE A NOVEL TWO- MOLECULE DUOCAR ARCHITECTURE TO CO-EXPRESS TWO INDEPENDENT CARS, EACH RECOGNIZING A DISTINCT GP120 EPITOPE. HIV-SPECIFIC T CELL RESPONSES OR CAR-T CELL TREATMENTS FAIL TO PROVIDE SUSTAINED CONTROL OF HIV INFECTION BECAUSE OF THE EVENTUAL REDUCTION OR LOSS OF THEIR FUNCTIONAL ANTI-HIV ACTIVITY, EVEN IN THE ABSENCE OF MUTATIONAL IMMUNE ESCAPE. IN CONTRAST, CMV-SPECIFIC T CELL RESPONSES CONSIST OF EFFECTOR MEMORY CD8 T CELLS THAT MAINTAIN THEIR CAPACITY FOR CYTOKINE RELEASE, KILLING AND PROLIFERATION AND ACTUALLY EXPAND OVER TIME, A PHENOTYPE DESCRIBED AS MEMORY INFLATION. WE HYPOTHESIZE THAT COMBINING THE CAPACITY OF SYNTACS TO ACTIVATE AND MARKEDLY EXPAND CMV- SPECIFIC CD8 T CELLS WITH NOVEL STRATEGIES TO REDIRECT THEM TO ELIMINATE HIV-INFECTED CELLS, WOULD EXPLOIT THE HIGHLY FUNCTIONAL AND RESILIENT CMV-SPECIFIC CD8 T CELL RESPONSES TO PROVIDE IMPROVED IMMUNE CONTROL OF HIV INFECTION. WE PROPOSE TO COMBINE THE CAPACITY OF SYNTACS TO SELECTIVELY ACTIVATE AND MARKEDLY EXPAND CMV-SPECIFIC CD8 T CELLS WITH POTENT AND SUSTAINED ANTI-VIRAL ACTIVITY WITH THREE SPECIFIC AIMS (SA) TO REDIRECT THEM TO TARGET HIV- INFECTED CELLS. WE WILL EITHER CONVERT THE EXPANDED CMV CD8 T CELLS INTO HIV-SPECIFIC CAR T CELLS (SA 1), OR ANTI-HIV T CELLS (SA 2), OR MODIFY THE SYNTAC STRUCTURE TO LINK CMV-C-PMHC, GP120-BINDERS AND COSTIMULATORY LIGANDS, TO BOTH FULLY ACTIVATE AND DIRECT CMV CD8 T CELLS TO TARGET HIV-INFECTED CELLS (SA 3), THEREBY MOBILIZING AN IN VIVO IMMUNE RESPONSE THAT CONTROLS HIV INFECTION, ELIMINATES REACTIVATED LATENTLY INFECTED CELLS AND PROVIDES SUSTAINED ART-FREE REMISSION OF HIV INFECTION TO PWH. FURTHERMORE, WE WILL ALSO UTILIZE SYNTACS DELIVERING DEFINED COSTIMULATORY SIGNALS, TO EXTEND OUR KNOWLEDGE REGARDING THE CAPACITY OF DIFFERENT COSTIMULATORY SIGNALS TO GENERATE THE MOST POTENT CD8+ T CELLS AND CAR-T CELLS FOR ELIMINATING REACTIVATED LATENTLY INFECTED T CELLS.

DECREASED PROTEIN DEGRADATION IN AGING

DISSECTING THE CANONICAL AND NON-CANONICAL FUNCTIONS OF TET2 IN HEMATOPOIETIC STEM CELLS AND HEMATOLOGIC DISORDERS

DYSREGULATION OF MTOR SIGNALING IN FRAGILE X SYNDROME

THYROGLOBULIN PEPTIDE PRESENTATION BY HLA-DR IN THYROIDITIS

NEAR-INFRARED FLUORESCENT PROTEINS, BIOSENSORS AND OPTOGENETIC TOOLS

SOMATOTROPIC SIGNALING AND RESILIENCE TO AGING AND ALZHEIMER'S DISEASE

ED2PREP - PATIENT FOCUSED, LOW-BURDEN STRATEGIES FOR PREP UPTAKE AMONG EMERGENCY DEPARTMENTS PATIENTS: A CROSS-OVER HYBRID IMPLEMENTATION-EFFECTIVENESS TRIAL - SEVERE INEQUITIES IN HIV PRE-EXPOSURE PROPHYLAXIS (PREP) ACCESS AND USE PERSIST AMONG BLACK AND LATINX COMMUNITIES MOST IMPACTED BY THE HIV EPIDEMIC. THE BRONX, NY, WITH OVER 90% OF THE POPULATION IDENTIFYING AS BLACK OR LATINX, IS AN ENDING THE HIV EPIDEMIC (EHE) PRIORITY COUNTY WITH THE FIFTH HIGHEST HIV DIAGNOSIS RATE IN THE U.S. AND THE LOWEST PREP USE IN NY. RESEARCH ON BARRIERS TO PREP ENGAGEMENT INDICATE THAT THE CURRENT STRUCTURE OF PREP ACCESS AND MANAGEMENT IS NOT CONSONANT WITH THE LIVES, PRIORITIES, OR NEEDS OF THE HARDEST HIT COMMUNITIES, FURTHER EXACERBATING ONGOING RACIAL/ETHNIC AND SOCIOECONOMIC DISPARITIES IN HIV INCIDENCE. MANY OF THE SAME BARRIERS LEADING TO POOR PREP UPTAKE IN BLACK/LATINX COMMUNITIES ALSO DRIVE MEMBERS OF THESE COMMUNITIES TO SEEK CARE FOR SEXUALLY TRANSMITTED INFECTIONS (STIS), A KNOWN RISK FACTOR FOR HIV, IN EMERGENCY DEPARTMENTS (EDS). HOWEVER, THERE IS A DISCORDANCE BETWEEN THE TYPE OF CARE LIKELY TO PRESERVE THE LONG-TERM HEALTH OF THOSE SEEKING STI CARE IN EDS (LONGITUDINAL, BEHAVIORAL, AND PREVENTION-ORIENTED) AND THE CARE THE ED IS OPTIMIZED TO PROVIDE (ACUTE, HIGH INTENSITY, LIFE-SAVING/STABILIZING), MEANING THAT BOTH PATIENTS AND HEALTH SYSTEMS STAND TO GAIN FROM A RESTRUCTURING OF HOW STI CARE IS DELIVERED IN EDS. INNOVATIVE, EFFICIENT, AND SUSTAINABLE STRATEGIES FOR IDENTIFYING AND ENGAGING HIGH PRIORITY POPULATIONS FOR HIV PREVENTION SEEKING SEXUAL HEALTHCARE IN EDS ARE THUS NEEDED. WE THEREFORE PROPOSE ED2PREP, A PRAGMATIC TYPE III HYBRID EFFECTIVENESS-IMPLEMENTATION TRIAL COMPARING TWO STRATEGIES FOR INCREASING PREP UPTAKE AMONG PATIENTS AT RISK FOR HIV ACCESSING CARE IN BRONX EDS. THE TWO STRATEGIES ARE (1) POST-VISIT OUTREACH (PVO) INVOLVING PROACTIVE OUTREACH TO PATIENTS FOLLOWING A STI-RELATED ED VISIT. PVO WILL BE INITIATED BY A SEXUAL HEALTH NAVIGATOR WHO WILL PROVIDE PREP EDUCATION, COUNSELING, AND LINKAGE TO EXISTING SEXUAL HEALTH/PREP CLINICS. (2) TELE-PREP (TP) WILL INVOLVE A REAL-TIME TELEHEALTH VISIT WITH A SEXUAL HEALTH PROVIDER DURING STI-RELATED ED VISITS. TP WILL ALSO INCLUDE EDUCATION, COUNSELING, AND LINKAGE, IN ADDITION TO THE PROVIDER’S ABILITY TO PRESCRIBE PREP AT THE TIME OF THE VISIT. TO TEST THE EFFECTIVENESS OF PVO AND TP FOR INCREASING PREP UPTAKE AMONG PATIENTS ACCESSING STI CARE IN THE ED, WE WILL PERFORM A CROSSOVER TRIAL IN WHICH THE STRATEGIES ARE IMPLEMENTED IN TWO DIFFERENT EDS FOR 9 MONTHS AND THEN SWITCHED FOR ANOTHER 9 MONTHS (AIM 1). NEXT, GUIDED BY THE RE-AIM FRAMEWORK, WE WILL ASSESS IMPLEMENTATION OUTCOMES FOR THE STRATEGIES TO IDENTIFY HOW EACH STRATEGY’S EFFECTIVENESS IS IMPACTED BY IMPLEMENTATION CONSIDERATIONS (AIM 2). FINALLY, TO INFORM SCALE-OUT LOCALLY AND NATIONALLY, WE WILL PERFORM AN ECONOMIC ANALYSIS TO DETERMINE EACH STRATEGY’S COST PER OUTCOME AND RELATIVE COST-EFFECTIVENESS (AIM 3). ED2PREP WILL GENERATE CRITICAL DATA THAT COULD TRANSFORM HOW EDS INITIATE PREP AND ENGAGE POPULATIONS AT THE HIGHEST RISK FOR HIV AND ACCELERATE EHE GOALS IN ONE HARDEST HIT JURISDICTIONS IN THE U.S. FINDINGS COULD ALSO BE INFORMATIVE TO OTHER JURISDICTIONS, HAVING DRAMATIC EFFECTS ON HOW HIV PREVENTION IS DELIVERED.

EPIDEMIOLOGY OF THE GUT MICROBIOME, PREDIABETES AND DIABETES IN LATINOS

A MULTIMODAL PARENT-FOCUSED INTERVENTION FOR VULNERABLE POPULATIONS IN THE BRONX - PROJECT SUMMARY / ABSTRACT IN RESPONSE TO PAR-20-237, “COMMUNITY INTERVENTIONS TO ADDRESS THE CONSEQUENCES OF THE COVID-19 PANDEMIC AMONG HEALTH DISPARITY AND VULNERABLE POPULATIONS,” WE PROPOSE TO STUDY A PARENT-FOCUSED MENTALIZING INTERVENTION WITH A SMARTPHONE HEALTH PLATFORM IN VULNERABLE POPULATIONS IN THE BRONX. THE BRONX—THE POOREST BOROUGH IN NEW YORK CITY (NYC) WITH 84% OF ITS POPULATION COMPRISED OF MINORITIES—HAS BEEN HIT DISPROPORTIONALLY BY THE COVID-19 PANDEMIC. FOR CAREGIVERS IN THE BRONX, THE PANDEMIC HAS CAUSED UNPRECEDENTED PSYCHOLOGICAL DISTRESS; IN ADDITION TO COMBATING SOCIAL DETERMINANTS OF HEALTH (SDOH), THESE FAMILIES NOW FACE GREATER FINANCIAL INSECURITY AND CHALLENGES RELATED TO THEIR SCHOOL-AGED CHILDREN. FURTHERMORE, SOCIAL DISTANCING REQUIREMENTS AND LIMITED TELEHEALTH RESOURCES FOR BRONX FAMILIES HAVE POSED GREATER BARRIERS TO HEALTHCARE. SUCH PARENTAL DISTRESS CONTRIBUTES TO HEIGHTENED RISK OF TRANSGENERATIONAL CYCLES OF PSYCHOLOGICAL STRESS, TRAUMA AND MALTREATMENT. ADDRESSING THESE CHALLENGES, WE PROPOSE A MULTIMODAL STUDY TACKLING BOTH PARENTAL VULNERABILITY AND HEALTHCARE ACCESS. A) TARGETING PARENTAL VULNERABILITY, WE PROPOSE TO BUILD UPON OUR 12-SESSION THERAPEUTIC CARE PROGRAM, WHICH UTILIZES MENTALIZATION BASED THERAPY AND DESIGNED FOR PARENTS OF CHILDREN IN TREATMENT IN A COMMUNITY PSYCHIATRY CLINIC IN OUR HEALTH SYSTEM. MULTIPLE RANDOMIZED CONTROLLED TRIALS (RCTS) OF ATTACHMENT-BASED PARENTING INTERVENTIONS, INCLUDING FROM OUR GROUP IN DISADVANTAGED COHORTS FROM THE BRONX. B) TARGETING HEALTHCARE ACCESS, WE PROPOSE TO UTILIZE THE HIPAA-COMPLIANT AND IRB-APPROVED VALERA HEALTH SMARTPHONE APPLICATION (“APP”), WHICH HAS BEEN STUDIED IN OUR HEALTH SYSTEM IN SELECTED COHORTS AND RESULTED IN GREATER ACCESS TO HEALTHCARE. BUILDING UPON OUR WORK AND CLINICAL INFRASTRUCTURE, WE HYPOTHESIZE THAT BOTH THE CARE PROGRAM AND THE VALERA APP WILL MITIGATE THE PSYCHOLOGICAL EFFECTS OF COVID-19 WHILE ENHANCING ACCESS TO HEALTHCARE IN THE BRONX. THE STUDY WILL TAKE PLACE AT MONTEFIORE MEDICAL CENTER (MMC), THE LARGEST HEALTH SYSTEM IN THE BRONX, WHICH SERVES PREDOMINANTLY RACIAL AND ETHNIC MINORITY INDIVIDUALS FROM UNDERSERVED FAMILIES. WE WILL FOCUS ON THREE HIGHLY VULNERABLE COHORTS: A) CAREGIVERS OF CHILDREN WITH PSYCHIATRIC CONDITIONS (N=130); B) CAREGIVERS OF CHILDREN WITH AUTOIMMUNE ILLNESSES (N=130), AND; C) CAREGIVERS WHO ARE FRONTLINE HEALTHCARE WORKERS AT MMC (N=100); ALL PRESENTING WITH MODERATE STRESS. A RCT WITH 4 ARMS (2 X 2 DESIGN) WILL TEST OUR HYPOTHESIS: A) CARE PROGRAM ALONE; B) CARE PROGRAM + VALERA APP; C) PARENT EDUCATION (PE) ALONE; D) PE + VALERA APP. SMARTPHONES AND CONNECTIVITY WILL BE PROVIDED AS NEEDED. SURVEYS AT STUDY ENROLLMENT, 6-, 12- AND 24-WEEKS WILL ASSESS PARENTAL STRESS, MENTALIZING CAPACITY (REFLECTIVE FUNCTIONING), ACCESS TO HEALTHCARE, MOOD AND ANXIETY AND ADDITIONAL PARENT AND CHILD CLINICAL MEASURES. MACHINE LEARNING APPROACHES WILL EXPLORE COMPLEX PATTERNS AS PREDICTORS OF OUTCOME INCLUDING COVID-19 ILLNESS/DEATHS, MEDICAL COMORBIDITY, HOUSING, POVERTY, PSYCHOPATHOLOGY, AGE, FAMILY FUNCTIONING, AND TRAUMA. IMPACT. THIS MULTIMODAL STUDY ADDRESSES KEY STRATEGIES TO MITIGATE THE PSYCHOLOGICAL AND HEALTH IMPACT OF COVID-19 IN VULNERABLE POPULATIONS.

A COMPUTATIONAL BIOMECHANICAL AIRWAY MODEL FOR OBESE CHILDREN AT RISK FOR OSAS

MICROSPORIDIA: INVASION APPARATUS

PROMOTING ASTHMA GUIDELINES AND MANAGEMENT THROUGH TECHNOLOGY-BASED INTERVENTION AND CARE COORDINATION (PRAGMATIC)

MECHANISMS OF OPIOID- MEDIATED HIV NEUROPATHOGENESIS

NOVEL BIOLOGICS DESIGNED TO MOBILIZE HIV-SPECIFIC CTL FOR SUSTAINED HIV REMISSION

GENE REGULATION OF RETINAL CELL DIFFERENTIATION

TMEM, MENACALC, AND MENAINV AS PROGNOSTIC AND PREDICTIVE MARKERS FOR BREAST CANCER METASTASIS

IMPACT OF HIV, ORAL MICROBIOME AND MYCOBIOME ON ORAL HPV PERSISTENCE - ABSTRACT ORAL HUMAN PAPILLOMAVIRUS (HPV) INFECTIONS AND HPV-ASSOCIATED PAPILLOMAS AND CANCERS CONTINUE TO RISE, ESPECIALLY IN PEOPLE LIVING WITH HIV (PLWH). SPECIFICALLY, RATES OF HPV-ASSOCIATED ORAL AND OROPHARYNGEAL CANCER ARE INCREASING AT AN ALARMING RATE. USING LARGE POPULATION-BASED LONGITUDINAL STUDIES, OUR WORK INDICATED AN INCREASED RISK OF ORAL LESIONS AND HEAD AND NECK CANCERS WITH NOT ONLY HPV16, BUT UNEXPECTEDLY CUTANEOUS BETA AND GAMMA HPVS AS WELL. STUDYING RISK FACTORS, WE IDENTIFIED AN INTERACTION BETWEEN SMOKING AND HIV SEROSTATUS WITH INCREASED PREVALENCE OF ORAL HIGH-RISK ALPHA AND BETA-HPV DETECTION. IN ADDITION TO ORAL HPV, HIV AFFECTS THE COMPOSITION OF THE ORAL MICROBIOME, WHICH HAS ALSO BEEN ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO ORAL HPV INFECTION, PERSISTENCE, AND PROGRESSION TO HPV-DRIVEN CANCER. TAKEN TOGETHER, THESE FINDINGS INDICATE A CONTINUING PUBLIC HEALTH CONCERN OF HPV-RELATED ORAL DISEASES FOR PLWH. THE PROPOSED STUDY WILL LEVERAGE REPEAT ORAL SALIVA SAMPLES COLLECTED FROM N=2046 MALE AND FEMALE PLWH, AND N=1334 HIV[-] INDIVIDUALS ENROLLED IN THE MACS-WIHS COMBINED COHORT STUDY (MWCSS). SPECIFICALLY, WE WILL INVESTIGATE THE ASSOCIATIONS BETWEEN THE ORAL MICROBIOME AND MYCOBIOME AND RISK OF ACQUISITION AND PERSISTENCE OF HIGH-RISK ALPHA, BETA, AND GAMMA ORAL HPV. THE SCIENTIFIC PREMISE OF THE STUDY IS THAT ALTERATIONS IN THE ORAL MICROBIOME / MYCOBIOME RESULTING FROM HIV AND SMOKING INFLUENCE ORAL HPV NATURAL HISTORY. WE WILL USE NOVEL SEQUENCING METHODS DEVELOPED BY OUR TEAM, INCLUDING NEXT GENERATION SEQUENCING AND METAGENOMICS, TO PROFILE THE HPV VIROME (ALPHA, BETA, AND GAMMA HPV), ORAL BACTERIAL (16S RRNA) AND FUNGAL COMMUNITIES (USING A RECENTLY DEVELOPED ITS1 ASSAY WITH INCREASED SENSITIVITY FOR CANDIDA DEVELOPED IN THE BURK LAB), FUNCTIONAL GENE CAPACITY (DETERMINED FROM SHOTGUN METAGENOMIC SEQUENCING), AND CYTOKINE PROFILES (DERIVED FROM ORAL SALIVA PROTEIN ANALYSES). DIFFERENCES IN THE ORAL MICROBIOME / MYCOBIOME BETWEEN PLWH AND HIV[-] INDIVIDUALS WILL BE ASSESSED, AS WELL AS MARKERS OF HIV DISEASE AND SMOKING, WITH RESPECT TO ORAL HPV PERSISTENCE. TAKING ADVANTAGE OF SERIAL SAMPLES COLLECTED IN MWCCS PARTICIPANTS, WE WILL CHARACTERIZE ORAL MICROBIOME / MYCOBIOME CHANGES OVER TIME IN RESPONSE TO CD4 COUNT AND HIV RNA LEVEL, SMOKING, AND THE ORAL MICROBIOME / MYCOBIOME TO ADDRESS THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE THE COMBINED EFFECTS OF HIV AND SMOKING ON RISK OF ORAL HPV PERSISTENCE; 2) STUDY THE ASSOCIATIONS BETWEEN THE ORAL MICROBIOME / MYCOBIOME AND RISK OF ORAL HPV PERSISTENCE; 3) CHARACTERIZE THE MICROBIAL FUNCTION AND ORAL INFLAMMATION/IMMUNE PATHWAYS ASSOCIATED WITH RISK OF ORAL HPV PERSISTENCE. WE HYPOTHESIZE THAT THE ORAL MICROBIOME AND MYCOBIOME INFLUENCED BY HIV AND SMOKING EXHIBIT SIGNIFICANTLY HIGHER PROPORTIONS OF VIRULENCE FACTORS, WHICH IN TURN DYSREGULATE THE ORAL BARRIER IMMUNITY AND INTEGRITY, FACILITATING PERSISTENCE OF ORAL HIGH-RISK HPV TYPES ASSOCIATED WITH INCREASED RISKS FOR ORAL AND OROPHARYNGEAL CANCER.

TAXOL: MECHANISMS OF ACTION AND RESISTANCE

SWAN-STUDY OF WOMEN'S HEALTH ACROSS THE NATION-N.J.SITE

HIV/HPV CANCER PREVENTION, TREATMENT & PATHOGENESIS: RWANDA/EINSTEIN CONSORTIUM

ACTIVITY-DEPENDENT SYNAPTIC PLASTICITY EXPRESSED BY NMDA RECEPTORS

IMPACT OF ILLICIT DRUGS, HIV, AND ART ON NEUROINFLAMMATION AND BBB DISRUPTION

IDENTIFICATION AND TARGETING OF PATHWAYS SEPARATING HEALTHY STEM CELL AGING FROM MALIGNANT TRANSFORMATION

CELL FATE CHOICES BY TBX1 IN FORMING THE MAMMALIAN HEART

EINSTEIN POST-BACCALAUREATE RESEARCH EDUCATION PROGRAM

DNA MISMATCH REPAIR AND CANCER IN MURINE MODELS

ENDOSOMAL MICROAUTOPHAGY IN DROSOPHILA

CHARACTERISTICS AND PROTECTIVE EFFICACY OF HUMAN ANTIBODIES AGAINST M. TUBERCULOSIS

MTORC1-DEPENDENT REGULATION OF THE CYCC/CDK8 COMPLEX

DOES MEDICAL CANNABIS REDUCE OPIOID ANALGESICS IN HIV+ AND HIV- ADULTS WITH PAIN?

ROLE OF IKK-BETA/NF-KAPPAB IN HYPOTHALAMIC DYSREGULATION OF ENERGY BALANCE

NEW YORK CONSORTIUM FOR INTERDISCIPLINARY TRAINING IN KIDNEY, UROLOGICAL AND HEMATOLOGICAL RESEARCH (NYC TRAIN KUHR)

COGNITIVE INTERVENTION TO IMPROVE SIMPLE AND COMPLEX WALKING

MECHANISMS OF GATING AND PERMEATION IN GAP JUNCTIONS

CD138 REGULATES COMPETITION OF ANTIBODY SECRETING CELLS FOR SURVIVAL

EVALUATION OF THE ASTHMA MANAGEMENT PROGRAM TO PROMOTE ACTIVITY FOR STUDENTS IN SCHOOLS (ASTHMA-PASS) - PROJECT SUMMARY/ABSTRACT ASTHMA PREVALENCE IN BRONX, NY SCHOOLS IS 20-25%. PHYSICAL ACTIVITY (PA) IS AN IMPORTANT COMPONENT OF ASTHMA MANAGEMENT IN CHILDREN. STUDIES SHOW THAT PA IS ASSOCIATED WITH DECREASED SEVERITY OF ASTHMA SYMPTOMS, AS WELL AS IMPROVED DISEASE CONTROL AND QUALITY OF LIFE. HOWEVER, URBAN MINORITY CHILDREN WITH ASTHMA FACE BARRIERS TO PA ON MULTIPLE LEVELS. IN OUR PRIOR WORK (K23HD065742), WE IDENTIFIED SEVERAL BARRIERS TO PA IN URBAN MINORITY SCHOOLCHILDREN WITH ASTHMA. THESE BARRIERS INCLUDE: INADEQUATE ACCESS TO ASTHMA RESCUE MEDICATIONS IN SCHOOL, SUBOPTIMAL PRESCRIBING OF PREVENTIVE ASTHMA THERAPY BY PRIMARY CARE PHYSICIANS (PCPS), LACK OF SCHOOL PA OPPORTUNITIES, STIGMA ASSOCIATED WITH ASTHMA, PARENT/CHILD FEAR OF AN ASTHMA ATTACK WITH PA, AND LACK OF TEACHER CONFIDENCE IN ASSISTING STUDENTS WITH ASTHMA. WE DEVELOPED A NOVEL ASTHMA MANAGEMENT PROGRAM TO PROMOTE ACTIVITY FOR STUDENTS IN SCHOOLS (ASTHMA-PASS) IN COLLABORATION WITH STAKEHOLDERS TO ADDRESS THESE KEY BARRIERS. WE PILOT TESTED ASTHMA-PASS WITH 109 STUDENTS WITH ASTHMA FROM 4 BRONX ELEMENTARY SCHOOLS AND THEIR PARENTS TO DEMONSTRATE PROOF OF CONCEPT AND PRELIMINARY EVIDENCE OF INTERVENTION EFFECTIVENESS. RESULTS FROM THE PILOT STUDY DEMONSTRATED SIGNIFICANTLY GREATER INCREASE IN SYMPTOM-FREE DAYS (SFDS) (PRIMARY OUTCOME MEASURE) AND PA LEVELS. IN ADDITION, PRELIMINARY MEDIATION ANALYSES SUGGESTED VIGOROUS PA AND STEP COUNTS ARE MEDIATORS OF SFDS. WE NOW PLAN TO BUILD UPON THIS WORK AND EVALUATE IN A FULL-SCALE RANDOMIZED TRIAL WHETHER THE ASTHMA- PASS INTERVENTION REDUCES ASTHMA MORBIDITY AMONG HIGH-RISK URBAN SCHOOLCHILDREN. WE PROPOSE A CLUSTER- RANDOMIZED CONTROLLED TRIAL WITH 416 CHILDREN AGES 5-11 YEARS WITH PERSISTENT OR UNCONTROLLED ASTHMA FROM 26 BRONX SCHOOLS. SCHOOLS WILL BE STRATIFIED BY SIZE AND THEN RANDOMLY ASSIGNED TO EITHER (1) THE ASTHMA-PASS INTERVENTION (PCP COLLABORATION TO ENSURE OPTIMAL GUIDELINE-BASED PREVENTIVE ASTHMA CARE AND COMMUNITY HEALTH WORKERS TO FACILITATE RESCUE MEDICATION AVAILABILITY IN SCHOOL AND PROVIDE ASTHMA AWARENESS PROGRAMMING AND EDUCATION FOR CHILDREN, PARENTS AND SCHOOL PERSONNEL TO REDUCE STIGMA AROUND ASTHMA AND PA) OR (2) AN ASTHMA MANAGEMENT (AM) COMPARISON GROUP (PCP AND PARENT NOTIFICATION OF CHILD’S ASTHMA STATUS AND GENERAL ASTHMA EDUCATION). BOTH GROUPS WILL PARTICIPATE IN AN EXISTING DISTRICT-WIDE CLASSROOM-BASED DAILY ACTIVITY PROGRAM (‘MOVE TO IMPROVE’). WE WILL ASSESS THE EFFECTIVENESS OF ASTHMA-PASS IN REDUCING ASTHMA MORBIDITY (PRIMARY OUTCOME - SFDS), AND IMPROVING PA (SECONDARY OUTCOME) AS WELL AS ADDITIONAL CLINICAL AND FUNCTIONAL OUTCOMES. WE WILL MEASURE PA WITH ACCELEROMETERS USING PREVIOUSLY ESTABLISHED PROCEDURES. WE WILL ALSO IDENTIFY POTENTIAL MEDIATORS AND MODERATORS OF THE INTERVENTION EFFECT. WE WILL EVALUATE THE PROCESS OF INTERVENTION IMPLEMENTATION BY APPLYING THE RE-AIM FRAMEWORK. THIS PROPOSAL DIRECTLY BUILDS ON OUR PRIOR WORK IN SCHOOLS TO IMPROVE ASTHMA OUTCOMES AND REDUCE HEALTH DISPARITIES. IF ASTHMA-PASS SUCCESSFULLY REDUCES SYMPTOMS AND IMPROVES HEALTH, IT WILL PROVIDE A POWERFUL ARGUMENT FOR POLICY CHANGE IN SCHOOLS AND URBAN COMMUNITIES NATIONWIDE.

EFFECTS OF VITAMIN D AND FISH OIL ON THE KIDNEY IN HYPERTENSIVES

MOLECULAR BASIS OF EARLY CHILDHOOD OBESITY PROGRAMMING BY INTRAUTERINE GROWTH RESTRICTION

MECHANISMS OF HYPOGLYCEMIA ASSOCIATED AUTONOMIC FAILURE

DEVELOPMENTAL NEPHROLOGY

LNCRNA MECHANISM OF HEART FAILURE

ROLES OF GLYCOSLYATION IN NOTCH SIGNALING

CELL-CELL INTERACTIONS IN DEVELOPING RETINA

TRAJECTORIES AND MODIFIABLE RISK FACTORS OF BRAIN, GAIT, AND COGNITIVE DECLINE IN AGING AND PRE-DEMENTIA

BUPRENORPHINE TREATMENT AT SYRINGE EXCHANGES TO REDUCE OPIOID MISUSE AND HIV RISK

STRUCTURE-BASED DESIGN OF BROAD FLAVIVIRUS IMMUNOGENS - SUMMARY DENGUE VIRUS IS A MOSQUITO-TRANSMITTED FLAVIVIRUS THAT CAUSES AN ESTIMATED 390 MILLION HUMAN INFECTIONS EACH YEAR. THERE ARE FOUR SEROTYPES OF DENGUE (DENV1-4) THAT CO-CIRCULATE IN HYPERENDEMIC REGIONS. PRIMARY INFECTION BY A SINGLE DENV SEROTYPE RESULTS IN FEBRILE ILLNESS AND SUBSEQUENT DURABLE IMMUNITY TO THAT SEROTYPE. SECONDARY INFECTIONS BY HETEROTYPIC SEROTYPES CAN LEAD TO SEVERE SHOCK SYNDROME AND DEATH. SEVERE DENGUE DISEASE IS CAUSED IN PART BY CROSS-REACTIVE ANTIBODIES ELICITED DURING PRIMARY INFECTION THAT CAN BIND HETEROLOGOUS DENV SEROTYPES BUT CANNOT NEUTRALIZE THEM. INSTEAD, THESE NON-NEUTRALIZING ANTIBODIES FACILITATE ENTRY AND INFECTION IN FC RECEPTOR-POSITIVE CELLS, THUS CAUSING "ANTIBODY-DEPENDENT ENHANCEMENT" (ADE) OF INFECTION. WHILE A LIVE-ATTENUATED FOUR-COMPONENT CHIMERIC VACCINE WAS RECENTLY DEPLOYED IN 19 COUNTRIES AND EUROPE, THIS VACCINE DOES NOT PROTECT NAÏVE INDIVIDUALS AGAINST SYMPTOMATIC OR SEVERE INFECTION, AND MAY EVEN EXACERBATE DISEASE IN SOME CASES. FURTHERMORE, THE GLOBAL EMERGENCE OF ZIKA VIRUS (ZIKV), AND THE POTENTIAL FOR ADE BETWEEN DENV AND ZIKV, RAISES CONCERNS FOR VACCINE STRATEGIES CONTAINING MOST OR ALL EPITOPES IN THE E GLYCOPROTEIN. NONETHELESS, THE ISOLATION AND CHARACTERIZATION OF PROTECTIVE AND, IN SOME CASES, BROADLY-NEUTRALIZING ANTIBODIES INDICATES THAT CERTAIN EPITOPES WITHIN THE E GLYCOPROTEIN MAY HAVE THE CAPACITY TO ELICIT BROADLY PROTECTIVE RESPONSES. HERE, WE UTILIZE INNOVATIVE PROTEIN ENGINEERING APPROACHES TO DEVELOP “IMMUNE-FOCUSED” ANTIGENS AS POTENTIAL VACCINE CANDIDATES, IN WHICH EPITOPES THAT INDUCE NON-NEUTRALIZING ANTIBODIES ARE MASKED BY ENGINEERED MUTATIONS OR GLYCOSYLATION. OUR HYPOTHESIS IS THAT MASKING OF THESE UNFAVORABLE EPITOPES WILL SKEW THE IMMUNE RESPONSE TOWARD A STRONGER NEUTRALIZING, PROTECTIVE, AND BROAD RESPONSE. AIMS 1 AND 2 FOCUS ON CRITICAL EPITOPES IN DENV AND ZIKV E DOMAIN III (EDIII), AND AIM 3 EXPLORES GLYCAN MASKING OF THE ZIKV E PREFUSION DIMER TO IMMUNE FOCUS ON THE E-DIMER EPITOPE (EDE). EDIII IS ATTRACTIVE FOR SUBUNIT VACCINE DESIGN BECAUSE IT IS THE TARGET OF POTENTLY NEUTRALIZING AND PROTECTIVE ANTIBODIES FOR BOTH DENV AND ZIKV. HOWEVER, IMMUNIZATION WITH WILD-TYPE EDIII PROTEIN RESULTS IN INDUCTION OF BOTH NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES THAT ENGAGE A VARIETY OF EPITOPES. WE HAVE USED PHAGE DISPLAY TO MASK UNPRODUCTIVE EPITOPES OF DENV AND ZIKV EDIIIS BY MUTATION, WHILE MAINTAINING NEUTRALIZING EPITOPES. THESE “RESURFACED EDIIIS” (RSDIIIS) WILL BE CONJUGATED TO PROTEIN NANOPARTICLES AND THEIR CAPACITY TO INDUCE NEUTRALIZING AND PROTECTIVE ANTIBODY RESPONSE IN MICE EVALUATED. TO IMMUNE FOCUS THE PREFUSION E DIMER ON THE EDE, WE HAVE DEVELOPED A MAMMALIAN DISPLAY SYSTEM THAT ALLOWS FOR RAPID EVALUATION OF E DIMER CONSTRUCTS FOR BINDING TO EDE MABS. WE WILL UTILIZE THIS SYSTEM TO SCREEN VARIANTS WITH MULTIPLE ENGINEERED GLYCOSYLATION SITES THAT MASK THE SURFACE OUTSIDE OF THE EDE. THE MOST PROMISING CANDIDATES WILL BE TESTED FOR THEIR CAPACITY TO INDUCE EDE-LIKE MABS IN MICE. THIS WORK WILL PROVIDE A PROOF-OF-CONCEPT FOR NOVEL SUBUNIT VACCINE CANDIDATES AGAINST DENV, ZIKV, AND POSSIBLY OTHER FLAVIVIRUSES OF GLOBAL CONCERN.

THE ROLE OF MACROH2A VARIANTS IN CANCER AND SENESCENCE

THE DYNAMIC MECHANISM OF NUCLEAR TRANSPORT VISUALIZED AT THE ATOMIC SCALE

SIGNAL TRANSDUCTION & ACTIN DURING AMOEBOID CHEMOTAXIS

ASTHMA SYMPTOM PERCEPTION FEEDBACK INTERVENTION FOR ETHNIC MINORITY ADOLESCENTS

ADAPTATION TO VISUAL MOTION

SMALL MOLECULE ACTIVATORS OF PRO-APOPTOTIC BAX FOR CANCER THERAPY

MONOCYTE CNS HIV ENTRY & NEURODEGENERATION: TRANSLATIONAL STUDIES IN THE CART ERA

SAFETY, PHARMACOKINETICS, AND RESISTANCE TO BEDAQUILINE IN XDR TB AND HIV

OBESITY AND CARIES IN YOUNG SOUTH ASIAN CHILDREN: A COMMON RISK FACTOR APPROACH

ENERGY HOMEOSTASIS: GABAERGIC AND NON-GABAERGIC POMC NEURONS

RNA TRANSPORT AND LOCALIZATION IN YEAST IN SITU

PRESYNAPTIC FORMS OF LONG-TERM PLASTICITY IN THE CNS

HIV/ART, LOW BIRTH WEIGHT, AND MORTALITY IN HIV-EXPOSED UNINFECTED CHILDREN: A TRANSLATIONAL MECHANISTIC STUDY - ABSTRACT DESPITE THE RAPID SCALE-UP OF LIFELONG TRIPLE ANTIRETROVIRAL THERAPY (ART) AMONG PREGNANT WOMEN LIVING WITH HIV (WLH), CHILDREN BORN TO WLH CONTINUE TO HAVE AN INCREASED RISK OF LOW BIRTH WEIGHT (LBW), MORBIDITY, AND MORTALITY COMPARED TO INFANTS BORN TO WOMEN WHO ARE NOT LIVING WITH HIV. ALTHOUGH THE ASSOCIATION BETWEEN LBW AND DECREASED CHILD SURVIVAL HAS BEEN WELL STUDIED, THE BIOLOGICAL MECHANISMS LINKING HIV OR ART AND LBW ARE NOT WELL DESCRIBED. TO BETTER UNDERSTAND HOW HIV/ART INCREASES THE RISK OF LBW, WE LEVERAGE AN ONGOING, WELL-CHARACTERIZED COHORT OF WOMEN LIVING WITH HIV ENROLLED IN A TRIAL OF DATA-DRIVEN CONTINUOUS QUALITY INTERVENTION TO IMPROVE LONG TERM OUTCOMES OF ART IN KINSHASA, DEMOCRATIC REPUBLIC OF CONGO; OUR SPECIFIC FOCUS IS ON HIV-ASSOCIATED INFLAMMATION, IMMUNE ACTIVATION, AND MICROBIAL COMMUNITIES IN THE CONTEXT OF UNIVERSAL ART. A COHORT OF 600 WOMEN LIVING WITH HIV ON ART AND 600 HIV-NEGATIVE CONTROL ALONG WITH THEIR HIV-EXPOSED UN-INFECTED (HEU) AND HIV UNEXPOSED (HU) INFANTS WILL BE RECRUITED AND FOLLOWED UP THROUGH DELIVERY AND UP TO 12 MONTHS POSTPARTUM TO DETERMINE HOW HIV/ART-INDUCED PLACENTAL DYSFUNCTION (AIM 1) OR MICROBIAL DYSBIOSIS (AIM 2) MODULATE THE RISK OF LBW AND SUBSEQUENT INFANT MORTALITY. USING BIOLOGICAL SPECIMEN OBTAINED FROM THOSE WOMEN, WE WILL DOCUMENT HISTOPATHOLOGIC PLACENTAL ABNORMALITIES (E.G. NECROSIS) AND MEASURE LEVELS OF MARKERS OF INFLAMMATION, IMMUNE ACTIVATION, AND MICROBIAL TRANSLOCATION. WE WILL ALSO USE A CUTTING-EDGE MICROBIOME AND VIROME TOOLKIT WITH MACHINE LEARNING AND ECOSYSTEM MODELING APPROACHES TO EVALUATE ASSOCIATIONS BETWEEN THESE ENTITIES AND INFLAMMATION AND LBW, AS WELL AS IN SILICO TEST MYRIAD MECHANISTIC HYPOTHESES DERIVED FROM FUNCTIONAL ANALYSES. WE EXPECT THAT COMPLETION OF THESE COMPLEMENTARY AIMS WILL PROVIDE INSIGHT INTO THE BIOLOGICAL MECHANISM(S) ASSOCIATED WITH INCREASED RISK OF LBW AMONG HIV-EXPOSED INFANTS. THIS INSIGHT COULD ULTIMATELY IDENTIFY AN OPTIMAL HIV- TREATMENT OR CARE MODALITY FOR PREGNANT WLH: ONE WHICH PROMOTES MATERNAL HEALTH, PREVENTS HIV MOTHER-TO-CHILD TRANSMISSION, AND MAXIMIZES INFANT SURVIVAL.

POWER-UP: AN EFFECTIVENESS TRIAL OF THE DIABETES PREVENTION PROGRAM TAILORED FOR BLACK AND LATINO MEN

HOST BIOMARKERS FOR M. TUBERCULOSIS INFECTION ACTIVITY IN HIV-INFECTED PERSONS

EMERGENCE OF BEDAQUILINE AND CLOFAZIMINE RESISTANCE AFTER INTERRUPTION OF DRUG-RESISTANT TB THERAPY IN A HIGH HIV PREVALENCE SETTING

PC4PREP: INTEGRATING PREP INTO PRIMARY CARE

STRUCTURAL, FUNCTIONAL, AND MECHANISTIC ANLAYSIS OF AUTOREACTIVE CD8 T CELLS

CEREBELLUM AND ADDICTION

LECTIN RESISTANT TUMOR CELLS AND FUNCTIONAL GLYCOMICS

ROLE OF INNATE IMMUNITY IN HIV RELATED VASCULAR DISEASE: BIOMARKERS & MECHANISMS

A TRIAL OF POSITIVELY SMOKE FREE GROUP THERAPY FOR HIV-INFECTED SMOKERS

BRAIN INJURY DUE TO SOCCER HEADING AND OPPORTUNITIES FOR ITS MITIGATION

BIOLOGICAL AND NEURAL MECHANISMS OF FALLS

DYSREGULATION OF GLUCOSE HOMEOSTASIS IN AGING

ATTENUATED HSV VACCINES THAT INDUCE PROTECTIVE MUCOSAL ANTIBODIES

PRESYNAPTIC FORMS OF LONG-TERM PLASTICITY IN THE CNS

ROLE OF NEURON-SATELLITE GLIA CELL SIGNALING IN PELVIC PAIN AND VISCERAL CROSS-SENSITIZATION - ABSTRACT MILLIONS OF PEOPLE SUFFER FROM CHRONIC PELVIC PAIN THAT IS OFTEN ASSOCIATED WITH INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS) AND IRRITABLE BOWEL SYNDROME (IBS). SEVERAL FACTORS HAVE BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF THESE DISORDERS BUT MECHANISMS UNDERLYING PAIN CHRONIFICATION ARE STILL POORLY UNDERSTOOD. THIS PROPOSAL IS MOTIVATED BY OUR PREVIOUS STUDIES CHARACTERIZING NEURON-GLIAL INTERACTIONS IN SENSORY GANGLIA AND DEMONSTRATING THEIR IMPORTANCE IN CHRONIC PAIN MODELS INVOLVING OROFACIAL AND HINDLIMB INFLAMMATION. BASED ON THESE FINDINGS, WE FOCUS ON NEURAL INTEGRATION PROCESSES THAT OCCUR WITHIN THE SENSORY GANGLIA (DORSAL ROOT GANGLIA: DRG) THAT INNERVATE PELVIC ORGANS, AND INVESTIGATE WHETHER AND TO WHAT EXTENT ALTERED INTERCELLULAR SIGNALING BETWEEN DRG SENSORY NEURONS AND SATELLITE GLIAL CELLS (SGCS) PROVIDES A COMMON MECHANISM IN BLADDER AND COLON PAIN. MOREOVER, WE PROPOSE THAT SUCH NEURON-GLIA INTERACTIONS MAY CONTRIBUTE TO PELVIC ORGAN CROSSTALK THAT UNDERLIES THE KNOWN COMORBIDITY OF IC/BPS AND IBS. WE HAVE SHOWN THAT NEURONS IN SENSORY GANGLIA ARE IN CLOSE SPATIAL AND FUNCTIONAL CONTACT WITH SGCS. SGCS SUPPORT NEURONAL HOMEOSTASIS BUT ALSO RESPOND TO NEURONAL STIMULATION THROUGH RELEASE OF “GLIOTRANSMITTERS” AND OTHER CHEMICAL MEDIATORS, SUCH AS ATP AND CYTOKINES, WHICH MODULATE NEURONAL EXCITABILITY. THERE IS STRONG EVIDENCE THAT ACTIVATION OF GLIA IN THE CNS AND PNS PLAY KEY ROLES IN DEVELOPMENT AND MAINTENANCE OF PAIN, AND THE IMPORTANCE OF THE CROSSTALK BETWEEN SGCS AND NEURONS IN PATHOLOGICAL PAIN IS BECOMING INCREASINGLY EVIDENT. LITTLE IS STILL KNOWN, HOWEVER, OF WHETHER AND TO WHAT EXTENT THE CROSSTALK BETWEEN SGCS AND NEURONS CONTRIBUTES TO PELVIC ORGAN SENSITIZATION AND CROSS-SENSITIZATION, AND THROUGH WHICH MECHANISMS SGC-NEURON SIGNALING MAY BE ENHANCED AND THEREBY CONTRIBUTE TO PELVIC PAIN. WE HAVE SHOWN THAT IN EXPERIMENTAL COLITIS, GAP JUNCTION (GJ) MEDIATED NEURON-SGC SIGNALING IS ENHANCED IN THE DRG INNERVATING THE COLON. MOREOVER, FINDINGS FROM OUR STUDIES WITH DELETION OF P2X7 RECEPTORS AND PANNEXIN 1 (PANX1) CHANNELS, MAIN MOLECULAR MEDIATORS OF SGC-NEURON SIGNALING, SUGGEST THAT ENHANCED SGC-NEURON COMMUNICATION THROUGH ACTIVATION OF THE P2X7R-PANX1 COMPLEX PLAYS A KEY ROLE IN DEVELOPMENT OF DRG HYPEREXCITABILITY AND TACTILE HYPERSENSITIVITY. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT INTERCELLULAR GJ AND P2X7R-PANX1 MEDIATED SIGNALING IN THE DRG PLAY A KEY ROLE IN SENSITIZATION OF PELVIC AFFERENTS BY CONTRIBUTING MECHANISMS THAT ENHANCE SGC ACTIVATION AND NEURONAL EXCITABILITY AND CAN CONTRIBUTE TO COLON-BLADDER CROSS-SENSITIZATION. TO TEST THIS HYPOTHESIS, WE WILL EMPLOY WELL ESTABLISHED MODELS OF DIRECT BLADDER AND COLON INSULT, AND COMBINED BEHAVIORAL, FUNCTIONAL AND MOLECULAR APPROACHES USING WILDTYPE AND TRANSGENIC MICE WITH GLOBAL OR CELL-SPECIFIC DELETION OF CX43, PANX1 AND P2X7R. FINDINGS FROM THESE STUDIES ARE EXPECTED TO DEMONSTRATE THE KEY ROLE OF PATHOLOGICALLY ENHANCED SGC-NEURON SIGNALING IN THE DEVELOPMENT OF PELVIC PAIN AND VISCERAL CROSS-SENSITIZATION, AND REVEAL THAT GAP JUNCTIONS AND THE P2X7R-PANX1 FUNCTIONAL COMPLEX DRIVE THE ENHANCED SGC-NEURON INTERCELLULAR SIGNALING IN THIS PROCESS, PROVIDING NOVEL THERAPEUTIC TARGETS FOR FUTURE CLINICAL TRANSLATION.

INHIBITORS OF PURINE IMPORT INTO PLASMODIUM FALCIPARUM KILL MALARIA PARASITES

INTERNEURONS AS EARLY DRIVERS OF HUNTINGTON?S DISEASE PROGRESSION - HUNTINGTON’S DISEASE (HD) IS AN INSIDIOUS NEURODEGENERATIVE DISORDER CAUSED BY TRINUCLEOTIDE REPEAT EXPANSION IN EXON 1 OF THE GENE THAT CODES FOR HUNTINGTIN (MHTT). THE PATHOGENIC MECHANISMS UNDERLYING HD REMAIN POORLY UNDERSTOOD. STUDIES OF HD MODELS HAVE DOCUMENTED NUMEROUS DEVELOPMENTAL IMPAIRMENTS DURING ‘PRE- MANIFEST’ HD. USING CONDITIONAL HD MODELS, THE MEHLER LABORATORY TEAM HAS PREVIOUSLY SHOWN THAT SUCH DEVELOPMENTAL PROCESSES MEDIATE DISEASE PATHOGENESIS. NOW, THIS TEAM PROVIDES EVIDENCE DEMONSTRATING THAT INTERNEURON NEUROGENESIS IS PROMINENTLY DISRUPTED IN MOUSE MODELS OF HD, LEADING TO DEFICITS IN THE COMPLEMENT OF THESE INTERNEURONS WITHIN THE DEVELOPING CEREBRAL CORTEX. SUCH DEFICITS ARE OF GREAT IMPORTANCE, AS STUDIES HAVE SHOWN THESE LEAD TO PERMANENT CHANGES IN CORTICO-STRIATAL CONNECTIVITY LAYING THE FOUNDATION FOR CORTICAL HYPEREXCITABILITY, IMPAIRED EXCITATION-INHIBITION COUPLING, AND STRIATAL EXCITOTOXIC STRESS LATER IN LIFE. ALTHOUGH CORTICAL INTERNEURON DEFICITS HAVE PREVIOUSLY BEEN REPORTED IN HD CASES, THEIR ROLE IN HD PATHOGENESIS HAS NEVER BEEN FURTHER INTERROGATED. THIS APPLICATION TESTS THE CENTRAL HYPOTHESIS THAT HD IS CAUSED BY IMPAIRMENTS IN THE DEVELOPMENTAL ELABORATION OF SELECTIVE CORTICAL INTERNEURON SUBTYPES; THEREFORE, PREVENTION OF THE ADVERSE DEVELOPMENTAL EFFECTS OF THESE INTERNEURON DEFICITS WILL AMELIORATE OR EVEN PREVENT DISEASE OCCURRENCE. THIS HYPOTHESIS IS FURTHER SUPPORTED BY PRELIMINARY DATA SHOWING THAT GENETIC RESCUE OF DEVELOPING INTERNEURONS PRECLUDES THE ONSET OF CHARACTERISTIC FEATURES OF HD IN BACHD MICE: MOTOR COORDINATION DEFICITS, HYPOMYELINATION OF SUBCORTICAL WHITE MATTER TRACTS AND STRIATAL DEGENERATION. SPECIFIC AIM 1 (SA1) INITIALLY DEFINES WHETHER INTERNEURON PROGENITOR CELL SUPPLEMENTATION VIA HETEROCHRONIC GRAFTS INTO MUTANT NEONATAL PUPS FAVORABLY MODIFIES THE OCCURRENCE OF MOTOR DEFICITS AND STRIATAL DEGENERATION, TWO DISTINCTIVE TRAITS OF HD. THIS AIM ALSO EXAMINES WHETHER THE ROLE OF INTERNEURONS IN DISEASE PROGRESSION TAKES PLACE AT THE EXPENSE OF QUANTITATIVE DEFICITS OR THROUGH ADDITIONAL FACTORS ASSOCIATED WITH EXPRESSION OF MUTANT HUNTINGTIN IN THESE CELLS. SA2 INTERROGATES THE INTERNEURON-DEPENDENT PATHOGENIC MECHANISMS MEDIATING HD, FOCUSING ON PUTATIVE MODULATORY EFFECTS OF GABA, REELIN AND COMPLEMENTARY LIGAND RELEASE. FINALLY, SA3 EMPLOYS A LARGE ARRAY OF HD POSTMORTEM SPECIMENS FROM TWO MAJOR BRAIN BANKS TO DEFINE THE ROLE IN DISEASE PROGRESSION OF CORTICAL INTERNEURON DEFICITS. THIS AIM ALSO INTERROGATES WHETHER KNOWN HD GENETIC MODIFIERS, INCLUDING TRINUCLEOTIDE EXPANSION LENGTH AND/OR POLYMORPHISMS OF DNA DAMAGE RESPONSE GENES MODULATE THE EXTENT OF INTERNEURON ALTERATIONS, AS WELL AS WHETHER THESE CELLS MEDIATE THE PREDICTIVE EFFECTS OF THESE GENETIC MODIFIERS ON AGE AT DISEASE ONSET/PROGRESSION. OVERALL, CONFIRMATION OF THE CENTRAL HYPOTHESIS WOULD HAVE SUBSTANTIAL IMPLICATIONS FOR THE FIELD, AS IT WILL PROVIDE STRONG EVIDENCE REGARDING THE INTERSECTIONAL ROLES OF INTERNEURONS IN HD PATHOGENESIS AND ALSO DEFINE A NOVEL EARLY-STAGE THERAPEUTIC WINDOW FOR PREVENTING HD ONSET AND PROGRESSION FOR A NEURODEGENERATIVE DISORDER CURRENTLY LACKING SUBSTANTIVE AND EFFECTIVE THERAPEUTIC INTERVENTIONS.

LEVERAGING COMMUNITY HEALTH WORKERS TO IMPROVE SARS-COV-2 TESTING AND MITIGATION AMONG CRIMINAL JUSTICE-INVOLVED INDIVIDUALS ACCESSING A CORRECTIONS-FOCUSED COMMUNITY-BASED ORGANIZATION - ABSTRACT. THE UNITED STATES (U.S.) HAS EXPERIENCED HIGHER MORTALITY THAN ANY OTHER NATION DUE TO COVID-19 WITH NEARLY 13.5 MILLION CASES AND OVER 268,103 DEATHS. DUE TO THE LIMITED ABILITY TO SOCIALLY DISTANCE, POOR VENTILATION, AND LIMITED HYGIENE SUPPLIES, U.S. PRISONS AND JAILS HAVE OBSERVED EXPLOSIVE TRANSMISSION OF SARS-COV-2 ACCOUNTING FOR THE 10 LARGEST U.S. OUTBREAKS. BECAUSE 95% OF CRIMINAL JUSTICE-INVOLVED INDIVIDUALS REENTER SOCIETY COVID-19 TRANSMISSION EXTENDS BEYOND THOSE WHO ARE CURRENTLY INCARCERATED. AS JUSTICE-INVOLVED INDIVIDUALS REENTER THE COMMUNITY, THEY FACE HIGH RATES OF HOMELESSNESS, AND MANY OTHERS LIVE IN OTHER CONGREGATE SETTINGS SUCH AS CONVERTED HOTELS AND HALFWAY HOUSES. THE INCREASED RISK OF SARS-COV-2 WHILE INCARCERATED COUPLED WITH THE LIKELIHOOD OF LIVING IN CONGREGATE SETTINGS AFTER INCARCERATION, CREATE CONDITIONS RIPE FOR RAPID COVID-19 TRANSMISSION THAT WILL BE CRITICAL TO ADDRESS IN ORDER TO GAIN CONTROL OF COVID-19 IN THE U.S. THE GOAL OF THIS STUDY IS TO TEST THE IMPACT AND COST-EFFECTIVENESS OF AN INTERVENTION TO MITIGATE SARS-COV-2 TRANSMISSION AMONG JUSTICE-INVOLVED INDIVIDUALS RECENTLY RELEASED FROM INCARCERATION. WE WILL CONDUCT A RANDOMIZED TRIAL TO COMPARE THE EFFECTIVENESS OF AN ONSITE POINT-OF-CARE SARS-COV-2 TESTING AND EDUCATION INTERVENTION WITH COMMUNITY HEALTH WORKERS (CHWS) AS A CENTRAL COMPONENT COMPARED TO THE STANDARD OF CARE AT A COMMUNITY-BASED ORGANIZATION (CBO) THAT PROVIDES SERVICES TO JUSTICE-INVOLVED INDIVIDUALS IN NEW YORK CITY. WE WILL MEASURE COSTS OF TESTING, EDUCATION, AND NAVIGATION, AND EXPLORE THE COST-EFFECTIVENESS OF THE ONSITE POINT-OF-CARE INTERVENTION COMPARED TO THE STANDARD OF CARE. OUR SPECIFIC AIMS ARE TO: 1) TEST THE EFFECTIVENESS OF AN ONSITE POC SARS- COV-2 INTERVENTION IN A CORRECTIONS-FOCUSED CBO; 2) MODEL THE COST-EFFECTIVENESS OF AN ONSITE POC SARS-COV- 2 INTERVENTION AMONG CJIS COMPARED TO SOC. BECAUSE TESTING, EDUCATION, AND NAVIGATION WILL BE PROVIDED BY CHWS IN A CULTURALLY-SENSITIVE ENVIRONMENT AND TEST RESULTS WILL BE RECEIVED IN MINUTES (RATHER THAN DAYS), WE HYPOTHESIZE THAT O-POC WILL BE ASSOCIATED WITH IMPROVED TESTING UPTAKE AND RECEIPT OF TEST RESULTS, MITIGATION BEHAVIORS (MASK WEARING, HAND HYGIENE, SOCIAL DISTANCING), AND THOSE WHO ATTEND MORE O-POC SESSIONS WILL HAVE BETTER ADHERENCE TO MITIGATION BEHAVIORS.

PRESERVING PHYSICAL FUNCTION IN PATIENTS WITH KIDNEY DISEASE - PROJECT SUMMARY/ABSTRACT SKELETAL MUSCLE DYSFUNCTION CONTRIBUTES TO FRAILTY, DISABILITY, AND MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). THIS PROPOSAL SEEKS TO DETERMINE IF MUSCLE DYSFUNCTION IN CKD CAN BE ALLEVIATED BY DIALYSIS (BLOOD FILTRATION FOR KIDNEY FAILURE). WE RECENTLY DISCOVERED THAT PATIENTS WITH CKD EXPERIENCE PROGRESSIVELY WORSENING MUSCLE FIBROSIS, AND THAT GREATER SEVERITY OF FIBROSIS IS ASSOCIATED WITH REDUCED MUSCLE STRENGTH AND PHYSICAL FUNCTION. IN PATIENTS WITH SEVERE CKD, FIBROTIC CHANGES ARE EXTENSIVE. HOWEVER, DESPITE THE SEEMINGLY ADVANCED NATURE OF THIS FIBROTIC TRANSFORMATION, PATIENTS STARTING DIALYSIS EXPERIENCED MARKED IMPROVEMENT IN FIBROSIS. THIS SUGGESTS THAT, IN PATIENTS WITH SEVERE CKD AND MUSCLE FIBROSIS, THE INITIATION OF DIALYSIS COULD IMPROVE PHYSICAL FUNCTION. THEREFORE, THIS PROPOSAL TESTS THE HIGHLY INNOVATIVE HYPOTHESIS THAT THE INITIATION OF DIALYSIS IN PATIENTS WITH SEVERE CKD REVERSES MUSCLE FIBROSIS AND IMPROVES PHYSICAL FUNCTION. WE WILL ACCOMPLISH THIS OBJECTIVE USING A TRANSLATIONAL APPROACH THAT INTEGRATES CLINICALLY RELEVANT FUNCTIONAL ENDPOINTS WITH STATE-OF-THE-ART METHODS INCLUDING MUSCLE TISSUE MECHANICS, QUANTITATIVE MAGNETIC RESONANCE IMAGING (QMR), AND TRANSCRIPTOMIC AND PROTEOMIC STUDIES OF HUMAN SKELETAL MUSCLE. THE PROPOSED HUMAN STUDIES WILL (1) DEFINE THE EFFECT OF DIALYSIS INITIATION ON MUSCLE FIBROSIS BY EXAMINING CHANGES IN MUSCLE COLLAGEN CONTENT, COLLAGEN CROSS-LINKING, TISSUE PASSIVE STIFFNESS, AND QMR MEASURES; (2) DETERMINE THE EXTENT TO WHICH REGRESSION OF FIBROSIS AFTER DIALYSIS INITIATION TRANSLATES INTO FUNCTIONAL IMPROVEMENTS BY TESTING THE ASSOCIATION OF ALTERATIONS IN THE STRUCTURAL PARAMETERS FROM AIM 1 WITH CHANGES IN MUSCLE STRENGTH, ENDURANCE, AND LOWER EXTREMITY PERFORMANCE; AND (3) IDENTIFY MOLECULAR AND CELLULAR PREDICTORS OF THE RESOLUTION OF FIBROSIS USING TRANSCRIPTOMIC AND PROTEOMIC ANALYSES OF SKELETAL MUSCLE. IF OUR HYPOTHESES ARE CORRECT: (1) MUSCLE FIBROSIS COULD BE AN INDICATOR FOR PHYSICIANS TO START DIALYSIS THERAPY; AND (2) THIS PROPOSAL WILL IDENTIFY AN INTERVENTION TO ALLEVIATE MUSCLE DYSFUNCTION IN PATIENTS WITH CKD.

ACHIEVING SMOKING CESSATION MILESTONES IN OPIOID TREATMENT PATIENTS: A RANDOMIZED 2 X 2 FACTORIAL TRIAL OF DIRECTLY OBSERVED AND LONG-TERM VARENICLINE

BRAIN PREDICTORS OF MOBILITY AND FALLS IN OLDER ADULTS WITH MULTIPLE SCLEROSIS

CHARACTERIZING PERSISTENT SUBCLINICAL NEUROBEHAVIORAL EFFECTS OF COVID-19 IN A DIVERSE URBAN POPULATION - PROJECT SUMMARY/ABSTRACT EXCESS COGNITIVE DYSFUNCTION HAS BEEN IDENTIFIED IN OLDER ADULT SURVIVORS OF COVID-19, COMPARED TO OTHER RESPIRATORY INFECTIONS. SARS-COV-2 MAY THUS ADVERSELY IMPACT THE BRAIN BEYOND WHAT THE CASES OF ACUTE STROKE, ETC. SUGGEST. UNRECOGNIZED BRAIN EFFECTS OF SARS-COV-2 INFECTION MAY IMPACT CURRENT BRAIN FUNCTIONING AND PRESAGE FUTURE NEURODEGENERATION AND OVERT NEUROLOGIC DYSFUNCTION. HOWEVER, ABSENT KNOWN BASELINE FUNCTIONING, DETECTION OF SUBCLINICAL EFFECTS WILL BE CONFOUNDED BY NORMAL VARIATION BETWEEN CASES AND CONTROLS. WE WILL THEREFORE LEVERAGE DETAILED PRE-PANDEMIC NEUROCOGNITIVE AND IMAGING ASSESSMENTS TO CHARACTERIZE SUBCLINICAL EFFECTS ON BRAIN STRUCTURE AND FUNCTION AMONG A LARGE COHORT OF YOUNGER PATIENTS WHO EXPERIENCED MILD OR ASYMPTOMATIC SARS-COV-2 INFECTION. WE WILL IDENTIFY 3 GROUPS UTILIZING DETAILED SEROLOGIC ANALYSIS AND NOVEL HIGHLY SPECIFIC SARS-COV-2 T-CELL ASSAYS TO ALLOW CONFIRMATION OF PRIOR SARS-COV-2 INFECTION, EVEN IN THE SETTING OF COVID-19 VACCINATION: (1) M ILD COVID-19: 35 PATIENTS WITH LABORATORY CONFIRMED COVID-19 WHO WERE NOT HOSPITALIZED; (2) ASYMPTOMATIC: 35 WITH LABORATORY EVIDENCE OF SARS-COV-2 INFECTION, BUT NO HISTORY OF COVID-19 SYMPTOMS; AND (3) CONTROLS: 70 MATCHED INDIVIDUALS WITHOUT LABORATORY OR CLINICAL EVIDENCE OF PRIOR SARS-COV-2 INFECTION. ALL PARTICIPANTS WERE HEALTHY PRIOR TO COVID-19, WITH NO COMORBID RISK FACTORS OR BRAIN IMAGING ABNORMALITY AND NORMAL NEUROCOGNITIVE PERFORMANCE. AGAINST THIS ROBUST QUANTITATIVE BASELINE, WE WILL ASSESS CHANGE DUE TO SARS-COV-2 INFECTION BY REPEATING A SUITE OF NEUROLOGICAL ASSESSMENTS, INCLUDING BRAIN IMAGING AND ASSESSMENTS OF NEUROCOGNITIVE FUNCTION, MOOD, ANXIETY, STRESS AND SOCIAL ISOLATION DUE TO THE PANDEMIC. IN ADDITION TO THEIR PRE-PANDEMIC BASELINE, WE WILL ASSESS PARTICIPANTS (1) AT ENTRY INTO THIS PROPOSED STUDY, (2) 6 MONTHS AFTER ENTRY, (3) 18 MONTHS AFTER ENTRY AND (3) THREE YEARS AFTER ENTRY, TO ADDRESS THE FOLLOWING: AIM 1 BRAIN TISSUE EFFECTS: CHARACTERIZE CHANGE OF MACRO/MICROSTRUCTURE AND FUNCTIONAL CONNECTIVITY FROMPRE- PANDEMIC, AMONG SARS-COV-2 INFECTED PATIENTS AND NON-INFECTED CONTROLS, OVER THREE YEARS. AIM 2 FUNCTIONAL EFFECTS: ASSESS CHANGE IN NEUROCOGNITIVE FUNCTION FROM PRE-PANDEMIC, AMONG SARS-COV-2 PATIENTS, AND IN NON-INFECTED CONTROLS, OVER THREE YEARS, WHILE ACCOUNTING FOR MOOD, STRESS AND SOCIAL ISOLATION. AIM 3 INDIVIDUAL RISK FACTORS [EXPLORATORY]:EXPLORE WHETHER INDIVIDUAL CHARACTERISTICS, SUCH AS SEX, BMI, SES AND RACE/ETHNICITY, MODIFY THE ASSOCIATIONS OF SARS-COV-2 INFECTION WITH MRI AND NEUROCOGNITIVE CHANGES. CONFIRMING NEUROLOGICAL MORBIDITY IN MILD SARS-COV-2 WILL HAVE KEY IMPLICATIONS FOR SCREENING, CARE AND FOLLOW- UP FOR BRAIN DYSFUNCTION AMONG THOSE AT RISK. THESEPROBLEMS WOULD OTHERWISE GO UNRECOGNIZED, DESPITE POTENTIAL FOR LONG-TERM, YET-UNRECOGNIZED MORBIDITY. OUR EXISTING SAMPLE OF PREVIOUSLY HEALTHY, YOUNG, ETHNICALLY DIVERSE WOMEN AND MEN FROM A HIGH PREVALENCE AND HIGH MORBIDITY REGION, WELL-CHARACTERIZED PRIOR TO THE COVID-19 PANDEMIC, UNIQUELY POSITIONS US TO CHARACTERIZE SUBCLINICAL BRAIN INJURY AND DYSFUNCTION DUE TO SARS-COV-2.

TARGETING CLOSTRIDIOIDES DIFFICILE WITH MICROBIOME-SPARING, RESISTANT-PROOF ANTI-TOXINS - ABSTRACT: HUMAN GUT INFECTIONS BY CLOSTRIDIOIDES (CLOSTRIDIUM) DIFFICILE (HERE, C.DIFF.) ARE THE MOST LETHAL URGENT THREAT IN THE 2019 CDC ANTIBIOTIC RESISTANCE THREATS REPORT. EXCESS HEALTHCARE COSTS FROM THESE INFECTIONS HAVE BEEN ESTIMATED TO BE OVER $5 BILLION ANNUALLY. ANTIBIOTIC RESISTANCE HAS ELICITED AN INSIGHTFUL RFA RA18-725, `GENERATING NEW INSIGHTS AND MECHANISTIC UNDERSTANDING OF ANTIBIOTIC RESISTANCE'. C.DIFF. INFECTIONS (CDI) TYPICALLY ARISE FOLLOWING TREATMENT OF OTHER CLINICAL DISORDERS WITH ANTIBIOTICS. ANTIBIOTIC THERAPY DISRUPTS NORMAL GUT MICROBIOTA, ALLOWING C.DIFF. TO PROLIFERATE AND TO REPOPULATE THE GUT FOLLOWING TREATMENT. ADDITIONAL ANTIBIOTIC THERAPY TO TREAT CDI PREVENTS RETURN OF NORMAL GUT MICROBIOTA, LEADING TO RECURRENT INFECTIONS IN OVER 20% OF PATIENTS. C.DIFF. HAS ACQUIRED RESISTANCE TO SEVERAL COMMON ANTIBIOTICS, COMPOUNDING ITS THERAPY. RECENT CLINICAL GUIDELINES (2018) FOR C.DIFF. INFECTIONS ARE ORAL VANCOMYCIN FOR PATIENTS IN SHOCK, HYPOTENSION, ILEUS OR MEGACOLON. FECAL TRANSPLANT IS RECOMMENDED FOR NONRESPONSIVE INFECTIONS FOLLOWING VANCOMYCIN TREATMENT. MAB THERAPIES HAVE BEEN FDA- APPROVED, BUT ARE NOT RECOMMENDED. DESPITE THESE THERAPIES, C. DIFFICILE CAUSES AN ESTIMATED 224,000 INFECTIONS AND 13,000 DEATHS PER YEAR (CDC IN 2017). GUT EPITHELIAL CELL CYTOTOXICITY RESULTS FROM C.DIFF. PRODUCTION OF SECRETED TOXINS, PRIMARILY TCDA AND TCDB (TCDS). TCDS ARE PROCESSED IN GUT CELLS TO FORM ACTIVE UDP-GLUCOSYL TRANSFERASES THAT GLUCOSYLATE CYTOSKELETAL-REGULATING RHO, RAC AND CDC42 GTP-BINDING PROTEINS ON SPECIFIC THREONINES. LOSS OF CYTOSKELETAL INTEGRITY CAUSES SEVERE COLITIS AND CAN HAVE A FATAL OUTCOME. ANTI-TOXIN IMMUNITY IS A HISTORIC APPROACH TO PREVENT HOST DAMAGE FROM CIRCULATING BACTERIAL TOXINS. WE PROPOSE THAT SMALL MOLECULE, TIGHT-BINDING INHIBITORS TARGETING C.DIFF. TCDS CAN PREVENT THE MORBIDITY AND MORTALITY FROM GUT TOXINS IN C.DIFF. INFECTIONS. OUR TRANSITION STATE ANALOG APPROACH USES KINETIC ISOTOPE EFFECTS AND QUANTUM CHEMISTRY TO SOLVE TRANSITION STATE STRUCTURES OF TCDS. SOLVING THE FIRST TRANSITION STATE STRUCTURES OF G-PROTEIN GLUCOSYLTRANSFERASES, AND DEVELOPING THE FIRST TRANSITION STATE ANALOG OF ANY UDP-SUGAR TRANSFERASE IS INNOVATIVE. ELECTROSTATIC POTENTIAL MODELS OF TCD TRANSITION STATES WILL GUIDE THE DESIGN AND SYNTHESIS OF TRANSITION STATE ANALOGS. LEAD TRANSITION STATE ANALOG CANDIDATES WILL BE ELABORATED BY CYCLES OF CRYSTALLOGRAPHY AND CHEMICAL DESIGN. CANDIDATE COMPOUNDS AND CRYSTAL STRUCTURES OF TCD COMPLEXES HAVE BEEN OBTAINED IN PRELIMINARY STUDIES. INHIBITORS WILL BE CHARACTERIZED AGAINST TCDS IN HUMAN CELLS AND IN MOUSE MODELS. AGENTS TO PREVENT TISSUE DAMAGE FROM C.DIFF. INFECTIONS, WITHOUT DISRUPTION OF THE GUT MICROBIOME OR PRESSURE FOR MICROBIAL RESISTANCE HAVE IMPORTANT MEDICAL RELEVANCE. INHIBITION OF TCDS IN GUT EPITHELIAL CELLS PLACES NO SELECTIVE PRESSURE FOR ANTIBIOTIC OR ANTI-TOXIN RESISTANCE ON C.DIFF. OR ON THE GUT MICROBIOME, WHILE PROTECTING THE GUT BY NEUTRALIZING TCDS. MECHANISTICALLY, THIS APPROACH IS INNOVATIVE IN RECAPITULATING VACCINE-BASED ANTIBODY NEUTRALIZATION OF TOXINS USING THE POWERFUL APPROACH OF TRANSITION STATE ANALOGS.

HOSPITAL AIRWAY RESUSCITATION TRIAL - ABSTRACT IN-HOSPITAL CARDIAC ARREST OCCURS IN NEARLY 300,000 HOSPITALIZED PATIENTS IN THE UNITED STATES EACH YEAR AND RESULTS IN SUBSTANTIAL MORBIDITY AND MORTALITY. NEVERTHELESS, THE EVIDENCE BASE GUIDING THE MANAGEMENT OF IN- HOSPITAL CARDIAC ARREST IS QUITE LIMITED AND SOCIETY GUIDELINES GENERALLY EXTRAPOLATE DATA FROM THE OUT-OF-HOSPITAL CARDIAC SETTING TO INFORM IN-HOSPITAL ARREST CARE. AS COMPARED TO OUT-OF-HOSPITAL ARREST, HOWEVER, IN-HOSPITAL ARREST VICTIMS TEND TO HAVE MORE MEDICAL COMORBIDITIES, HAVE A WITNESSED ARREST, AND BE ATTENDED TO BY PROFESSIONAL FIRST RESPONDERS WITH ADVANCED MONITORING AND TREATMENT CAPABILITIES. ADVANCED AIRWAY MANAGEMENT IS A KEY ELEMENT OF CARDIAC ARREST RESUSCITATION. THE AMERICAN HEART ASSOCIATION MAKES BROAD RECOMMENDATIONS REGARDING AIRWAY MANAGEMENT DURING IN-HOSPITAL CARDIAC, SUPPORTING ENDOTRACHEAL INTUBATION (A COMPLEX PROCEDURE REQUIRING PLACEMENT OF AN ENDOTRACHEAL TUBE THROUGH THE VOCAL CORDS) AND SUPRAGLOTTIC AIRWAY PLACEMENT (A LESS COMPLEX ADVANCED AIRWAY MODALITY WHEREIN THE DEVICE IS PLACED BLINDLY IN THE SUPRAGLOTTIC SPACE). DATA FROM THE OUT-OF-HOSPITAL CARDIAC ARREST SETTING HAS FOUND THAT A SUPRAGLOTTIC AIRWAY STRATEGY MAY BE SIMILAR OR SUPERIOR TO A MORE COMPLEX ENDOTRACHEAL INTUBATION STRATEGY. THERE IS NO RANDOMIZED DATA TO GUIDE PRACTICE IN THE IN-HOSPITAL SETTING. WE INTEND TO ADDRESS THIS KNOWLEDGE GAP BY PERFORMING THE HOSPITAL AIRWAY RESUSCITATION TRIAL (HART)—A HIGHLY-INNOVATIVE, PRAGMATIC CLUSTER-RANDOMIZED TRIAL LEVERAGING THE UNIFIED CLINICAL AND RESEARCH INFRASTRUCTURE WITHIN THE MONTEFIORE HEALTHSYSTEM (NEW YORK CITY) TO CONDUCT A FIRST-OF-ITS-KIND IN-HOSPITAL ARREST TRIAL IN A HIGHLY DIVERSE PATIENT POPULATION. SPECIFICALLY, A MIXTURE OF ACADEMIC AND COMMUNITY HOSPITALS WITHIN THE MONTEFIOREHEALTH SYSTEM WILL BE RANDOMIZED TO EITHER A STRATEGY OF FIRST-CHOICE ENDOTRACHEAL INTUBATION OR A STRATEGY OF FIRST CHOICE SUPRAGLOTTIC AIRWAY, WITH CROSSOVERS OCCURRING AT REGULAR INTERVALS. THE PRIMARY OUTCOME FOR THE TRIAL WILL BE ALIVE-AND-VENTILATOR-FREE DAYS, A COMMON OUTCOME IN CRITICAL CARE TRIALS THAT ACCOUNTS FOR THE IMPACT OF THE INTERVENTION ON BOTH MORBIDITY AND MORTALITY. WE HYPOTHESIZE THAT IN-HOSPITAL ARREST PATIENTS MANAGED WITH A STRATEGY OF FIRST-CHOICE SUPRAGLOTTIC AIRWAY WILL HAVE MORE ALIVE-AND-VENTILATOR-FREE DAYS THAN THOSE MANAGED WITH A STRATEGY OF ENDOTRACHEAL INTUBATION. SECONDARY OUTCOMES WILL INCLUDE RATES OF RETURN OF SPONTANEOUS CIRCULATION, SURVIVAL TO 72-HOURS AND 28-DAYS, AND FUNCTIONAL STATUS AT DISCHARGE. IN ADDITION, WE AIM TO UNDERSTAND MECHANISTIC EXPLANATIONS FOR THE EFFICACY OF AIRWAY MANAGEMENT STRATEGIES BY COMPARING ACCEPTED METRICS OF CARDIOPULMONARY RESUSCITATION QUALITY BETWEEN GROUPS. THIS WILL BE DONE USING DATA CAPTURED BY STATE-OF-THE-ART BEDSIDE ADVANCED CARDIAC MONITORS/DEFIBRILLATORS IN USE THROUGHOUT THE MONTEFIORE SYSTEM. WE WILL ENROLL 1060 PATIENTS IN THIS TRIAL. THE RESULTS OF THIS TRIAL PROMISE TO IMPACT AIRWAY MANAGEMENT STRATEGIES DURING IN-HOSPITAL CARDIAC ARREST WORLDWIDE AND, IF OUR HYPOTHESIS IS TRUE, RESULT IN A SUBSTANTIAL NUMBER OF LIVES SAVED.

CATALYTIC AND REGULATORY MECHANISMS OF HUMAN TRYPTOPHAN DIOXYGENASE

TARGETING DKK-1 TO PREVENT OSTEOSARCOMA METASTASIS - ABSTRACT OSTEOSARCOMA IS THE MOST COMMON PRIMARY BONE TUMOR OF ADOLESCENTS AND YOUNG ADULTS. AGGRESSIVE SURGERY AND INTENSIVE CHEMOTHERAPY PROVIDE LONG TERM SURVIVAL TO UP TO 75% OF PATIENTS DIAGNOSED WITH LOCALIZED DISEASE, BUT THIS APPROACH ONLY CURES 20% OF PATIENTS WHO PRESENT WITH METASTASIS. NUMEROUS ATTEMPTS AT TREATMENT INTENSIFICATION HAVE FAILED TO IMPROVE THIS DISMAL PROGNOSIS, SO THERE IS AN URGENT NEED FOR NEW TREATMENT APPROACHES BASED ON A DEEPER UNDERSTANDING OF OSTEOSARCOMA BIOLOGY. THE WNT SIGNALING PATHWAY HAS BEEN A FOCUS OF INVESTIGATION IN OSTEOSARCOMA BECAUSE OF ITS ROLE IN NORMAL BONE BIOLOGY. CANONICAL, SS-CATENIN- DEPENDENT WNT SIGNALING DRIVES NORMAL OSTEOBLAST DIFFERENTIATION. IT HAS BEEN REPORTED THAT THE SECRETED INHIBITOR OF CANONICAL WNT (CWNT) SIGNALING, DICKKOPF-1 (DKK-1) IS FOUND AT HIGH LEVELS IN THE BLOOD OF NEWLY DIAGNOSED OSTEOSARCOMA PATIENTS AND IS PREFERENTIALLY EXPRESSED BY OSTEOSARCOMA CELLS AT THE INVASIVE EDGE OF GROWING TUMORS. INHIBITION OF DKK-1 INCREASES NONCANONICAL WNT (NCWNT) SIGNALING IN MURINE OSTEOSARCOMA CELLS. OUR LABORATORY DEMONSTRATED THAT HUMAN DKK-1 CAN BE DETECTED IN THE BLOOD OF IMMUNE DEFICIENT MICE BEARING OSTEOSARCOMA PATIENT-DERIVED XENOGRAFTS AND THAT A NEUTRALIZING ANTIBODY AGAINST DKK-1 INCREASED CWNT SIGNALING IN THE PRIMARY TUMOR, INDUCING MARKERS OF DIFFERENTIATION AND ABOLISHING METASTASIS. TAKEN TOGETHER, THESE FINDINGS SUGGEST THE HYPOTHESIS THAT DKK-1 REGULATES THE BALANCE BETWEEN CWNT AND NCWNT SIGNALING IN OS, AFFECTING EXPRESSION OF GENES IMPORTANT FOR TUMOR CELL DIFFERENTIATION AND METASTASIS. WE WILL TEST THIS HYPOTHESIS AND GENERATE PRECLINICAL DATA TO GUIDE THE IMPLEMENTATION OF TREATMENTS TARGETING DKK-1 IN OSTEOSARCOMA PATIENTS THROUGH THREE SPECIFIC AIMS. SA1: TO DEFINE THE MECHANISM BY WHICH DKK-1 REGULATES THE BALANCE BETWEEN CWNT AND NCWNT SIGNALING IN OSTEOSARCOMA. SA2: TO OPTIMIZE THE TIMING AND IMPLEMENTATION OF DKK-1 INHIBITION IN PRECLINICAL MODELS OF OSTEOSARCOMA. SA3: TO VALIDATE SERUM DKK-1 LEVEL AS A BIOMARKER OF DISEASE BURDEN AND RESPONSE TO THERAPY IN OSTEOSARCOMA PATIENTS. SUCCESSFUL COMPLETION OF THIS STUDY WILL BETTER DEFINE THE ROLE OF WNT SIGNALING IN OS BIOLOGY, PROVIDE ROBUST PRECLINICAL DATA TO INFORM A CLINICAL TRIAL OF DKK-1 TARGETED THERAPY TO PREVENT OS METASTASIS, AND DEVELOP A NOVEL, NONINVASIVE BIOMARKER OF RELAPSE RISK AND RESPONSE TO TREATMENT.

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