Wayne State University

HIGHER EDUCATION EMERGENCY RELIEF FUND - CARES ACT - WAYNE STATE UNIVERSITY

CANCER CENTER SUPPORT GRANT

CARES ACT FUNDING

ACHIEVE GREATER: ADDRESSING CARDIOMETABOLIC HEALTH INEQUITIES BY EARLY PREVENTION IN THE GREAT LAKES REGION - ABSTRACT BUILDING UPON THE STRENGTH OF EXISTING COLLABORATIONS AND LEVERAGING THE INTELLECTUAL RESOURCES AND INFRASTRUCTURE ACROSS THREE MAJOR RESEARCH INSTITUTIONS, TWO IN DETROIT (WAYNE STATE UNIVERSITY AND THE HENRY FORD HEALTH SYSTEM) AND ONE IN CLEVELAND (CASE WESTERN RESERVE UNIVERSITY/UNIVERSITY HOSPITALS), THE ACHIEVE GREATER CENTER WILL, I) INCREASE REACH IN AREAS WITH EXTREME SOCIAL VULNERABILITY BY DEPLOYING A SUITE OF COMMUNITY ENGAGEMENT RESOURCES IN CENSUS TRACTS WITH HEIGHTENED SOCIAL VULNERABILITY, II) IMPLEMENT, EVALUATE AND MAINTAIN AN UPSCALED VERSION OF AN EVIDENCE-BASED COMMUNITY HEALTH WORKER INTERVENTION TO CONTROL MULTI-COMORBID CHRONIC CARDIOMETABOLIC DISEASES BY ADDRESSING MULTIPLE LEVELS OF INFLUENCE ACROSS DIFFERENT DOMAINS, AND III) FOSTER A DIVERSE WORKFORCE OF WELL-TRAINED, EARLY-CAREER STAGE INVESTIGATORS WHO COLLECTIVELY FOCUS ON ALLEVIATING CHRONIC CARDIOVASCULAR DISEASE DISPARITIES THAT DRIVE U.S. LIFESPAN INEQUALITY. IN ADDITION TO CONDUCTING A PILOT GRANTS PROGRAM ACROSS THE THREE PARTNERING INSTITUTIONS, ACHIEVE GREATER WILL PERFORM THREE DISTINCT BUT CLOSELY RELATED SPECIAL PROJECTS THAT FOCUS ON INTERRUPTING EARLY STAGES OF PATHOGENESIS IN DIFFERENT CONTEXTS (E.G., MOBILE HEALTH UNITS VERSUS FIXED COMMUNITY LOCATIONS). IMPORTANTLY, THIS WORK WILL BE NESTED IN A LARGER EPIDEMIOLOGIC STUDY OF MULTI-LEVEL CARDIOMETABOLIC RISK FACTORS. OUR TEAM WILL DEVELOP A DISTRIBUTED CLOUD-BASED DATABASE COMPLETE WITH A CUSTOMIZED SET OF INFORMATICS TOOLS THAT WILL ENABLE INVESTIGATORS IN THE HEART OF EACH CITY TO ROBUSTLY PROFILE MULTI-LEVEL RISK FACTORS ACROSS DIFFERENT DOMAINS USING BOTH PUBLICLY AVAILABLE INFORMATION AND INVESTIGATOR- GENERATED DATA. OUR EVIDENCE-BASED INTERVENTION PATHWAYS ARE DESIGNED TO CONTROL RISK FACTORS, ESPECIALLY ELEVATED BLOOD PRESSURE, WHICH IS THE MOST IMPORTANT MODIFIABLE CONTRIBUTOR TO HEART DISEASE - FAR AND AWAY THE LEADING CAUSE OF DEATH IN OUR REGION. BY INCREASING REACH IN CENSUS TRACTS WITH INCREASED SOCIAL VULNERABILITY WHERE LIFESPAN DISPARITIES AND UNCONTROLLED CARDIOMETABOLIC RISK FACTORS ARE MOST PREVALENT, OUR STUDY DESIGN OPTIMIZES BOTH RECRUITMENT OPPORTUNITIES AND POTENTIAL INTERVENTION IMPACT. MOREOVER, THE ALIGNMENT OF RESOURCES ACROSS THREE INSTITUTIONS WILL EFFICIENTLY ENHANCE REGIONAL COORDINATION, WHILE INCREASING THE NUMBER AND DIVERSITY OF RESEARCH PARTICIPANTS AND HIGHLY TRAINED EARLY-CAREER STAGE DISPARITIES INVESTIGATORS. IF WE ARE SUCCESSFUL AND COST-EFFECTIVE, THEN WE WILL HAVE DEMONSTRATED A SCALABLE MEANS OF IMPROVING FUTURE LIFESPAN EQUALITY BY PRIORITIZING RISK FACTOR CONTROL IN HIGH-RISK POPULATIONS FROM AREAS WITH EXTREME SOCIAL VULNERABILITY.

DETROIT RESEARCH ON CANCER SURVIVORS (DETROIT ROCS)

THIS EDA INVESTMENT SUPPORTS THE GLOBAL EPICENTER OF MOBILITY (GEM) COALITION, LED BY THE DETROIT REGIONAL PARTNERSHIP FOUNDATION, WITH CATALYZING THE MOBILITY SECTOR IN MICHIGAN BY TRANSFORMING THE DETROIT AREA'S LEGACY AUTOMOTIVE INDUSTRY INTO A HIGHLY COMPETITIVE ADVANCED MOBILITY CLUSTER. THE PROJECTS FUNDED AS PART OF THIS AWARD INCLUDE THE NEW SUPPLY CHAIN TRANSFORMATION CENTER THAT WILL PROVIDE DIRECT ASSISTANCE TO EXISTING LEGACY MANUFACTURERS TO TRANSITION TO THE NEEDS OF BROADER MOBILITY PRODUCTS AND THE MOBILITY ACCELERATOR INNOVATION NETWORK TO IDENTIFY AND SUPPORT START-UPS IN THE MOBILITY SPACE. ONCE IMPLEMENTED, THE INVESTMENT WILL HELP DEVELOP AND STRENGTHEN REGIONAL INDUSTRY CLUSTERS - ALL WHILE EMBRACING ECONOMIC EQUITY, CREATING GOOD-PAYING JOBS, AND ENHANCING U.S. COMPETITIVENESS GLOBALLY.

RELATIVISTIC HEAVY ION RESEARCH

CENTER FOR LEADERSHIP IN ENVIRONMENTAL AWARENESS AND RESEARCH - ABSTRACT: EVIDENCE SUGGESTS THAT EXPOSURE TO VOLATILE ORGANIC COMPOUNDS (VOCS), SUCH AS BENZENE, TOLUENE, ETHYLBENZENE, AND XYLENE (BTEX), TRICHLOROETHYLENE (TCE), AND TETRACHLOROETHYLENE (PCE), IS AN IMPORTANT DETERMINANT OF MATERNAL-OFFSPRING HEALTH, WITH IMPLICATIONS FOR PRETERM BIRTH (PTB) AND ASSOCIATED ADVERSE HEALTH OUTCOMES. VOCS EMANATE FROM LANDFILLS, BROWNFIELDS, AND SUPERFUND SITES, CONTAMINATING SHALLOW SOILS AND GROUNDWATER BELOW RESIDENTIAL, COMMERCIAL, AND INDUSTRIAL PROPERTIES, LEADING TO EXPOSURES VIA VAPOR INTRUSION. THE CENTER FOR LEADERSHIP IN ENVIRONMENTAL AWARENESS AND RESEARCH (CLEAR) IS DEDICATED TO UNDERSTANDING AND MITIGATING THIS SERIOUS ENVIRONMENTAL HEALTH PROBLEM WITH A FOCUS ON POST-INDUSTRIAL URBAN CENTERS. HEADQUARTERED IN DETROIT, MICHIGAN, CLEAR WILL USE DETROIT AS A STUDY SITE, WHICH HAS THE HIGHEST PTB RATE IN THE COUNTRY (15.2%) AND IS LOCATED IN A STATE WHERE 37 OF THE 67 SUPERFUND SITES MUST MANAGE VOC CONTAMINATION. CLEAR HYPOTHESIZES THAT VOC EXPOSURE THROUGH VAPOR INTRUSION DURING EARLY LIFE INCITES INFLAMMATORY RESPONSES IN MATERNAL TISSUES AND/OR THE DEVELOPING OFFSPRING THAT RE-PROGRAM THE DEVELOPING IMMUNE AND OTHER CRITICAL SYSTEMS, SETTING THE STAGE FOR PTB AND/OR ASSOCIATED ADVERSE HEALTH OUTCOMES. FIVE INTEGRATIVE ENVIRONMENTAL SCIENCE AND ENGINEERING AND BIOMEDICAL RESEARCH PROJECTS (E1, E2, B1, B2, B3), SUPPORTED BY FIVE CORES, WILL INVESTIGATE TOXIC MECHANISMS, EXPOSURE PATHWAYS, BIOMARKERS, AND STRATEGIES TO PREVENT EXPOSURES AND IMPROVE PUBLIC HEALTH OUTCOMES BY: (1) DEVELOPING AND TESTING NEW DETECTION METHODOLOGIES, INCLUDING PHYTOSCREENING (E1); SENSOR TECHNOLOGY THAT INTEGRATES INTERNET OF THINGS AND EDGE COMPUTING FOR REAL-TIME CONTAMINANT DETECTION AND RAPID-RESPONSE, MITIGATION, AND REMEDIATION (E2); AND A CONTROLLED TOXICITY BIOASSAY USING WSU-DESIGNED SEALED CHAMBERS FOR EVALUATING REPRODUCTIVE, NEUROLOGICAL, BEHAVIORAL, IMMUNOLOGICAL AND MULTIGENERATIONAL RESPONSES IN ZEBRAFISH (B1); (2) STUDYING MECHANISTIC EFFECTS OF VOC EXPOSURE IN A PREGNANT MOUSE MODEL (B2); (3) APPLYING EPIDEMIOLOGIC METHODS FOR ESTIMATING EXPOSURE EFFECTS VIA HUMAN BIOLOGICAL SPECIMEN ANALYSIS (B3); APPLYING ADVANCED CHEMICAL ANALYSIS, STATISTICAL APPROACHES AND VISUALIZATION TOOLS TO OBTAIN AND INTEGRATE PROJECT DATA (CHEMICAL ANALYSIS, AND DATA MANAGEMENT AND ANALYSIS CORES), THEREBY ESTABLISHING THE IMPACT OF VOC EXPOSURES ON PTB AND ASSOCIATED ADVERSE HEALTH OUTCOMES; (4) CREATING AN INNOVATIVE MODEL FOR TRANSDISCIPLINARY EDUCATION AND WORKFORCE DIVERSITY BY ENGAGING NEW TRAINEES TO SOLVE COMPLEX ENVIRONMENTAL HEALTH PROBLEMS (RESEARCH EXPERIENCE AND TRAINING COORDINATION CORE); (5) ENGAGING STAKEHOLDERS AND THE COMMUNITY TO INFORM OUR INQUIRY/ANALYSIS, PARTICIPATE IN SAMPLING, AND EMPLOY HEALTH INTERVENTIONS (COMMUNITY ENGAGEMENT CORE); AND (6) UNITING AROUND AN ADMINISTRATIVE CORE THAT CONDUCTS TARGETED RESEARCH TRANSLATION TO ENSURE A LEGACY OF SCIENTIFIC AWARENESS AND SUPPORTS THE SUPERFUND RESEARCH PROGRAM TO IMPROVE PUBLIC HEALTH IN URBAN CENTERS IMPACTED BY ENVIRONMENTAL CONTAMINATION TO PROTECT AFFECTED COMMUNITIES.

CENTER FOR URBAN RESPONSES TO ENVIRONMENTAL STRESSORS (CURES)

CORE GRANT FOR VISION RESEARCH

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

INFLAMMATION PATHWAYS AND COPD IN THE DEVELOPMENT OF LUNG CANCER

CLINICAL TRIAL OF ETANERCEPT (TNF-ALPHA BLOCKER) FOR TREATMENT OF BLAST-INDUCED TINNITUS

BEDSIDE EXCLUSION OF PULMONARY EMBOLISM IN CHILDREN WITHOUT RADIATION (BEEPER)

GENOTYPE-PHENOTYPE ASSOCIATIONS IN PEDIATRIC CARDIOMYOPATHY

BRAIN CHEMISTRY AND TREATMENT RESPONSES IN PEDIATRIC OCD

WSU ADVANCED TECHNOLOGY CENTER: CENTRALIZATION AND MODERNIZATION OF CORE FACILITIES - THIS PROPOSAL AIMS TO ESTABLISH THE WAYNE STATE UNIVERSITY ADVANCED TECHNOLOGY CENTER (ATC) FOR CUTTING-EDGE ANALYTICAL TECHNOLOGIES OCCUPYING 10,425 SQUARE FEET IN THE NEW HEALTH SCIENCES BUILDING (HSB) ON THE WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE (WSU-SOM) CAMPUS. DEVELOPED WITH THE MOTT CENTER, BARBARA ANN KARMANOS CANCER INSTITUTE (KCI), AND THE INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES (IEHS), THIS INITIATIVE WILL FACILITATE INNOVATIVE BIOMEDICAL RESEARCH THROUGH TECHNOLOGIES PROVIDED BY CORE FACILITY LABORATORIES. THE ATC WILL PROVIDE STATE-OF-THE-ART INSTRUMENTATION AND EXPERTISE TO SUPPORT MULTIDISCIPLINARY EFFORTS IN UNDERSTANDING DISEASE MECHANISMS, DEVELOPING NOVEL THERAPIES, AND ADDRESSING CRITICAL HEALTH CHALLENGES, PARTICULARLY THOSE AFFECTING URBAN AND RURAL POPULATIONS. THE ATC WILL CENTRALIZE THE MICR (MICROSCOPY, IMAGING AND CYTOMETRY, RESOURCES), PROTEOMIC, AND LIPIDOMIC CORE FACILITIES, WHICH ARE CURRENTLY DISPERSED ACROSS FOUR AGING BUILDINGS. THESE CORES EVOLVED INDEPENDENTLY OVER DECADES, RESULTING IN PHYSICAL SEPARATION AND LIMITED INTERACTION. CENTRALIZATION IN THE ATC WHILE MODERNIZING ITS INFRASTRUCTURE WILL OPTIMIZE RESOURCE UTILIZATION AND FOSTER COLLABORATIVE RESEARCH. WSU INVESTIGATORS AND EXTERNAL USERS RELY ON THESE CORES TO ANALYZE SAMPLES FROM PRECIOUS PATIENT BIOPSIES, CONTROLLED ANIMAL STUDIES, AND IN VITRO EXPERIMENTS. HOWEVER, THEIR PHYSICAL SEPARATION LIMITS THE FEASIBILITY AND EFFICIENCY OF MULTI-OMIC RESEARCH EFFORTS. SAMPLES OFTEN REQUIRE PARTITIONING FOR SEPARATE ANALYSES AT DIFFERENT FACILITIES, CREATING REDUNDANCY IN RECORD KEEPING AND REGULATORY OVERSIGHT WHILE AT THE SAME TIME REDUCING THE ABILITY TO EXTRACT COMPREHENSIVE, INTERCONNECTED DATA. THE CENTRALIZED ATC ADDRESSES THESE CHALLENGES BY FACILITATING THE DEVELOPMENT OF PROTOCOLS ACROSS CORES, UTILIZING A SINGLE REPORTING AND OVERSIGHT MECHANISM WHILE PROVIDING DIFFERENT TECHNOLOGIES, AND ENABLING SEAMLESS INTEGRATION OF ADVANCED EXPERIMENTAL DESIGN. FOR INSTANCE, BIOBANK SPECIMENS, PATIENT SAMPLES, OR TOXICANT-EXPOSED TISSUES CAN UNDERGO SPECIALIZED IMAGING, CELL SORTING, AND OMICS ANALYSES IN A SEAMLESS WORKFLOW. THIS INTEGRATED APPROACH WILL MAXIMIZE DATA GENERATION, ENHANCE SCIENTIFIC DISCOVERY, AND ADVANCE INVESTIGATOR INITIATIVES. THE ATC WILL DRIVE INNOVATION BEYOND WHAT EACH CORE COULD ACHIEVE INDIVIDUALLY, YIELDING BENEFITS FAR GREATER THAN THE SUM OF ITS PARTS. WSU’S CORE LABORATORIES SUPPORT A BROAD USER BASE, INCLUDING INVESTIGATORS FROM REGIONAL, NATIONAL, AND INTERNATIONAL INSTITUTIONS. THE ATC WILL ENHANCE WSU’S REPUTATION AS A PREMIER RESOURCE FOR ADVANCED TECHNOLOGICAL SOLUTIONS, OFFERING HIGH-QUALITY SERVICES, TRAINING, WORKSHOPS, AND EDUCATIONAL OPPORTUNITIES. THE ATC WILL IMPROVE THE EFFICIENCY AND IMPACT OF RESEARCH WHILE ALSO PREPARING THE NEXT GENERATION OF SCIENTISTS THROUGH COMPREHENSIVE TRAINING PROGRAMS, INCLUDING EXPERIENTIAL LEARNING OPPORTUNITIES DESIGNED TO ENGAGE YOUNG SCIENTISTS. ONGOING OUTREACH TO AREA SCHOOLS, INCLUDING A SUMMER TRAINING PROGRAM, DEMONSTRATES OUR STRUCTURED AND SUSTAINABLE COMMITMENT TO EDUCATIONAL OUTREACH.

IMSD PROGRAM AT WAYNE STATE UNIVERSITY

BLOOD PRESSURE CONTROL DURING EXERCISE IN HEART FAILURE

ANALYSIS OF LIPOLYTIC TRAFFICKING IN ADIPOCYTES

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

AHEC POINT OF SERVICE MAINT & ENHANCEMENT

ANALYSIS OF CELLULAR PLASTICITY IN WHITE ADIPOSE TISSUE

EARLY PHARMACOTHERAPY GUIDED BY BIOMARKERS IN AUTISM

AHEC POINT OF SERVICE MAINT & ENHANCEMENT

FUNCTIONAL BRAIN MAPPING IN PEDIATRIC NEUROSURGERY

MOLECULAR REGULATION OF CORNEAL WOUND HEALING

PARTICLE PHYSICS RESEARCH PROGRAM

POISON CONTROL STABILIZATION AND ENHANCEMENT PROGRAM

RISKY FAMILY ENVIRONMENTS AND CHILDHOOD ASTHMA

INTERVENTIONIST PROCEDURES FOR ADHERENCE TO WEIGHT LOSS RECS IN BLACK ADOLESCENTS

CARDIAC BIOMARKERS IN PEDIATRIC CARDIOMYOPATHY

ROLE OF TOLL-LIKE RECEPTORS IN BACTERIAL KERATITIS

ADVANCED NURSING EDUCATION WORKFORCE

HEPATIC STEATOSIS AND ER STRESS-INDUCIBLE TRANSCRIPTION FACTOR CREBH

TAS::89 0331::TAS RECOVERY ACT - TRANSPORTATION ELECTRIFICATION AWARD TO WAYNE STATE UNIVERSITY

LONGITUDINAL NEUROIMAGING IN STURGE-WEBER SYNDROME

MOLECULAR MECHANISMS OF NEUROPROTECTION IN POLYGLUTAMINE-DEPENDENT DEGENERATION

MECHANISMS OF FLAGELLIN INDUCED PROTECTION AGAINST BACTERIAL KERATITIS

EXPRESSION, REGULATION AND FUNCTION OF THE SULT1C CARCINOGEN-ACTIVATING ENZYMES

RELATIVISTIC HEAVY ION RESEARCH

EARLY CLINICAL TRIALS OF NEW ANTI-CANCER AGENTS

GENETIC VARIATION IN CANCER RISK AND OUTCOMES IN AFRICAN AMERICANS - PROJECT SUMMARY/ABSTRACT—OVERALL PROGRAM GENETIC TESTING FOR BOTH GERMLINE AND SOMATIC MUTATIONS HAS IMPROVED OUR UNDERSTANDING OF THE BASIC BIOLOGY OF CARCINOGENESIS, IDENTIFIED HIGH-RISK POPULATIONS FOR TARGETED PREVENTION AND SCREENING, IDENTIFIED TARGETS FOR NEW TREATMENT STRATEGIES, AND HAS LED TO SOME OF THE MOST SIGNIFICANT INROADS IN REDUCING CANCER BURDEN. YET, THERE IS STILL MUCH TO LEARN ABOUT THE ROLE OF INHERITED GENETIC SUSCEPTIBILITY AND CANCER, AND THE SIGNIFICANT BARRIERS TO ACCESSING GENETIC COUNSELING AND TESTING SERVICES, PARTICULARLY IN UNDER-REPRESENTED POPULATIONS. WE HAVE ASSEMBLED ONE OF THE LARGEST POPULATIONS OF AFRICAN AMERICAN CANCER SURVIVORS TO DATE TO STUDY GENETIC SUSCEPTIBILITY IN THIS POPULATION. THE DETROIT RESEARCH ON CANCER SURVIVORS (ROCS) (U01CA199240) COHORT INCLUDES PARTICIPANTS CONSIDERED TO BE AT PARTICULARLY HIGH-RISK DUE TO FAMILY HISTORY OF CANCER, AGE AT DIAGNOSIS OR A DIAGNOSIS OF A SECOND PRIMARY CANCER, AND THE INFRASTRUCTURE WILL BE USED TO EXPAND PARTICIPATION. THE PROGRAM INCLUDES THREE PROJECTS AND TWO CORES WITH AN OVERALL GOAL OF IMPROVING THE IDENTIFICATION AND CLINICAL MANAGEMENT OF HEREDITARY AND MULTIPLE PRIMARY CANCERS IN AFRICAN AMERICANS, WHO ARE CURRENTLY UNDERREPRESENTED IN GENETIC RESEARCH. TO DO THIS WE WILL: 1) USE BIOINFORMATIC ANALYSES, FAMILY STRUCTURE, GENE EXPRESSION, AND SOMATIC ALTERATIONS TO IDENTIFY AFRICAN AMERICAN CANCER SURVIVORS MOST LIKELY TO HARBOR HIGH- PENETRANCE GENETIC VARIANTS CURRENTLY CLASSIFIED AS PATHOGENIC OR HAVING UNCERTAIN SIGNIFICANCE; 2) CHARACTERIZE THE SPECTRUM OF GERMLINE GENETIC VARIATION IN AFRICAN AMERICANS WITH MULTIPLE PRIMARY CANCERS IN RELATION TO KNOWN PATHOGENIC MUTATIONS, SITE-SPECIFIC POLYGENIC RISK SCORES (PRS), AND LARGELY MODIFIABLE NON-GENETIC RISK FACTORS; AND 3) DEVELOP AN ONLINE, CULTURALLY ADAPTED EDUCATIONAL INTERVENTION TO INCREASE ACCESS TO GENETIC COUNSELING INFORMATION AMONG MEDICALLY UNDERSERVED AFRICAN AMERICANS AND UPTAKE OF RISK-APPROPRIATE GENETIC TESTING AMONG THOSE AT INCREASED RISK SO THAT WE ARE POISED TO TRANSLATE NOVEL GENETIC DISCOVERIES INTO CLINICAL PRACTICE.

NOVEL EARLY RETINAL IMAGING BIOMARKERS FOR TREATING LATER SPATIAL MEMORY LOSS IN EXPERIMENTAL ALZHEIMER'S DISEASE - THERAPEUTICALLY DELAYING THE PROGRESSIVE DECLINE IN COGNITION IN PATIENTS WITH ALZHEIMER’S DISEASE (AD) WOULD TRANSFORM AD INTO A MANAGEABLE MORBIDITY, A GOAL THAT HAS NOT BEEN ACHIEVED USING DRUGS TARGETED TO SS-AMYLOID (ASS) PLAQUE DEPOSITION. ACCUMULATING RESULTS INDICATE THAT COGNITIVE LOSS (LINKED TO CIRCUIT / SYNAPTIC DYSFUNCTION) AND SS-AMYLOID (ASS) PLAQUE DEPOSITION CAN OCCUR INDEPENDENT OF EACH OTHER, WITH BOTH DRIVEN BY A CROSS-LINKED SOLUBLE AMYLOID SS-PEPTIDE OLIGOMER - NEURONAL HYPERACTIVITY “AD CYCLE”. REMARKABLY, THE PREDICTION THAT COGNITIVE DYSFUNCTION CAN BE RESTORED WITHOUT ALTERING PLAQUE DEPOSITION HAS BEEN CONFIRMED IN SEVERAL AD MODELS, FOR EXAMPLE, BY DRUGS THAT PROLONG THE OPENING TIME OF THE ENDOPLASMIC RETICULUM (ER) RYANODINE RECEPTOR TYPE 2 (RYR2) CALCIUM CHANNEL AND SUPPRESS NEURONAL HYPERACTIVITY. CONVENTIONAL BIOMARKERS ARE UNABLE TO INTERROGATE EITHER PART OF THE “AD CYCLE” IN PATIENTS AT CELLULAR RESOLUTION, AN UNMET GOAL FOR EVALUATING TREATMENT EFFICACY AT THE PRODROMAL STAGE. HERE, WE PROPOSE A NOVEL SOLUTION TO THIS PROBLEM BASED ON THE RETINA, A READILY ACCESSIBLE PART OF THE NERVOUS SYSTEM WITH DAMAGE SIMILAR TO THAT FOUND IN THE BRAIN OF PATIENTS WITH AD. THE RETINA DEVELOPS SOLUBLE AMYLOID SS-PEPTIDE OLIGOMERS AND PLAQUE DEPOSITION BEFORE THEIR APPEARANCE IN THE BRAIN, AS WELL AS PHOSPHORYLATED TAU AND NEUROFIBRILLARY TANGLES. BEFORE OVERT AD PATHOLOGY AND COGNITIVE DECLINE ARE EVIDENT, PATIENTS REPORT IMPAIRED CONTRAST SENSITIVITY (CS), A MAJOR RISK FACTOR FOR FALLS AS WELL AS DECREASED SURVIVAL. CS IS DRIVEN BY PHOTORECEPTORS. OUR FIRST-IN-KIND PRELIMINARY RESULTS IN AN AD MODEL WHEN THERE IS SPARSE PLAQUE DEPOSITION IN THE RETINA SHOW EARLY IMPAIRMENT OF CS, AND ROD HYPERACTIVITY MEASURED USING THREE OCT MITOCHONDRIA-DRIVEN BIOMARKERS DEVELOPED IN OUR LABORATORY. WE HAVE ALSO DISCOVERED THAT CS IMPAIRMENT AND ROD HYPERACTIVITY BIOMARKERS IN 5XFAD MALE C57BL6/J (B6J) MICE OCCUR FASTER THAN IN 5XFAD MALE C57BL/6TAC (B6NTAC) MICE. IN WT MALE B6J MICE, RODS SHOWED A LOWER OCT ENERGY SIGNATURE THAN IN AGE-MATCHED WT MALE B6NTAC MICE, INDICATING STRAIN DIFFERENCES IN BASELINE MITOCHONDRIA ACTIVITY. WE PROPOSE TO TEST TWO WORKING HYPOTHESES WITH THREE SPECIFIC AIMS. FIRST, THAT IMPAIRED CS, A HYPERACTIVE ROD ENERGY SIGNATURE, AND/OR SYNAPTIC DYSFUNCTION OCCUR EARLIER B6J 5XFAD MICE THAN IN B6NTAC 5XFAD MICE. SECOND THAT IN 5XFAD MICE, RYR2-TARGETED TREATMENTS THAT DELAY COGNITIVE DECLINES MITIGATE CHANGES IN EARLY CS AND ENERGY BIOMARKERS, DECLINES IN ROD SYNAPTIC ACTIVITY, AND LATER SPATIAL MEMORY DEFICITS BUT DO NOT CHANGE THE RATE OF PLAQUE DEPOSITION.

CHEMICAL APPROACHES TO STUDY PROTEIN POST-TRANSLATIONAL MODIFICATIONS

MOLECULAR REGULATION OF FOLATE AND ANTIFOLATE TRANSPORT

CSSI: FRAMEWORKS: X-ION COLLISIONS WITH A STATISTICALLY AND COMPUTATIONALLY ADVANCED PROGRAM ENVELOPE (X-SCAPE)

NEW; SISGR: A CONCERTED SYNTHETIC, SPECTROSCOPIC, AND COMPUTATIONAL APPROACH TOWARDS WATER SPLITTING BY HETEROMETALLIC COMPLEXES IN SOLUTION AND ON S

SOUTHEAST MICHIGAN COMMUNITY NETWORK PROGRAM

INVESTIGATING THE CELLULAR MECHANISMS LEADING TO REPETITIVE SHUNT FAILURE IN THE TREATMENT OF PEDIATRIC HYDROCEPHALUS

UPWARD BOUND

TRAINING PROGRAM IN THE BIOLOGY OF CANCER

ROLE OF RAS IN RETINAL CELL DEATH IN DIABETES

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

CENTER FOR URBAN RESPONSES TO ENVIRONMENTAL STRESSORS - SITUATED IN THE HEART OF DETROIT, THE CENTER FOR URBAN RESPONSES TO ENVIRONMENTAL STRESSORS (CURES) AIMS TO UNDERSTAND AND MITIGATE THE ADVERSE HEALTH IMPACTS OF EXPOSURES TO A COMPLEX ARRAY OF CHEMICAL AND NON- CHEMICAL STRESSORS IN A POSTINDUSTRIAL URBAN ENVIRONMENT. CURES RECOGNIZES THAT EACH URBAN NEIGHBORHOOD HAS A UNIQUE COMBINATION OF GEOGRAPHIC (E.G., LOCALE RELATIVE TO LEGACY AND EMERGING POLLUTION SOURCES), HISTORIC (E.G., LAND USE, AGE AND CONDITION OF HOUSING STOCK), AND DEMOGRAPHIC (E.G., SOCIOECONOMICS, RACE, ETHNICITY, AGE) CHARACTERISTICS THAT TOGETHER CREATE THE SPECTRUM OF ENVIRONMENTAL RISK AND ENVIRONMENTAL JUSTICE ISSUES THAT PRODUCE DISPARITIES IN THE INCIDENCE AND SEVERITY OF ADVERSE HEALTH OUTCOMES INCLUDING PRETERM BIRTH, CANCER, CARDIOVASCULAR DISEASE, AND DIABETES. A COMMUNITY-ENGAGED, TRANSDISCIPLINARY TEAM SCIENCE APPROACH IS ESSENTIAL TO ADDRESS THE MAJOR ENVIRONMENTAL HEALTH CHALLENGES FACING DETROIT’S RACIALLY AND ETHNICALLY DIVERSE POPULATION. WE HAVE ASSEMBLED A TALENTED INTERDISCIPLINARY TEAM OF ESTABLISHED AND EMERGING ENVIRONMENTAL HEALTH SCIENTISTS WHO WORK WITH OUR COMMUNITY PARTNERS TO ACCOMPLISH THIS WORK. WE LISTEN TO OUR COMMUNITY PARTNERS, AND THEIR CONCERNS INFORM THE CENTER AND PROVIDE DIRECTION FOR BUILDING OUR RESEARCH CAPACITY SO THAT OUR RESEARCH TRANSLATES BACK TO THE COMMUNITY. CURES ADVANCES THE NIEHS 2018- 2023 STRATEGIC PLAN BY PERFORMING RESEARCH THAT INCREASES ENVIRONMENTAL HEALTH SCIENCE KNOWLEDGE, CONVERTS “DATA TO KNOWLEDGE TO ACTION,” AND SUPPORTS THE GROWTH OF WORKFORCE DIVERSITY, TEAM-BUILDING, AND COLLABORATION. TO CREATE A GATEWAY TO A HEALTHY URBAN ENVIRONMENT STARTING WITH DETROIT, CURES’ SHORT-TERM GOALS ARE TO 1) STRENGTHEN CURES EXISTING PARTNERSHIPS AND DEVELOP NEW ONES WITHIN THE DETROIT COMMUNITY, AND IN COLLABORATION WITH OUR COMMUNITY PARTNERS IDENTIFY ENVIRONMENTAL THREATS COMMON TO US URBAN POPULATIONS AND PROVIDE SCIENTIFICALLY-BASED STRATEGIES TO MITIGATE THEM; 2) CONDUCT INTEGRATED MECHANISTIC, EPIDEMIOLOGICAL, AND COMMUNITY-ENGAGED RESEARCH THAT ADDRESSES THE CONSEQUENCES OF URBAN CHEMICAL AND NON-CHEMICAL EXPOSURES ON HUMAN HEALTH; 3) BUILD CURES’ INVESTIGATOR CAPABILITIES BY PROVIDING FACILITY CORES THAT PROVIDE STATE-OF-THE-ART ANALYTICAL SERVICES AS WELL AS PILOT FUNDS TO EXPLORE THE FEASIBILITY OF NEW AREAS OF STUDY; 4) SECURE THE LONG TERM CONTRIBUTION OF CURES ON THE DISCIPLINE OF EHS BY MENTORING NEW AND ESTABLISHED INVESTIGATORS TO ATTAIN THEIR PROFESSIONAL GOALS AND PREPARE THEM FOR EHS LEADERSHIP; AND 5) FOSTER A CULTURE OF ANTIRACISM, INCLUSION, AND ENVIRONMENTAL HEALTH EQUITY THROUGHOUT THE CENTER. OUR LONG-TERM GOAL IS FOR CURES TO BE A PREMIER ENVIRONMENTAL HEALTH SCIENCES CORE CENTER THAT IS FOCUSED ON URBAN ENVIRONMENTAL HEALTH, ENVIRONMENTAL JUSTICE, AND RESILIENCE IN THE FACE OF CHEMICAL AND NON-CHEMICAL STRESSORS. CURES IS OPTIMALLY POSITIONED TO PURSUE INNOVATIVE, COMMUNITY-ENGAGED, TEAM SCIENCE RESEARCH OPPORTUNITIES THAT HAVE THE GREATEST PROMISE TO DELIVER TRANSFORMATIVE GAINS IN THE EARLY DETECTION, PREVENTION, AND EVENTUAL ERADICATION OF URBAN ENVIRONMENTAL DISEASE IN OUR LIFETIME.

DELINEATING FUNCTIONAL IMMUNITY VIA IMAGE-GUIDED PET

NEURAL CORRELATES AND MODIFIERS OF COGNITIVE AGING

MECHANISMS OF MOTION DETECTION IN RETINAL NEURAL NETWORK

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF CHOLINE SUPPLEMENTATION DURING PREGNANCY TO MITIGATE ADVERSE EFFECTS OF PRENATAL ALCOHOL EXPOSURE ON GROWTH AND COGNITIVE DEVELOPMENT

GLYCEMIC CONTROL AND PROGRESSION OF DIABETIC RETINOPATHY

UPWARD BOUND PROGRAM

MULTISYSTEMIC THERAPY TO REDUCE HEALTH DISPARITIES IN ADOLESCENTS WITH ASTHMA

ROLE OF AMP-ACTIVATED PROTEIN KINASE IN BACTERIAL ENDOPHTHALMITIS

NEURAL CORRELATES AND MODIFIERS OF COGNITIVE AGING

NOVEL DWI METHODS TO MINIMIZE POSTOPERATIVE DEFICITS IN PEDIATRIC EPILEPSY SURGERY

THE MIR-183/96/182 CLUSTER IN PSEUDOMONAS AERUGINOSA-INDUCED KERATITIS

BIOBEHAVIORAL STUDIES OF OPIOID DRUG SEEKING BEHAVIOR

NURSE FACULTY LOAN PROGRAM

TEENS AT RISK: PRENATAL COCAINE AND POSTNATAL CHALLENGES

ALCOHOL AND MATERNAL UTERINE VASCULAR ADAPTATIONS IN PREGNANCY

A HARMONIZED MEDIAL TEMPORAL LOBE SUBREGION SEGMENTATION PROTOCOL: AN ESSENTIAL ELEMENT FOR DEMENTIA RESEARCH - THE HIPPOCAMPUS AND THE PARAHIPPOCAMPAL REGION OF THE MEDIAL TEMPORAL LOBE (MTL) CONSIST OF ANATOMICALLY AND FUNCTIONALLY DISTINCT SUBREGIONS THAT ARE SELECTIVELY TARGETED BY DIFFERENT PATHOLOGICAL PROCESSES IN NEURODEGENERATIVE DISORDERS, SUCH AS ALZHEIMER’S DISEASE (AD) AND SEMANTIC VARIANT PRIMARY PROGRESSIVE APHASIA (SVPPA). IN AD, IN VIVO MRI STUDIES INVESTIGATING MTL SUBREGIONS HAVE OFTEN SHOWN MIXED FINDINGS THAT ARE INCONSISTENT WITH POST-MORTEM PATHOLOGY STUDIES. THESE INCONSISTENCIES LIKELY RESULT FROM THE LACK OF VALIDITY AND STANDARDIZATION IN MTL SEGMENTATION APPROACHES. IN SVPPA, MTL SUBREGIONS ARE SEVERELY AFFECTED, AND AUTOMATED TOOLS FAIL TO SEGMENT THE SUBREGIONS ACCURATELY. SUFFICIENT SPATIAL RESOLUTION OF IMAGING VOXELS IS REQUIRED TO VISUALIZE THE INTERNAL MTL STRUCTURES AND LANDMARKS THAT ARE CRITICAL FOR VALID SEGMENTATION OF THE SUBREGIONS. WHILE MORE THAN 15,000 HIGH-RESOLUTION SCANS HAVE BEEN COLLECTED WORLDWIDE, THE LACK OF STANDARDIZATION AMONG MTL SUBREGIONAL SEGMENTATION PROTOCOLS IS STILL A SIGNIFICANT BARRIER. VARIABILITY IN THE DEFINITION OF THE MTL SUBREGIONAL BOUNDARIES AMONG EXISTING SEGMENTATION PROTOCOLS HAVE CONTRIBUTED TO THE CONFLICTING FINDINGS IN THE FIELD. THIS PROPOSAL SEEKS TO ACCELERATE PROGRESS MADE BY OUR GROUP, THE HIPPOCAMPAL SUBFIELDS GROUP, AND COMPLETE OUR STANDARDIZED, VALID, AND RELIABLE HARMONIZED PROTOCOL FOR THE SEGMENTATION OF MTL SUBREGIONS IN HIGH-RESOLUTION MRI SCANS. WE WILL LEVERAGE OUR ONGOING, SUCCESSFUL EFFORTS, AND EVALUATE THE PROPOSED HARMONIZED PROTOCOL IN SCANS FROM MULTICENTRIC DATASETS. IN AIM 1, WE WILL FINALIZE OUR HARMONIZED SEGMENTATION PROTOCOL THAT IS A) BASED ON A LARGE HISTOLOGY DATASET AND DEVELOPED IN COLLABORATION WITH NEUROANATOMISTS, B) ASSESSED BY THE LARGER COMMUNITY TO REACH CONSENSUS, C) TESTED FOR RELIABILITY, AND D) IMPLEMENTED IN AN EXISTING AUTOMATED SOFTWARE PROGRAM. IN AIM 2, WE WILL VALIDATE THE HARMONIZED PROTOCOL IN EARLY-STAGE AD THROUGH ASSOCIATIONS WITH MARKERS OF SPECIFIC PATHOLOGIES: A) TEST FOR ANATOMICAL SPECIFICITY OF THE ASSOCIATIONS BETWEEN ATROPHY RATES ACROSS MTL SUBREGIONS TO PET MEASURES OF MTL TAU-PATHOLOGY AND MARKERS OF CARDIOVASCULAR RISK IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND CEREBRAL SS-AMYLOID. IN AIM 3, WE WILL FURTHER EVALUATE THE VALIDITY AND UTILITY OF THE HARMONIZED PROTOCOL IN SVPPA BY PERFORMING MANUAL SEGMENTATION OF THE MTL SUBREGIONS USING THE HSG PROTOCOL AND TESTING FOR ANATOMICAL SPECIFICITY OF VOLUME ATROPHY. IN AIM 4, WE WILL FACILITATE WIDE ADOPTION OF OUR PROTOCOL BY PROVIDING TRAINING AND EDUCATION MATERIALS, IN-PERSON WORKSHOPS FOR MANUAL AND AUTOMATED SEGMENTATION, AND MAKING OUTCOME MEASURES PUBLICLY AVAILABLE. OUR VALID, RELIABLE, AND REPRODUCIBLE PROTOCOL FOR MTL SUBREGIONS SEGMENTATION WILL BENEFIT GROUPS WORLDWIDE THAT HAVE AND CONTINUE TO COLLECT THOUSANDS OF HIGH-RESOLUTION DATA TO STUDY A VARIETY OF NEUROLOGICAL AND PSYCHIATRIC CONDITIONS. IT ALSO LAYS THE FOUNDATION FOR FUTURE RESEARCH ON HOW DISTINCT DISEASE PROCESSES IN THE MTL SUBREGIONS MAY LEAD TO IMPAIRMENTS IN SPECIFIC COGNITIVE FUNCTIONS. OUR HARMONIZATION PROCESS CAN BE ADAPTED FOR ACHIEVING VALID, HARMONIZED SEGMENTATION FOR OTHER BRAIN REGIONS.

PREVENTION OF BLAST-RELATED INJURIES

PATHOPHYSIOLOGY OF CONDUCTION BLOCK IN HNPP.

REGULATION OF HEPATIC P450S BY ANTI-CHOLESTEROL DRUGS

SYNTHESIS OF COMPLEX CARBOHYDRATES.

IMPROVING OUTCOMES FOR PATIENTS WITH SDB AND INSUFFICIENT SLEEP

NCI NATIONAL CLINICAL TRIALS NETWORK ? NETWORK LEAD ACADEMIC PARTICIPATING SITE

CANNABIDIOL-ENHANCED COGNITIVE BEHAVIORAL THERAPY FOR GENERALIZED ANXIETY DISORDER - THE LONG-TERM OBJECTIVE OF THIS R61/R33 IS TO EVALUATE CANNABIDIOL AS A “COGNITIVE ENHANCER” TO INCREASE EFFICACY OF COGNITIVE BEHAVIORAL THERAPY (CBT) FOR GENERALIZED ANXIETY DISORDER (GAD). EMOTION REGULATION DIFFICULTIES, PARTICULARLY A DIMINISHED ABILITY TO MANAGE NEGATIVE EMOTIONS, ARE CENTRAL TO THE DEVELOPMENT OF GAD AND OTHER ANXIETY DISORDERS, WHICH ARE OFTEN LINKED TO IRREGULARITIES IN PREFRONTAL BRAIN REGIONS. HOWEVER, DESPITE THE GENERAL EFFECTIVENESS OF CBT, NEARLY HALF OF ALL PATIENTS DO NOT SHOW SIGNIFICANT IMPROVEMENT. SUCCESSFUL RESPONSE TO CBT IS EVIDENCED BY IMPROVED EMOTION REGULATION AND ENHANCED ACTIVITY OF THE DORSOMEDIAL PREFRONTAL CORTEX (DMPFC) DURING COGNITIVE REAPPRAISAL, WHICH IS A PROXY OF THE INTERVENTIONS PRACTICED IN CBT (E.G., COGNITIVE RESTRUCTURING). OUR PRIOR WORK SUGGESTS THAT ADMINISTRATION OF AN EXOGENOUS CANNABINOID FACILITATES EMOTION REGULATION AND ENHANCES DMPFC ACTIVATION IN POSTTRAUMATIC STRESS DISORDER— AN ANXIETY-RELATED CONDITION SHARING SIMILARITIES IN PREFRONTAL ENGAGEMENT DURING EMOTION REGULATION. FURTHER, CANNABIDIOL, A WELL-TOLERATED NON-INTOXICATING COMPONENT OF CANNABIS, HAS BEEN LINKED TO SIGNIFICANT REDUCTIONS IN ANXIETY. ACUTE CANNABIDIOL ADMINISTRATION ALSO MODULATES DMPFC ACTIVITY DURING EMOTION PROCESSING. THEREFORE, BOTH CANNABIDIOL AND CBT HAVE CONVERGING EFFECTS ON DMPFC ACTIVITY, INDICATING THAT A COMBINED THERAPY MAY HAVE SYNERGISTIC BENEFITS. THE OBJECTIVE OF THIS PROJECT IS TO TEST THE NOVEL HYPOTHESIS THAT THE COMBINATION OF CBD+CANNABIDIOL WILL RESULT IN GREATER REDUCTIONS IN GAD SYMPTOM SEVERITY COMPARED TO CBT ALONE, AND THIS EFFECT WILL BE ASSOCIATED WITH INCREASED DMPFC ACTIVATION DURING AN EMOTION REGULATION TASK. IN THE R61 PHASE, INDIVIDUALS WITH GAD WILL BE RANDOMLY ASSIGNED TO ONE OF THREE ARMS TO IDENTIFY POTENTIAL DOSE- DEPENDENT EFFECTS OF CANNABIDIOL (FDA-APPROVED EPIDIOLEX®)-ASSISTED CBT: (1) 5-WEEK BRIEF CBT PLUS MODERATE-DOSE CANNABIDIOL (5 MG/KG BID); (2) BRIEF CBT PLUS LOW-DOSE CANNABIDIOL (2.5 MG/KG BID); OR (3) BRIEF CBT PLUS PLACEBO. THE “GO” CRITERION FOR PROGRESSION FROM R61 TO R33 IS TARGET ENGAGEMENT, DEFINED AS A LARGE EFFECT SIZE (D≥0.8) IN WITHIN-SUBJECT CHANGE IN DMPFC RESPONSE DURING THE EMOTION REGULATION TASK FROM PRE- TO POST-CBT FOLLOWING CBT+CANNABIDIOL. IN THE R33 PHASE, WE WILL COMBINE THE MINIMUM EFFECTIVE DOSE FROM THE R61 PHASE WITH A STANDARD 8-WEEK BRIEF CBT PROTOCOL TO (1) REPLICATE TARGET ENGAGEMENT AND (2) TEST WHETHER CANNABIDIOL AUGMENTS THE REDUCTION IN SYMPTOM SEVERITY AND THE MAINTENANCE OF TREATMENT GAINS BETWEEN ONCE-WEEKLY SESSIONS AND POST-CBT. INDIVIDUALS WITH GAD WILL BE RANDOMIZED TO EITHER A (1) CBT+CANNABIDIOL OR (2) CBT+PLACEBO ARM. LIKE THE R61 PHASE, PARTICIPANTS WILL COMPLETE THE EMOTION REGULATION FMRI TASK PRE- AND POST-CBT TO DETERMINE WHETHER CBT+CANNABIDIOL LEADS TO GREATER INCREASES IN DMPFC ACTIVATION VS. CBT+PLACEBO. WE WILL ALSO ASSESS TREATMENT RESPONSE (REDUCED GAD SYMPTOM SEVERITY) AT EACH CBT SESSION AND AT 3 MONTHS POST-TREATMENT TO EXPLORE LONG-TERM EFFECTS. TOGETHER THE R61 AND R33 PHASES WILL PROVIDE THE MOST DIRECTLY TRANSLATIONAL AND CRITICAL TEST OF CANNABIDIOL-ASSISTED CBT FOR GAD.

NADPH OXIDASE, MITOCHONDRIAL DYSFUNCTION AND DIABETIC RETINOPATHY

MECHANISMS AND REGULATION OF 5-HT RECEPTORS IN THE CNS

NOVEL HDAC CLASS III SPECIFIC RADIOTRACERS FOR PET IMAGING.

UPWARD BOUND

PSYCHOSOCIAL AND GENETIC EFFECTS ON GENE EXPRESSION AND ASTHMA - ABSTRACT IN THE PAST 8 YEARS, WE HAVE STUDIED A COHORT OF YOUTH FROM METROPOLITAN DETROIT TO INVESTIGATE THE EFFECTS OF PSYCHOSOCIAL STRESSORS AND RESOURCES ON HEALTH, WITH A SPECIC FOCUS ON ASTHMA SYMPTOMS (ASTHMA IN THE LIVES OF FAMILIES TODAY, ALOFT STUDY). OUR PRELIMINARY RESULTS FROM BULK RNA-SEQ ANALYSIS IN PERIPHERAL LEUKOCYTES DEMONSTRATE THAT PSYCHOSOCIAL FACTORS ARE ASSOCIATED WITH TRANSCRIPTIONAL CHANGES FOR A LARGE NUMBER OF GENES, MANY OF THEM INVOLVED IN IMMUNOLOGICAL FUNCTIONS. IMPORTANTLY, WE AND OTHERS HAVE UNCOVERED AN IMPORTANT ROLE FOR BLOOD CELL TYPE COMPOSITION IN INTER-INDIVIDUAL VARIATION IN RESPONSE TO PSYCHOSOCIAL ENVIRONMENTS AND THEIR EFFECTS ON IMMUNOLOGICAL HEALTH AND ASTHMA SYMPTOMS. HERE, WE PROPOSE 1) TO DISENTANGLE THE CONTRIBUTION OF PSYCHOSOCIAL FACTORS AND ASTHMATIC STATE ON PATTERNS OF TRANSCRIPTIONAL DYSREGULATION; 2) TO INVESTIGATE THE EFFECTS OF PSYCHOSOCIAL FACTORS ON TRANSCRIPTIONAL REGULATION IN BLOOD CELL TYPE SUBPOPULATIONS; AND 3) TO DETERMINE THE ROLE OF GENETIC VARIATION IN MODULATING THESE EFFECTS AND THEIR CONSEQUENCES FOR ASTHMATIC CHILDREN'S HEALTH. TO THIS END, WE WILL USE A COMBINATION OF BULK AND SINGLE CELL RNA-SEQUENCING ON IMMUNE CELLS COLLECTED FROM CHILDREN WITH ASTHMA AND THEIR ASYMPTOMATIC SIBLINGS. THE COMPLEMENTARY EXPERTISE OF OUR TEAM WILL UNCOVER SPECIC GENETIC AND PSYCHOSOCIAL FACTORS ASSOCIATED WITH INCREASED RISK FOR POOR PHYSICAL HEALTH AND WELLBEING. THESE RESULTS WILL BE IMPORTANT TO DESIGN PERSONALIZED MEDICAL AND BEHAVIORAL INTERVENTIONS TO ALLEVIATE DISEASE SEVERITY IN CHILDREN WITH ASTHMA.

UPWARD BOUND PROGRAM

STRESS AND CARDIOVASCULAR RISK AMONG URBAN AFRICAN AMERICAN ADULTS: A MULTILEVEL, MIXED METHODS APPROACH - DESPITE THE STEADY DECLINE IN CARDIOVASCULAR DISEASES (CVD) MORBIDITY AND MORTALITY IN THE US IN THE LAST FEW DECADES, AFRICAN AMERICAN (AA) ADULTS BEAR A DISPROPORTIONATE SHARE OF CARDIOVASCULAR DISEASE (CVD) BURDEN. PSYCHOSOCIAL FACTORS—INCLUDING NEIGHBORHOOD ADVERSITY, DAILY INTERPERSONAL STRESSORS (I.E., RACIAL DISCRIMINATION, SOCIAL ISOLATION, NEGATIVE INTERACTIONS WITH OTHERS), AND EMOTIONAL REACTIVITY TO THESE STRESSORS— ARE BELIEVED TO CONTRIBUTE TO THE ETIOLOGY AND PROGRESSION OF CVD THROUGH THEIR EFFECTS ON HEALTH BEHAVIORS, THE STRESS-RESPONSIVE NEUROENDOCRINE AXES, AND IMMUNE PROCESSES. THESE FACTORS ARE PARTICULARLY SALIENT FOR URBAN-DWELLING MIDDLE-AGED AND OLDER AAS, WHO EXPERIENCE UNIQUE STRESSORS (E.G., RESIDENTIAL SEGREGATION, RACIAL DISCRIMINATION, PREJUDICE) AND ARE MORE LIKELY TO LIVE IN SITUATIONS OF SOCIOECONOMIC DISADVANTAGE THAN WHITES. HOWEVER, PSYCHOSOCIAL FACTORS AND THEIR LINK TO CVD RISK, AND INFLAMMATION MORE BROADLY, HAVE BEEN REMARKABLY UNDERSTUDIED AMONG AA ADULTS. A FINE-GRAINED CHARACTERIZATION OF THE DAILY STRESSORS, HEALTH BEHAVIORS, AND EMOTIONAL RESPONSES RELATED TO CVD—AND UNDERSTANDING OF THE SITUATIONAL CONTEXTS IN WHICH THOSE OCCUR—WILL SIGNIFICANTLY ADVANCE THE SCIENCE OF CVD RISK. ACCORDINGLY, THE PURPOSE OF THE PROPOSED PROJECT IS TO IDENTIFY AND CONCEPTUALIZE—THROUGH A MIXED-METHOD APPROACH—THE PSYCHOSOCIAL STRESSORS MOST SALIENT FOR THIS POPULATION AND TO MODEL THE DAILY PSYCHOLOGICAL, BEHAVIORAL, AND BIOLOGICAL PATHWAYS THROUGH WHICH THESE FACTORS MAY EXACERBATE CVD RISK AMONG MIDDLE-AGED AND OLDER AAS. BY ADOPTING A PROSPECTIVE (TWO WAVES OVER TWO YEARS) AND MULTIPLE-TIME-SCALE DESIGN (DAILY ASSESSMENTS NESTED WITHIN WAVES), WE WILL TEST THIS IDEA IN A SAMPLE OF 500 ASYMPTOMATIC AAS AGED 55-75 YEARS LIVING IN DETROIT. WE WILL ALSO USE SEMI- STRUCTURED INTERVIEWS TO COLLECT QUALITATIVE DATA FROM 60 PARTICIPANTS TO CONTEXTUALIZE THE QUANTITATIVE RESULTS. OUR CENTRAL HYPOTHESIS IS THAT INTERPERSONAL STRESSORS WILL PREDICT DECREASES IN RESTING HEART RATE VARIABILITY AND INCREASES IN RESTING BLOOD PRESSURE, POOR SLEEP, CHRONIC PHYSIOLOGICAL STRESS (HAIR CORTISOL), AND INFLAMMATION (BASAL AND STIMULATED CYTOKINES AND BASAL CRP) BY ALTERING DAILY AFFECT, DAILY HEALTH BEHAVIORS, AND DAILY PHYSIOLOGICAL STRESS (SALIVARY CORTISOL). WE PROPOSE TO INCREASE THE INNOVATION OF OUR WORK BY (1) USING A SMARTPHONE-BASED ECOLOGICAL MOMENTARY ASSESSMENT PROTOCOL TO MEASURE PSYCHOSOCIAL STRESS, (2) INCLUDING A SEQUENTIAL EXPLANATORY MIXED-METHOD DESIGN, (3) ADOPTING A MULTIPLE-TIME-SCALE RESEARCH DESIGN AND A STANDARDIZED MEASURE OF NEIGHBORHOOD DEPRIVATION CREATED AD HOC FOR DETROIT, AND (4) SIMULTANEOUSLY CONSIDERING MULTIPLE MEASURES OF PHYSIOLOGICAL STRESS, INFLAMMATION, AND SURROGATE ENDPOINTS OF CVD. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT ONCE A CLEAR PICTURE OF THE DAILY PSYCHOSOCIAL RISK FACTORS FOR CVD IS FORMULATED, AND THEIR BIOLOGICAL INTERMEDIARIES ARE IDENTIFIED, MORE CULTURALLY AND INDIVIDUALLY TAILORED TREATMENTS CAN BE DEVELOPED TO REDUCE CVD IN THIS POPULATION.

COMMUNITY-BASED APPROACH TO EARLY IDENTIFICATION OF TRANSITIONS TO MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER?S DISEASE (AD) IN AFRICAN AMERICANS

MECHANISMS OF INFLAMMATION RESOLUTION IN BACTERIAL ENDOPHTHALMITIS

ALCOHOL'S EFFECTS ON AFFECTIVE, COGNITIVE, AND BEHAVIORAL RESPONSES IN A VIRTUAL REALITY DATING SIMULATION - ABSTRACT APPROXIMATELY HALF OF ALL SEXUAL ASSAULTS INVOLVE ALCOHOL CONSUMPTION BY THE PERPETRATOR, VICTIM, OR BOTH. SELF- REPORT SURVEYS CONDUCTED WITH VICTIMS AND PERPETRATORS HAVE PROVIDED VALUABLE INFORMATION ABOUT ALCOHOL'S ROLE IN SEXUAL ASSAULT; HOWEVER, CAUSALITY CANNOT BE ESTABLISHED FROM CORRELATIONAL DESIGNS. WHEN PARTICIPANTS ARE RANDOMLY ASSIGNED TO DRINK CONDITIONS IN LABORATORY STUDIES, CAUSAL CONCLUSIONS CAN BE MADE REGARDING THE EFFECTS OF ACUTE ALCOHOL CONSUMPTION ON BEHAVIOR. THE MAJOR CHALLENGE FOR EXPERIMENTALISTS IS TO DEVELOP PROXIES FOR SEXUAL ASSAULT THAT HAVE STRONG CONSTRUCT VALIDITY AND EXPERIMENTAL REALISM. VIRTUAL REALITY ENVIRONMENTS (VRE) PROVIDE THE OPPORTUNITY FOR PARTICIPANTS TO BECOME IMMERSED IN THE SIMULATED ENVIRONMENT; THUS, PARTICIPANTS ARE EXPECTED TO BEHAVE IN WAYS AND TO MAKE CHOICES THAT CLOSELY RELATE TO THEIR BEHAVIOR OUTSIDE THE LABORATORY. THE GOAL OF THE PROPOSED RESEARCH IS TO BUILD ON THE PROMISING FINDINGS FROM THE PIS RECENT R21 GRANT (AA020876) THAT DEVELOPED A DATING SIMULATION AS A NEW EXPERIMENTAL PARADIGM FOR EXAMINING ALCOHOL'S ROLE IN ACQUAINTANCE SEXUAL ASSAULT PERPETRATION COMMITTED BY MEN AGAINST WOMEN. THE FIRST SPECIFIC AIM OF THE PROPOSED RESEARCH INVOLVES ENHANCING THE VR DATING SIMULATION BASED ON INSIGHTS FROM OUR EMPIRICAL FINDINGS AND NEW TECHNOLOGICAL DEVELOPMENTS. THE UPDATED SIMULATION WILL BE 3-DIMENSIONAL, WITH PARTICIPANTS WEARING HEAD MOUNTED DISPLAYS THAT IMMERSE THEM IN THE VIRTUAL WORLD WITH THEIR FEMALE COMPANION. CHANGES WILL BE DEVELOPED AND EVALUATED IN FOCUS GROUPS AND COGNITIVE INTERVIEWS WITH MALE AND FEMALE PARTICIPANTS TO MAXIMIZE ECOLOGICAL VALIDITY. THE SECOND SPECIFIC AIM INVOLVES SYSTEMATICALLY EVALUATING THE IMPACT OF SITUATIONAL CUES MANIPULATED WITHIN THE VIRTUAL REALITY ENVIRONMENT WHICH ARE EXPECTED TO EVOKE THE "IN THE MOMENT" COGNITIONS AND FEELINGS THAT ARE HYPOTHESIZED TO INCREASE THE LIKELIHOOD OF SEXUAL AGGRESSION AMONG MEN PREDISPOSED TO BE SEXUALLY AGGRESSIVE. THE THIRD SPECIFIC AIM INVOLVES EXAMINING THE EFFECTS OF ACUTE ALCOHOL CONSUMPTION ON MEN'S SEXUALLY AGGRESSIVE RESPONSES IN THE VIRTUAL REALITY SIMULATION. BASED ON THE FINDINGS FROM THE STUDIES ASSOCIATED WITH SPECIFIC AIM 2, SITUATIONAL FACTORS WILL BE MANIPULATED RESULTING IN A 2 (ALCOHOL CONDITION: SOBER VS. INTOXICATED; TARGET BRAC = .08) X 2 (HIGH OR LOW LEVEL OF CUE THAT AFFECTS PARTICIPANTS' PERCEPTIONS OF THE WOMAN'S SEXUAL INTEREST) X 2 (HIGH OR LOW LEVEL OF CUE THAT AFFECTS PARTICIPANTS' SENSE OF ENTITLEMENT AND ANGER AFTER A REFUSAL) DESIGN. RISK FACTORS ASSOCIATED WITH SEXUAL ASSAULT PERPETRATION WILL BE ASSESSED IN A SEPARATE SESSION AND ARE EXPECTED TO INTERACT WITH ALCOHOL AND CUE CONDITIONS, SUCH THAT INTOXICATED MEN WHO ARE PREDISPOSED TO SEXUAL AGGRESSION (E.G., HIGH PRE-EXISTING LEVELS OF HOSTILE MASCULINITY) AND EXPOSED TO SEXUAL INTEREST AND ENTITLEMENT/ANGER CUES ARE HYPOTHESIZED TO BE MOST LIKELY TO BE SEXUALLY AGGRESSIVE. FUTURE STUDIES CAN ALTER ASPECTS OF THE SIMULATION TO INCREASE GENERALIZABILITY TO DIFFERENT POPULATIONS. THE APPLICANTS’ LONG-TERM GOAL IS TO IDENTIFY MODIFIABLE RISK AND PROTECTIVE FACTORS THAT CAN BE USED TO DEVELOP EVIDENCE-BASED PREVENTION AND TREATMENT INTERVENTIONS TO REDUCE SEXUAL VIOLENCE.

EFFECTIVENESS TRIAL OF AN E-HEALTH INTERVENTION TO SUPPORT DIABETES CARE IN MINORITY YOUTH

INACTIVITY AND ENHANCED SYMPATHOEXCITATION: ROLE OF NEUROPLASTICITY IN THE RVLM

SYNTHESIS AND EVALUATION OF CARBOHYDRATE VACCINE ADJUVANTS - PROJECT SUMMARY THE SUCCESS OF VACCINATION REQUIRES THE GENERATION OF A STRONG IMMUNE RESPONSE TO THE INOCULATED ANTIGENS IN ORDER TO PROVIDE LONG-TERM PROTECTIVE IMMUNITY AGAINST MANY INFECTIOUS DISEASES. TO ACHIEVE THIS GOAL OFTEN REQUIRES THE ADDITION OF VACCINE ADJUVANTS, SUBSTANCES THAT A SUBSTANCE THAT BOOSTS THE BODY’S IMMUNE RESPONSE TO THE VACCINE. HOWEVER, THERE ARE ONLY A FEW HUMAN VACCINE ADJUVANTS WITH AN EXTENSIVE SAFETY RECORD AND MINIMAL TOXICITY APPROVED FOR CLINICAL USE. AT PRESENCE, MORE STUDIES ARE NEEDED TO IDENTIFY NOVEL ADJUVANTS THAT NOT ONLY SIGNIFICANTLY ENHANCE THE IMMUNE RESPONSE FOR A PARTICULAR VACCINE, BUT ALSO MUST BE MINIMALLY TOXIC AND MAXIMALLY SAFE FOR CLINICAL USE. IN EFFORTS TO DISCOVER NOVEL VACCINE ADJUVANTS, AN IN VIVO SCREENING OF FORTY-SEVEN SAPONINS FROM MEDICINAL PLANTS FOR THEIR IMMUNOSTIMULATORY AND HEMOLYTIC ACTIVITIES HAS LED TO THE DISCOVERY OF NEW EXCITING VACCINE ADJUVANTS. AMONG FORTY- SEVEN SAPONINS EVALUATED, SOYASAPONINS HAVE EMERGED AS THE MOST POTENT ADJUVANTS. THESE NEWLY-DISCOVERED CARBOHYDRATES EXHIBITED A SIGNIFICANTLY ENHANCED ADJUVANT ACTIVITY WITH ALMOST NEGLIGIBLE TOXICITY WHEN DIRECTLY COMPARED TO QS-21 WHICH HAS EMERGED AS A VACCINE ADJUVANT IN NUMEROUS CLINICAL TRIALS. HOWEVER, OBTAINING THEM FROM NATURAL SOURCES IS A COMPLICATED PROCESS OF EXTRACTION AND PURIFICATION THAT RESULT IN THE PRODUCTION OF MINUTE. AS A RESULT, ISOLATION OF SOYASAPONINS IS ECONOMICALLY UNFEASIBLE AND UNSUSTAINABLE IF SUFFICIENT QUANTITIES ARE REQUIRED FOR IMMUNOLOGICAL STUDIES AND CLINICAL APPLICATIONS. SINCE FDA HAS STRICT REGULATIONS REGARDING TO THE PURITY AND QUALITY OF ADJUVANTS FOR USE IN HUMAN, A SYNTHETIC SOURCE MUST BE DEVELOPED FOR SOYASAPONINS TO BE UTILIZED AS CLINICALLY RELEVANT ADJUVANTS. THE OBJECTIVE OF THIS PROPOSAL WILL ADDRESS THESE CHALLENGES THROUGH THE CHEMICAL SYNTHESIS FOR PROCURING SUFFICIENT QUANTITIES OF SOYASAPONINS IN PURE FORM. THIS EFFORT WILL DELIVER WELL-DEFINED SOYASAPONINS WITHOUT BATCH-TO- BATCH VARIATION AND PROVIDE TOOLS FOR STUDIES OF THEIR ROLES AS VACCINE ADJUVANTS AND EXPLORATION OF STRUCTURE-ADJUVANT POTENCY PROFILES FOR THE DISCOVERY OF NON-NATURAL SOYASAPONIN IMPROVED ADJUVANTS.

A MULTILEVEL INTERVENTION TO INCREASE THE PARTICIPATION OF AFRICAN AMERICANS IN PROSTATE CANCER CLINICAL TRIALS

RNA BIOSIGNATURES IN THE EMERGENCY EVALUATION OF FEBRILE INFANTS

EMOTIONAL EXPOSURE AND COGNITIVE BEHAVIORAL THERAPIES FOR FIBROMYALGIA

TRYPTOPHAN METABOLISM IN HUMAN BRAIN TUMORS

NCI NATIONAL CLINICAL TRIALS NETWORK-NETWORK LEAD ACADEMIC PARTICIPATING SITE

RARE EARTHS FROM U.S. EXTRACTIONS (REUSE)

PROBING ROLE OF TETRAHYDROBIOPTERIN IN CEREBRAL PALSY BY USING TRANSGENIC RABBITS - PROJECT SUMMARY/ABSTRACT CHILDREN WITH MOVEMENT DISORDERS ARE A BIG BURDEN TO SOCIETY. THE BURDEN OF DISEASE IS VERY HIGH BECAUSE OF THE LIFE-LONG CONSEQUENCES TO THE PATIENT, CARETAKERS, AND SOCIAL INSTITUTIONS. CURRENTLY THERE ARE NO CURES OR PREVENTATIVE TREATMENTS FOR CEREBRAL PALSY (CP), AS THE MECHANISMS OF DISEASE REMAIN POORLY DEFINED. HUMAN MUTATIONS IN KEY ENZYMATIC PATHWAYS CONSTITUTE GENETIC CAUSES OF CHILDHOOD MOVEMENT DISORDERS. WITH THE ADVENT OF TRANSGENIC RABBIT MODELS, A GOLDEN OPPORTUNITY HAS ARISEN TO STUDY THE PATHOGENETIC MECHANISMS IN BRAIN LEADING TO MOVEMENT DISORDERS, AS RABBITS ARE MORE LIKELY TO PRESENT WITH MOVEMENT DISORDERS MIMICKING THAT OF HUMANS. RABBITS ARE PERINATAL BRAIN DEVELOPERS LIKE HUMANS. MUTATIONS IN ENZYMES OF TETRAHYDROBIOPTERIN PATHWAY RESULT IN MOVEMENT DISORDERS. TETRAHYDROBIOPTERIN IS AN ENZYME CO-FACTOR AND ITS SUPPLEMENTATION IN CONGENITAL DEFICIENCY DISORDERS AMELIORATES THE MOVEMENT DISORDER. THUS, THERE MAY BE A CRITICAL ROLE OF TETRAHYDROBIOPTERIN IN THE DEVELOPMENT OF MOVEMENT DISORDERS, SUCH AS CP. WE DEVELOPED A KNOCKOUT RABBIT THAT INTRODUCING A SPECIFIC MUTATION IN ONE OF THE TETRAHYDROBIOPTERIN SYNTHESIS ENZYMES, SEPIAPTERIN REDUCTASE. FOLLOWING FETAL HYPOXIA-ISCHEMIA, NEWBORN RABBITS PRESENT WITH HYPERTONIA AND DIFFICULTY WITH BALANCE. FETAL RABBITS SHOWING LOW DEVELOPMENTAL TETRAHYDROBIOPTERIN IN DISCRETE BRAIN REGIONS HAVE A GREATER DISPOSITION TO DEVELOP HYPERTONIA. MAGNETIC RESONANCE IMAGING (MRI) ALLOWS US TO PREDICT WHICH FETUSES WILL DEVELOP POSTNATAL HYPERTONIA. THIS ADVANCE ALLOWS THE IDENTIFICATION OF EARLY CRITICAL PATHWAYS CAUSING HYPERTONIA. OUR OBJECTIVE IS TO ELUCIDATE MOLECULAR MECHANISMS OF PERINATAL BRAIN INJURY IN HUMAN MUTATIONS CAUSING CHILDHOOD MOVEMENT DISORDERS, BY DECREASING TETRAHYDROBIOPTERIN LEVELS USING A HETERO- AND HOMOZYGOUS KNOCKOUT TRANSGENIC APPROACH IN THE RABBIT. THE MAIN QUESTION ASKED IN THIS PROPOSAL IS WHETHER TETRAHYDROBIOPTERIN IN SELECTIVE BRAIN REGIONS CONTRIBUTES TO THE DEVELOPMENT OF MOTOR DISORDERS WITH A SEVERITY DETERMINED BY AN ADDED PRENATAL INSULT SUCH AS HYPOXIA-ISCHEMIA OR INFLAMMATION. USING GENETIC KNOCKOUT OF SEPIAPTERIN REDUCTASE, WE CAN FURTHER LOWER THE TETRAHYDROBIOPTERIN LEVELS IN BRAIN AND INVESTIGATE WHETHER THE RESULTING MOTOR DEFICITS ARE INCREASED OR THAT WE NEED LESS DEGREE OF INSULT TO ACHIEVE THE SAME MOTOR DEFICITS. THE FIRST AIM DETERMINES WHETHER AN ADDED FETAL INSULT, HYPOXIA-ISCHEMIA OR INFLAMMATION FROM LIPOPOLYSACCHARIDE, ENHANCES MOVEMENT DISORDERS IN THE SEPIAPTERIN HET/HOMOZYGOUS REDUCTASE KNOCKOUT RABBIT. THE SECOND AIM WILL DETERMINE IF NEURONAL OR OLIGODENDROGLIAL INJURY EXPLAINS THE DEVELOPMENT OF MOVEMENT DISORDERS IN THE KNOCKOUT RABBIT. WE USE INNOVATIVE PRE- AND POSTNATAL MRI BIOMARKERS OF HYPERTONIA WITH TISSUE FLOW CYTOMETRY AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION. BY CONDUCTING A TIME-DEPENDENT, ORGAN-SPECIFIC AND CELL-SPECIFIC PATHOGENETIC STUDY, WE WILL OBTAIN A COMPREHENSIVE PICTURE OF THE ROLE OF THIS COFACTOR IN PERINATAL PATHOGENESIS OF MOVEMENT DISORDERS.

DEVELOPMENT OF ERBB2 BASED BREAST CANCER VACCINES

MULTI-COMPONENT TECHNOLOGY INTERVENTION FOR AFRICAN AMERICAN EMERGING ADULTS WITH ASTHMA