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 URBAN RESPONSES TO ENVIRONMENTAL STRESSORS (CURES)

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

CORE GRANT FOR VISION 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.

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

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

ANALYSIS OF LIPOLYTIC TRAFFICKING IN ADIPOCYTES

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

ANALYSIS OF CELLULAR PLASTICITY IN WHITE ADIPOSE TISSUE

AHEC POINT OF SERVICE MAINT & ENHANCEMENT

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

LONGITUDINAL NEUROIMAGING IN STURGE-WEBER SYNDROME

HEPATIC STEATOSIS AND ER STRESS-INDUCIBLE TRANSCRIPTION FACTOR CREBH

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

MOLECULAR MECHANISMS OF NEUROPROTECTION IN POLYGLUTAMINE-DEPENDENT DEGENERATION

POISON CONTROL STABILIZATION AND ENHANCEMENT PROGRAM

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

ADVANCED NURSING EDUCATION WORKFORCE

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.

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

ROLE OF RAS IN RETINAL CELL DEATH IN DIABETES

TRAINING PROGRAM IN THE BIOLOGY OF CANCER

DELINEATING FUNCTIONAL IMMUNITY VIA IMAGE-GUIDED PET

NEURAL CORRELATES AND MODIFIERS OF COGNITIVE AGING

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

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

CHEMICAL APPROACHES TO STUDY PROTEIN POST-TRANSLATIONAL MODIFICATIONS

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

BIOBEHAVIORAL STUDIES OF OPIOID DRUG SEEKING BEHAVIOR

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

NURSE FACULTY LOAN PROGRAM

TEENS AT RISK: PRENATAL COCAINE AND POSTNATAL CHALLENGES

NCI NATIONAL CLINICAL TRIALS NETWORK ? NETWORK LEAD ACADEMIC PARTICIPATING SITE

ALCOHOL AND MATERNAL UTERINE VASCULAR ADAPTATIONS IN PREGNANCY

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

MECHANISMS OF MOTION DETECTION IN RETINAL NEURAL NETWORK

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

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

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

UPWARD BOUND

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.

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.

NEUROPROTECTION BY NNOS INHIBITORS IN PERINATAL HYPOXIA-ISCHEMIA

DEVELOPMENT OF ERBB2 BASED BREAST CANCER VACCINES

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

AFRICAN AMERICAN RESILIENCE IN SURVIVING CANCER

TRANSLATING AN EFFICACIOUS ILLNESS MANAGEMENT INTERVENTION FOR AFRICAN AMERICAN YOUTH WITH POORLY CONTROLLED ASTHMA TO REAL WORLD SETTINGS

PDGF D AND PROSTATE CANCER BONE METASTASIS

THERAPEUTIC TARGETING MITOCHONDRIAL C1 METABOLISM - ABSTRACT METABOLIC REPROGRAMMING IS AN IMPORTANT HALLMARK OF CANCER. OF THE ALTERED METABOLIC PATHWAYS ASSOCIATED WITH MALIGNANCY, ONE-CARBON (C1) METABOLISM IS PARTICULARLY NOTABLE. THE 3-CARBON OF SERINE IS THE MAJOR C1 DONOR FOR DE NOVO SYNTHESIS OF PURINES AND THYMIDYLATE IN THE CYTOSOL, AND THE PRIMARY CATABOLIC PATHWAY FOR SERINE AND SYNTHESIS OF GLYCINE OCCURS IN THE MITOCHONDRIA. THE MITOCHONDRIAL C1 PATHWAY ALSO GENERATES REDUCING EQUIVALENTS AND IS AN IMPORTANT SOURCE OF ATP. THE FIRST ENZYME OF THE MITOCHONDRIAL C1 PATHWAY, SERINE HYDROXYMETHYLTRANSFERASE (SHMT) 2, IS AN ONCODRIVER WHICH IS UPREGULATED IN A SUBSTANTIAL NUMBER OF CANCERS. GROWING EVIDENCE SUGGESTS THAT SHMT2 COULD BE AN INDEPENDENT PROGNOSTIC FACTOR AND AN IMPORTANT THERAPEUTIC TARGET FOR CANCER. WE DISCOVERED NOVEL 5-SUBSTITUTED PYRROLO[3,2-D]PYRIMIDINE COMPOUNDS AGF291, AGF347, AND AGF359. FOLLOWING THEIR INTERNALIZATION BY THE PROTON-COUPLED FOLATE TRANSPORTER (PCFT), THESE COMPOUNDS INHIBIT MITOCHONDRIAL C1 METABOLISM AT SHMT2, WITH DIRECT SECONDARY INHIBITIONS OF CYTOSOLIC TARGETS IN DE NOVO PURINE (DNP) BIOSYNTHESIS (AT 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE AND GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE) AND SHMT1. OUR COMPOUNDS INHIBIT PROLIFERATION OF EPITHELIAL OVARIAN CANCER, NON-SMALL CELL LUNG CANCER, COLORECTAL CANCER, AND PANCREATIC CANCER (PAC) CELLS, SUGGESTING THEIR POTENTIAL AS BROAD-SPECTRUM ANTI-TUMOR AGENTS. AGF347 EXHIBITED SIGNIFICANT IN VIVO ANTITUMOR EFFICACY WITH POTENTIAL FOR COMPLETE RESPONSES AGAINST BOTH EARLY AND UPSTAGE PAC XENOGRAFT MODELS. WE POSIT THAT OUR NOVEL COMPOUNDS OFFER AN ENTIRELY NEW APPROACH FOR TREATING CANCER. OUR OBJECTIVE IS TO OPTIMIZE OUR LEAD STRUCTURES FOR TUMOR TARGETING VIA PCFT AND INHIBITION OF MITOCHONDRIAL AND CYTOSOLIC C1 METABOLISM AT MODEST DOSES WITH MINIMAL TOXICITY. WE WILL USE PAC AS A DISEASE PROTOTYPE FOR FURTHER DEVELOPMENT OF OUR NOVEL MULTI-TARGETED INHIBITORS. IN AIM 1, WE WILL SYNTHESIZE UP TO 100 COMPOUNDS BASED ON LEAD COMPOUNDS TO OPTIMIZE UPTAKE BY TUMORS, AND INHIBITION OF SHMT2 AND CYTOSOLIC PATHWAYS INCLUDING DNP BIOSYNTHESIS. IN AIM 2, WE WILL TEST ANALOGS FROM AIM 1 FOR ANTITUMOR POTENCIES TOWARD CLINICALLY RELEVANT PAC CELL LINES, TUMOR SELECTIVITY AND PLASMA MEMBRANE AND MITOCHONDRIAL DRUG TRANSPORT, DRUG METABOLISM, AND INHIBITION OF SHMT2 AND CYTOSOLIC PATHWAYS INCLUDING DNP BIOSYNTHESIS. WE WILL MEASURE DOWNSTREAM IMPACTS ON MTOR SIGNALING, MITOCHONDRIAL RESPIRATION, GLUTATHIONE POOLS, AND REACTIVE OXYGEN SPECIES. IN AIM 3, WE WILL EVALUATE PHARMACOKINETICS, TOLERABILITY, AND IN VIVO ANTITUMOR ACTIVITIES OF COMPOUNDS FROM AIMS 1 AND 2 BY TOXICITY/EFFICACY TRIALS WITH HUMAN PAC CELL LINE XENOGRAFT AND PDX MODELS, AND WITH THE KPC MOUSE PAC MODEL. OUR LEAD ANALOGS ARE “FIRST-IN-CLASS” AND OUR PROPOSED STUDIES WILL AFFORD OPTIMIZED COMPOUNDS WITH THE BEST BALANCE OF SELECTIVE TUMOR TARGETING AND ANTI-TUMOR EFFICACY, RESULTING FROM INHIBITION OF SHMT2 AND DOWNSTREAM ANABOLIC PATHWAYS. WE ANTICIPATE DEVELOPING SHMT2/DNP-TARGETED COMPOUNDS FOR IND SUBMISSION AND CLINICAL TRIALS BASED ON OUR STUDIES.

EXPLOITING NON-EQUILIBRIUM CHARGE DYNAMICS IN POLYATOMIC MOLECULES TO STEER CHEMICAL REACTIONS

ESTABLISHMENT AND OPERATION OF THE LEVIN CENTER’S STATE OVERSIGHT ACADEMY

NRT: TRANSFORMATIVE RESEARCH IN URBAN SUSTAINABILITY TRAINING (T-RUST)

DEVELOPING AND STUDYING THE REPLICATION OF MATH CORPS, AN OUT-OF-SCHOOL-TIME MATHEMATICS PROGRAM FOR URBAN YOUTH

THE ROLE OF CARDIOLIPIN IN THE TCA CYCLE: IMPLICATIONS FOR BARTH SYNDROME

RESOURCES, PARENT-CHILD COMMUNICATION AND ADJUSTMENT TO PEDIATRIC CANCER

WSU - STUDENT SUCCESS THROUGH EVIDENCE-BASED PEDAGOGIES (WSU-SSTEP)

EFFECTS OF COCAINE TAKING AND SEEKING ON HISTONE DEACETYLASE CLASS IIA ENZYME ACTIVITY IN THE NUCLEUS ACCUMBENS OF RATS

HUMAN SKELETAL MUSCLE PROTEOME AND PHOSPHOPROTEOME IN OBESITY AND TYPE 2 DIABETES

REDUCING CANCER HEALTH DISPARITIES IN DETROIT - OVERALL PROGRAM SUMMARY THIS APPLICATION FOR FEASIBILITY AND PLANNING STUDIES OF A P20 SPECIALIZED PROGRAM OF RESEARCH EXCELLENCE (SPORE) TO INVESTIGATE CANCER HEALTH DISPARITIES WILL ADDRESS RACIAL DISPARITIES IN METROPOLITAN DETROIT, A UNIQUELY IMPORTANT UNDERSERVED POPULATION WHERE GREAT CANCER DISPARITIES EXIST. THE APPLICATION INCLUDES TWO SCIENTIFIC PROJECTS FOCUSED ON TREATMENT WITH IMMUNE CHECKPOINT INHIBITORS (ICIS) NOW BEING USED IN THE STANDARD OF CARE SETTING FOR LUNG CANCER, AN ADMINISTRATIVE CORE, A BIOSPECIMEN CORE, A PATIENT AND COMMUNITY ENGAGEMENT CORE, AND A DEVELOPMENTAL RESEARCH PROGRAM. THE DECISION TO USE ICIS RELIES HEAVILY ON PRIOR TREATMENT RESPONSE AND IMPERFECT TUMOR BIOMARKERS, AND IMMUNE-RELATED ADVERSE EVENTS (IRAES) DICTATE CONTINUED THERAPY, AND ULTIMATELY OUTCOMES, YET LITTLE IS KNOWN ABOUT WHAT FACTORS DRIVE DISEASE COURSE IN RACIALLY DIVERSE POPULATIONS. THE OVERALL AIM 1 OF THIS PROGRAM IS TO ACCELERATE TRANSLATIONAL RESEARCH TO REDUCE HEALTH DISPARITIES IN LUNG CANCER OUTCOMES BY: A) CHARACTERIZING RACE-SPECIFIC IMMUNE PROFILES WITH RESPECT TO THE TUMOR ENVIRONMENT AND HOST GENETIC BACKGROUND TO DETERMINE THEIR CONTRIBUTION TO RESPONSE TO ICIS (PROJECT 1); AND B) CHARACTERIZING PATIENT-REPORTED SIDE EFFECTS, QUALITY OF LIFE, AND IRAES IN A RACIALLY DIVERSE GROUP OF LUNG CANCER PATIENTS AND IDENTIFYING THE INDIVIDUAL, BEHAVIORAL, MOLECULAR/GENETIC AND DISEASE-SPECIFIC DETERMINANTS OF THESE END POINTS (PROJECT 2). THE OVERALL AIM 2 IS TO STRENGTHEN THE EXISTING PROGRAMMATIC STRUCTURE TO ENCOURAGE TRANSLATIONAL RESEARCH INTO THE BIOLOGY OF CANCER HEALTH DISPARITIES, ACHIEVE FULL P50 SPORE FUNDING, AND ULTIMATELY REDUCE CANCER HEALTH DISPARITIES BY: A) EXPANDING OUR CANCER BIOLOGY OF HEALTH DISPARITIES INITIATIVE, FACILITATING USE OF BIOSPECIMENS FROM KCI'S RACIALLY DIVERSE POPULATION, AND FUNDING DEVELOPMENTAL RESEARCH PROJECTS; B) MENTORING INVESTIGATORS IN CANCER HEALTH DISPARITIES; AND C) EXPANDING OUR COMMUNITY OUTREACH AND ENGAGEMENT EFFORTS THROUGH A ROBUST PATIENT AND COMMUNITY ENGAGEMENT CORE (PCEC) TO SUPPORT RECRUITMENT AND RETENTION OF DIVERSE STUDY PARTICIPANTS AND DISSEMINATION OF RESEARCH PROJECT PROGRESS AND FINDINGS TO PARTICIPANTS AND LAY AUDIENCES. THIS P20 APPLICATION WILL ENABLE CLINICAL, BASIC AND POPULATION SCIENTISTS TO TRANSLATE RELEVANT, HIGH-IMPACT SCIENTIFIC DISCOVERIES IN DIVERSE PATIENTS TO REDUCE RACIAL DISPARITIES IN CANCER OUTCOMES, MOVING TOWARDS A MORE RACE-INCLUSIVE, EQUITY-FOCUSED PRECISION MEDICINE APPROACH TO CANCER TREATMENT AND PREVENTION.

IMPACT OF TRAUMA EXPOSURE ON CRITICAL PERIODS IN BRAIN DEVELOPMENT AND FEAR PROCESSING IN CHILDREN

ADVANCING INNOVATIVE BRAIN IMAGING TO DETECT ALTERED GLUTAMATE MODULATION AND NETWORK DYNAMICS IN SCHIZOPHRENIA

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING (BHWET) PROGRAM

TREATMENT OF SLEEP APNEA IN PATIENTS WITH CERVICAL SPINAL CORD INJURY

PROCESSING AND DEGRADATION OF PROTEOLIPID PROTEIN

NOVEL IMAGING BIOMARKER FOR TREATING SPATIAL MEMORY LOSS IN PRODROMAL ALZHEIMER'S DISEASE MODELS

OPTIMIZING AND VALIDATING A BRIEF ASSESSMENT FOR IDENTIFYING CHILD. OF SEVS MEMBS AT RISK FOR PSYCHOLOGICAL HEALTH PROBLEMS FOLLOWING PARENT DEPLOYM

PRIMARY VESICOURETERAL REFLUX IN CHILDREN

MECHANISMS OF INFLAMMATION RESOLUTION IN BACTERIAL ENDOPHTHALMITIS

RRM1 IN THE MANAGEMENT OF LUNG CANCER

MULTI-COMPONENT CAVITY POLARITONS FOR TUNABLE INTERMOLECULAR ENTANGLEMENT AND CONTROLLED PHOTON-TO-ELECTRON QUANTUM TRANSDUCTION

FETAL EXPOSURE TO ENVIRONMENTAL TOXICANTS AND CHILD OUTCOME

STUDY OF THE PRODUCTION AND DECAY OF BEAUTY AND CHARM PARTICLE

NOVEL NEUROPROTECTIVE TREATMENT FOR PARKINSON'S DISEASE

PREVENTING ISCHEMIA/REPERFUSION DAMAGE VIA NONINVASIVE MITOCHONDRIA-TARGETED THERAPY

IMPROVING DIABETES HEALTH IN EMERGING ADULTHOOD THROUGH AN AUTONOMY SUPPORTIVE INTERVENTION.

PRECLINICAL VALIDATION OF ABHD5 AS A TARGET FOR TREATMENT OF OBESITY.

INTRATUMORAL IMAGING OF HYPOXIA USING 1H- AND 19F-MRI WITH REDOX-RESPONSIVE EU-BASED CONTRAST AGENTS

ASSESSING DEVELOPMENT TRAJECTORIES OF THE BRAIN BIOCHEMISTRY IN ADHD AT 4 TESLA

EDUCATIONAL OPPORTUNITY CENTERS PROGRAM

THE ROLE OF TUMOR CELL SURFACE LECTIN IN METASTASES

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.

BIOLOGICAL AND ENVIRONMENTAL FACTORS AFFECTING RISK AND RESILIENCE AMONG SYRIAN REFUGEE CHILDREN

INFUSION DEVICE OPTIMIZATION BY ADDRESSING ROOT CAUSES OF THE INFLAMMATORY RESPONSE - SIGNIFICANT PROGRESS IN DIABETES DEVICE TECHNOLOGY HAS BEEN REALIZED OVER THE PAST TWO DECADES. THESE NOVEL TECHNOLOGIES IMPROVE GLYCEMIC CONTROL OVER DAILY INJECTIONS THUS REDUCING THE PROBABILITY OF ENCOUNTERING DIABETIC COMPLICATIONS. INSULIN INFUSION PUMP SETS PROVIDE DOSING FLEXIBILITY AND ENHANCED CLINICAL EFFICACY IN TERMS OF REDUCING HBA1C AND SEVERE HYPOGLYCEMIC EVENTS. DESPITE THESE TECHNOLOGICAL IMPROVEMENTS IN INSULIN DELIVERY SYSTEMS, CURRENT BEST-PRACTICE SET WEAR IS TYPICALLY LIMITED TO THREE DAYS. CURRENT CHALLENGES TO EXTENDING THE LIFESPAN OF SUBCUTANEOUS INSULIN ADMINISTRATION SETS AND INFUSION PUMPS INVOLVE UNRELIABLE INSULIN EFFICACY THROUGH THE DEVELOPMENT OF SKIN PATHOLOGIES. CURRENTLY, ALL COMMERCIALLY AVAILABLE INSULIN FORMULATIONS CONTAIN INSULIN PHENOLIC PRESERVATIVES (IPP) KNOWN AS EXCIPIENTS THAT ARE A DOUBLE EDGE SWORD. WHILE THEY PROVIDE INSULIN PROTEIN STABILITY, STERILITY AND PROLONG INSULIN SHELF LIFE, OUR LABORATORY HAS RECENTLY SHOWN THAT THESE ARE CYTOTOXIC, INDUCE INFLAMMATION AND SECONDARY FIBROSIS. SUBSEQUENTLY, OUR DATA IN MURINE AND PORCINE MODELS DEMONSTRATED THAT PROXIMATE PRE-INFUSION IPP REMOVAL SIGNIFICANTLY REDUCES INFUSION SITE INFLAMMATION WHILE MAINTAINING PROTEIN FUNCTIONALITY. THUS, THE TWO MAJOR OBSTACLES TO INCREASED INFUSION SET WEAR TIME ARE THE CHEMOTOXICITY OF THE IPP AND THE TRANSDERMAL CANNULA INDUCED TISSUE INJURY, BOTH OF WHICH ARE INFLAMMATION DRIVEN. MATURE MAST CELLS (MC) RESIDE IN CUTANEOUS TISSUE. THUS, MC ARE ONE OF THE FIRST RESPONDER IN SKIN INJURY AND ARE KEY CONTRIBUTORS IN ORCHESTRATING THE INFLAMMATORY RESPONSE ONCE THE SKIN IS BREACHED. THEREFORE, OUR CENTRAL HYPOTHESIS, SUPPORTED BY OUR PUBLISHED AND PRELIMINARY DATA, IS THAT ACCUMULATIVE IPP AND THE TRANSDERMAL INJECTION AND INFUSION DEVICES CONTRIBUTE TO LOCAL SKIN IRRITATION DUE TO MAST CELL ACTIVATION AND SUBSEQUENT LEUKOCYTE RECRUITMENT, THUS INITIATING THE INFLAMMATORY CASCADE. AS MC INTERACT WITH MACROPHAGES (MQ) WE FURTHER HYPOTHESIZE THAT INCREASED MC DEGRANULATION PROMOTES M1 PHENOTYPE LEADING TO PHAGOCYTOSIS INSULIN UPTAKE/DEGRADATION BY NEUTROPHILS & MQ AND THUS ALTERING BLOOD GLUCOSE CONTROL. THEREFORE, OUR OVERALL GOALS ARE, FIRST, TO DETERMINE HOW MC ACTIVATION OCCURS, AND, SECOND, THE CONTRIBUTION TO THE RESULTING TISSUE REACTIONS (INFLAMMATION AND FIBROTIC CASCADES) WHILE CORRELATING IPP CONCENTRATION AND COMPOSITION FOR THE DURATION OF THE INFUSION PERIOD. WE WILL TEST OUR HYPOTHESIS IN THREE SPECIFIC AIMS: 1) DETERMINE IPP INDUCED MC ACTIVATION AND INSULIN DEGRADATION, 2) EMPLOY NOVEL TRANSGENIC MOUSE MODELS (CRE/LOXP) TO DETERMINE THE MECHANISMS AND MEDIATORS OF IPP AND DEVICE MC INDUCED INFLAMMATION, AND 3) PRESERVE LONG-TERM TISSUE INTEGRITY DURING INSULIN INFUSION PUMP THERAPY IN A PRE-CLINICAL PORCINE MODEL. ULTIMATELY, THE SUCCESSFUL ACCOMPLISHMENT OF THIS PROPOSAL COULD RESULT IN TRANSFORMING CURRENT DIABETES MANAGEMENT PRACTICES THAT WOULD ACHIEVE THE GOALS OF INCREASING THE LIFESPAN OF INSULIN INFUSION DEVICES AND MOST IMPORTANTLY, SUSTAINING A TISSUE SITE AVAILABLE FOR FUTURE RECURRENT INSULIN ADMINISTRATIONS.

CELL CYCLE REGULATION OF MEMBRANE TRAFFICKING

UNIVERSITY CENTERS FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES - CORE GRANT

PATERNAL PRECONCEPTION PHTHALATES AND REPRODUCTIVE HEALTH - POTENTIAL MEDIATION THROUGH SPERM DNA METHYLATION

COMMUNITY HEALTH WORKER TRAINING PROGRAM - ADDRESS: DIVISION OF KINESIOLOGY, HEALTH AND SPORT STUDIES; WAYNE STATE UNIVERSITY; 2177 FACULTY ADMINISTRATION BUILDING; 656 W. KIRBY ST.; DETROIT, MI 48202 PROJECT DIRECTOR: NATHAN MCCAUGHTRY, PH.D. CONTACT PHONE NUMBERS PHONE: 248-495-3465 FAX: NONE EMAIL ADDRESS: NATEMCCAUGHTRY@WAYNE.EDU WEBSITE ADDRESS: WWW.WAYNE.EDU ALL GRANT FUNDS REQUESTED: $2,618,267 FUNDING PREFERENCE: NONE THE DIVISION OF KINESIOLOGY, HEALTH AND SPORT STUDIES IN THE COLLEGE OF EDUCATION AT WAYNE STATE UNIVERSITY REQUESTS $2,618,267 FROM THE HRSA COMMUNITY HEALTH WORKER TRAINING PROGRAM (CHWTP) FUNDING PROGRAM OVER THREE YEARS TO LAUNCH A PROJECT CALLED “COMMUNITY HEALTH WORKER ACADEMY: WORKFORCE DEVELOPMENT TO IMPROVE URBAN HEALTH CARE AND ADVANCE HEALTH EQUITY” IN ORDER TO ENHANCE AND BRING TO SCALE OUR COMMUNITY HEALTH WORKER ACADEMY. THE PROJECT WOULD TAKE PLACE IN THREE COUNTIES IN METRO DETROIT (WAYNE, OAKLAND, MACOMB) FOCUSING ON THE UNDERSERVED COMMUNITIES IN THIS REGION DETERMINED BY THEIR SOCIAL VULNERABILITY INDEX SCORE, HEALTH DISPARITIES RELATIVE TO OTHER REGIONS, DOCUMENTED HEALTH CARE AND PUBLIC HEALTH WORKFORCE SHORTAGE, IMPACT FROM COVID 19, RACIAL AND ETHNIC DIVERSITY, AND SOCIO-ECONOMIC STATUS. THE PROJECT COMBINES THE INTERDISCIPLINARY EXPERTISE OF FACULTY AND STAFF FROM THE COLLEGE OF EDUCATION, SCHOOL OF MEDICINE, AND SCHOOL OF SOCIAL WORK, AS WELL AS THE MICHIGAN COMMUNITY HEALTH WORKER ALLIANCE AND MANY REGIONAL HEALTH CARE AND PUBLIC HEALTH PARTNERS. THE PROJECT WILL EXPAND AND EXTEND/UPSKILL THE CHW WORKFORCE BY OFFICIALLY CERTIFYING 140 TRAINEES AS CHWS (EXPANDING), PROVIDING COMPREHENSIVE FOUNDATIONAL AND ADVANCED SPECIALIZED TRAININGS (EXTENDING/UPSKILLING), AND PLACING THEM IN REGISTERED APPRENTICESHIPS AND INTERNSHIPS IN INTEGRATED CARE TEAMS AT HEALTH CARE AND PUBLIC HEALTH ORGANIZATIONS AND AGENCIES. THE ENTIRE PROGRAM INTEGRATES THE PUBLIC HEALTH CORE COMPETENCIES, INCLUDING TRAINING IN HEALTH EQUITY, SOCIAL DETERMINANTS OF HEALTH, EM ERGENCY RESPONSE, TREATMENT, VACCINE HESITANCY, COVID 19, CAREER DEVELOPMENT AND JOB PREPARATION, AND DIGITAL LITERACY AMONG MANY OTHERS. AT LEAST 60% OF THE TRAINEES WILL REPRESENT UNDERSERVED COMMUNITIES, AND WILL RECEIVE JOB PLACEMENT ASSISTANCE TO SO THEY GAIN EMPLOYMENT AS CHWS WITHIN ONE YEAR OF ACADEMY COMPLETION.

MOTIVATIONAL ENHANCEMENT SYSTEM FOR ADHERENCE (MESA) FOR YOUTH STARTING ART

UNIVERSITY CENTERS FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES EDUCATION, RESEARCH AND SERVICE - CORE GRANT

SERINE/THREONINE PROTEIN PHOSPHATASE 1 IN INSULIN RESISTANCE AND TYPE 2 DIABETES

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.

MATERNAL LIFESTYLES STUDY PHASE V

OCTOPAMINE CONTROLS ADAPTATION TO ENDURANCE EXERCISE IN DROSOPHILA

NEURAL BASES OF EYEBLINK CONDITIONING IN FASD

CHEMICAL APPROACHES TO CHARACTERIZING KINASE-CATALYZED MODIFICATIONS

STRUCTURAL INSIGHTS INTO THE FUNCTION OF FRATAXIN

IMPACT OF DIETARY FRUCTOSE AND HIGH SALT DIET ON NEUROCARDIOVASCULAR AND RENAL FUNCTION - PROGRAM DIRECTOR/PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): ROSSI, NOREEN F. NEARLY HALF OF US ADULTS HAVE HYPERTENSION. FRUCTOSE INTAKE PREDISPOSES TO SALT-SENSITIVE HYPERTENSION, AN INDEPENDENT RISK FACTOR FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) AND CHRONIC KIDNEY DISEASE (CKD). INCREASED SALT INTAKE IMPAIRS VASCULAR COMPLIANCE EVEN BEFORE FRANK HYPERTENSION DEVELOPS. AORTIC STIFFNESS IS NOW RECOGNIZED AS A ROBUST PREDICTOR OF MACE AND CKD. SYMPATHOEXCITATION INCREASES CARDIOVASCULAR RISK AND STRONGLY IMPACTS AORTIC STIFFNESS. OUR PRELIMINARY DATA SHOW THAT COMBINED FRUCTOSE AND SALT INTAKE CONTRIBUTES TO INSULIN RESISTANCE AND HYPERTENSION THAT DISPLAYS INCREASED RENAL SYMPATHETIC ACTIVITY AND AORTIC AS WELL AS RENAL ARTERY STIFFNESS. THE GOAL OF THIS APPLICATION IS TO ACHIEVE EARLY IDENTIFICATION AND TIMELY INTERVENTION OF VASCULAR STIFFNESS TO MITIGATE MACE AND CKD. ROBUST, RIGOROUS PRECLINICAL DATA ARE NEEDED TO JUSTIFY TESTING AND TREATMENT. OUR CENTRAL HYPOTHESIS IS THAT A DIET MODERATELY HIGH IN FRUCTOSE AND SALT (FHS) RESULTS IN HYPERTENSION, VASCULAR STIFFNESS AND RENAL DYSFUNCTION DRIVEN BY SYMPATHETIC NERVE ACTIVITY (SNA) AND/OR THE RENIN-ANGIOTENSIN- SYSTEM (RAS). WE PROPOSE TO INTERROGATE THE MECHANISM THAT THIS NEUROEXCITATION AND INCREASED RAS ARE DRIVEN BY AFFERENT INPUTS FROM THE KIDNEY TO THE BRAIN AT THE SUBFORNICAL ORGAN AND, THENCE, TO SNA AND/OR ANGIOTENSINERGIC INPUTS TO HEART, VASCULATURE AND KIDNEY. DIRECT INTERRUPTION OF THE AFFERENT RENAL NERVES, SNA OR PHARMACOLOGICAL INHIBITION OF SNA OR RAS, ALONE OR IN COMBINATION, WILL DECREASE BLOOD PRESSURE, CONDUIT VASCULAR COMPLIANCE, AND AMELIORATE CARDIAC AND RENAL FUNCTION. WE PROPOSE THREE AIMS: 1) ASCERTAIN THE RESPECTIVE CONTRIBUTION OF AFFERENT VS EFFERENT RENAL NERVES ON BLOOD PRESSURE, LV FUNCTION, VASCULAR COMPLIANCE, AND RENAL FUNCTION IN FHS RAT MODEL, 2) ASSESS THE IMPACT OF ACUTE OR CHRONIC PHARMACOLOGIC BLOCKADE OF SNA AND/OR RAS ON LV FUNCTION, VASCULAR COMPLIANCE AND RENAL FUNCTION IN FHS RATS, AND 3) EVALUATE THE CONTRIBUTION OF THE ARTERIAL BAROREFLEX, AT1R AND TNFR1 IN THE SUBFORNICAL ORGAN THAT LIES OUTSIDE THE BLOOD BRAIN BARRIER ON BLOOD PRESSURE, LV-GLS, PP, PWV, RRI AND RENAL FUNCTION IN RATS ON FHS DIET. RAS AND AORTIC COMPLIANCE DISPLAY SEXUAL DIMORPHISM, SO WE WILL EVALUATE SPRAGUE DAWLEY RATS OF BOTH SEXES. WE WILL USE STATE-OF-THE-ART ULTRASONOGRAPHY, REAL-TIME RENAL BLOOD FLOW AND FITC-SINISTRIN MEASUREMENTS OF GLOMERULAR FILTRATION RATE TO ASSESS AORTIC AND RENAL ARTERY COMPLIANCE, LV AND RENAL FUNCTION. WE WILL DIRECTLY ASSESS THE IMPACT OF AFFERENT AND EFFERENT RENAL NERVES WITH SELECTIVE DEAFFERENTATION VS TOTAL DENERVATION IN CONSCIOUS RATS. WE WILL VALIDATE THE IN VIVO FINDINGS BY EX VIVO MYOGRAPHY OF AORTIC RINGS AND ASSESS MARKERS OF OXIDATIVE STRESS IN VASCULATURE. WE WILL TEST WHETHER CHRONIC PHARMACOLOGIC THERAPIES TO INHIBIT SYMPATHETIC INPUTS AND/OR RAS WILL ALSO ACHIEVE IMPROVEMENTS IN CONDUIT VASCULAR COMPLIANCE, CARDIAC AND RENAL FUNCTION. OUR STUDIES WILL IDENTIFY THERAPEUTIC INTERVENTIONS THAT CAN BE TRANSLATED TO SCREENING AND TREATMENT OF HUMANS WITH PRE-DIABETES AND STAGE 1 HYPERTENSION TO IMPROVE VASCULAR AND RENAL FUNCTION TO MITIGATE MACE AND CKD. OMB NO. 0925-0001/0002 (REV. 03/2020 APPROVED THROUGH 02/28/2023) PAGE CONTINUATION FORMAT PAGE

TARGETING THE VASCULARITY FOR DELIVERY OF INHIBITORS OF METASTASIS IN OVARIAN CANCER

CATALYTIC METHODS FOR STEREOSELECTIVE 1,2-CIS GLYCOSYLATION

CONTRIBUTION OF NEUROPLASTICITY IN THE ROSTRAL VENTROLATERAL MEDULLA TO PHYSICAL INACTIVITY-RELATED CARDIOVASCULAR DISEASE - PHYSICAL INACTIVITY IS A MAJOR INDEPENDENT RISK FACTOR FOR CARDIOVASCULAR DISEASE (CVD) AND IS NOW CONSIDERED THE LEADING CAUSE OF PREMATURE DEATH (BLAIR, 2009). RATES OF PHYSICAL INACTIVITY CONTINUE TO INCREASE ALONG WITH HEALTH CARE COSTS TO TREAT CVD. DESPITE THESE DISTURBING TRENDS, THE MECHANISMS BY WHICH A SEDENTARY LIFESTYLE LEADS TO CVD ARE NOT FULLY KNOWN. CVD IS ASSOCIATED WITH INCREASED SYMPATHETIC NERVOUS SYSTEM ACTIVITY AND OVERACTIVITY OF A BRAINSTEM REGION KNOWN AS THE ROSTRAL VENTROLATERAL MEDULLA (RVLM) (SVED ET AL., 2003;GUYENET, 2006). SYMPATHOEXCITATORY RESPONSES TO DIRECT ACTIVATION OF THE RVLM ARE ENHANCED IN SEDENTARY VERSUS PHYSICALLY ACTIVE ANIMALS (MISCHEL AND MUELLER, 2011) AND ARE ASSOCIATED WITH CHANGES IN DENDRITIC BRANCHING (MISCHEL ET AL., 2014). THESE DATA SUGGEST THAT A SEDENTARY LIFESTYLE MAY CONTRIBUTE TO THE DEVELOPMENT OF CVD BY INCREASED SENSITIVITY OF RVLM NEURONS. OUR LONG TERM GOAL IS TO UNDERSTAND THE CENTRAL SYMPATHETIC MECHANISMS BY WHICH PHYSICAL INACTIVITY CONTRIBUTES TO THE DEVELOPMENT OF CVD. THIS IS AN IMPORTANT CLINICAL, ECONOMIC AND PUBLIC HEALTH CARE PROBLEM. THE OVERALL OBJECTIVE OF THIS APPLICATION IS TO DEFINE THE MECHANISMS BY WHICH PHYSICAL INACTIVITY INCREASES, AND PHYSICAL ACTIVITY PREVENTS OVER-ACTIVATION OF PRESYMPATHETIC NEURONS IN THE RVLM. OUR CENTRAL HYPOTHESIS IS THAT SEDENTARY AND HYPERTENSIVE CONDITIONS EACH ENHANCE GLUTAMATERGIC SIGNALING, INITIATE BDNF-DEPENDENT MECHANISMS AND FURTHER PROPAGATE ENHANCED GLUTAMATERGIC SIGNALING; SUCH THAT IN COMBINATION, PRODUCE CLINICALLY RELEVANT INCREASES IN SYMPATHETIC OUTFLOW AND BLOOD PRESSURE. THIS PROJECT IS EXPECTED TO SHIFT CURRENT PARADIGMS REGARDING THE MECHANISMS BY WHICH PHYSICAL INACTIVITY AND PRO-HYPERTENSIVE STIMULI COMBINE TO INCREASE SYMPATHETIC ACTIVITY AND EXAGGERATE THE HYPERTENSIVE PHENOTYPE. WE WILL TEST OUR CENTRAL HYPOTHESIS IN DISTINCT BUT INTERRELATED AIMS USING OUR WELL- ESTABLISHED MODELS OF SEDENTARY OR ACTIVE CONDITIONS AND 2K-1C HYPERTENSION WITH SHAM-OPERATED RATS AS CONTROLS. AIM 1: UTILIZE IN VIVO GENE TARGETING TO DETERMINE THE CONTRIBUTION OF BDNF-TRKB SIGNALING IN SEDENTARY AND 2K1C MEDIATED NEUROPLASTICITY IN THE RVLM. AIM 2: ESTABLISH RELATIONSHIPS BETWEEN BDNF AND SYNAPTIC PLASTICITY-ASSOCIATED MRNA AND PROTEIN EXPRESSION IN THE RVLM OF SEDENTARY VERSUS ACTIVE, NORMOTENSIVE AND 2K1C RATS USING LASER CAPTURE MICRODISSECTION OF PRESYMPATHETIC RVLM NEURONS AND TRACT-TRACING, TRIPLE- IMMUNOFLUORESCENT LABELING. AIM 3: QUANTIFY GLUTAMATERGIC TONE AND NEURONAL ACTIVITY IN THE RVLM OF SEDENTARY VERSUS ACTIVE, NORMOTENSIVE OR 2K1C RATS USING MAGNETIC RESONANCE SPECTROSCOPY (MRS) AND MAGNETIC RESONANCE IMAGING (MRI) OF THE RVLM. OUR STUDIES COMBINE STATE-OF-THE ART TECHNIQUES WITH CONCEPTUALLY INNOVATIVE HYPOTHESES TO FILL SIGNIFICANT KNOWLEDGE GAPS TOWARDS UNDERSTANDING TWO FUNDAMENTALLY IMPORTANT AND INTERTWINED, YET UNRESOLVED HEALTH PROBLEMS, I.E. PHYSICAL INACTIVITY AND HYPERTENSION.

ADOLESCENT RISK REDUCTION IN THE PEERS & PARENTS

PIRE: A U.S. - DUTCH MASS SPECTROMETRY CONSORTIUM FOR ADVANCED MODELING AND BIOLOGICAL STRUCTURE AND IMAGING APPLICATIONS

DETROIT REPRODUCTIVE CAREER DEVELOPMENT RESEARCH CENTER

DUAL-OREXIN ANTAGONISM AS A MECHANISM FOR IMPROVING SLEEP AND DRUG ABSTINENCE IN OPIOID USE DISORDER

MENTAL HEALTH IN IRAQI REFUGEES: IMPORTANCE OF POST-DISPLACEMENT SOCIAL STRESSORS

USING LIGHT-SENSITIVE CHANNELS TO RESTORE VISION FOR BLINDING RETINAL DISEASES

RECOGNIZING, REFLECTING, AND RESPONDING TO INFANT/TODDLER CUES: AN INTEGRATED PARENT-TEACHER INTERVENTION TO SUPPORT SOCIAL-EMOTIONAL DEVELOPMENT THR

FUNCTIONAL PLASTICITY IN THE MAMMALIAN SPINAL CORD

AGING COMPROMISES NEUTROPHIL-MEDIATED INNATE PROTECTION AGAINST HIV IN THE HUMAN FEMALE GENITAL TRACT.

FAMILY MHEALTH INTERVENTION TO IMPROVE HEALTH OUTCOMES IN BLACK YOUTH WITH TYPE 1 DIABETES: A MULTI-CENTER RANDOMIZED CONTROLLED TRIAL - BLACK ADOLESCENTS WITH TYPE 1 DIABETES (T1D) FACE DISPARITIES IN DIABETES-RELATED HEALTH OUTCOMES SUCH AS HIGHER RISK FOR SUBOPTIMAL GLYCEMIC CONTROL, WHICH CAN LEAD TO DIABETES COMPLICATIONS. GIVEN THE CRITICAL PROTECTIVE ROLE PLAYED BY FAMILIES IN THE HEALTH OF ADOLESCENTS WITH T1D, FAMILY-BASED INTERVENTIONS HAVE COMMONLY BEEN USED AS A STRATEGY TO PROMOTE OPTIMAL ADOLESCENT HEALTH. HOWEVER, DESPITE THE EXTENSIVE LITERATURE DOCUMENTING HEALTH DISPARITIES, FEW RANDOMIZED CLINICAL TRIALS, INCLUDING THOSE TESTING FAMILY-BASED- INTERVENTIONS, HAVE INCLUDED ADEQUATE SAMPLES OF BLACK ADOLESCENTS WITH T1D. MOREOVER, RIGOROUS, ADEQUATE POWERED CLINICAL TRIALS TESTING BEHAVIORAL INTERVENTIONS SPECIFICALLY DESIGNED AND TAILORED FOR BLACK ADOLESCENTS WITH T1D AND THEIR FAMILIES ARE LACKING. PRIMARY CAREGIVERS OF YOUTH WITH T1D EXPERIENCE ELEVATED LEVELS OF STRESS, DEPRESSION AND ANXIETY, AND CAREGIVERS OF BLACK YOUTH ARE AT HIGHER RISK FOR SUCH DISTRESS. FAMILY-BASED INTERVENTIONS FOR BLACK ADOLESCENTS WITH T1D HOLD THE POTENTIAL TO IMPROVE THE HEALTH NOT ONLY OF THE INDIVIDUAL YOUTH BUT OF THE CAREGIVER AS WELL, AS IMPROVED FAMILY INTERACTIONS CAN HAVE SPILLOVER EFFECTS FOR CAREGIVER MENTAL HEALTH. EHEALTH INTERVENTIONS HAVE SHOWN PROMISING EFFECTS IN A NUMBER OF AREAS OF BEHAVIORAL HEALTH CARE AND MAY ALSO INCREASE THE ACCESSIBILITY OF BEHAVIORAL HEALTH INTERVENTIONS TO BLACK FAMILIES. OUR GROUP HAS DEVELOPED AND TESTED A CULTURALLY TAILORED, BRIEF EHEALTH INTERVENTION DESIGN TO PROMOTE OPTIMAL PARENTING PRACTICES FOR PRIMARY CAREGIVERS OF BLACK ADOLESCENTS WITH T1D. RESULTS OF OUR RECENT CLINICAL TRIAL WHERE THE INTERVENTION WAS DELIVERED DURING DIABETES CLINIC VISITS SHOWED PROMISING RESULTS, AS ADOLESCENTS WHOSE CAREGIVERS RECEIVED THE INTERVENTION HAD IMPROVED GLYCEMIC CONTROL AND FAMILIES REPORTED REDUCED DIABETES- RELATED FAMILY CONFLICT. HOWEVER, FINDINGS ALSO SUGGESTED THE NEED FOR FURTHER REFINEMENT OF THE INTERVENTION, INCLUDING THE DEVELOPMENT OF ADDITIONAL CONTENT TO HELP PARENTS SUPPORT THEIR ADOLESCENT WITH DIABETES MANAGEMENT. THE PROPOSED STUDY WILL INCLUDE AN INTERVENTION ADAPTATION PHASE WHERE WE WILL CONVENE COMMUNITY ADVISORY BOARDS TO DEVELOP NEW MATERIAL DESIGNED TO OPTIMIZE DIABETES-RELATED FAMILY INTERACTIONS THAT CAN BE INTEGRATED INTO THE EXISTING INTERVENTION. SUBSEQUENTLY, WE WILL TEST THE EFFICACY OF THE NEW INTERVENTION TO IMPROVE YOUTH GLYCEMIC CONTROL, IMPROVE DIABETES-RELATED FAMILY RELATIONSHIPS AND REDUCE CAREGIVER DIABETES-RELATED DIABETES DISTRESS IN A MULTI-CENTER, RANDOMIZED CONTROLLED TRIAL. THE NEW INTERVENTION WILL BE DELIVERED VIA A MOBILE HEALTH APPROACH TO OPTIMIZE ITS ACCESSIBILITY. 216 BLACK ADOLESCENTS WITH T1D AND THEIR PRIMARY CAREGIVER WILL BE RECRUITED FROM TWO CLINICAL SITES AND RECEIVE THE INTERVENTION OR AN ATTENTION CONTROL INTERVENTION DURING A SIX-MONTH WINDOW. ADDITIONALLY, WE WILL EVALUATE THE INTERVENTION’S POTENTIAL TO BUFFER THE IMPACT OF SOCIAL AND CONTEXTUAL STRESSORS ON ADOLESCENT AND CAREGIVER HEALTH. DOSE EFFECTS AND INTERVENTION COST-EFFECTIVENESS WILL ALSO BE EVALUATED. IF SUCCESSFUL, THE INTERVENTION HAS THE POTENTIAL TO IMPROVE HEALTH OUTCOMES IN A VULNERABLE POPULATION OF YOUTH AND THEIR FAMILY MEMBERS.

UNIVERSITY CENTERS FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES EDUCATION, RESEARCH, AND SERVICE

FIDELITY AND OUTCOMES OF NATIONAL IMPLEMENTATION OF FOYC+CIMPACT IN THE BAHAMAS

NICHD COOPERATIVE MULTICENTER NEONATAL RESEARCH NETWORK

CLINICAL TRANSLATION OF NUCLEAR EXPORT INHIBITOR IN METASTATIC PANCREATIC CANCER

INTRAFLAGELLAR TRANSPORT (IFT) AND SPERM FORMATION - SUMMARY INTRAFLAGELLAR TRANSPORT (IFT) IS AN EVOLUTIONARILY CONSERVED MECHANISM FOR CILIA FORMATION. DEFECTS IN IFT/CILIA HAVE BEEN LINKED TO CILIA-RELATED DISEASES. ALTHOUGH THE ROLES OF IFT IN SOMATIC TISSUES HAVE BEEN EXTENSIVELY STUDIED, LITTLE IS KNOWN ABOUT ITS ROLE IN SPERM FLAGELLA FORMATION, WHICH ARE SPECIALIZED MOTILE CILIA WITH ACCESSORY STRUCTURES. USING CONDITIONAL KNOCKOUT (CKO) STRATEGIES, OUR LABORATORY ANALYZED MALE GERM CELL- SPECIFIC IFT MUTANT MICE AND DISCOVERED THAT ALL THE ANALYZED IFTS ARE REQUIRED FOR NORMAL SPERM FORMATION/FUNCTION. AMONG THE IFT GENES, IFT25 AND IFT27 HOLD PARTICULAR INTEREST. THE TWO IFTS FORM A HETERODIMER THROUGH THEIR UNIQUE CHARACTERIZED STRUCTURES. ALTHOUGH THESE TWO GENES ARE NOT REQUIRED FOR CILIA ASSEMBLY IN SOMATIC CELLS, BOTH ARE ESSENTIAL FOR SPERM FORMATION AND FUNCTION. SPECIFIC ELIMINATION OF EACH OF THESE GENES IN MALE GERM CELLS RESULTED IN ALMOST IDENTICAL STERILE PHENOTYPES. SPERM FROM THESE MICE WERE IMMOTILE AND HAD DISORGANIZED ACCESSORY STRUCTURES, ESPECIALLY THE FIBROUS SHEATH. LEVELS OF TESTICULAR PRO- AKAP4, THE PRECURSOR PROTEIN OF AKAP4, AN A-KINASE ANCHOR PROTEIN (AKAP) AND SIGNIFICANT COMPONENT OF THE SPERM FIBROUS SHEATH, WERE INCREASED; ON THE CONTRARY, THE MATURE AKAP4 WAS SIGNIFICANTLY REDUCED IN BOTH IFT25 AND IFT27 CKO MICE. IFT25 ASSOCIATES WITH DYNACTIN 4 (DCTN4), A DYNEIN-ASSOCIATED PROTEIN. IN ADDITION TO IFT25, IFT27 ALSO ASSOCIATES WITH SIGNAL PEPTIDE PEPTIDASES LIKE 2A (SPPL2A), WHICH FUNCTIONS AS A PROTEASE AND IS PRESENT IN DEVELOPING SPERM FLAGELLA. THE FORMATION OF MATURE AKAP4 WAS ALSO AFFECTED IN THE SPPL2A KO MICE. BASED ON THESE OBSERVATIONS, WE PROPOSE THE FOLLOWING CENTRAL HYPOTHESES: 1 ) IFT25 AND IFT27 ARE DEDICATED TO THE MOVEMENT AND PLACEMENT OF ACCESSORY STRUCTURE COMPONENTS CRITICAL FOR FUNCTIONAL SPERM, AND 2) THE IFT25/IFT27 COMPLEX USE SPECIFIC DOMAINS TO FORM IFT COMPLEX PARTICLES FOR SPERM FLAGELLA ASSEMBLING. TO TEST THESE HYPOTHESES, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: 1. TO CHARACTERIZE THE IFT25/IFT27 COMPLEX COMPONENTS IN THE TESTIS ESSENTIAL FOR NORMAL SPERM MORPHOGENESIS, PARTICULARLY THE FORMATION OF ACCESSORY STRUCTURES; 2. TO INVESTIGATE SPERM ACCESSORY STRUCTURE DEFECTS OF IFT25 CKO MICE DYNAMICALLY AND DEVELOP AN IN VIVO SYSTEM TO TRACK THE IFT25 COMPLEX TRAFFICKING IN LIVE GERM CELLS FOR SPERM FLAGELLA ASSEMBLY; AND 3. TO EXPLORE FUNCTIONAL CONSEQUENCES OF IFT25/27 DISRUPTION IN SPERM SIGNALING. WE PROPOSE THAT THE IFT25/IFT27 HETERODIMER FORMS A TRANSPORTING COMPLEX CONTAINING SPPL2A AND DCTN4 THROUGH SPECIFIC DOMAINS IN MALE GERM CELLS FOR NORMAL SPERM ACCESSORY STRUCTURE ASSEMBLY; WE EXPECT DEFECTS IN ACCESSORY STRUCTURES IN THE IFT25 CKO MICE WILL OCCUR AT SPECIFIC DEVELOPMENTAL STEPS. THE DYNAMIC TRAFFICKING PROCESS OF THE IFT25 COMPLEX IN LIVE MALE GERM CELLS CAN BE TRACKED. WE HYPOTHESIZE THAT SPPL2A IS INVOLVED IN PROCESSING PRO-AKAP4 TO MATURE INTO AKAP4, RESULTING IN NORMAL PKA SIGNALING IN MATURE SPERM. THE PROPOSED RESEARCH WILL ELUCIDATE THE MECHANISMS OF THE TWO IFT PROTEINS IN THE FORMATION OF FUNCTIONAL SPERM AND BUILD A PLATFORM TO STUDY THE ROLES OF OTHER IFT COMPONENTS IN MALE AND FEMALE REPRODUCTION. .

INTERACTION BETWEEN GENOME AND HEAVY METALS IN NONALCOHOLIC FATTY LIVER DISEASE - ABSTRACT THE ULTIMATE GOAL OF THIS PROJECT IS TO DISCOVER AND VALIDATE THE GENE HEAVY METAL (GXM) INTERACTIONS IN HUMAN LIVERS AND TO UNDERSTAND THEIR ROLE IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD). NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE AFFECTING OVER 30% OF THE U.S POPULATION, RESULTING IN A HEAVY SOCIAL BURDEN. NAFLD IS CHARACTERIZED BY A SPECTRUM OF HISTOLOGICAL CHANGES WITH MULTIPLE CELLS INVOLVED. CURRENTLY, NO APPROVED DRUG TREATMENT IS AVAILABLE FOR NAFLD. THEREFORE, IT IS AN URGENT NEED TO IDENTIFY BOTH GENETIC AND ENVIRONMENTAL RISK FACTORS TO FACILITATE THE DEVELOPMENT OF NEW DIAGNOSTIC, PREVENTIVE, AND THERAPEUTIC STRATEGIES. NAFLD IS A TYPICAL COMPLEX DISEASE INVOLVING GENE-ENVIRONMENT (GXE) INTERACTIONS. OVER THE PAST DECADE, WHILE GWAS FOR NAFLD HAVE IDENTIFIED NUMEROUS GENETIC RISK ALLELES, A GROWING BODY OF RESEARCH HAS DEMONSTRATED THAT EXPOSURE TO HEAVY METALS (PB, CD, HG, AS, ETC.) ARE ASSOCIATED WITH INCREASED NAFLD RISK. HOWEVER, THERE IS NO COMPELLING STUDY THUS FAR TO ASSESS THE CORRELATION BETWEEN VARIOUS NATURALLY ACCUMULATED METALS IN HUMAN LIVERS AND THE NAFLD HISTOLOGY, ESPECIALLY IN CLINICALLY DEFINED PATIENT COHORTS. MORE IMPORTANTLY, THERE LACKS CRITICAL KNOWLEDGE ABOUT HOW NATURALLY AND CHRONICALLY ACCUMULATED METALS INTERACT WITH THE LIVER GENOME AND TOGETHER CONFER RISKS FOR NAFLD. OUR PRELIMINARY STUDIES IN HUMAN LIVER TISSUES HAVE SUCCESSFULLY DEMONSTRATED THAT MULTIPLE METALS ARE INDEED CORRELATED WITH NAFLD. BY LEVERAGING OUR PREVIOUSLY COLLECTED MULTI-OMICS DATA, WE HAVE PRELIMINARILY IDENTIFIED NUMEROUS METAL-RESPONSE GENES (MR-GENES), EXPRESSION QUANTITATIVE TRAITS LOCI (EQTLS), AND ALLELE-SPECIFIC EXPRESSION LOCI (ASES), WHICH ARE FURTHER ENRICHED TO NAFLD AND ITS RELATED PATHWAYS. WE AIM IN THIS STUDY TO FURTHER EXPAND OUR STUDY TO A LARGE-SCALE, HIGHLY DETAILED, AND INTEGRATED ANALYSIS TO THOROUGHLY UNDERSTAND THE ROLE OF GXM INTERACTIONS IN NAFLD IN HUMANS. TO THIS END, OUR TEAM HAS BEEN COLLABORATING TO ESTABLISH COLLECTIONS FOR HUMAN LIVER TISSUE, CELLS AND NAFLD PATIENT COHORTS. WE HAVE ALSO DEVELOPED VARIOUS TECHNICAL PLATFORMS E.G. BULK/SINGLE CELL (SC) RNASEQ AND ATAC-SEQ, AS WELL AS MULTIPLE BIOINFORMATICS AND STATISTICAL TOOLS FOR GXE DATA ANALYSES. WITH THESE PREPARATIONS, WE SPECIFICALLY AIM: 1) TO PROFILE HEAVY METALS IN FROZEN HUMAN LIVER TISSUES (N=560), IDENTIFY MR-GENES, EQTLS/ASES, AND TEST THEIR ASSOCIATIONS WITH NAFLD; 2) TO TREAT THE PRIMARY LIVER CELL POPULATIONS WITH VARIOUS METALS AND TO ELUCIDATE HOW THE GENOME OF DIFFERENT LIVER CELLS RESPOND TO METALS WITH SC-RNASEQ AND ATAC-SEQ, AND 3) TO VALIDATE THE ASSOCIATION BETWEEN GXM INTERACTIONS AND NAFLD HISTOLOGY SEVERITY IN A LARGE CLINICALLY DEFINED NAFLD PATIENT COHORT (N=1313). OUR STUDY WILL FOR THE FIRST TIME EVALUATE THE ROLE AND MECHANISM OF GXM INTERACTIONS IN NAFLD AND WILL PROVIDE THE SCIENTIFIC COMMUNITY IMPORTANT DATA TO OPEN NEW AVENUES TO NAFLD RESEARCH, DRUG DISCOVERY, AND BEYOND.

IMPACT OF RACISM ON RISK OF PRETERM BIRTH IN BLACK WOMEN

EDUCATIONAL OPPORTUNITY CENTERS PROGRAM

COCAINE-BINDING DOPAMINE TRANSPORTER: MOLECULAR BIOLOGY

MOLECULAR AND CELLULAR ANALYSIS OF THE ABHD5/PNPLA3 METABOLON IN LIPID HOMEOSTASIS - PROJECT SUMMARY/ABSTRACT THE BALANCE BETWEEN TRIACYLGLYCEROL (TAG) STORAGE AND MOBILIZATION IN ADIPOSE TISSUE AND LIVER IS CRITICAL TO METABOLIC HEALTH AS THE DYSREGULATION DURING OBESITY CAN PRODUCE ECTOPIC ACCUMULATION OF LIPIDS IN MUSCLE AND LIVER, RESULTING IN THE PROGRESSION TO DIABETES AND FATTY LIVER DISEASE (FLD). THUS, AN IMPORTANT LONG-TERM SCIENTIFIC GOAL IS TO UNDERSTAND THE TISSUE-SPECIFIC MOLECULAR MECHANISMS THAT CONTROL TAG METABOLISM IN ORDER TO DISCOVER NOVEL THERAPIES. PATATIN-LIKE PHOSPHOLIPASE DOMAIN CONTAINING 3 (PNPLA3) IS A PROTEIN THAT IS HIGHLY EXPRESSED IN LIPOGENIC TISSUES, LIKE FAT AND LIVER, AND IS HIGHLY UPREGULATED UNDER CONDITIONS THAT PROMOTE FAT STORAGE. IMPORTANTLY, A COMMON GENETIC VARIANT OF PNPLA3, I148M, IS THE GREATEST KNOWN RISK FACTOR FOR DEVELOPING FLD AND ITS PATHOLOGICAL SEQUELAE. IN RECENTLY PUBLISHED AND PRELIMINARY DATA, WE DEMONSTRATE THAT A/SS HYDROLASE DOMAIN CONTAINING PROTEIN 5 (ABHD5), AN ENZYME CO-ACTIVATOR, STRONGLY INTERACTS WITH PNPLA3 AND THE DISEASE-CAUSING I148M VARIANT IS A GAIN-OF-FUNCTION. FURTHERMORE, THE INTERACTION BETWEEN PNPLA3 I148M AND ABHD5 IS PARTICULARLY EFFECTIVE IN PROMOTING CELLULAR TAG RETENTION, WHICH LIKELY PLAYS A CENTRAL ROLE IN DISEASE PROGRESSION. IMPORTANTLY, THE ABHD5/PNPLA3 INTERACTION CAN BE DYNAMICALLY REGULATED BY ENDOGENOUS FATTY ACIDS AND SYNTHETIC ABHD5 LIGANDS. THIS WORK WILL EXAMINE THE BASIC MECHANISM OF HOW ABHD5 REGULATES THE FUNCTION OF PNPLA3 AND THE I148M VARIANT IN ADIPOCYTES AND HEPATOCYTES USING HIGH RESOLUTION IMAGING TECHNIQUES, PROXIMITY PROTEOMICS AND METABOLIC TRACERS/LIPIDOMICS IN CONJUNCTION WITH ROBUST GENETIC MODELS AND AN INTEGRATIVE PANEL OF ENDOGENOUS FATTY ACID LIGANDS AND CHEMICAL PROBES. OUR SPECIFIC AIMS ARE: 1) TO DETERMINE THE MOLECULAR BASIS FOR THE INTERACTION OF ABHD5 WITH WT PNPLA3 AND I148M AND THE SUBCELLULAR LOCATION AND DYNAMIC TRAFFICKING OF ABHD5 COMPLEXES IN ADIPOCYTES AND HEPATOCYTES USING HIGH RESOLUTION FLUORESCENCE AND TRANSMISSION ELECTRON MICROSCOPY. 2) TO DETERMINE THE LOCATION AND LIGAND-DEPENDENT PROTEIN COMPOSITION OF THE ABHD5/PNPLA3 AND ABHD5/ PNPLA3 I148M METABOLONS USING NONBIASED PROXIMITY PROTEOMICS AND DIRECTED IMMUNOPRECIPITATION. 3) TO DISSECT THE METABOLIC FUNCTION OF THE ABHD5/PNPLA3 AND ABHD5/PNPLA3 I148M METABOLONS IN ADIPOCYTES AND HEPATOCYTES USING GAIN- AND LOSS- OF-FUNCTION GENETICS AND SELECTIVE ENDOGENOUS AND SYNTHETIC ABHD5 LIGANDS IN CONJUNCTION WITH ISOTOPE TRACERS AND LIPIDOMICS. THESE GOALS, WHICH ARE WELL ALIGNED WITH THE MISSION OF THE NIH WILL BE IMPLEMENTED WITHIN A DISCOVERY PLATFORM THAT MAXIMIZES INTEGRATION ACROSS LEVEL OF ANALYSIS (MOLECULAR, ORGANELLE, CELLS AND TISSUES) TO PROVIDE A ROBUST ANALYSIS OF ABHD5/PNPLA3 FUNCTION, THEREBY IMPROVING OUR UNDERSTANDING OF HOW LIPIDS LEVELS ARE REGULATED AND IDENTIFY NOVEL POINTS FOR THERAPEUTIC INTERVENTION IN OBESITY RELATED DISORDERS.

MICHIGAN SIREN COLLABORATIVE

SMALL RNA AND WHOLE CHROMOSOME RECOGNITION IN DROSOPHILA MELANOGASTER.

LIFE, DEATH, AND FUNCTION: THE PRIMATE-SPECIFIC LONG NON-CODING RNA TRANSCRIPTOME

VETERANS UPWARD BOUND PROGRAM

COLLABORATIVE PEDIATRIC CRITICAL CARE RESEARCH NETWORK

DISCOVERY OF NOVEL PCFT-TARGETED AGENTS

MECHANISMS OF ARRHYTHMIA SUSCEPTIBILITY IN SPINAL CORD INJURED RATS

REGULATION OF VISCEROSENSORY SYMPATHETIC REFLEXES: THE ROLE OF DIET-DERIVED LIPID MEDIATORS.

SI2-SSI: COLLABORATIVE RESEARCH: JET ENERGY-LOSS TOMOGRAPHY WITH A STATISTICALLY AND COMPUTATIONALLY ADVANCED PROGRAM ENVELOPE (JETSCAPE)

REDUCING STRESS IN ADOLESCENTS AND YOUNG ADULTS WITH T1D TO IMPROVE DIABETES CARE

UNDERSTANDING THE CONNECTION BETWEEN EXPOSURE TO MERCURY, AUTO-IMMUNITY AND TOLERANCE IN B CELLS.

EXERCISE FACILITATION OF ADOLESCENT FEAR EXTINCTION, FRONTOLIMBIC CIRCUITRY, AND ENDOCANNABINOIDS - ANXIETY AFFECTS NEARLY ONE IN THREE ADOLESCENTS AND CONTRIBUTES TO SUBSTANTIAL BURDEN ON BOTH INDIVIDUALS AND SOCIETY. ALTHOUGH EVIDENCE-BASED INTERVENTIONS FOR ADOLESCENT ANXIETY EXIST, TREATMENT RESPONSE IS MODEST AND RELAPSE RATES ARE UNACCEPTABLY HIGH. OUTCOMES ARE EVEN WORSE AMONG LOW RESOURCE AND RACIAL/ETHNIC MINORITY POPULATIONS. RECENT STUDIES HAVE PINPOINTED NEURODEVELOPMENTALLY-INFORMED TARGETS THAT ARE RELEVANT TO CURRENT EVIDENCE-BASED TREATMENTS FOR ADOLESCENT ANXIETY; NAMELY, EXPOSURE-BASED COGNITIVE BEHAVIORAL THERAPY (CBT), WHICH RELIES ON PRINCIPLES OF FEAR EXTINCTION. OUR GROUP AND OTHERS HAVE SHOWN THAT FEAR EXTINCTION AND FRONTOLIMBIC CIRCUITRY CHANGE DYNAMICALLY ACROSS THE FIRST TWO DECADES OF LIFE, AND IS MODULATED BY THE ENDOCANNABINOID (ECB) SYSTEM. FURTHER, OUR EXCITING PRELIMINARY DATA SHOW THAT ACUTE EXERCISE IS ASSOCIATED WITH LOWER ANXIETY AND ELEVATED ECB SIGNALING IN YOUTH, AND IS THEREFORE A PROMISING APPROACH FOR OPTIMIZING EFFICACIOUS TREATMENTS FOR ADOLESCENT ANXIETY. HOWEVER, THESE ADVANCES HAVE NOT YET TRANSLATED TO IMPROVED THERAPEUTIC OUTCOMES FOR YOUTH. THE PROPOSED PROJECT WILL LEVERAGE A MULTI-MODAL EXPERIMENTAL THERAPEUTICS APPROACH TO TEST WHETHER ACUTE EXERCISE MODIFIES HYPOTHESIZED TARGETS THAT ARE RELEVANT FOR THE PATHOPHYSIOLOGY AND TREATMENT OF ANXIETY IN YOUTH. ONE HUNDRED AND TWENTY ADOLESCENTS WILL BE RECRUITED FROM A DIVERSE POPULATION AT ELEVATED RISK OF ANXIETY AND RANDOMIZED INTO EITHER AN ACUTE MODERATE-INTENSITY AEROBIC EXERCISE OR SEDENTARY CONTROL CONDITION, PERFORMED IMMEDIATELY AFTER A FEAR EXTINCTION PARADIGM (I.E., DURING THE MEMORY CONSOLIDATION PHASE). OUR HYPOTHESIS IS THAT ACUTE EXERCISE WILL BOOST ECB SIGNALING, WHICH WILL RESULT IN INCREASED FEAR EXTINCTION RECALL AND ENHANCED FRONTOLIMBIC ACTIVATION AND COUPLING. CONCURRENT NEUROIMAGING, PSYCHOPHYSIOLOGICAL RECORDINGS, SELF-REPORTED FEAR AND ANXIETY, AND CIRCULATING BIOMARKERS WILL ALLOW US TO EVALUATE TARGET ENGAGEMENT AT SEVERAL LEVELS; SPECIFICALLY, WE WILL TEST FEAR EXTINCTION, FRONTOLIMBIC CIRCUITRY, AND ECB SIGNALING AS TARGETS FOR EXERCISE’S EFFECTS ON FEAR EXTINCTION AND ANXIETY RISK. THIS PROJECT IS IDEALLY SUITED FOR THE NIMH BRAINS AWARD BECAUSE IT WILL SUPPORT THE DEVELOPMENT OF A PRODUCTIVE EARLY-STAGE INVESTIGATOR IN INNOVATIVE, HIGH-IMPACT RESEARCH. RESULTS OF THE PROPOSED PROJECT WILL DEMONSTRATE THAT A RELATIVELY LOW COST AND LOW RISK (COMPARED TO PHARMACOTHERAPY, FOR EXAMPLE) BEHAVIORAL INTERVENTION MAY BE USED ALONE OR IN CONJUNCTION WITH CURRENT TREATMENTS TO IMPROVE OUTCOMES FOR YOUTH. THIS SIGNIFICANT AND TIMELY STUDY IS AN ESSENTIAL FIRST STEP IN A CONTINUUM OF RESEARCH THAT WILL ULTIMATELY LEAD TO EFFICACIOUS TREATMENTS FOR ADOLESCENT ANXIETY, AND NOVEL PREVENTIVE INTERVENTIONS FOR AT-RISK YOUTH. THIS WORK WILL ALSO FURTHER OUR UNDERSTANDING OF HOW FEAR IS ACQUIRED AND REGULATED IN THE ADOLESCENT BRAIN. THESE OUTCOMES ARE HIGHLY ALIGNED WITH THE NIMH GOALS OF DELINEATING BRAIN MECHANISMS (GOAL 1), UNDERSTANDING RISK FACTORS AND BIOMARKERS OF ILLNESS AND TREATMENT RESPONSE (GOAL 2), IMPROVING PREVENTION (GOAL 3), AND STRENGTHENING THE PUBLIC HEALTH IMPACT (GOAL 4), GIVEN OUR GROUP’S TIES TO MENTAL HEALTH PROVIDERS AND SCHOOL PROGRAMS.

REGULATION OF NKCC2 AND RENAL NACL TRANSPORT BY PROTEIN-PROTEIN INTERACTIONS - ABSTRACT IN THE KIDNEY, THE THICK ASCENDING LIMB (TAL) OF THE LOOP OF HENLE IS CRITICAL FOR NACL HOMEOSTASIS AND BLOOD PRESSURE REGULATION. IN HUMANS AND ANIMAL MODELS OF SALT-SENSITIVE HYPERTENSION, NACL ABSORPTION IS ABNORMALLY INCREASED IN THE TAL, WHERE NACL ABSORPTION DEPENDS ON THE RENAL TRANSPORTER NKCC2, AN APICAL NA+/K+/2CL- CO-TRANSPORTER. WE SHOWED THAT THE PRESENCE OF NKCC2 AT THE TAL APICAL MEMBRANE CONTROLS NACL ABSORPTION IN THIS EPITHELIUM. THE MOLECULAR MECHANISMS THAT CONTROL APICAL MEMBRANE NKCC2 LEVELS INVOLVE ENDOCYTOSIS, RECYCLING AND EXOCYTIC INSERTION. INHIBITION OF ENDOCYTIC RETRIEVAL CAUSES NKCC2 ACCUMULATION AT THE MEMBRANE AND INCREASED NACL ABSORPTION. ANY GENE OR PROTEIN AFFECTING NKCC2 ENDOCYTOSIS COULD POTENTIALLY INFLUENCE NKCC2 ACTIVITY AND RENAL SALT TRANSPORT BUT ONLY FEW PROTEINS ARE KNOWN TO BIND NKCC2. USING A TARGETED PROTEOMICS SCREEN, WE IDENTIFIED ALMS1 (ALSTRÖM SYNDROME 1) AND ACTN4 (ALPHA-ACTININ 4) AS INTERACTING PARTNERS OF NKCC2. WE ALSO FOUND THAT ALMS1 AND ACTN4 INTERACT WITH EACH OTHER, RAISING THE POSSIBILITY THAT THESE PROTEINS FORM A COMPLEX. SINGLE NUCLEOTIDE POLYMORPHISMS IN ALMS1 AND ACTN4 ARE ASSOCIATED WITH HYPERTENSION AND DECREASED KIDNEY FUNCTION. WE FOUND THAT ALMS1 KNOCKOUT RATS HAVE HIGHER SURFACE NKCC2 AND HIGH BLOOD PRESSURE. WE FOUND THAT ACTN4, A PROTEIN INVOLVED IN PODOCYTE BIOLOGY, IS ALSO EXPRESSED THROUGHOUT THE NEPHRON, INCLUDING THE TAL. THE ROLES OF ALMS1 AND ACTN4 IN RENAL NACL HANDLING BY THE TAL AND THEIR ROLE IN BLOOD PRESSURE REGULATION ARE UNKNOWN. WE HYPOTHESIZE THAT ALMS1 CONTROLS SURFACE NKCC2 LEVELS AND NKCC2-MEDIATED NACL ABSORPTION BY BINDING THE CARBOXYL-TERMINUS OF NKCC2 AND ACTN4 TO MEDIATE NKCC2 ENDOCYTOSIS FROM THE APICAL MEMBRANE. A DECREASE IN ALMS1 OR ACTN4 EXPRESSION IN THE TAL INCREASES SURFACE NKCC2, NKCC2-MEDIATED NACL REABSORPTION, TUBULO-GLOMERULAR FEEDBACK (TGF) SENSITIVITY AND LEADS TO SALT-SENSITIVE HYPERTENSION. OUR LONG-TERM GOAL IS TO INCREASE OUR UNDERSTANDING OF THE ROLE OF ALMS1 AND ACTN4 IN KIDNEY NACL TRANSPORT.

OPPOSING EFFECTS OF PROSTAGLANDIN E2 EP3 AND EP4 RECEPTORS ON MITOCHONDRIAL FUNCTION IN THE FAILING HEART

MALE PRECONCEPTION PHTHALATES AND OFFSPRING EMBRYO AND SPERM ALLELE-SPECIFIC METHYLOME PROGRAMMING

NEUROLOGICAL EMERGENCIES TREATMENT TRIALS (NETT) NETWORK

ENHANCING NEOADJUVANT CHEMOTHERPAY RESPONSES WITH TARGETED T CELLS

REGULATION OF RHYTHMIC M6A RNA MODIFICATION BY ER?ASSOCIATED DEGRADATION - ENDOPLASMIC RETICULUM (ER)-ASSOCIATED DEGRADATION (ERAD) IS A MAJOR ER QUALITY-CONTROL PROGRAM THAT MONITORS AND TRANSLOCATES UNFOLDED OR MISFOLDED PROTEIN SUBSTRATES FROM THE ER TO CYTOSOL FOR POLYUBIQUITINATION AND PROTEASOMAL DEGRADATION. N6-METHYLADENOSINE (M6A) METHYLATION, THE MOST PREVALENT INTERNAL MODIFICATION OF MAMMALIAN MRNAS, IS KNOWN TO REGULATE THE STABILITY, TRANSLATION, AND FUNCTION OF ALMOST EVERY MAJOR CLASS OF HUMAN RNAS. THREE MAJOR FAMILIES OF PROTEINS, INCLUDING WRITERS, READERS, AND ERASERS, ARE KNOWN TO BE RESPONSIBLE FOR THE REVERSIBLE RNA M6A METHYLATION PROCESS. HOWEVER, THE SIGNAL TRANSDUCTION PATHWAY UNDERLYING THE REGULATION OF RNA M6A MODIFICATION REMAIN ELUSIVE. HEREIN, WE ACCUMULATED STRONG PRELIMINARY EVIDENCE FOR AN UNPRECEDENTED CIRCADIAN-REGULATED ERAD PATHWAY THAT CONTROLS MRNA M6A MODIFICATION AND SUBSEQUENT LIPID HOMEOSTASIS, WHICH WE CALLED “CIRCADIAN ERAD-M6A”. OUR MAJOR PRELIMINARY FINDINGS INCLUDE: (I) THE ER-RESIDENT E3 UBIQUITIN LIGASE HRD1 AND ITS CO-FACTOR SEL1L, THE MAJOR COMPONENTS OF ERAD MACHINERY, ARE REGULATED BY THE CIRCADIAN CLOCK IN THE LIVER; (II) HRD1 INTERACTS WITH AND MEDIATES POLYUBIQUITINATION AND DEGRADATION OF THE SPECIFIC M6A WRITER METTL14 AND THE READER YTHDF3; (III) HRD1 LIVER-SPECIFIC KO (LKO) MICE DISPLAY REVERSED FASHIONS WITH METTL14-LKO OR YTHDF3-KNOCKDOWN MICE IN HEPATIC M6A MRNA METHYLATION LEVELS, EXPRESSION OF LIPID METABOLIC REGULATORS, AND METABOLIC PHENOTYPES ASSOCIATED WITH HEPATIC STEATOSIS AND HYPERLIPIDEMIA; AND (IV) UNLIKE THE CLASSIC ERAD, THE NEWLY-IDENTIFIED ERAD-M6A REGULATORY AXIS AND ITS FUNCTION IN HEPATIC LIPID METABOLISM ARE UNDER THE CONTROL OF CIRCADIAN RHYTHM. THESE OBSERVATIONS LED TO OUR CENTRAL HYPOTHESIS THAT THE LIVER HRD1-ERAD PROGRAM, WHICH IS OSCILLATED UNDER THE CIRCADIAN CLOCK, REGULATES HEPATIC M6A RNA MODIFICATION BY CONTROLLING RHYTHMIC DEGRADATION OF THE SPECIFIC M6A WRITER METTL14 AND THE READER YTHDF3. THIS UNPRECEDENTED CIRCADIAN ERAD-M6A RNA MODIFICATION REGULATORY NETWORK, WHICH MAY BE DYSREGULATED BY CIRCADIAN-DISRUPTING CUES, REPRESENTS A MAJOR PATHWAY THAT CONTROLS METABOLIC HOMEOSTASIS ASSOCIATED WITH HEPATIC STEATOSIS AND HYPERLIPIDEMIA. IN THIS APPLICATION, WE WILL UTILIZE MOLECULAR AND CELLULAR APPROACHES, GENETICALLY ENGINEERED ANIMAL MODELS, AND HIGH-THROUGHPUT PROFILING OF M6A RNA MODIFICATION TO CRITICALLY ADDRESS THE FUNCTION AND MECHANISM BY WHICH CIRCADIAN ERAD REGULATES HEPATIC M6A RNA MODIFICATION AND LIPID METABOLISM. IN TWO AIMS, WE WILL: 1) DEFINE A NOVEL CIRCADIAN ERAD PATHWAY THAT MODULATES RHYTHMIC M6A RNA MODIFICATION THROUGH DEGRADING THE SPECIFIC M6A WRITER AND READER; AND 2) DETERMINE THE FUNCTIONAL SIGNIFICANCE OF CIRCADIAN ERAD-M6A RNA MODIFICATION PATHWAY IN MAINTAINING LIPID HOMEOSTASIS. UPON COMPLETION OF THIS PROJECT, WE WILL REVEAL THE FUNCTION AND MECHANISM BY WHICH A NOVEL CIRCADIAN ERAD-M6A RNA MODIFICATION PATHWAY REGULATES LIPID HOMEOSTASIS ASSOCIATED WITH METABOLIC DISORDERS. THE FINDINGS WILL OPEN UP NEW PARADIGMS FOR THE STUDIES ON THE PHYSIOLOGICAL ERAD AND M6A RNA MODIFICATION AND SHED NEW LIGHT ON DEVELOPING THERAPEUTICS FOR METABOLIC DISEASE.

MECHANISMS MEDIATING ENHANCED SYMPATHO-ACTIVATION DURING EXERCISE IN HYPERTENSION

QTL AND MICROARRAY MAPPING LEAD SENSITIVITY GENES

SPATIOTEMPORAL TOOLS TO INTERROGATE O-GLCNAC FUNCTIONS IN CELLULAR SIGNALING - ABSTRACT THE OVERALL GOAL OF THE FEHL LABORATORY IS TO DEVELOP CHEMICAL BIOLOGY STRATEGIES TO DETERMINE THE FUNCTIONAL IMPACT OF PROTEIN MODIFICATIONS DURING SIGNALING PROCESSES. SPECIFICALLY, CELLULAR METABOLISM AND STRESS EACH LEAD TO DIVERSE PROTEIN MODIFICATIONS WITH O-LINKED N-ACETYLGLUCOSAMINE SUGAR (O-GLCNAC) BUT NO TOOLS ARE CURRENTLY ABLE TO CAPTURE HIGHLY DYNAMIC AND TRANSIENT O-GLCNAC EVENTS WITH DEFINED TIME AND SPATIAL RESOLUTION. LACK OF “TIME AND SPACE” RIGOR HINDERS THE SCIENTIFIC COMMUNITY FROM CONNECTING METABOLISM WITH DISEASE PHYSIOLOGY, INCLUDING SIGNIFICANTLY ELEVATED CANCER RISK IN DIABETIC PATIENTS OBSERVED FOR MALIGNANCIES LIKE BREAST CANCER. IN THIS MIRA APPLICATION, WE POSE OUR STRATEGIES TO ADDRESS THIS CRITICAL GAP THROUGH THE DEVELOPMENT OF REAL-TIME AND SPACE MOLECULAR TOOLS THAT BRIDGE CELL METABOLISM AND CANCER PROCESSES USING O-GLCNAC AS THE KEYSTONE. EXCELLENT NIH-FUNDED RESEARCH HAS DISCOVERED OVER 2000 O-GLCNAC ON PROTEINS IN HUMAN CELLS, BUT CURRENT TOOLS RELY ON DISRUPTED PHYSIOLOGY, LEADING TO ARTIFACTS, OR MISS KEY GLCNAC-DRIVEN SIGNALING EVENTS THAT OCCUR BEFORE GLOBAL METABOLIC REBALANCING OCCURS IN LESS THAN AN HOUR. WE HYPOTHESIZE THAT THE KEY DRIVERS OF HYPERGLYCEMIC METABOLISM AND PATHOLOGY LIE WITHIN THE FIRST FEW MINUTES OF NUTRIENT AND SIGNALING STIMULATION, WHICH TO DATE IS NOT POSSIBLE TO OBSERVE IN LIVING CELLS. OUR PUBLISHED WORK IN PHOTOCHEMISTRY AND SYSTEMS GLYCOBIOLOGY SUPPORT OUR UNIQUE STRATEGIES TO TRIGGER O-GLCNAC PROCESSES IN MINUTES, BEFORE O-GLCNAC REBALANCING OCCURS. OUR PHOTOCAGED SUGAR TOOL IS ABLE TO TRIGGER THE ONCOGENIC TRANSCRIPTION FACTOR NFKB MOVEMENT BETWEEN CYTOSOL OR ENDOPLASMIC RETICULUM INTO THE NUCLEUS, SIMULATING PHYSIOLOGICAL EVENTS THAT POTENTIALLY LINK ABERRANT INSULIN AND GLUCOSE RELEASE IN DIABETES WITH BREAST CANCER RISK. OUR REAL TIME SYSTEM CAN BE USED TO TRACK O-GLCNAC EVENTS DURING INSULIN SIGNALING FOR THE FIRST TIME DURING THE RAPID, 15-MINUTE PULSES OF DISEASED INSULIN PHYSIOLOGY. ANOTHER TOOL FOR TARGETED INTRACELLULAR O-GLCNAC-TARGETED PROXIMITY LABELING IS ABLE TO TRACK O-GLCNACYLATED PROTEINS IN SUBCELLULAR SPACE, WHICH NO REPORTED TOOL HAS THE CAPABILITY TO SPECIFICALLY LABEL IN LIVE CELLS. WE PROPOSE IN THE NEXT 5 YEARS TO DEVELOP OUR “TIME AND SPACE” MOLECULAR TOOLS AND APPLY THEM FOR UNIQUE MECHANISTIC STUDIES IN DISEASE BIOLOGY THROUGH NFKB TARGETING. WE ACTIVELY COLLABORATE WITH METABOLIC DISEASE AND CANCER SPECIALISTS TO ENSURE DISEASE RELEVANCE, AS WELL AS WITH INDUSTRIAL SCIENTISTS FOR TECHNOLOGY DEVELOPMENT TO EXPAND INDUSTRIAL AWARENESS OF O-GLCNAC BIOLOGY IN METABOLISM-DRIVEN DISEASE PATHWAYS. THE RESEARCH OUTPUTS OF THIS PROPOSAL INCLUDE MOLECULAR PROBES, SPATIOTEMPORAL STRATEGIES, AND TARGETS TO CONNECT CELLULAR METABOLISM WITH SIGNALING. OUR ENABLING CHEMICAL STRATEGIES HAVE THE POTENTIAL FOR BROAD IMPACT IN THE SCIENTIFIC COMMUNITY BY ESTABLISHING TEMPORAL AND SPATIAL METHODS TO STUDY PROTEIN MODIFICATIONS. OUR PLATFORMS CAN BE EXTENDED TO OTHER PTMS AND DRUG TARGETS, SUCH AS SIALIC ACID MODIFICATIONS THAT REGULATE THE INTERFACE OF CANCER METABOLISM AND INFLAMMATION. SUCCESS WILL ESTABLISH A LASTING INDEPENDENT RESEARCH NICHE.

ALTERATION WITH AGE OF RESISTANCE TO EYE INFECTIONS

UCEDD-CORE GRANT PROPOSAL

SOUTHEASTERN MICHIGAN TRAUMATIC BRAIN INJURY SYSTEM

INTERPLAY BETWEEN HYPOXIA AND OXIDATIVE PHOSPHORYLATION IN HERPES STROMAL KERATITIS

VENUE-BASED HIV AND ALCOHOL USE RISK REDUCTION AMONG FEMALE SEX WORKERS IN CHINA

NOVEL ACTION OF GRAPE SKIN COMPONENTS ON POSTPRANDIAL HYPERGLYCEMIA

THE REGULATORY ROLES OF NUCLEAR SM22 IN SMOOTH MUSCLE PHENOTYPIC MODULATION

DYNAMIC REGULATION OF MT1-MMP AT THE TUMOR CELL SURFACE AND MALIGNANCY