Institute For Medical Research Inc

WOMEN'S INTERAGENCY HIV STUDY (WIHS) IV, CHICAGO CONSORTIUM

THE NIGMS HUMAN GENETIC CELL REPOSITORY COOPERATIVE AGREEMENT (U42) APPLICATION

MACS/WIHS COMBINED COHORT STUDY: COOK COUNTY CLINICAL RESEARCH SITE (CC_CRS)

EPIGENETIC THERAPIES - NEW APPROACHES - ABSTRACT (OVERALL) EPIGENETICS REFERS TO STABLE GENE EXPRESSION PATTERNS MEDIATED BY DNA METHYLATION AND/OR CHROMATIN REMODELING AND IS INVOLVED IN CELLULAR IDENTITY AND REPRESSION OF SPURIOUS TRANSCRIPTION, INCLUDING FROM REPETITIVE ELEMENTS. OVER THE PAST 20 YEARS, IN WORK LED IN PART BY INVESTIGATORS IN THIS APPLICATION, EPIGENETIC CHANGES WERE RECOGNIZED AS IMPORTANT DRIVERS OF CANCER FORMATION, PROGRESSION AND RESISTANCE TO THERAPY. THIS RECOGNITION, ALONG WITH THE REVERSIBLE NATURE OF THE BIOCHEMICAL MODIFICATIONS REQUIRED FOR EPIGENETICS LED TO THE FIELD OF EPIGENETIC THERAPY, WHICH AIMS TO REPROGRAM GENE EXPRESSION TO ACHIEVE A THERAPEUTIC EFFECT. THIS FIELD, WHICH STARTED WITH DNA METHYLTRANSFERASE (DNMT) INHIBITORS, HAS GROWN TO A DOZEN EPIGENETIC TARGETS AND OVER 30 DRUGS IN CLINICAL TRIALS. FOUR TARGETS HAVE MADE IT TO US-FDA APPROVAL (DNMTS, HISTONE DEACETYLASES (HDACS), EZH2 AND ISOCITRATE DEHYDROGENASES) AND TENS OF THOUSANDS OF CANCER PATIENTS BENEFIT FROM THIS EVERY YEAR. WITH THE IDENTIFICATION OF NEW TARGETS AND THE RECOGNITION THAT EPIGENETICS IS INVOLVED IN SENSITIVITY AND RESISTANCE TO CHEMOTHERAPY AND IMMUNOTHERAPY, THE CLINICAL POTENTIAL OF EPIGENETIC THERAPY HAS BEGUN TO BE EXPLORED IN EARNEST. THERE REMAIN FUNDAMENTAL CHALLENGES, FROM THE LACK OF ROBUST BIOMARKERS OF ACTIVITY, TO THE EMERGENCE OF RESISTANCE, AND TO THE UNEXPLAINED DIVIDE IN RESPONSES BETWEEN HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. THIS SPORE APPLICATION WILL ADDRESS ALL OF THESE CHALLENGES. THE SPORE TEAM CONSISTS OF INVESTIGATORS WHO ARE PIONEERS IN THE FIELDS OF CANCER EPIGENETICS AND EPIGENETIC THERAPY AND EXPLORES NEW EPIGENETIC TARGETS AND COMBINATION STRATEGIES ALONG WITH A ROBUST BIOMARKER ANALYSIS PIPELINE TO IDENTIFY PATIENTS LIKELY TO RESPOND AND PHARMACODYNAMIC MARKERS OF RESPONSE. THE TEAM LEVERAGES A STRONG CLINICAL AND TRANSLATIONAL PIPELINE BUILT THROUGH THE VAN ANDEL INSTITUTE STAND UP TO CANCER EPIGENETICS DREAM TEAM, WHICH HAS CONDUCTED 14 EPIGENETIC THERAPY CLINICAL TRIALS IN THE PAST FEW YEARS, AND IS FULLY COMMITTED TO THE CLINICAL TRIALS PROPOSED IN THIS APPLICATION. THIS EPIGENETIC THERAPY SPORE ENCOMPASSES FOUR MAJOR THEMES: (I) DEVELOP AND TEST DRUGS AGAINST NEW EPIGENETIC TARGETS (PROJECTS 1, 2), (II) MECHANISTIC AND TRANSLATIONAL STUDIES OF IMMUNOSENSITIZATION BY EPIGENETIC THERAPY (PROJECTS 1-3), (III) STUDIES OF DRUG COMBINATIONS THAT ENHANCE THE EFFICACY OF KNOWN EPIGENETIC DRUGS (PROJECTS 1-3); AND (IV) BIOMARKER STUDIES TO DEFINE SENSITIVITY AND RESISTANCE TO EPIGENETIC THERAPY IN THE CLINIC (ALL PROJECTS). THESE THEMES WILL BE ADDRESSED THROUGH 3 PROJECTS: (I) CYCLIN DEPENDENT KINASES AS EPIGENETIC THERAPY TARGETS; (II) EPIGENETIC SYNERGY BETWEEN DNMT AND EZH1/2 INHIBITORS; (III) LINKING EPIGENETIC-THERAPY INDUCTION OF INFLAMMASOME SIGNALING TO GENERATION OF A BRCANESS PHENOTYPE. THESE PROJECTS WILL BE SUPPORTED BY THREE CORES (ADMINISTRATIVE, PATHOLOGY, GENOMICS) AND A KEY GOAL WILL ALSO BE TO MENTOR THE NEXT GENERATION OF EPIGENETIC THERAPY INVESTIGATORS AND SUPPORT CUTTING-EDGE SCIENCE THROUGH THE CAREER ENHANCEMENT AND DEVELOPMENTAL RESEARCH PROGRAMS.

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

REGENERATIVE WOUND HEALING VIA INFLAMMATION-MODULATING BIOMATERIALS

TAS: :97 0130: :CORIELL PERSONALIZED MEDICINE COLLABORATIVE (CPMC) CLINICAL UTILITY STUDY (CUS)".

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

ISOLATION AND CHARACTERIZATION OF INTESTINAL STEM CELLS

H3AFRICA KIDNEY DISEASE RESEARCH NETWORK

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

ENHANCING GLOBAL HEALTH SECURITY: EXPANDING EFFORTS AND STRATEGIES TO PROTECT AND IMPROVE PUBLIC HEALTH GLOBALLY

RYAN WHITE TITLE IV PROGRAM

NATIONAL CENTER ON DOMESTIC VIOLENCE, TRAUMA & MENTAL HEALTH

NHGRI SAMPLE REPOSITORY FOR HUMAN GENETIC RESEARCH - PROJECT SUMMARY SPONSORED BY THE NHGRI AND ESTABLISHED AT THE CORIELL INSTITUTE IN 2006, THE NHGRI SAMPLE REPOSITORY FOR HUMAN GENETIC RESEARCH PROVIDES A PUBLICALLY ACCESSIBLE, AND CENTRALIZED RESOURCE OF WELL-CHARACTERIZED BIOSPECIMENS FROM A WIDE RANGE OF GLOBAL HUMAN POPULATIONS, INCLUDING THE 1000 GENOMES PROJECT COLLECTION, FOR USE IN BIOMEDICAL RESEARCH. THE OBJECTIVES OF THE NHGRI REPOSITORY ARE TO STIMULATE AND FACILITATE THE STUDY OF HUMAN GENETIC AND GENOMIC VARIATION BY ESTABLISHING, MAINTAINING, AND DISTRIBUTING A REPOSITORY OF HIGH-QUALITY, RENEWABLE, REPRODUCIBLE, WELL-CHARACTERIZED, AND BROADLY CONSENTED CELL LINES AND DNA. THE NHGRI REPOSITORY IS A GLOBAL RESOURCE THAT HAS BEEN USED BY THOUSANDS OF INVESTIGATORS TO SUPPORT COUNTLESS RESEARCH STUDIES. SINCE ITS INCEPTION, OVER TWO HUNDRED THOUSAND CELL LINES, DNA AND RNA SAMPLES HAVE BEEN DISTRIBUTED TO RESEARCHERS IN 50 COUNTRIES AROUND THE WORLD, AND THOUSANDS OF SCIENTIFIC ARTICLES HAVE RESULTED FROM STUDIES USING THESE SAMPLES AND ASSOCIATED DATA. PROPOSED NHGRI REPOSITORY ACTIVITIES INCLUDE: (1) MAINTAINING INVENTORY AND DISTRIBUTING NHGRI REPOSITORY CELL LINES AND DNA SAMPLES FOR THE EXISTING REPOSITORY COLLECTION, (2) DISTRIBUTING CUSTOM PREPARATIONS AND LOTS OF DNA, HIGH MOLECULAR WEIGHT (HMW) DNA, RNA, CELL PELLETS, AND CUSTOM PLATES AND PANELS AS REQUESTED BY THE SCIENTIFIC COMMUNITY, (3) EXPANDING THE REPOSITORY TO INCLUDE BIOSPECIMEN SUBMISSIONS FROM THE HUMAN PANGENOME REFERENCE CONSORTIUM AND CREATING A NEW PANEL OF INDUCED PLURIPOTENT STEM CELLS THAT WILL ENCOMPASS A WIDE RANGE OF GENOMIC VARIATION TO MEET THE GROWING NEEDS OF THE RESEARCH COMMUNITY, AND (4) MAINTAINING A COMPREHENSIVE AND SECURE DATABASE AND PUBLIC ONLINE CATALOG FOR NHGRI REPOSITORY ACTIVITIES, AND ENGAGING THE SCIENTIFIC COMMUNITY AND PUBLIC AT LARGE THROUGH SCIENTIFIC PRESENTATIONS, CONFERENCES, EDUCATIONAL EVENTS, AND COMMUNITY REPORTS. WITH OVER 50 YEARS OF NIH-SPONSORED BIOBANKING EXPERTISE, CORIELL IS UNIQUELY QUALIFIED TO ACHIEVE THESE AIMS AND STRATEGICALLY EXPAND THE OPERATIONS AND OFFERINGS OF THE NHGRI REPOSITORY. THE GOALS OF THE NHGRI REPOSITORY ARE CONSISTENT WITH THE NHGRI’S MISSION TO SUPPORT DEVELOPMENT OF RESOURCES AND TECHNOLOGY THAT ACCELERATE GENOMIC RESEARCH. CORIELL IS A TRUSTED NIH PARTNER AND HAS THE INFRASTRUCTURE, EXPERTISE, AND TRACK-RECORD TO ENSURE THE SUCCESSFUL OPERATIONS, MAINTENANCE AND GROWTH OF THIS IMPORTANT AND UNIQUE GENOMIC RESOURCE.

NATIONAL CENTER ON DOMESTIC VIOLENCE, TRAUMA & MENTAL HEALTH

FAMILY VIOLENCE PREVENTION AND SERVICES

BUILDING CAPACITY FOR HIV OPERATIONAL RESEARCH AND PUBLIC HEALTH EVALUATION FOR

CHICAGO ADOLESCENT TRIALS UNIT

CORIELL CELL ENGINEERING CENTER TO SUPPORT NATIONAL BIOBANKING INFRASTRUCTURE - CORIELL INSTITUTE FOR MEDICAL RESEARCH APPLICATION TO ORIP C06 FUNDING OPPORTUNITY ANNOUNCEMENT PAR- 25-061, BIOMEDICAL RESEARCH FACILITIES. PROJECT TITLE: “CORIELL CELL ENGINEERING CENTER TO SUPPORT NATIONAL BIOBANKING INFRASTRUCTURE” PROJECT SUMMARY/ABSTRACT: CORIELL INSTITUTE FOR MEDICAL RESEARCH’S MISSION IS TO CONDUCT AND SUPPORT RESEARCH TO BENEFIT HUMAN HEALTH AND HELP CURE DISEASE. A LEADER IN BIOBANKING, CORIELL HAS HOSTED NIH BIOBANKS SINCE 1972, BUILDING AND DISTRIBUTING WORLD CLASS SAMPLE COLLECTIONS, ENABLING BIOMEDICAL RESEARCH. CORIELL’S BIOBANK IS COMMITTED TO MEETING THE EVOLVING NEEDS OF RESEARCHERS BY ADOPTING NEW TECHNOLOGIES AS WELL AS DIVERSIFYING AND INCLUDING MINORITIES AND UNDERREPRESENTED POPULATIONS IN ITS BIOSPECIMEN COLLECTIONS. CORIELL SCIENTISTS ARE SUPPORTED BY THE NIH, NJ STATE, AND OTHER PARTIES, IN FIELDS INCLUDING BUT NOT LIMITED TO CANCER AND DISEASE RESEARCH, AGING BIOLOGY, BIOBANKING, AND PERSONALIZED MEDICINE. CORIELL’S PRIMARY FACILITY, 403 HADDON AVENUE, CAMDEN, NJ, IS OWNED BY, AND RESIDES ON, THE CAMPUS OF COOPER UNIVERSITY HOSPITAL. THERE IS LIMITED ROOM FOR GROWTH AND PLANS ARE UNDERWAY FOR CORIELL TO RELOCATE TO A NEW HEADQUARTERS BUILDING, ON ITS OWN SITE IN CAMDEN, IN APPROXIMATELY THREE YEARS. IF AWARDED, ORIP C06 FUNDS WOULD HELP CREATE A >7,495 SQUARE FOOT CELL ENGINEERING CENTER ON THE FIRST FLOOR OF CORIELL’S NEW FACILITY, TO ENABLE EXPANSION OF BIOBANKING INFRASTRUCTURE AND PRODUCT AND SERVICE OFFERINGS. OF THESE OFFERINGS, STEM CELLS OFFER UNIQUE INSIGHTS INTO CELL AND DEVELOPMENTAL BIOLOGY, DISEASE ETIOLOGY, AND EXPEDITION OF DRUG DISCOVERY. ADVANCES IN GENE ENGINEERING AND TOOLS LIKE 3D “MINI-ORGAN” MODELS ARE REVOLUTIONIZING RESEARCH. SUCH TOOLS ALSO REPRESENT NEW APPROACH MODELS (NAMS) THAT COMPLEMENT AND REDUCE THE NEED FOR VERTEBRATE ANIMALS IN RESEARCH. THIS CENTER WILL SERVE AS A CORE LABORATORY, OFFERING CANCER CELL LINES, NEWLY CREATED IPSCS, DIFFERENTIATED CELLS, 3D ORGANOID MODELS, CELL GENE ENGINEERING, QUALITY CONTROL, GENOMIC/EPIGENOMIC PROFILING, AND BIOINFORMATIC SERVICES, FOR NIH-FUNDED SCIENTISTS AT CORIELL, IN THE REGION, AND ACROSS THE COUNTRY. THIS PROJECT EPITOMIZES CORIELL’S MISSION TO SUPPORT ROBUST RESEARCH BY PROVIDING SCIENTISTS A NEW GENERATION OF REPRODUCIBLE, HIGHLY CHARACTERIZED, HIGH-QUALITY BIOSPECIMENS AND SERVICES TO ACCELERATE THE PACE OF BIOMEDICAL DISCOVERIES. CORIELL SAMPLES HAVE BEEN INSTRUMENTAL FOR ELUCIDATING MECHANISMS OF DISEASES TO ALLOW NEW REGENERATIVE AND PRECISION MEDICINE THERAPEUTICS. THIS CENTER WILL PROVIDE CRITICAL, AFFORDABLE NEW PRODUCTS AND SERVICES TO SUPPORT RESEARCHERS. AN EXPERIENCED AND COLLABORATIVE TEAM OF DEDICATED PROFESSIONALS, WITH AN EXPERT PRINCIPAL INVESTIGATOR, CONSTRUCTION PROJECT MANAGER, AND FACILITY MANAGER WILL LEAD THIS PROJECT. THIS PROJECT IS PART OF A LARGER NEW BUILDING INVESTMENT WHICH IS ALREADY UNDERWAY WITH AN ANTICIPATED COMPLETION DATE OF 2027-2028, AND CORIELL LEADERSHIP COMMITS TO STAFFING AND SUPPORTING THIS CENTER FOR 10+ YEARS POST-COMPLETION, USING BUSINESS TACTICS DEVELOPED AS AN INDEPENDENT RESEARCH INSTITUTE FOR OVER 70 YEARS. IN ADDITION TO INSTITUTIONAL, LOCAL AND REGIONAL BENEFITS, THIS PROJECT WILL HAVE A SUBSTANTIAL NATIONAL IMPACT. THE CENTER WILL INCREASE CURRENT CAPABILITIES >20 FOLD, SUPPORT UP TO 30 SCIENTISTS/TECHNICIANS, AND ENABLE BIOBANKING OF NEW, NEEDED SAMPLE TYPES, SUPPORTING CORIELL INTERNAL GRANTS, CONTRACTS, AND FEDERALLY FUNDED RESEARCHERS, AS WELL AS SCIENTISTS NATIONWIDE.

GENETIC MAPPING OF FUNCTIONAL VOMERONASAL CIRCUIT

STROGER HOSPITAL OF COOK COUNTY, DEPARTMENT OF SURGERY,*

CHICAGO PREVENTION AND INTERVENTION EPICENTER (CHICAGO PIE)

SAMPLE REPOSITORY FOR HUMAN GENETIC RESEARCH

MECHANISMS OF TRANSCRIPTION REGULATION IN CHROMATIN

INVESTIGATION OF EXPERIENCE-DEPENDENT POST TRANSCRIPTIONAL REGULATION OF DROSOPHI

MECHANISMS AND TARGETED THERAPY OF NRF2-HIGH ESOPHAGEAL SQUAMOUS CELL CARCINOMA

NCI COMMUNITY ONCOLOGY RESEARCH PROGRAM (NCORP) COMMUNITY SITES

BUILDING CAPACITY FOR EVIDENCE UTILIZATION AND EVALUATION WITHIN THE GOVERNMENT OF TANZANIA UNDER PEPFAR

POSSE PROJECT: A COMMUNITY-LEVEL INTERVENTION FOR BLACK YMSM

EPIDEMIOLOGY, PREVENTION AND TREATMENT OF INFLUENZA AND OTHER RESPIRATORY INFECTI

HUMAN MONOCLONAL ANTIBODIES THAT BIND BOTULINUM TOXINS

TRANSGENDER YOUTH AND PREP: PK, SAFETY, UPTAKE & ADHERENCE

ZEBRAFISH SENSORY HAIR CELL REGENERATION

NRF2-ACSS2 AXIS IN ALCOHOL-INDUCED METABOLIC REPROGRAMMING AND ESOPHAGEAL PATHOLOGY - PROJECT SUMMARY THIS MULTIPLE-PI R01 PROPOSAL IS DESIGNED TO INCORPORATE BOTH IN VITRO AND IN VIVO APPROACHES TO ELUCIDATE THE ROLE OF THE NRF2-ACSS2 AXIS IN ALCOHOL-INDUCED METABOLIC REPROGRAMMING AND ESOPHAGEAL PATHOLOGY. WE HYPOTHESIZE THAT THE NRF2-ACSS2 AXIS MEDIATES METABOLIC REPROGRAMMING IN ALCOHOL-ASSOCIATED ESOPHAGEAL PATHOLOGY. WE WILL TEST THIS HYPOTHESIS USING HUMAN CELLS AND GENETICALLY MODIFIED MICE THROUGH THREE INDEPENDENT AND COMPLEMENTARY SPECIFIC AIMS. IN AIM 1, WE WILL CHARACTERIZE THE ROLE OF NRF2-ACSS2 AXIS IN MEDIATING ALCOHOL-INDUCED METABOLIC REPROGRAMMING IN HUMAN ESOPHAGEAL SQUAMOUS EPITHELIAL CELLS IN VITRO. IN AIM 2, WE WILL VALIDATE THE ROLE OF THE NRF2-ACSS2 AXIS IN MEDIATING ALCOHOL-INDUCED METABOLIC REPROGRAMMING IN MOUSE ESOPHAGUS IN VIVO. IN AIM 3, WE WILL EXAMINE THE INHIBITORY EFFECTS OF NRF2 AND ACSS2 INHIBITORS ON ALCOHOL-INDUCED METABOLIC REPROGRAMMING AND ESOPHAGEAL PATHOLOGY IN VIVO. IF THE HYPOTHESIS PROVED TO BE TRUE, THESE STUDIES WILL LAY DOWN A SOLID MECHANISTIC FOUNDATION FOR NRF2/ACSS2 INHIBITION AS A NOVEL MECHANISM-BASED PREVENTIVE MEASURE AGAINST ALCOHOL-ASSOCIATED ESOPHAGEAL PATHOLOGY IN THE FUTURE.

THE MOLECULAR BASIS OF PLANARIAN REGENERATION

MAIN LINE HEALTH CCOP

ROLE OF THE MICROBIOTA IN DNA METHYLATION AND CRC DEVELOPMENT

DEVELOPMENT OF A WHOLE HEART MODEL OF THE J WAVE SYNDROMES AND NOVEL APPROACHES TO PHARMACOLOGIC MANAGEMENT OF ASSOCIATED LIFE-THREATENING ARRHYTHMIAS

KEEPING IT LITE: EXPLORING HIV RISK IN VULNERABLE YOUTH WITH LIMITED INTERACTION

STARVATION RESISTANCE AND RESILIENCE OF METABOLIC DYSFUNCTION IN CAVEFISH

INVESTIGATING DEVELOPMENTAL POTENTIAL BASED ON GENOME-WIDE CHROMATIN STATUS

MODELS OF SELFISHNESS: MOLECULAR AND EVOLUTIONARY ANALYSES OF THE WTF MEIOTIC DRIVERS

INTRINSIC AND EXTRINSIC REGULATION OF CRANIAL MESODERM

IMPROVING ADHERENCE AMONG HIV+ RWANDAN YOUTH: A TI-CBTE INDIGENOUS LEADER MODEL

TANZANIA GLOBAL HEALTH SECURITY PRIORITIES - ADVANCING EFFORTS AND STRATEGIES TO PROTECT AND IMPROVE HEALTH SECURITY (TAGHESP)

H-STAR PROJECT: (HIV SUBSTANCE TREATMENT AND RECOVERY)

A TRANSPOSASE SYSTEM FOR INTEGRATIVE CHIP-EXO AND ATAC-SEQ ANALYSIS AT SINGLE-CELL RESOLUTION

SUSTAINING AND IMPROVING SURVEILLANCE OF HUMAN AND ANIMAL INFLUENZA AND OTHER RESPIRATORY PATHOGENS IN GHANA. (SHARPEN-FLU) - ABSTRACT INFLUENZA REMAINS A DISEASE WHICH POSES A HUGE GLOBAL PUBLIC HEALTH THREAT. MAINLY BECAUSE INFLUENZA VIRUSES CAN CAUSE DEVASTATING PANDEMICS WITH THE MOST DEVASTATING TO DATE BEING THE SPANISH `FLU? PANDEMIC, WHICH LED TO THE DEATH OF ~40 MILLION PEOPLE WORLDWIDE. THE RECENT COVID-19 PANDEMIC HAS EMPHASIZED THE NEED FOR CONSTANT SURVEILLANCE FOR RESPIRATORY PATHOGENS SUCH AS INFLUENZA AND EMERGING AND RE-EMERGING PATHOGENS LIKE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS-2 (SARS-COV-2). EARLY DETECTION AND CHARACTERIZATION OF THESE RESPIRATORY PATHOGENS IS THE KEY TO MITIGATING THEIR EFFECTS. THE NOGUCHI MEMORIAL INSTITUTE FOR MEDICAL RESEARCH (NMIMR) WITH SUPPORT FROM THE GHANA HEALTH SERVICE (GHS) AND THE UNITED STATES NAVAL MEDICAL RESEARCH UNIT (US NAMRU#3), STARTED SURVEILLANCE FOR INFLUENZA VIRUSES IN GHANA IN 2007; WHEN OUTBREAKS OF HIGHLY PATHOGENIC AVIAN INFLUENZA A H5N1 AMONG POULTRY LED TO THE DEATH AND CULLING OF THOUSANDS OF BIRDS. THIS SENTINEL SURVEILLANCE SYSTEM PROVIDES EPIDEMIOLOGIC AND VIROLOGIC DATA ON CIRCULATING INFLUENZA VIRUS STRAINS IN THE COUNTRY. IT IS ALSO ABLE TO DETECT AND RESPOND TO INFLUENZA OUTBREAKS. THROUGH THIS ESTABLISHED INFLUENZA SURVEILLANCE SYSTEM, GHANA IS ABLE TO CONTRIBUTE TO THE WHO GLOBAL INFLUENZA AND SURVEILLANCE RESPONSE SYSTEM (GISRS) BY UPDATING DATA ON THE WHO FLUNET AS WELL AS SUBMITTING SAMPLES TO THE WHO CC IN LONDON. AGAIN, THE NMIMR COLLABORATES WITH THE VETERINARY SERVICES DIRECTORATE (VSD) TO CONDUCT SURVEILLANCE FOR AVIAN INFLUENZA AMONG POULTRY IN SELECTED AREAS IN THE COUNTRY. ALTHOUGH THE ESTABLISHED SENTINEL SYSTEM HAS BEEN EXTREMELY USEFUL, THERE ARE A FEW CHALLENGES. THIS SYSTEM IS HEAVILY BIASED TOWARDS INFLUENZA VIRUSES. THIS CURRENT COVID-19 PANDEMIC HAS DEMONSTRATED THE NEED TO INCLUDE OTHER NON-INFLUENZA RESPIRATORY VIRUSES AS WELL AS BACTERIAL PATHOGENS TO BE ABLE TO HAVE A ROBUST SYSTEM THAT CAN DETECT EARLY THREATS. AGAIN, DUE TO REGIONAL RE-ORGANIZATION, SOME N EW REGIONS CURRENTLY DO NOT HAVE INFLUENZA SENTINEL SURVEILLANCE SITES. THERE IS THE NEED THEREFORE TO EXPAND TO INCLUDE DETECTION OF OTHER PATHOGENS AS WELL AS INVOLVE NEW REGIONS AND PRIMARY HEALTHCARE FACILITIES. FURTHERMORE, THERE IS AN URGENT NEED FOR CLOSE COLLABORATIONS WITH THE VSD FOR IMPROVED CONTINUOUS SURVEILLANCE AMONG ANIMAL POPULATIONS AS MOST EMERGING AND RE-EMERGING PATHOGENS ARE ZOONOTIC IN NATURE. ULTIMATELY IN ORDER TO BE ABLE TO DETECT THREATS EARLY, A HOLISTIC ONE HEALTH APPROACH, WITH COLLABORATIONS AND DATA SHARING AMONG ALL INTEREST GROUPS IS IMPORTANT. THIS NOTICE OF FUNDING OPPORTUNITY PROVIDES GHANA WITH THE UNIQUE CHANCE TO EXPAND INFLUENZA AND OTHER RESPIRATORY PATHOGENS SURVEILLANCE IN GHANA IN ORDER TO BE ABLE TO CHARACTERIZE AND MONITOR RESPIRATORY PATHOGENS AMONG BOTH HUMANS AND ANIMALS; WHILE STRENGTHENING COLLABORATIONS AND COMMUNICATION AMONG INTEREST GROUPS FOR ADEQUATE UTILIZATION OF DATA TO PREVENT OR MITIGATE EFFECTS OF OUTBREAKS AND PANDEMICS.

STRUCTURE AND FUNCTION OF MAMMALIAN CPEB2 AGGREGATES IN NORMAL AND AD BRAIN - PROJECT SUMMARY THE AGGREGATE FAILURE OF PRE-CLINICAL AND CLINICAL TRIALS IN AD HAS DEMONSTRATED THAT AN IMPROVED FUNDAMENTAL UNDERSTANDING OF MEMORY AND HOW THE MOLECULAR COMPONENTS OF MEMORY ARE ALTERED IN THE AD DISEASE PROCESS IS NECESSARY TO DEVELOP EFFECTIVE TREATMENT. THE BROAD OBJECTIVE OF THE PROJECT IS TO IDENTIFY THE BIOCHEMICAL SUBSTRATES OF LONG-LASTING MEMORIES IN MAMMALS. THE CURRENT PROPOSAL FOCUSES ON A FAMILY OF RNA-BINDING, CYTOPLASMIC POLYADENYLATION ELEMENT BINDING PROTEIN (CPEB), THAT STABILIZES MEMORY IN INVERTEBRATES AND MICE. REMARKABLY, CPEB FAMILY PROTEIN FORMS NON-DISEASE-CAUSING AMYLOIDOGENIC AGGREGATES AND AGGREGATION OF CPEB IS NECESSARY TO STABILIZE MEMORY. AS AMYLOIDS ARE TYPICALLY LINKED TO DISEASE STATES, THE QUESTION REMAINS HOW SIMILARLY STRUCTURED ASS42 OR TAU PROTEINS CAN HAVE OPPOSING EFFECTS ON MEMORY. THEREFORE, TO DEVELOP A BETTER UNDERSTANDING OF THE RELATIONSHIP BETWEEN AMYLOIDS THAT SUPPORT MEMORY AND AMYLOIDS THAT DISRUPT MEMORY, WE WILL USE A VARIETY OF TECHNIQUES TO SOLVE THE STRUCTURE AND FUNCTION OF THE CPEB FAMILY MEMBERS, CPEB2 AND CPEB3, IN HUMAN AND MICE. IN AIM 1, WE WILL USE CRYO- ELECTRON MICROSCOPY TO SOLVE THE STRUCTURE OF CPEB AGGREGATES FROM FRESH HUMAN FRONTOTEMPORAL LOBE TISSUE COLLECTED FROM 25-50-YEAR-OLD HUMAN SUBJECTS UNDERGOING TISSUE REMOVAL UNDER THE STANDARD OF CARE FOR THEIR DISEASE. THESE TISSUES WOULD HAVE BEEN OTHERWISE DISCARDED. IN AIM 2, MICE LACKING THE ABILITY TO FORM AGGREGATES OF CPEB2 AND CPEB3 WILL BE TRAINED AND TESTED IN A ONE-TRIAL INHIBITORY AVOIDANCE TASK TO ASSAY THEIR ABILITY TO FORM, MAINTAIN, AND RECALL MEMORY. IN AIM 2 WE WILL ALSO INVESTIGATE THE CONSEQUENCE OF CPEB2 AND CPEB3 AGGREGATION IN TRANSLATION OF MRNA ENCODING SYNAPTIC PROTEINS. THE RESULTS WOULD BE THE FIRST TO PROVIDE DIRECT STRUCTURAL ANALYSIS OF A FUNCTIONAL AMYLOID LINKED TO MEMORY IN MAMMALS, THE STRUCTURAL DISTINCTIONS, IF ANY, BETWEEN FUNCTIONAL AND TOXIC AMYLOID IN THE HUMAN BRAIN, AND PRECISELY LINK CPEB2 AND CPEB3 AGGREGATION AND ACTIVITY TO ANIMALS’ ABILITY TO FORM OR STABILIZE MEMORY. THIS KNOWLEDGE WOULD PROVIDE THE FOUNDATION TO INVESTIGATE IN THE FUTURE HOW TOXIC AMYLOIDS OF ASS42 OR TAU SPECIFICALLY PERTURB MEMORY.

KEEPING IT LITE 2: EXPLORING HIV RISK IN VULNERABLE YOUTH WITH LIMITED INTERACTION AND DIGITAL HEALTH INTERVENTION (LITE-2) - ABSTRACT DESPITE ADVANCES IN HIV DIAGNOSTICS, CARE AND PREVENTION STRATEGIES, INFECTION RATES AMONG ADOLESCENT AND YOUNG ADULT SEXUAL AND GENDER MINORITIES (SGM) CONTINUE TO RISE IN THE UNITED STATES (US). THERE IS AN URGENT NEED TO DESCRIBE THE EPIDEMIOLOGY AND TRAJECTORIES OF HIV ACQUISITION IN THIS POPULATION AND TO OFFER AGE AND CULTURALLY APPROPRIATE SCALABLE PREVENTION INTERVENTIONS TO THOSE AT HIGHEST RISK OF INFECTION IN THE US. THIS PROJECT WILL ENGAGE AND RETAIN YOUNG SGM IN AN INNOVATIVE LONGITUDINAL COHORT, ENROLL THEM IN A DYNAMIC ESTABLISHED DIGITAL HEALTH RETENTION PLATFORM (HMP; HEALTHMPOWERMENT), MONITOR HIV RISK AND PREVENTION BEHAVIORS AND EXPLORE THE SOCIOECOLOGICAL FACTORS THAT INFLUENCE THE USE OF NEW HIV PREVENTION TECHNOLOGIES (UG3 PHASE), WHILE ALSO ALLOWING TARGETED TESTING OF NOVEL DIGITAL HEALTH INTERVENTIONS (UH3 PHASE). WE WILL ALSO TEST THE EFFICACY OF EXPANDING THE CORE VERSION OF HMP (HMP BASIC) BY ADDING ADHERENCE TOOLS (HMP ENHANCED) FOR THOSE WHO ARE ON PREP OR ART TO IMPROVE ADHERENCE AND PERSISTENCE. IN AIM 1, WE WILL ENROLL AND RETAIN A LARGE (N=6000; 3000/YEAR), DIVERSE COHORT OF SEXUALLY ACTIVE, SGM ADOLESCENTS AND YOUNG ADULTS, AGES 13-34, USING INNOVATIVE DIGITAL RECRUITMENT, ENGAGEMENT AND RETENTION STRATEGIES. OVER THE COURSE OF THE STUDY, WE WILL LONGITUDINALLY CHARACTERIZE THE SEXUAL BEHAVIOR, HIV TRANSMISSION RISK, AND PREP UPTAKE TRAJECTORIES OF SGM YOUTH UTILIZING EPIDEMIOLOGICAL TRAJECTORY ANALYSES TO IDENTIFY THE MOST EFFECTIVE POINTS OF INTERVENTION (AIM 2). FOR AIM 3, WE WILL LAUNCH A RANDOMIZED CLINICAL TRIAL TO EXAMINE THE EFFICACY OF HMP ENHANCED TO IMPROVE PREP ADHERENCE AMONG HIV-NEGATIVE YOUTH (N =750) AND ART ADHERENCE AMONG HIV-POSITIVE YOUTH (N =150) COMPARED TO HMP BASIC. FINALLY, WE WILL MAXIMIZE THE PRODUCTIVITY OF THE COHORT BY TESTING NEW AND INNOVATIVE DIGITAL HEALTH DEVICES, HIV/STI DIAGNOSTICS AND INTERVENTIONS, INFORMED BY THE PREVIOUS AIMS AS WELL AS EMERGING NIH PREVENTION PRIORITIES (AIM 4). OUR INVESTIGATIVE TEAM HAS DECADES OF EXPERIENCE WITH RECRUITMENT, PREVENTION AND CARE OF SGM YOUTH AND LARGE-SCALE LONGITUDINAL COHORT STUDIES. THIS STUDY WILL CAPITALIZE UPON PRODUCTIVE EXISTING PARTNERSHIPS AND DIGITAL HEALTH EXPERTISE TO ARTICULATE THE DRIVERS OF THE ONGOING HIV EPIDEMIC AMONG THE MOST VULNERABLE POPULATIONS IN THE US IN ORDER TO IDENTIFY THE MOST EFFECTIVE, EXPEDITIOUS AND SCALABLE STRATEGIES TO ADDRESS THIS ONGOING PUBLIC HEALTH CRISIS.

IMPROVING EVALUATION CAPACITY WITHIN THE GOVERNMENT OF TANZANIA UNDER PEPFAR

VIOLENCE AGAINST WOMEN AND SUBSTANCE USE PREVENTION INITIATIVE - THERE IS A HIGH LEVEL OF NEED FOR COORDINATED INTIMATE PARTNER VIOLENCE (IPV) AND SUBSTANCE USE DISORDER (SUD) SERVICES IN WEST VIRGINIA, PARTICULARLY FOR PREGNANT AND PARENTING WOMEN (PPW), AS EVIDENCED BY HIGH RATES OF SUBSTANCE USE, POOR INFANT AND MATERNAL HEALTH OUTCOMES, AND RACIAL DISPARITIES IN HEALTH, HEALTHCARE ACCESS AND IPV. THE PURPOSE OF THIS PROJECT IS TO CREATE A STATEWIDE PILOT INITIATIVE TO TRAIN SUBSTANCE USE DISORDER (SUD) TREATMENT PROVIDERS ON INTIMATE PARTNER VIOLENCE (IPV) AND IPV PROVIDERS ON SUBSTANCE USE AND TO ADDRESS THE INTERSECTION OF IPV AND SUD DURING THE PREGNANCY AND POSTPARTUM PERIOD. PROJECT GOALS ARE TO ENGAGE STATE AGENCIES, IPV PROGRAMS, TREATMENT PROVIDERS, AND OTHER KEY STAKEHOLDERS FROM DIVERSE COMMUNITIES IN INCREASING THE USE OF EVIDENCE-BASED AND PROMISING PRACTICES IN SERVICE DELIVERY; TO CREATE AND DELIVER TRAINING FOR SUD, IPV, AND HEALTHCARE PROVIDERS; AND TO BUILD A COLLABORATIVE STATEWIDE NETWORK OF REGIONAL TEAMS TO PROMOTE SERVICE IMPLEMENTATION AT THE LOCAL LEVEL AND ADDRESS ACCESS AND OUTCOME DISPARITIES AND UNMET NEEDS. TO ACHIEVE THESE GOALS, THE NATIONAL CENTER ON DOMESTIC VIOLENCE, TRAUMA, AND MENTAL HEALTH IS PARTNERING WITH THE WEST VIRGINIA DEPARTMENT OF HEALTH AND HUMAN RESOURCES' BUREAU FOR BEHAVIORAL HEALTH, THE WEST VIRGINIA COALITION AGAINST DOMESTIC VIOLENCE, THE WEST VIRGINIA PERINATAL PARTNERSHIP, AND THE MARSHALL UNIVERSITY RESEARCH CORPORATION’S WEST VIRGINIA BEHAVIORAL HEALTH WORKFORCE AND HEALTH EQUITY TRAINING CENTER TO ENGAGE IN SIX KEY ACTIVITIES. FIRST, WE WILL INCENTIVIZE SUD PROVIDERS TREATING PREGNANT AND POSTPARTUM WOMEN TO RECEIVE TRAINING ON IDENTIFYING IPV IN THEIR CLIENT POPULATION. SECOND, WE WILL TRAIN SUD TREATMENT PROVIDERS TO ADDRESS IPV WITH PATIENTS AND TRAIN IPV STAFF ON SUD. THIRD, WE WILL IDENTIFY RESEARCH-BASED SERVICES FOR SCREENING, ASSESSMENT, BRIEF INTERVENTION, AND REFERRAL. FOURTH WE WILL INTEGRATE IPV AND SUD PROTOCOLS INTO MEDICAL PRAC TICE. FIFTH WE WILL INTEGRATE PERINATAL AND POSTPARTUM PROGRAMS INTO EXISTING SUBSTANCE USE PROGRAMS. SIXTH, WE WILL CONDUCT PROCESS AND OUTCOMES EVALUATIONS TO DETERMINE CHANGES IN PROVIDERS' KNOWLEDGE, SKILL, AND COMFORT IN ADDRESSING IPV/SU, DOCUMENT CHANGES IN REFERRALS AND COLLABORATION AMONG STATE PARTNERS, AND ASSESS IMPROVEMENT IN IPV-SUD HEALTH OUTCOMES AMONG PREGNANT AND POSTPARTUM WOMEN. OUR APPROACH BUILDS ON WEST VIRGINIA’S EXISTING STATEWIDE PARTNERSHIPS AND NETWORKS, INCORPORATES THE PROMISING PRACTICE OF REDUCING SUBSTANCE USE COERCION, AND RESPONDS TO THE HIGH OVERDOSE AND DRUG-RELATED DEATH RATE FOR WOMEN IN WV.

THE ROLE OF GSK3/PPAR-/MITOPHAGY PATHWAY IN REGULATING HEMATOPOIA - THE ROLE OF GSK3/PPAR-D/FAO/MITOPHAGY PATHWAY IN REGULATING HEMATOPOIETIC STEM CELL HOMEOSTASIS AND FUNCTION ABSTRACT HEMATOPOIETIC STEM CELLS (HSCS) POSSESS THE ABILITIES TO BOTH PRODUCE STEM CELLS, A PROPERTY KNOWN AS SELF-RENEWAL, AND GIVE RISE TO ALL DIFFERENTIATED HEMATOPOIETIC LINEAGES. CLINICALLY, HSCS ARE THERAPEUTICALLY VALUABLE FOR TRANSPLANTATION IN TREATMENT OF VARIOUS HEMATOLOGIC MALIGNANCES. DESPITE REMARKABLE PROGRESS MADE IN THE RESEARCH OF HSCS DURING THE PAST THREE DECADES, THE MOLECULAR MECHANISMS REGULATING HSC HOMEOSTASIS AND FUNCTION ARE STILL NOT FULLY UNDERSTOOD. OUR PREVIOUS PUBLISHED SHOWED THAT GSK3 PLAYS AN ESSENTIAL ROLE IN REGULATING HSC HOMEOSTASIS. SPECIFICALLY, KNOCKDOWN OF GSK3 PROMOTE TRANSIENT EXPANSION AND LONG-TERM EXHAUSTION OF HSC IN VIVO. OUR NEW PRELIMINARY STUDIES DEMONSTRATED THAT GSK3 FUNCTIONS THROUGH PPAR-D/FAO/MITOPHAGY PATHWAY TO REGULATE HSC DIVISION SYMMETRY; INHIBITION OF GSK3 INDUCES MITOPHAGY AND CONVERSELY, BLOCKING PPAR-D/FAO/MITOPHAGY CAN REVERSE THE ENHANCED SELF-RENEWAL PHENOTYPE THAT IS ASSOCIATED WITH GSK3 INHIBITION. IN THIS STUDY, WE WILL FIRST EXAMINE HOW GSK3 REGULATES PPAR-D, WHICH IN TURN REGULATES MITOPHAGY AND HSC DIVISION SYMMETRY. SECONDLY, WE WILL INVESTIGATE WHETHER LOSS-OF- FUNCTION OF PPAR-D, PARK2 OR PINK1 (TWO MITOPHAGY KEY REGULATORS) REVERSE THE FUNCTIONAL DEFECT OF GSK3B-DEFICIENT HSC IN VIVO. LASTLY, WE WILL EXPLORE WHETHER GSK3 CONTROLS FAO AND LIPID METABOLISM TO REGULATE HSC FUNCTION AND HOMEOSTASIS. OUR STUDY WILL PROVIDE SIGNIFICANT NEW INSIGHTS INTO THE MOLECULAR MECHANISMS UNDERLYING GSK3-DEPENDENT REGULATION OF HSC HOMEOSTASIS AND FUNCTION. THE KNOWLEDGE LEARNED MAY FACILITATE BONE MARROW TRANSPLANTATION FOR TREATING DIVERSE HEMATOLOGICAL DISEASES.

SMALL TRANSLATED ORFS IN THE 3'UTR ENHANCE TRANSLATION IN VERTEBRATES - PROJECT SUMMARY THE PREVAILING DOCTRINE THAT MESSENGER RNAS (MRNAS) IN HIGHER ORGANISMS ENCODE FOR A SINGLE PROTEIN HAS UNDERGONE A DRAMATIC REVISION IN RECENT YEARS. RIBOSOME AND PROTEOMIC PROFILING HAVE REVEALED A LARGE NUMBER OF SMALL TRANSLATED OPEN READING FRAMES (ORF) WITHIN PREVIOUSLY DESCRIBED “UNTRANSLATED REGIONS” (UTRS) AND LONG NON-CODING RNAS. INDEED, SOME OF THE PEPTIDES DERIVED FROM SMALL ORFS HAVE BEEN IMPLICATED IN VARIOUS FUNDAMENTAL PROCESSES (E.G., DEVELOPMENT). TRANSLATION OF SMALL ORFS IN THE 5’UTR, KNOWN AS UPSTREAM-ORFS (UORFS), HAS BEEN SHOWN TO HAVE A PROFOUND REGULATORY EFFECT ON GENE REGULATION, INDEPENDENT OF THE ENCODED PEPTIDE. FURTHER, TRANSLATION OF UORFS VARY UNDER PATHOLOGIC CONDITIONS SUCH AS CANCER, AND MUTATIONS AFFECTING UORFS ARE ASSOCIATED WITH VARIOUS HUMAN DISEASES. WE AND OTHERS HAVE ALSO INDICATED THE EXISTENCE OF TRANSLATED SMALL ORFS IN THE 3’UTR KNOWN AS DOWNSTREAM OPEN READING FRAMES (DORFS) IN HUMAN CELLS AND ZEBRAFISH EMBRYOS. HOWEVER, CONTRARY TO UORFS, THERE HAS BEEN NO SYSTEMATIC STUDY OF DORF FUNCTIONS, AND THEIR RELATIONSHIP TO HUMAN HEALTH AND DISEASE REMAINS UNTESTED. FURTHER, GIVEN THEIR LOCATION IN THE 3’UTR, THE MOLECULAR MECHANISM BY WHICH DORFS ENGAGE THE TRANSLATIONAL MACHINERY REMAIN COMPLETELY UNKNOWN. OUR LONG-TERM GOAL IS TO UNDERSTAND HOW POST-TRANSCRIPTIONAL REGULATION (MRNA HALF-LIFE AND TRANSLATION) SHAPES GENE EXPRESSION IN VERTEBRATES, AND ITS IMPACT ON HUMAN DISEASE. THE CENTRAL HYPOTHESIS OF THIS APPLICATION IS THAT TRANSLATION OF DORFS REGULATES GENE EXPRESSION. OUR PRELIMINARY DATA STRONGLY INDICATE THAT, CONTRARY TO UORFS, DORFS STRONGLY ENHANCE TRANSLATION OF THE CANONICAL ORF AND EMERGE AS AN UNCHARACTERIZED AND POTENT REGULATORY MECHANISM ACROSS VERTEBRATES. THE OBJECTIVES ARE TO: 1) IDENTIFY FACTORS INVOLVED IN ENHANCING TRANSLATION OF THE MAIN ORF. 2) DISSECT THE REGULATORY INFORMATION DRIVING DORF TRANSLATION, AND 3) CHARACTERIZE THE BIOLOGICAL IMPACTS OF DORF-MEDIATED REGULATION. THE RATIONALE FOR THE PROPOSED RESEARCH IS TO GAIN A MECHANISTIC UNDERSTANDING OF DORF-MEDIATED REGULATION IN ORDER TO ASSESS THE POSSIBLE BIOLOGICAL IMPORTANCE OF DORF DYSREGULATION UNDER STRESS OR DISEASE CONDITIONS. THIS PROPOSAL IS CONCEPTUALLY INNOVATIVE AS IT IS BASED ON THE EXPLORATION OF A NOVEL, YET WIDESPREAD AND POTENT TRANSLATION REGULATORY MECHANISM CONSERVED ACROSS VERTEBRATES. TECHNICALLY, THIS PROPOSAL WILL COMBINE GENOMIC PROFILES (RNA-SEQ, RIBOSOME PROFILING); REPORTER (CYTOMETRY); BIOCHEMISTRY TOOLS: RNA PULLDOWNS FOLLOW BY PROTEOMICS, CRISPR-CAS-9 AND - 12A (TO EDIT) AND OUR NOVEL CAS13D TOOL (KNOCK-DOWN IN EMBRYOS); COMBINING HUMAN CELL AND ZEBRAFISH EMBRYOS. THE OUTCOMES FROM THIS PROJECT WILL HELP UNDERSTAND HOW DORFS ARE TRANSLATED, SHAPE GENE EXPRESSION AND GENERATE PHENOTYPES. THIS NOVEL FUNCTION OF THE RIBOSOME ADDS TO THE RECENTLY EMERGING REGULATORY EFFECTS OF TRANSLATION ON GENE EXPRESSION (E.G. UORF, CODON OPTIMALITY). UNDERSTANDING DORF BIOLOGY WILL PROVIDE AN ENTRY POINT AND PERHAPS EVEN A DIAGNOSTIC TOOL TO ASSOCIATE MUTATIONS WITH HUMAN DISEASES. IDENTIFYING THE MOLECULAR MACHINERY INVOLVED IN THIS PATHWAY MIGHT PROVIDE TARGETS FOR THERAPEUTIC INTERVENTIONS.

EXPLORE THE SIGNALING MECHANISMS OF ACQUIRED RESISTANCE TO TYROSINE KINASE INHIBITORS IN AML - EXPLORE THE SIGNALING MECHANISMS OF ACQUIRED RESISTANCE TO TYROSINE KINASE INHIBITORS IN AML ABSTRACT ACUTE MYELOID LEUKEMIA (AML) IS A MALIGNANT HEMATOPOIETIC DISEASE AND THE MOST COMMON TYPE OF ACUTE LEUKEMIA IN ADULTS. ONE MAJOR OBSTACLE TO GREATER SUCCESS WITH TARGET THERAPY OF LEUKEMIA IS DRUG RESISTANCE. THE MECHANISMS UNDERLYING DRUG RESISTANCE IN AML ARE POORLY UNDERSTOOD. FLT3 IS A CYTOKINE RECEPTOR WHICH BELONGS TO THE RECEPTOR TYROSINE KINASE (RTK) CLASS III. ACTIVATING MUTATIONS IN FMS-LIKE TYROSINE KINASE 3 (FLT3) ARE NOW RECOGNIZED AS THE MOST COMMON MOLECULAR ABNORMALITY IN AML AND FLT3ITD MUTATIONS ARE FOUND IN NEARLY 30% OF AML PATIENTS. QUIZARTINIB (AC220) IS A POTENT AND SELECTIVE SECOND-GENERATION INHIBITOR OF FLT3. IT IS IN CLINICAL TRIALS FOR THE TREATMENT OF RELAPSED OR REFRACTORY FLT3ITD POSITIVE AND NEGATIVE AML PATIENTS AND AS MAINTENANCE THERAPY. REMARKABLY, THOSE CLINICAL TRIALS HAVE SHOWED VERY PROMISING RESULT. HOWEVER, DRUG RESISTANCE TO AC220 HAS ALSO BEEN REPORTED THROUGH THE EARLY CLINICAL STUDIES. TO UNDERSTAND THE UNDERLYING MECHANISMS OF DRUG RESISTANCE TO AC220, WE UNDERTOOK AN UNBIASED APPROACH WITH A NOVEL CRISPR POOLED LIBRARY TO SCREEN NEW GENES WHOSE LOSS OF FUNCTION CONFERS RESISTANCE TO AC220. IN OUR SCREEN, WE IDENTIFIED SPRY3, AN INTRACELLULAR INHIBITOR OF RTK SIGNALING, AND GSK3, A CANONICAL WNT SIGNALING ANTAGONIST, AND DEMONSTRATED THAT RE-ACTIVATION OF DOWNSTREAM RTK/RAS/ERK AND WNT SIGNALING AS MAJOR MECHANISMS OF RESISTANCE TO THE FLT3 INHIBITOR. FURTHERMORE, WE ALSO CONFIRMED OUR FINDINGS IN PRIMARY AML PATIENT SAMPLES. WE DEMONSTRATED THAT THE EXPRESSION LEVEL OF SPRY3 AND GSK3A IS DRAMATICALLY REDUCED IN AC220 RESISTANT AML SAMPLES AND SPRY3 DELETED PRIMARY AML CELLS ARE RESISTANT TO AC220. ADDITIONALLY, WE TREATED SPRY3 AND GSK3 KNOCKOUT AML CELLS WITH A POTENT MAP KINASE INHIBITOR AND SS- CATENIN INHIBITOR RESPECTIVELY, DEMONSTRATED THAT BOTH INHIBITORS RE-SENSITIZED AML CELLS TO AC220. INTRIGUINGLY, WE FOUND THAT EXPRESSION OF SPRY3 IS GREATLY REDUCED IN GSK3 KNOCKOUT AML CELLS, WHICH POSITIONED SPRY3 DOWNSTREAM OF GSK3 IN THE RESISTANCE PATHWAY. IN THIS PROPOSAL, WE HYPOTHESIZE THAT SPROUTY (SPRY) AND GSK3 PLAY CRITICAL ROLES IN THE RESPONSE TO TYROSINE KINASE INHIBITOR IN AML. THE RAS/MEK/ERK AND WNT PATHWAYS REGULATED BY SPRY3 AND GSK3 ARE IMPORTANT FOR THE ACQUIRED DRUG RESISTANCE IN AML. NEXT, WE WILL PERFORM A SERIES COMPREHENSIVE STUDY TO EXPLORE NOVEL DOWNSTREAM EFFECTORS/ INTERACTING PARTNERS OF SPRY3 AND GSK3 IN AMLS AND THE MOLECULAR MECHANISMS OF THEIR ACTION. FURTHERMORE, WE WILL EXAMINE THE POSSIBILITY TO TRANSLATE OUR FINDINGS INTO NEW CLINICAL THERAPIES. TAKEN TOGETHER, OUR STUDY IDENTIFIED NOVEL GENES WHOSE LOSS OF FUNCTION CONFERS RESISTANCE TO A SELECTIVE FLT3 INHIBITOR AND REVEALED THE UNDERLYING MECHANISM, THEREBY PROVIDING NEW INSIGHT INTO SIGNALING PATHWAYS THAT CONTRIBUTE TO THE ACQUIRED RESISTANCE IN AML. THE KNOWLEDGE LEARNED MAY LEAD TO THE DEVELOPMENT OF MORE EFFICIENT COMBINED THERAPEUTIC AVENUES FOR AML.

HOW CELLS MONITOR THE INTEGRITY OF THEIR TRANSLATION APPARATUS

IDO2 TARGETING IN PANCREATIC CANCER

MOLECULAR DISSECTING AND TARGETING YAP1 MEDIATED CANCER STEMNESS AND IMMUNE SUPPRESSION IN ADVANCED GASTRIC ADENOCARCINOMA - PROJECT ABSTRACT THE MAIN OBJECTIVES OF THIS PROPOSAL ARE TO ELUCIDATE THE MECHANISMS OF YAP1-MEDIATED METASTATIC NICHE AND IMMUNOSUPPRESSION IN GASTRIC ADENOCARCINOMA (GAC) WITH PERITONEAL CARCINOMATOSIS (PC) FOR NOVEL THERAPEUTIC DISCOVERIES. GAC IS A MAJOR HEALTH BURDEN IN THE US AND WORLDWIDE. PC IS COMMON AFFECTING ~45% OF GAC PATIENTS. GAC PATIENTS WITH PC HAVE SHORT SURVIVAL AND TREATMENTS ARE INEFFECTIVE. MOLECULAR UNDERSTANDING FOR PC IS LIMITED. TO ADDRESS THIS UNMET CLINICAL CHALLENGE, WE HAVE ESTABLISHED PC BANKING INFRASTRUCTURE AIMING TO UTILIZE THESE PATIENT-DERIVED SPECIMENS TO DISCOVER AND VALIDATE OUR NOVEL TARGETS. OUR PRELIMINARY RNASEQ PROFILING OF PC SPECIMENS REVEALED AN ENRICHMENT OF UNIQUE IMMUNE SUPPRESSIVE MOLECULES, INCLUDING TIM3 AND IT’S LIGAND GALECTIN-9 (GAL-9), TGF-SS AND VISTA, BUT LESS EXPRESSION OF PD-1/PDL-1 AND CTLA-4. YAP1 HAS BEEN IMPLICATED IN HUMAN DEVELOPMENT, LINEAGE PLASTICITY, AND UPREGULATED IN MANY TUMOR TYPES. HOWEVER, ITS ROLE IN MEDIATING PC METASTASES AND IMMUNE SUPPRESSION IN TUMOR MICROENVIRONMENT (TME) REMAIN UNCLEAR. OUR PRELIMINARY DATA SUGGEST THAT YAP1 IS HIGHLY EXPRESSED IN PRIMARY AND METASTATIC TUMOR CELLS OF GAC PATIENTS AND IS SIGNIFICANTLY ASSOCIATED WITH POOR SURVIVAL. GENETIC KNOCKOUT (KO) YAP1 SIGNIFICANTLY DECREASED CANCER STEMNESS TRAITS, TUMOR FORMATION AND PC IN MICE. FURTHER, DEPLETION OF YAP1 IN TUMOR CELLS CONSISTENTLY INCREASED CD3 AND CD8 T CELL RESPONSES FROM GAC. THROUGH A SINGLE CELL RNASEQ (SCRNASEQ) OF PC SAMPLES AND VALIDATION USING IMMUNOFLUORESCENT STAINING, WE NOTICED THAT YAP1, TIM3 LIGAND GAL-9 AND DKK1 ARE HIGHLY EXPRESSED IN TUMOR CELLS OF PC; WHILE TIM3 IS ENRICHED IN IMMUNE CELLS. RNASEQ FROM YAP1HIGH AND YAP1 KO PATIENT-DERIVED TUMOR CELLS REVEALED THAT GAL-9 AND DKK1 WERE SIGNIFICANTLY DECREASED UPON DEPLETION OF YAP1 AND THESE FACTORS ARE ASSOCIATED WITH POOR SURVIVAL OF PATIENTS. WE HYPOTHESIZE THAT YAP1HIGH PC CELLS ARE METASTASIS-INITIATING CELLS THAT ORCHESTRATE A NICHE BY CONFERRING CANCER STEMNESS ATTRIBUTES TO THE TUMOR CELLS AND PROMOTE TUMOR IMMUNOSUPPRESSION THROUGH ACTIVATING TIM3/GAL-9 AXIS AND INCREASING PARACRINE OF DKK1 IN PC TME. THEREFORE, SIMULTANEOUSLY TARGETING HIPPO/YAP1 AND IMMUNE CHECKPOINT (TIM3/GAL-9) COULD BE AN ENHANCED STRATEGY. TO TEST OUR HYPOTHESIS, WE PROPOSE THREE SPECIFIC AIMS: AIM 1. DETERMINE THE FUNCTIONAL RELEVANCE OF YAP1 IN PC STEMNESS AND METASTASES IN TUMOR CELLS USING NOVEL STEM CELL CLONING TECHNOLOGY AND PDX/PDO MODELS IN VIVO. AIM 2. TO INVESTIGATE THE MECHANISMS WHEREBY YAP1 MEDIATES IMMUNOSUPPRESSION IN TME OF PC. AIM 3. ELUCIDATING EFFICACY OF INHIBITION OF YAP1 ALONE OR IN COMBINATION WITH TIM3 INHIBITION USING THE PDO MODELS, KP-LUC2 SYNGENEIC MOUSE MODEL, GEMM, AND ONGOING YAP1 CLINICAL TRIAL. BY UTILIZING PATIENT- DERIVED PC CELLS, WE WILL UNCOVER FUNCTIONAL IMPORTANCE OF YAP1-MEDIATED PC AND ELUCIDATE THE MECHANISMS BY WHICH YAP1 MEDIATED IMMUNOSUPPRESSION FOR NOVEL THERAPEUTIC STRATEGIES. UPON COMPLETION OF THIS STUDY, WE WILL HAVE A STRONG RATIONALE FOR A NOVEL COMBINATION THAT COULD OVERCOME THE SHORTCOMINGS WE EXPERIENCE IN THE CLINICS TODAY.

MECHANISMS OF TUMOR INITIATION UPON DISRUPTION OF THE RB/E2F INTERACTION - ABSTRACT E2F (E2F1-8) TRANSCRIPTION FACTORS ARE CRITICAL REGULATORS OF CELL CYCLE AND THEIR ACTIVITY IS PHYSICALLY REGULATED BY RB FAMILY PROTEINS (RB, P107 AND P130). DISRUPTION OF THE RB/E2F INTERACTION IS A HALLMARK OF CANCER, AS DEFINED BY HANAHAN&WEINBERG. THE ACQUIRED RESISTANCE TO ANTIGROWTH SIGNALS RESULTING FROM THIS DISRUPTION IS THOUGHT TO BE NECESSARY FOR TUMOR INITIATION. HOWEVER, HOW DOES UNRESTRICTED E2F ACTIVITY INITIATES TUMORIGENESIS IN VIVO IS POORLY UNDERSTOOD AND REMAINS A FUNDAMENTAL GAP IN OUR UNDERSTANDING OF CANCER BIOLOGY. IN PARTICULAR, WHETHER THE DIFFERENTIATION STATUS AFFECT THE CAPACITY OF A CELL TO TRANSFORM UPON DISRUPTION OF RB/E2F INTERACTION IS UNKNOWN. IN ADDITION, WHETHER UNRESTRICTED E2F ACTIVATES OTHER ONCOGENIC FEATURES BESIDES ABERRANT PROLIFERATION IS STILL OBSCURE. HEPATOCELLULAR CARCINOMA (HCC) IS THE SECOND CANCER IN TERMS OF DEATH WORLDWIDE. LIMITED UNDERSTANDING OF THE FUNCTIONAL CONSEQUENCES FOR FREQUENT GENETIC EVENTS HAMPERS THE DEVELOPMENT OF EFFICIENT THERAPEUTICS. THE RB/E2F INTERACTION IS DISRUPTED IN THE VAST MAJORITY OF HCC, AS A CONSEQUENCE OF SEVERAL EVENTS THAT TARGET UPSTREAM COMPONENTS OF THE RB/E2F PATHWAY. THEREFORE, HCC IS A RELEVANT MODEL TO INVESTIGATE THE CONSEQUENCES OF UNRESTRICTED E2F ACTIVITY FOR CANCER INITIATION. ACCORDINGLY, PAN-LIVER INACTIVATION OF RB FAMILY GENES (TRIPLE KNOCK OUT, TKO) IS SUFFICIENT TO INITIATE HCC (TKO HCC) THAT RECAPITULATE MULTIPLE FEATURES OF THE HUMAN DISEASE. STUDIES OF CARCINOGEN-INDUCED MODELS OF HCC HAVE LED TO THE CONCLUSION THAT HEPATOCYTES ARE THE SOLE SOURCE OF HCC. SPECIFIC INACTIVATION OF RB FAMILY IN HEPATOCYTES TRIGGERS A SHORT PROLIFERATIVE BURST BUT FAILS TO INITIATE HCC. THIS RESULT CHALLENGES THE CURRENT HEPATO-CENTRIC MODEL IN THE FIELD AND SUGGESTS THAT OTHER LINEAGES CAN ALSO SERVE AS A CELL OF ORIGIN FOR HCC. ACCORDINGLY, INACTIVATION OF RB FAMILY IN MULTIPLE LIVER LINEAGES REVEALS THAT TKO HCC ARISES FROM A PERIDUCTAL PROGENITOR. IN PARTICULAR, OUR PRELIMINARY DATA INDICATES THAT UNRESTRICTED E2F ACTIVITY COUPLES ABERRANT PROLIFERATION WITH CELL FATE ALTERATION IN THIS POPULATION TO INITIATE HCC. BASED ON THESE DATA, WE PROPOSE TO:1) DETERMINE THE MOLECULAR MECHANISMS THAT ALTER THE CELL FATE OF A PERIDUCTAL PROGENITOR TO SERVE AS A CELL OF ORIGIN FOR TKO HCC. 2) DETERMINE THE INDIVIDUAL AND COMPOUND ROLE OF E2F FACTORS IN TKO HCC INITIATION AND DEVELOPMENT. 3) DETERMINE THERAPEUTIC VULNERABILITIES IN TKO HCC THAT COULD SERVE AS NOVEL TREATMENT FOR PATIENTS. WE BELIEVE THAT OUR PROPOSAL WILL ADDRESS FUNDAMENTAL QUESTIONS REGARDING THE ROLE OF E2F IN CANCER INITIATION, AS IDENTIFIED ABOVE. IN ADDITION, WE EXPECT THAT OUR RESULTS WILL ESTABLISH THAT DIFFERENT CELL LINEAGES CAN SERVE AS A CELL OF ORIGIN FOR HCC, WHICH WILL HAVE IMPORTANT CLINICAL IMPLICATIONS, IN PARTICULAR REGARDING THE CLASSIFICATION OF PATIENTS AND THE DEVELOPMENT OF THERAPIES TAILORED FOR DIFFERENT CLASSES OF HCC.

NOGUCHI INSTITUTE INITIATIVE FOR NTDS ELIMINATION (NIINE)

ENHANCEMENT OF HIV/AIDS LAB TRAINING AND QA CENTER IN THE UR OF TANZANIA

POLYAMINE-STIMULATED STEM CELL RECRUITMENT IN ARSENIC-INDUCED SKIN CANCER

MAINTAINING THE INTEGRITY OF A GENOME - PROJECT SUMMARY/ABSTRACT IN ORDER TO FULLY GRASP THE MOLECULAR ORIGINS OF GENOME INSTABILITY, THE FIELD MUST UNDERSTAND AT A MOLECULAR LEVEL HOW CENTROMERES WORK TO PROMOTE THE STABLE TRANSMISSION OF CHROMOSOMES. GENOME INSTABILITY UNDERLIES A VARIETY OF HUMAN PATHOLOGIES, INCLUDING CANCER AND REPRODUCTIVE AGING. OUR LONG-TERM GOAL IS TO DETERMINE HOW THE EVOLUTIONARILY CONSERVED COHESIN COMPLEX MAINTAINS GENOME INTEGRITY THROUGH ITS ROLES IN CHROMOSOME SEGREGATION, CHROMOSOME ORGANIZATION, AND DOUBLE-STRAND BREAK REPAIR. LOSS OF SISTER CHROMATID COHESION IS SPECULATED TO BE A MAJOR CONTRIBUTOR TO CHROMOSOME INSTABILITY. THE OBJECTIVE OF THIS APPLICATION IS TO PRODUCE A MOLECULAR MODEL FOR HOW COHESIN OPERATES AT INDIVIDUAL HUMAN CENTROMERES TO ACHIEVE CENTROMERIC COHESION AND ACCURATE CHROMOSOME SEGREGATION. THE CENTRAL HYPOTHESIS IS THAT COHESIN AND DNA CATENATION TOGETHER CREATE CENTROMERE-UNIQUE LANDSCAPES OF SISTER CHROMATID COHESION TO PREVENT CHROMOSOME INSTABILITY. THE VARIATION IN HUMAN CENTROMERES AND CENTROMERIC COHESION MAY THEREFORE IMPACT THE TRANSMISSION OF EACH CHROMOSOME. WE WILL TEST THE IDEA THAT CENTROMERE-SPECIFIC COHESION MUST BE CONSIDERED AS A GENETIC DETERMINANT OF SISTER CHROMATID COHESION AND SEGREGATION IN ORDER TO HAVE A COMPLETE MODEL FOR HOW CHROMOSOMAL INSTABILITY OCCURS THROUGH TWO SPECIFIC AIMS: 1) DISCOVER THE LANDSCAPE OF CENTROMERIC COHESION AT INDIVIDUAL HUMAN CENTROMERES AND 2) EXAMINE HOW CHROMOSOME CENTROMERIC COHESION MAINTAINS EUPLOIDY. UNDER THE FIRST AIM, CALIBRATED PAIRED-END CHIP SEQ WILL BE USED TO MAP COHESIN BINDING RELATIVE TO KINETOCHORE PROTEINS AND HUMAN CENTROMERIC ARRAYS IN HUMAN TISSUE CULTURE CELLS. THIS APPROACH WILL BE COMPLEMENTED BY SUPERRESOLUTION IMAGING OF THE SAME THREE COMPONENTS (CENTROMERES, KINETOCHORES, AND COHESIN) IN CELLS, AND WILL INCLUDE IMAGING-BASED DETERMINATION OF CENTROMERE-SPECIFIC COHESION. TOGETHER THESE APPROACHES WILL PRODUCE A LINEAR AND 3D MAP OF COHESION WITHIN AND AROUND INDIVIDUAL HUMAN CENTROMERES. IN THE SECOND AIM WE WILL EXAMINE HOW CENTROMERE-SPECIFIC PATTERNS OF CENTROMERIC COHESION PREVENT CHROMOSOME MISSEGREGATION EVENTS IN CULTURED CELLS AND IN XENOGRAFT TUMOR TISSUE. THE OUTCOME WILL BE FUNDAMENTAL PRINCIPLES OF CENTROMERIC ARRAY-BASED COHESION FATIGUE AND RESULTING PATTERNS OF CHROMOSOME INSTABILITY. THE RESEARCH IS INNOVATIVE BECAUSE IT INCORPORATES THE LATEST INFORMATION ON HUMAN CENTROMERIC DNA ARRAYS, A NEW WORKING MODEL FOR THE ORGANIZATION OF CENTROMERIC DNA BY COHESION, AND NEW QUANTITATIVE MOLECULAR, GENOMIC, AND IMAGING TOOLS TO PROBE HOW CENTROMERIC COHESION ENFORCES ACCURATE SISTER CHROMATID SEGREGATION. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE CENTROMERIC ARRAYS MAY BE UNRECOGNIZED GENETIC DETERMINANTS OF CHROMOSOME INSTABILITY. MANY TYPES OF CANCER ARE ASSOCIATED WITH SEEMINGLY RANDOM PATTERNS OF INSTABILITY THAT MAY HAVE MOLECULAR ORIGINS IN UNIQUE CENTROMERIC COHESION PROFILES. FURTHERMORE, MANY CANCERS ARE ASSOCIATED WITH MUTATIONS THAT IMPACT CHROMOSOME SEGREGATION MACHINERY, SUCH AS COHESIN. THE OUTCOME OF THIS PROJECT WILL BE A MORE COMPLETE PICTURE OF THE MECHANISMS UNDERLYING CHROMOSOMAL INSTABILITY.

THE CONTRIBUTION OF SLEEP AND CIRCADIAN DISRUPTION TO KYNURENINE PATHWAY ACTIVATION AND CARDIOMETABOLIC RISK IN WOMEN WITH HIV

PHYSIOLOGICAL ROLE OF MLL AND ELL PROTEINS IN LEUKEMIA

POWERING UP MALE PREVENTION (PUMP)

DISSECTING SOX9-MEDIATED CANCER STEMNESS AND IMMUNOSUPPRESSION FOR NOVEL STRATEGIES IN ADVANCED GASTRIC ADENOCARCINOMA

EXOSOMAL GALECTIN-3 MEDIATED STROMAL ACTIVATION AND IMMUNOSUPPRESSION IN ADVANCED GASTRIC ADENOCARCINOMA

IDO PATHWAYS IN INFLAMMATORY PATHOGENESIS AND TREATMENT OF RHEUMATOID ARTHRITIS

FEASIBILITY OF AN INGESTIBLE SENSOR SYSTEM TO MEASURE PREP ADHERENCE IN YMSM

CHICAGO ANTIMICROBIAL RESISTANCE AND INFECTION PREVENTION EPI-CENTER (CARPE)

IDENTIFICATION OF GENES ASSOCIATED WITH MYOBLAST FUSION

DEVELOPING BEST PRACTICES OF COMMUNITY ENGAGEMENT FOR GENOMICS AND BIOBANKING IN AFRICA - CEBIOGEN

PROBING AN UNEXPLORED INTRACELLULAR PATHWAY IN DIABETES PATHOGENESIS - ABSTRACT DIABETIC NEPHROPATHY AND OTHER DIABETES COMPLICATIONS IMPOSE ENORMOUS BURDENS ON PATIENTS AND HEALTHCARE SYSTEMS, MAKING IT IMPERATIVE TO DEFINE ACTIONABLE ETIOLOGIC FACTORS AND DEVELOP EFFECTIVE, LOW-COST THERAPEUTIC INTERVENTIONS. NONENZYMATIC PROTEIN GLYCATION AND THE FORMATION OF ADVANCED GLYCATION END PRODUCTS (AGES) ARE STRONGLY IMPLICATED IN PATHOGENESIS. THE DRIVER OF AGE FORMATION IS 3-DEOXYGLUCOSONE (3DG), A HIGHLY REACTIVE DICARBONYL SPECIES THAT ALSO CAUSES ACUTE CELLULAR TOXICITIES BY DAMAGING ENZYMES AND DNA AND INFLAMING THE VASCULATURE. ACCORDINGLY, THE ABILITY TO ACCURATELY MEASURE 3DG LEVELS AND UNDERSTAND ITS ETIOLOGY ARE PARAMOUNT TO ELUCIDATING PATHOGENESIS, LIMITING ITS PATHOGENIC EFFECTS, AND IMPROVING CLINICAL MANAGEMENT OF DIABETIC COMPLICATIONS. ENDOGENOUS 3DG WAS DEEMED TO ARISE NONENZYMATICALLY FROM THE SLOW DISINTEGRATION OF GLYCATED PROTEINS IN THE BODY OR ABSORBED FROM INGESTED HEAT-PROCESSED FOODS. WE DEVELOPED NEW METHODS TO STUDY THE ENZYMATIC ACTIVITY OF FRUCTOSAMINE-3-KINASE (FN3K), AN ENZYME THOUGHT TO REPAIR GLYCATED PROTEINS AND PREVENT AGE, BUT AN END-PRODUCT OF FN3K ACTIVITY IS 3DG. WE DISCOVERED THAT 3DG LEVELS IN KIDNEY ARE HIGHER THAN PREVIOUSLY ANTICIPATED. OUR CORE HYPOTHESIS IS THAT FN3K-MEDIATED 3DG FORMATION IN CELLS IS A KEY PATHOGENIC DRIVER IN DIABETIC COMPLICATIONS. SPECIFIC AIM 1: WE WILL MEASURE 3DG ARISING IN TISSUES IN RELATIONSHIP TO PATHOGENESIS IN THE KK.CG-AY/J MURINE MODEL OF TYPE-2 DIABETES. SPECIFIC AIM 2: THE IMPACT OF A HIGH GLYCATION DIET ON 3DG LEVELS WILL BE MEASURED IN TISSUES SENSITIVE TO DIABETIC COMPLICATIONS, INCLUDING IN THE KIDNEY, HEART, AND LIVER OF THE DIABETIC MICE. SPECIFIC AIM 3: WE WILL DEFINE THE PHARMACODYNAMIC PROPERTIES AND MODES OF ACTION FOR MEGLUMINE, AN AGENT, ALREADY PROVEN SAFE, THAT WE DISCOVERED HAS UNRECOGNIZED MEDICINAL EFFECTS, HAVING PROVIDED NEPHROPROTECTION AND PREVENTED TRIGLYCERIDE ACCUMULATION IN DIABETIC MICE. SPECIFIC AIM 4: A SERIES OF FN3K ANTAGONISTS THAT WE DISCOVERED WILL BE CHARACTERIZED TO IDENTIFY A PRECLINICAL DRUG DEVELOPMENT CANDIDATE. THIS PROPOSAL OFFERS SEVERAL MAJOR INNOVATIVE ELEMENTS OF HIGH SIGNIFICANCE AND IMPACT IN DIABETES TRANSLATIONAL RESEARCH. AIM 1 WILL PROVIDE NEW DATA DEVELOPED WITH METHODOLOGY WE REFINED TO MEASURE FN3K ACTIVITY AND 3DG FORMATION MORE ACCURATELY, ADDRESSING KEY GAPS IN KNOWLEDGE. AIM 2 WILL EXPLORE THE LINKAGE BETWEEN INTRACELLULAR 3DG ELEVATION AND THE CONSUMPTION OF ‘WESTERN’ DIETS RICH IN FRUCTOSAMINES—THE SUBSTRATE FOR FN3K. DRUG SAFETY IS PARAMOUNT FOR ANY NEW DIABETES DRUG. THE DATA FROM AIM 3 WILL ACCELERATE THE DEVELOPMENT OF MEGLUMINE AS AN INNOVATIVE TREATMENT MODALITY—A COMPOUND PROVEN EXTREMELY SAFE FOR CHRONIC ADMINISTRATION—TO AMELIORATE DIABETIC NEPHROPATHY, FATTY LIVER, AND POTENTIALLY OTHER DIABETIC COMPLICATIONS. AIM 4 OFFERS OPPORTUNITY TO DELIVER FIRST-IN-CLASS ENZYME INHIBITORS AS POTENTIAL DRUG LEAD CANDIDATES. IN SUMMARY, THIS RESEARCH PROGRAM WILL ILLUMINATE AN UNEXPLORED INTRACELLULAR PATHWAY IN DIABETES PATHOGENESIS AND DELIVER UNPRECEDENTED TOOLS FOR BROADER RESEARCH INTO THE ROLE OF 3DG IN DIABETIC NEPHROPATHY AND OTHER DIABETES COMPLICATIONS.

RYAN WHITE CARE ACT TITLE IV ADOLESCENT INITIATIVE

IN VIVO ANALYSIS OF THE MECHANISMS OF NEURAL CREST MIGRATION

CONTRIBUTIONS OF PROTEIN AGGREGATION TO GENE REGULATION AND PHENOTYPIC DIVERSITY

DRUG-INDUCED REGENERATION AND RE-INNERVATION IN A MOUSE DIGIT AMPUTATION MODEL

INHIBITOR REPROGRAMMING OF A HUMAN HISTONE DEACETYLASE PROTEIN INTERACTION NETWORK

BIOCHEMISTRY OF EUKARYOTIC MESSENGER RNA SYNTHESIS

PRIMARY CARE TRAINING AND ENHANCEMENT

MOLECULAR MECHANISMS OF CHROMOSOME SEGREGATION IN YEAST

MECHANISMS OF TRANSCRIPTIONAL REGULATION IN CHROMATIN

HEALTH CARE AND OTHER FACILITIES

IDO INHIBITORS FOR COMBINATORIAL CANCER THERAPY

SPECIAL PROJECTS OF NATIONAL SIGNIFICANCE

MITOTIC ROUNDING AND PLANAR SPINDLE ALIGNMENT IN PROLIFERATING EPITHELIA

MOLECULAR MECHANISMS AND EVOLUTIONARY IMPACTS OF THE WTF MEIOTIC DRIVERS - PROJECT SUMMARY/ABSTRACT GENOMES ARE PLAGUED BY PARASITIC DNA SEQUENCES THAT DO NOT PROMOTE HEALTH OR FERTILITY. MEIOTIC DRIVE GENES ARE ONE SUCH CLASS OF GENETIC PARASITE THAT SELFISHLY MANIPULATE GAMETOGENESIS TO INCREASE THEIR OWN TRANSMISSION INTO THE NEXT GENERATION. RATHER THAN BEING PASSED TO HALF OF AN INDIVIDUAL’S OFFSPRING, LIKE REGULAR ALLELES, MEIOTIC DRIVERS MANIPULATE GAMETOGENESIS TO ENSURE THEIR TRANSMISSION TO MOST, OR EVEN ALL, THE OFFSPRING. DRIVERS ARE FOUND THROUGHOUT EUKARYOTES, INCLUDING HUMANS, BUT MANY MORE LIKELY REMAIN TO BE IDENTIFIED. CHARACTERIZING MEIOTIC DRIVERS IS IMPORTANT BECAUSE THESE PARASITES CAN HAVE MAJOR IMPACTS ON FERTILITY AND HEALTH. MEIOTIC DRIVERS CAN CONTRIBUTE TO INFERTILITY DIRECTLY BY DISRUPTING MEIOTIC CHROMOSOME SEGREGATION OR BY DESTROYING GAMETES THAT INHERIT THE COMPETING ALLELE. MEIOTIC DRIVERS CAN ALSO CAUSE INFERTILITY OR OTHER DISEASE STATES INDIRECTLY BY PROMOTING THE SPREAD OF LINKED DELETERIOUS (E.G., DISEASE-ASSOCIATED) ALLELES. DESPITE THEIR LARGE IMPACT, THERE IS RELATIVELY LITTLE MOLECULAR UNDERSTANDING OF MEIOTIC DRIVERS OR THEIR EVOLUTIONARY IMPACTS. HOWEVER, THERE ARE EMERGING THEMES THAT UNITE MANY KNOWN DRIVE SYSTEMS, INCLUDING THE USE OF A POISON/ANTIDOTE MECHANISM AND THE ASSOCIATION OF MEIOTIC DRIVE GENES WITH DISTRIBUTED DNA SEQUENCE REPEATS. THIS PROPOSAL EXPLOITS A HIGHLY TRACTABLE MODEL, THE WTF GENE FAMILY FOUND IN FISSION YEASTS, TO INVESTIGATE THE MOLECULAR MECHANISMS AND EVOLUTIONARY IMPACTS OF DRIVE SYSTEMS. THE WTF GENES ENACT DRIVE BY DESTROYING THE WTF- GAMETES PRODUCED BY WTF+/WTF- HETEROZYGOTES. EACH WTF DRIVER ENCODES BOTH A POISON PROTEIN AND A SEPARATE ANTIDOTE PROTEIN ON OVERLAPPING CODING SEQUENCES. ALL DEVELOPING GAMETES ARE POISONED, BUT THOSE THAT INHERIT THE WTF+ ALLELE ARE RESCUED BY THE ANTIDOTE. THIS PROPOSAL AIMS TO UNDERSTAND THE MECHANISMS UNDERLYING THE TOXICITY OF WTF POISON PROTEINS AND HOW THE WTF ANTIDOTE PROTEINS RESCUE THAT TOXICITY. ANALOGOUS TO OTHER DRIVE SYSTEMS, THE WTF GENES ARE FLANKED BY SHORT REPETITIVE DNA SEQUENCES (TRANSPOSON-DERIVED REPEATS OR 5S RDNA GENES). THE PROPOSED WORK WILL TEST THE IDEA THAT THE REPEATS FLANKING WTF GENES AFFECT THEIR EVOLUTION BY PROMOTING NON-ALLELIC GENE CONVERSION. FINALLY, THE PROPOSED RESEARCH PROGRAM WILL EXPLORE THE EVOLUTIONARY IMPACT OF THE WTF GENES ON THE FLANKING 5S RDNA GENES. SPECIFICALLY, WE WILL TEST THE HYPOTHESIS THAT THE WTF DRIVERS HAVE PROMOTED THE MAINTENANCE OF DELETERIOUS VERSIONS OF THE 5S RDNA GENES, WHICH ENCODE AN ESSENTIAL COMPONENT OF RIBOSOMES. THIS RESEARCH PROGRAM WILL GREATLY EXPAND OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS AND MOLECULAR EVOLUTION OF MEIOTIC DRIVE SYSTEMS. THIS KNOWLEDGE WILL HELP GUIDE THE SEARCH FOR AND THE MOLECULAR CHARACTERIZATION OF MEIOTIC DRIVERS IN MORE COMPLEX SYSTEMS, INCLUDING HUMANS. MORE BROADLY, THIS WORK WILL EXPAND OUR UNDERSTANDING OF DNA PARASITES AND HOW THEY CAN DIRECTLY AND INDIRECTLY IMPACT HEALTH, PARTICULARLY INFERTILITY. THIS EXPANDED UNDERSTANDING SHOULD ULTIMATELY LEAD TO IMPROVED REPRODUCTIVE OUTCOMES IN HUMANS.

(PQA2) MAMMALIAN REGENERATION, HIGH FAT DIETS, AND BREAST CANCER: A COMMON LINK

TARGETED NANOPARTICLE DNA THERAPY FOR OVARIAN CANCER

FVPSA AMERICAN RESCUE PLAN COVID-19 TESTING, VACCINES, AND MOBILE HEALTH UNITS SUPPLEMENTAL FUNDING

PREPAREDNESS AND RESPONSE TO AVIAN AND PANDEMIC INFLUENZA IN UNITED REP OF TANZAN

ASSEMBLY AND REGULATION OF YEAST SPINDLE POLES

ELUCIDATING MECHANISMS OF AMYLOID NUCLEATION IN VIVO

MECHANISMS OF TRANSCRIPTIONAL REGULATION IN CHROMATIN

FAMILY VIOLENCE PREVENTION AND SERVICES PROGRAM

THE NETWORK BIOLOGY OF PATHOGEN-HOST INTERACTIONS DRIVING EXACERBATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

IMPROVING EVALUATION CAPACITY WITHIN THE GOVERNMENT OF TANZANIA UNDER PEPFAR