Baylor College Of Medicine

NATIONAL SPACE BIOMEDICAL RESEARCH INSTITUTE

GENOMES AND GENETICS AT THE BCM-HGSC

THIS PROPOSAL FOR A TRANSLATIONAL RESEARCH INSTITUTE IS SUBMITTED ON BEHALF OF A CONSORTIUM OF NON-PROFIT ACADEMIC INSTITUTIONS IN RESPONSE TO NASA C

GENOMIC ARCHITECTURE OF COMMON DISEASE IN DIVERSE POPULATIONS

THE GOAL OF THE CORE ACTIVITY IS TO REDUCE NEW HIV INFECTIONS AND HIV MORBIDITY AND MORTALITY RATES IN MALAWI THROUGH INCREASING ACCESS TO AND UTILIZATION OF HIGH-QUALITY, COMPREHENSIVE SERVICES ACROSS THE CONTINUUM OF HIV TREATMENT AND CARE WITHIN THE SUB-NATIONAL UNITS (SNUS) OR DISTRICTS WHERE IT OPERATES.

ACCELERATING EPIDEMIC CONTROL IN FORT PORTAL REGION IN THE REPUBLIC OF UGANDA UNDER THE PRESIDENT'S EMERGENCY PLAN FOR AIDS RELIEF (PEPFAR)

BAYLOR COLLEGE OF MEDICINE CANCER CENTER

SCALING UP COMPREHENSIVE HIV/AIDS SERVICES FOR ADULTS AND CHILDREN IN THE EASTERN

KARABO EA BOPHELO (KB) (WHICH TRANSLATES AS `A SOLUTION TO GOOD HEALTH¿) IS A FIVE-YEAR ACTIVITY TO PREVENT NEW HIV INFECTIONS AND REDUCE VULNERABILITY AMONG ORPHANS AND VULNERABLE CHILDREN (OVC) AND ADOLESCENT GIRLS AND YOUNG WOMEN (AGYW) IN LESOTHO. THE STRATEGIC OBJECTIVE SUPPORTS GOVERNMENT OF LESOTHO (GOL) MULTI-SECTOR STRATEGIES AND PRIORITIES FOR HIV MITIGATION AND PREVENTION, WITH AN EMPHASIS ON MINIMIZING NEGATIVE IMPACTS OF HIV ON OVC AND AGYW, ADDRESSING SOCIAL, BEHAVIORAL AND STRUCTURAL DRIVERS OF HIV, AND IMPROVING ACCESS TO COMPREHENSIVE SEXUAL REPRODUCTIVE HEALTH (SRH) SERVICES TO PREVENT NEW INFECTIONS.

TECHNICAL SUPPORT TO PEPFAR PROGRAMS IN THE SOUTHERN AFRICA REGION

CONSORTIUM FOR LARGE-SCALE PRODUCTION AND PHENOTYPING OF KNOCKOUT MICE (UM1)

SPORE IN LYMPHOMA

MULTI-REGIONAL MECHANISM FOR ACCELERATING AND SUSTAINING EPIDEMIC CONTROL IN FORT PORTAL REGION IN THE REPUBLIC OF UGANDA THROUGH THE PRESIDENT?S EMERGENCY PLAN FOR AIDS RELIEF (PEPFAR) - MULTI-REGIONAL MECHANISM FOR ACCELERATING AND SUSTAINING EPIDEMIC CONTROL IN FORT PORTAL REGION IN THE REPUBLIC OF UGANDA THROUGH THE PRESIDENT’S EMERGENCY PLAN FOR AIDS RELIEF (PEPFAR)

ACCELERATING AND SUSTAINING HIV EPIDEMIC CONTROL AND RELATED DISEASES IN WESTERN AND WEST NILE REGIONS IN THE REPUBLIC OF UGANDA UNDER THE PRESIDENT'S EMERGENCY PLAN FOR AIDS RELIEF (PEPFAR)

STRENGTHENING NATIONAL PEDIATRIC HIV/AIDS SCALING UP COMPREHENSIVE HIV/AIDS SERVI

GENOMIC APPROACHES TO UNDERSTAND DISEASE SUSCEPTIBILITY AND PATHOGENESIS OF SARS-COV-2

CENTER FOR PROTEIN FOLDING MACHINERY (RMI)

NOVEL DIAGNOSTICS AND THERAPEUTICS FOR CALICIVIRUSES

NEW CA IN THE AMOUNT OF THE AGREEMENT $45 000 000; TOTAL ESTIMATED GOVERNMENT FUNDING $22 500 000. OBLIGATED $500 000. ACTIVITIES: TO HELP GOVERNMENT

TO SUPPORT THE IMPLEMENTATION OF DISTRICT-BASED INTEGRATED HIV/AIDS AND TB SERVICES IN EASTERN UGANDA.

BAYLOR COLLEGE OF MEDICINE/STANFORD UNIVERSITY CLINICAL GENOME RESOURCE (CLINGEN) - PROJECT SUMMARY/ABSTRACT THE CLINICAL GENOME RESOURCE (CLINGEN) IS AN ESSENTIAL COMMUNITY RESOURCE DEVELOPING CLINICALLY RELEVANT GENOMIC KNOWLEDGE. THREE RESEARCH TEAMS AT HARVARD/GEISINGER, UNC/KAISER AND BAYLOR COLLEGE OF MEDICINE/STANFORD HAVE WORKED COLLABORATIVELY SINCE 2013 TO CREATE SUCCESSFUL FRAMEWORKS AND SOFTWARE SYSTEMS FOR SUSTAINED CURATION OF THE HUMAN GENOME. THE LANDMARK ACHIEVEMENT IN 2018 OF FDA RECOGNITION AS THE FIRST PUBLIC HUMAN GENETIC VARIANT DATABASE SIGNIFICANTLY INCREASED CLINGEN'S PROMINENCE AS AN INNOVATIVE GENOME CURATION PROGRAM. CLINGEN'S STRATEGY HAS BEEN HIGHLY SUCCESSFUL: CREATING THE TRAINING, FRAMEWORK AND OVERSIGHT FOR INTERNATIONAL EXPERT PANELS (OVER 1400 MEMBERS), WHILE GENERATING DYNAMIC USER- INFORMED PUBLIC TOOLS INCLUDING THE CLINGEN CURATION INTERFACES, ALLELE REGISTRY AND LINKED DATA HUB. THIS MULTI- INSTITUTIONAL APPLICATION FROM BAYLOR COLLEGE OF MEDICINE AND STANFORD UNIVERSITY IN RESPONSE TO PAR-20-100 GENOMIC COMMUNITY RESOURCES TO SUPPORT OUR ONGOING DEVELOPMENT OF THE INNOVATIVE ADVANCED WEB TECHNOLOGIES FOR SOFTWARE INFRASTRUCTURE THAT SUPPORTS CLINGEN’S GENE, VARIANT AND ACTIONABILITY CURATION EFFORTS. IN THIS APPLICATION WE SEEK TO OPERATE AT SCALE, GENERATING PROCEDURES AND INFORMATICS FOR HIGH-THROUGHPUT CURATION ACROSS CLINGEN DOMAINS. WE PROPOSE MULTIPLE IMPROVEMENTS TO SCALE OUR WORK THROUGH STREAMLINED AGGREGATION AND LINKING OF GENOMIC AND PHENOTYPIC DATA INCLUDING SOURCES FROM DIVERSE POPULATIONS (AIM 1) SEMI-AUTOMATION FOR GENE AND VARIANT CURATION (AIM 2) AND ACTIONABILITY CURATION (AIM 3). WE ANTICIPATE NEW FACETS OF CLINICAL GENOMICS INCLUDING STANDARDS FOR VARIANT CLASSIFICATION IN HEREDITARY AND SOMATIC CANCER, FORGING NOVEL CURATION APPROACHES INCLUDING CURATION OF POLYGENIC RISK SCORES (PRS) AND MODELING CURATION OF COMPLEX DISORDERS IN HLA-RELATED RHEUMATOLOGIC AND AUTOIMMUNE DISEASES (AIM 4). WE HAVE DEVELOPED INNOVATIVE FRAMEWORKS FOR APPROPRIATE USE OF ANCESTRY AND DIVERSITY IN CLINICAL GENOMICS, WHILE IN PARALLEL WORKING TO EXPAND THE DIVERSITY OF THE CLINGEN WORKFORCE AND USERS OF CLINGEN CURATED KNOWLEDGE (AIM 5).

VACCINE AND TREATMENT EVALUATION UNITS (VTEU)

EXPANSION OF NATIONAL PEDIATRIC HIV/AIDS PREVENTION, CARE AND TREATMENT AND TRAIN

TRANSLATIONAL RESEARCH IN BREAST CANCER (SPORE)

INCORPORATION OF GENOMIC SEQUENCING INTO PEDIATRIC CANCER CARE

CENTER FOR GI INFECTION AND INJURY

ENHANCING T CELL THERAPY OF CANCER

STRENGTHENING NATIONAL PEDIATRIC HIV/AIDS SCALING UP COMPREHENSIVE HIV/AIDS SERVI

IMPROVING HEALTH SECURITY AND BUILDING INTERNATIONAL HEALTH REGULATIONS CORE CAPACITIES IN THE REPUBLIC OF UGANDA

THE PATHOGENESIS OF HIV-ASSOCIATED NEPHROPATHY

CONSORTIUM FOR LARGE-SCALE PRODUCTION AND CRYOPRESERVATION OF KNOCKOUT MICE

CENTER FOR IDENTIFICATION AND STUDY OF INDIVIDUALS WITH ATYPICAL DIABETES MELLITUS (U54)

CONSORTIUM FOR BROAD BASED DISEASE PHENOTYPING OF KNOCKOUT MICE

BRITTLE BONE DISORDERS CONSORTIUM OF THE RARE DISEASE CLINICAL RESEARCH NETWORK

INTERNATIONAL CASE CONTROL STUDY OF MALIGNANT GLIOMA

NUCLEAR RECEPTORS AND COREGULATORS IN HEALTH AND DISEASE

DEVELOPMENT OF COACTIVATOR-DEPENDENT, FIRST-IN-CLASS THERAPIES FOR BREAST CANCER

COMPREHENSIVE SOMATIC VARIANT CHARACTERIZATION AT THE HGSC - STUDIES OF SOMATIC MUTATIONS HAVE SO FAR FOCUSED ON PATHOGENIC VARIATION, LEADING TO CANCER OR SEVERE DISEASE. THE SOMATIC MOSAICISM ACROSS HUMAN TISSUES (SMAHT) PROGRAM WILL NOW EXPAND KNOWLEDGE OF THIS CRITICAL CLASS OF GENOMIC VARIATION IN NORMAL TISSUES AND BUILD A COMPREHENSIVE UNDERSTANDING OF THE BIOLOGY OF SOMATIC VARIATION IN ALL CONTEXTS. THE GENOME CHARACTERIZATION CENTER AT THE BAYLOR COLLEGE OF MEDICINE HUMAN GENOME SEQUENCING CENTER (HGSC) WILL CHARACTERIZE VARIATION IN 750 TISSUE SAMPLES - 1/3 OF THE PROGRAM’S 15 SAMPLES FROM EACH OF 150 INDIVIDUALS. NOVEL STEPS HAVE BEEN INCORPORATED INTO OUR STUDY DESIGN TO ENABLE COMPREHENSIVE DISCOVERY OF SOMATIC MUTATIONS. BOTH COMMON CORE ASSAY TYPES (WGS SHORT-READ, LONG READ AND BULK RNASEQ) AND TWO ADDITIONAL ASSAYS (NANOSEQ AND SNRNASEQ) THAT OUR GROUP SPECIALIZES WILL BE USED FOR DATA GENERATION. BENCHMARK STANDARDS, HARMONIZED DATA STRUCTURES AND SOPS WILL BE CREATED IN COLLABORATION WITH OTHER NETWORK MEMBERS USING ESTABLISHED STATE-OF-THE-ART METHODS FOR DISCOVERY AND ORTHOGONAL APPROACHES FOR TECHNICAL VALIDATION. NEW TECHNOLOGIES THAT SATISFY PERFORMANCE CRITERIA WILL BE INTRODUCED INTO PRODUCTION. STATISTICAL MODELS WILL GUIDE TISSUE-SUBSAMPLING AND SEQUENCING STRATEGIES, SET THE CURRENT THRESHOLDS WITH FURTHER ROOM FOR IMPROVEMENT. NANOSEQ AND SINGLE NUCLEAR RNA PROCEDURES WILL EACH BE MODIFIED FOR ENHANCED PERFORMANCE AND CLOSE COLLABORATION WITH INVESTIGATORS DEVELOPING ADDITIONAL TOOLS WILL ENSURE OPTIMAL DISCOVERY. LOCAL ANALYSES WILL GENERATE LISTS OF PUTATIVE VARIANTS, WITH A PARTICULAR FOCUS UPON CHARACTERIZATION OF LONG READ SEQUENCE DATA. THE LATTER WILL ENABLE MODELLING OF TRANSPOSITION EVENTS, REVEALED WITHIN EVIDENCE FOR STRUCTURAL VARIATION, AS WELL AS CHANGES IN PATTERNS OF EPIGENETIC MARKS. ALL DATA WILL BE SUBJECTED TO RIGOROUS QA/QC, IN COLLABORATION WITH THE DAC, AND MIRRORED IN THE CENTRALIZED DATA REPOSITORY.

NRI BUILD-OUT: ADVANCING TRANSLATIONAL BRAIN RESEARCH

POLYCYCLIC AROMATIC HYDROCARBONS: ULTRASENSITIVE DETECTION, EARLY LIFE EXPOSURES-CLINICAL OUTCOMES (PRETERM BIRTHS, CHRONIC LUNG DISEASE, AND NEUROCOGNITIVE DEFICITS), PREVENTION AND REMEDIATION

BAYLOR MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIE*

DATA MANAGEMENT AND RESOURCE REPOSITORY FOR THE EXRNA ATLAS

PEDIATRIC CLINICAL ONCOLOGY RESEARCH TRAINING PROGRAM

MTOTO BOMBA ACTIVITY

BCM CLINICAL SITE FOR AN UNDIAGNOSED DISEASES NETWORK (UDN)

GENETIC AND METABOLIC FINGERPRINTS OF COACTIVATORS "PROGRAM PROJECT"

BAYLOR COLLEGE OF MEDICINE - MENDELIAN GENOMICS RESEARCH CENTER (BCM-MGRC) - PROJECT SUMMARY THE PROPOSED BAYLOR COLLEGE OF MEDICINE MENDELIAN GENOMICS RESEARCH CENTER (BCM-MGRC) BUILDS ON THE EXTENSIVE DISCOVERIES AND INFRASTRUCTURE ESTABLISHED IN THE BAYLOR HOPKINS CENTER FOR MENDELIAN GENOMICS. THIS RESEARCH PROGRAM IS NESTED WITHIN THE DEPARTMENT OF MOLECULAR AND HUMAN GENETICS AT BCM AND WILL BENEFIT FROM AN EXTENSIVE COLLABORATIVE RESEARCH INFRASTRUCTURE WHICH INCLUDES, THE HUMAN GENOME SEQUENCING CENTER, THE UNDIAGNOSED DISEASES NETWORK CLINICAL SITE, THE UNDIAGNOSED DISEASES NETWORK MODEL ORGANISM SCREENING CENTER, BAYLOR GENETICS DIAGNOSTIC LABORATORY, AND THE BAYLOR KNOCKOUT MOUSE PROGRAM. NOTABLY, EACH OF THESE PROGRAMS HAS ESTABLISHED THEIR OWN NATIONAL AND INTERNATIONAL COLLABORATIONS. A PHENOTYPICALLY AND ETHNICALLY DIVERSE, INTERNATIONAL COHORT OF ~15,000 INDIVIDUALS AND FAMILIES WITH CHALLENGING-TO-DIAGNOSE RARE DISEASE CONDITIONS (THOSE UNSOLVED BY ROUTINE CLINICAL STUDIES SUCH AS EXOME SEQUENCING) AND WHO ARE RE-CONTACTABLE AND CONSENTED FOR BROAD DATA-SHARING WILL FORM THE BASIS OF THE BCM- MGRC RESEARCH PROGRAM. THE CENTER WILL INTEGRATE NOVEL METHODS OF GENOMIC DATA ANALYSIS, DATA SHARING ACROSS NETWORKS, IMPLEMENTATION OF NEWER GENOMIC SEQUENCING TECHNOLOGIES, AND METHODS FOR MOLECULAR AND ORGANISMAL PHENOTYPIC INTERROGATION OF PRIORITIZED CANDIDATE DISEASE GENES AND VARIANTS. THE EXISTING DATA LAKE INFRASTRUCTURE WILL INTEGRATE WITH THE MENDELIAN GENOMICS DATA COORDINATING CENTER (MGDCC) AND ANVIL TO SHARE KEY DELIVERABLES INCLUDING GENOMIC AND PHENOTYPIC DATA, CASE METADATA, AND A BCM-MGRC- DEVELOPED GENOMIC MEDICINE TOOLBOX. AS A FULLY INTEGRATED MENDELIAN GENOMICS RESEARCH CENTER, THE BCM- MGRC WILL INFORM DEVELOPMENT AND DELIVERY OF AN ALGORITHM FOR SOLVING THE UNSOLVED THAT WILL TACKLE COMPLEX MOLECULAR MECHANISMS IN THE RARE AND COMMON DISEASE RESEARCH SPACE, WITH SEAMLESS INTEGRATION OF ANTICIPATED DISCOVERIES TO SUPPORT CLINICAL DIAGNOSTICS AND THE GENERATION OF MOLECULAR FLOORPLANS FROM WHICH TO DEVELOP PRECISION THERAPEUTICS.

LYSOSOME REGULATION AND SIGNALING IN AGING AND ALZHEIMER'S DISEASE - NO ABSTRACT AVAILABLE

PROVIDE A CONTINUUM OF CARE FOR INFECTED WOMEN AND THEIR INFANTS SATRTING AT ANC AND CONTINUING UNTIL A DEFINITIVE POSITIVE OR NEGATIVE DIAGNOSIS OF

PATHOGENESIS OF NOVEL FORMS OF OSTEOGENESIS IMPERFECTA

ENGINEERING NOVEL ENTEROID MODELS FOR UNDERSTANDING HUMAN ENTERIC DISEASE

BCM CENTER FOR PRECISION MEDICINE MODELS

ELIMINATION OF HIV THROUGH THE EXPANSION OF ACCESS TO SERVICES AND CAPACITY BUILDING TO IMPROVE COMMUNITY-BASED HIV PREVENTION, CASE IDENTIFICATION AND TREATMENT INITIATION - BAYLOR COLLEGE OF MEDICINE CHILDREN'S FOUNDATION LESOTHO (BAYLOR LESOTHO) PROPOSES THE RE PHELA METSENG ("WE LIVE IN COMMUNITIES" IN THE SESOTHO LANGUAGE) PROJECT, A HIGH-IMPACT COMMUNITY-BASED PLATFORM FOR DELIVERY OF COMPREHENSIVE, COORDINATED HIV PREVENTION, TESTING, AND TREATMENT INITIATION SERVICES FOR SUSTAINED EPIDEMIC CONTROL IN LESOTHO TO BE IMPLEMENTED IN ALL 10 DISTRICTS OF LESOTHO. LED BY BAYLOR LESOTHO, RE PHELA METSENG'S PARTNERS ARE THE LESOTHO NETWORK OF PEOPLE LIVING WITH HIV/AIDS AND ELIZABETH GLAZER PEDIATRIC AIDS FOUNDATION. OUR NETWORK OF LOCAL AND COMMUNITY-BASED PARTNERS WILL EXPAND ACCESS TO HARD-TO-FIND PLHIV IN COMMUNITIES AND IMPROVE ACCESS TO HIGH-IMPACT, COMMUNITY-BASED HIV PREVENTION, TREATMENT, AND SUPPORT SERVICES. WE WILL USE REAL-TIME PROGRAM AND SURVEY DATA TO MAP CLUSTERS OF NEW HIV INFECTIONS BY GEOGRAPHY AND POPULATION, AND DELIVER HIGH IMPACT EVIDENCE-BASED HIV PREVENTION, TESTING AND TREATMENT SERVICES TO ENSURE LESOTHO ENDS HIV/AIDS BY 2030. IN RECOGNITION OF COMMUNITY ENGAGEMENT AS A FIRST PRIORITY AND OF THE IMPACT OF PEER SUPPORT, WE WILL ENGAGE AND TRAIN YOUNG PEOPLE INCLUDING ADOLESCENTS LIVING WITH HIV TO CONDUCT LISTENING SESSIONS AT BASELINE, TO SENSITIZE PEERS FOR DEMAND GENERATION OF SERVICES AND TO PROVIDE HIV TESTING SERVICES. THROUGH THE DEPLOYMENT OF MULTI-DISCIPLINARY ROVING AND NON-ROVING TEAMS AT THE COMMUNITY LEVEL, RE PHELA METSENG WILL ENSURE THE UPTAKE OF COMPREHENSIVE BEHAVIORAL AND BIOMEDICAL PREVENTION INTERVENTIONS, IMMEDIATE ART INITIATION IN COMMUNITIES AND ADHERENCE SUPPORT. RECENCY TESTING DATA WILL BE ANALYZED REGULARLY TO DELIVER TARGETED INTERVENTIONS MAPPED TO GEOGRAPHIC HOT SPOTS TO ENSURE EFFICIENT USE OF RESOURCES. RE PHELA METSENG WILL ENSURE SEAMLESS BI-DIRECTIONAL REFERRALS BETWEEN COMMUNITY AND FACILITY SERVICE DELIVERY POINTS, USING APPROVED MOH REFERRAL TOOLS ALONG WITH PHYSICAL ACCOMPANIMENT AND TELEPHONE TRACKING OF CLIENTS AMONG COMPLEMENTAR Y PROGRAMS. AT COMMUNITY LEVEL, MULTI-DISCIPLINARY, MULTI-PARTNER ROVING TEAMS WILL COLLABORATE WITH NON-ROVING PERSONNEL AND COMMUNITY SYSTEMS STRENGTHENING STAFF TO ENSURE COMPREHENSIVE SERVICE DELIVERY, WITH DISTRICT-LEVEL COORDINATORS STRENGTHENING PROGRAM INTEGRATION AND ENSURING EFFICIENCY AND CLIENT ENGAGEMENT. NATIONAL, REGIONAL, AND DISTRICT-LEVEL PERSONNEL WILL SUPPORT ORGANIZATIONAL AND TECHNICAL CAPACITY BUILDING FOR LIPS; STRENGTHEN ENGAGEMENT WITH COMMUNITY LEADERSHIP STRUCTURES AND SUPPORT COORDINATION EFFORTS FOR A CONDUCIVE COMMUNITY HIV RESPONSE AND STRENGTHEN DISTRICT HEALTH MANAGEMENT TEAMS’ COMMUNITY-LEVEL ENGAGEMENT TO SUPPORT HEALTH FACILITY LINKAGES. THE SUCCESS OF THE RE PHELA METSENG PROJECT WILL BE MEASURED BY THE ACHIEVEMENT OF TARGETS AND DELIVERABLES IN ALIGNMENT WITH SHORT, MEDIUM AND LONG-TERM OUTCOMES. SHORT-TERM OUTCOMES WILL INCLUDE; INCREASED HIV CARE AND TREATMENT SERVICE PROVISION EFFICIENCY; INCREASED COMMUNITY-BASED HIV CASE-FINDING EFFICIENCY; INCREASED HIV SELF-TEST DISTRIBUTION FOR TARGETED POPULATIONS; IMPROVED COMMUNITY-BASED HIV PREVENTION SERVICES FOR VULNERABLE AND HIGH-RISK POPULATIONS; INCREASED KNOWLEDGE OF DATA USE AND EVIDENCE-BASED COMMUNITY HIV RESPONSE AMONG IDENTIFIED LOCAL PARTNERS; INCREASED CAPACITY OF LOCAL PARTNERS TO SUPPORT COMMUNITY-BASED HIV RESPONSE; INCREASED UPTAKE OF DREAMS PACKAGE OF SERVICES; INCREASED KNOWLEDGE OF HIV STATUS AMONG AGYWS; INCREASED TARGETING AND PARTICIPATION OF AGYW SEXUAL PARTNERS. INTERMEDIATE OUTCOMES WILL INCLUDE; INCREASED IDENTIFICATION OF NEW HIV INFECTION CLUSTERS; INCREASED AWARENESS AND UTILIZATION OF COMMUNITY-BASED HIV SERVICES IN PROJECT COMMUNITIES; INCREASED DATA USE BY LOCAL COMMUNITY PARTNERS TO INFORM SUSTAINABLE PROGRAM IMPLEMENTATION; INCREASED COVERAGE OF DREAMS PACKAGE ; REDUCED RISK OF HIV AND STI ACQUISITION IN AGYW AND S

MICROBIOME DISCOVERY AND MECHANISMS TO COMBAT ANTIBIOTIC RESISTANCE AT MUCOSAL SURFACES - OVERALL PROJECT SUMMARY THE ABILITY TO CONTROL BACTERIAL INFECTIONS WITH ANTIBIOTICS HAS BEEN ONE OF THE MOST IMPORTANT PUBLIC HEALTH ADVANCEMENTS IN HUMAN HISTORY. BEFORE THE DISCOVERY OF ANTIBIOTICS AND VACCINES, INFECTIOUS DISEASE WAS THE LEADING CAUSE OF DEATH AND CONSTITUTED NEARLY 50% OF DEATHS IN THE US ALONE. NOW, INFECTIOUS DISEASES AS A CAUSE OF DEATH BARELY MAKES THE TOP TEN AND WE NOW TREAT MOST BACTERIAL INFECTIONS AS A NUISANCE RATHER THAN LIFE-THREATENING DISEASES. UNFORTUNATELY, THIS IS RAPIDLY CHANGING WITH THE EMERGENCE OF ANTIBIOTIC RESISTANT BACTERIAL PATHOGENS. ULTIMATELY, OUR ABILITY TO DEVELOP NEW ANTIBIOTICS FASTER THAN RESISTANCE AMONGST PATHOGENS EMERGES HAS FAILED AND MANY SCIENTISTS EXPECT WE WILL EXPERIENCE A RETURN TO A PRE-ANTIBIOTIC ERA IN WHICH WE CANNOT TREAT WHAT ARE NOW EASY TO CURE BACTERIAL INFECTIONS. THEREFORE, NOVEL, NON-ANTIBIOTIC APPROACHES TO CONTROLLING BACTERIAL INFECTIONS ARE REQUIRED AND NEED TO BE EXPLORED. THE MAIN THEME OF THE BCM-CARBIRU IS TO USE MICROBIOME-BASED APPROACHES TO CONTROL BACTERIAL INFECTIONS AT MUCOSAL SURFACES. WE WILL INVESTIGATE ECOLOGICAL PRINCIPLES OF MICROBIAL COMMUNITY INHIBITION OF PATHOGEN COLONIZATION AS WELL AS THE USE OF BACTERIOPHAGE FOR PRECISION ELIMINATION OF BACTERIAL PATHOGENS. BOTH APPROACHES HAVE ADVANTAGES OVER THE USE OF ANTIBIOTICS IN THAT THEY LEAVE THE NATIVE MICROBIOME LARGELY INTACT, AVOIDING THE ELIMINATION OF BENEFICIAL MICROBES ALONG WITH THE PATHOGENS TARGETED BY ANTIMICROBIALS. WE PROPOSE THREE PROJECTS, SUPPORTED BY TWO SCIENTIFIC CORES AND THE ADMINISTRATIVE CORE, TO EXPLORE AND OPTIMIZE MICROBIOME-BASED STRATEGIES FOR THE PREVENTION AND TREATMENT OF BACTERIAL INFECTIONS. PROJECT 1. DISCOVERY AND MECHANISTIC UNDERSTANDING OF PHAGE ACTIVITY AND SYNERGISM AT HOST MUCOSAL SURFACES. PROJECT 2. DEFINED MICROBIAL COMMUNITIES TO PREVENT AND ERADICATE INFECTION BY ANTIBIOTIC RESISTANT PATHOGENS. PROJECT 3. NASAL MICROBIAL CONSORTIA COMBAT ANTIBIOTIC-RESISTANT BACTERIA. WE EXPECT TWO MAIN OUTCOMES FROM THE EXECUTION OF THESE PROJECTS. FIRST, WE EXPECT TO DEFINE AND UNDERSTAND THE ECOLOGICAL PRINCIPLES THAT ARE KEY FOR MICROBIAL COMMUNITIES AND BACTERIOPHAGE TO FUNCTION TO CONTROL PATHOGENS AT MUCOSAL SURFACES. SECOND, WE EXPECT TO HAVE IDENTIFIED ACTIONABLE PHAGE AND MICROBIAL COMMUNITIES THAT WILL BE AVAILABLE FOR TESTING IN HUMAN CLINICAL TRIALS AT THE END OF THE PROJECT PERIODS. TOGETHER, THESE PROJECTS WILL CAPITALIZE ON PROTECTIVE MEASURES AT THE MUCOSAL SURFACE, WHICH HAVE EXISTED FOR MILLENNIA PRIOR TO MODERN MEDICINE, AS WE ENTER THE NEXT ERA OF MICROBIOME-BASED THERAPIES.

BII-IMPLEMENTATION: BEHAVIORAL PLASTICITY RESEARCH INSTITUTE (BPRI): TRANSFORMING THE STUDY OF PHENOTYPIC PLASTICITY THROUGH BIOLOGICAL INTEGRATION

BAYLOR-UTHOUSTON CENTER FOR AIDS RESEARCH

REPRODUCTIVE HORMONES-BIOLOGICAL AND MOLECULAR ACTIONS

TRANSLATIONAL RESEARCH IN BREAST CANCER

TRANSPOSON INDUCED DISRUPTION OF MOST DROSOPHILA GENES

GULF COAST CENTER FOR PRECISION ENVIRONMENTAL HEALTH

CONSORTIUM FOR TRANSLATIONAL AND PRECISION HEALTH - THE CONSORTIUM FOR TRANSLATIONAL AND PRECISION HEALTH (CTPH) WILL SERVE AS A UNIQUE BI-INSTITUTIONAL HUB FOR INFRASTRUCTURE, SERVICES, COMMUNITY ENGAGEMENT, AND WORKFORCE DEVELOPMENT TO ADVANCE CLINICAL TRANSLATIONAL SCIENCE (CTS). LED BY BAYLOR COLLEGE OF MEDICINE (BCM) AND THE UNIVERSITY OF HOUSTON (UH), THE OVERALL MISSION OF CTPH IS TO FOSTER RESEARCH AND INNOVATIONS ACROSS THE TRANSLATIONAL SPECTRUM TO ADVANCE PRECISION HEALTH AND HEALTH EQUITY IN PARTNERSHIP WITH LOCAL AND REGIONAL STAKEHOLDERS. CTSA FUNDING WILL ENRICH THE CTPH’S ABILITY TO LAUNCH NEW INITIATIVES, ENHANCE OUR EXISTING EFFORTS, AND EFFECTIVELY DISSEMINATE DISCOVERIES AND INNOVATIONS TO DIVERSE POPULATIONS IN HOUSTON AND THE AMONG THE CTSA NETWORK. BUILDING ON OUR CURRENT HIGH-QUALITY PROGRAMS, WE WILL DEVELOP AN INTEGRATED, ADAPTABLE, AND SUSTAINABLE CLINICAL AND TRANSLATIONAL RESEARCH INFRASTRUCTURE PROVIDING SUPERIOR, ACCESSIBLE RESOURCES AND SERVICES, EXTENDING VALUE TO ALL STAKEHOLDERS. WE PROPOSE THE FOLLOWING OVERARCHING AIMS: AIM 1. DEVELOP, DEMONSTRATE, AND DISSEMINATE NEW TECHNOLOGIES, PLATFORMS, AND RESEARCH METHODS THAT ADVANCE INNOVATIONS IN PRECISION HEALTH. WE WILL SUPPORT PRECISION HEALTH INITIATIVES BY DEVELOPING ROBUST PLATFORMS TO ADVANCE TRANSLATIONAL SCIENCE AND ACCELERATE TRANSFORMATIVE BIOMEDICAL, ‘OMICS, CLINICAL, AND POPULATION HEALTH RESEARCH. COLLABORATIVE, INTERDISCIPLINARY TEAMS ARE POISED TO ESTABLISH NOVEL LINES OF RESEARCH IN CTS, PRECISION HEALTH, AND HEALTH EQUITY AND BOLSTER DIGITAL APPROACHES FOR CONTINUOUS HEALTH SCREENING, MONITORING, AND TAILORED INTERVENTIONS. AIM 2. REACH AND ENGAGE SPECIAL POPULATIONS AND ACROSS THE LIFESPAN TO REDUCE DISPARITIES AND IMPROVE POPULATION HEALTH. OUR DEEP COMMITMENT TO REDUCE LOCAL AND REGIONAL HEALTH DISPARITIES WILL BE STRENGTHENED THROUGH INCREASING ENGAGEMENT WITH SPECIAL POPULATIONS, INCORPORATING COMMUNITY PERSPECTIVES IN RESEARCH ACROSS THE LIFESPAN, AND REDUCING INSTITUTIONAL BARRIERS TO FULL PARTICIPATION OF COMMUNITY PARTNERS IN ALL ASPECTS OF THE CTPH. AIM 3. EDUCATE, TRAIN, AND SUSTAIN A DIVERSE AND INCLUSIVE TRANSLATIONAL WORKFORCE TO IMPROVE THE EFFICIENCY AND GENERALIZABILITY OF CLINICAL AND TRANSLATIONAL RESEARCH AND SUPPORT A PIPELINE OF NEW RESEARCHERS. WE WILL BUILD INNOVATIVE TRAINING AND CAREER DEVELOPMENT PROGRAMS ACROSS THE TRANSLATIONAL WORKFORCE TO DRIVE CHANGE, TRANSFORM SCIENCE, AND SIGNIFICANTLY IMPROVE POPULATION HEALTH. AIM 4. CREATE A CULTURE FOR CLINICAL TRANSLATIONAL SCIENCE TEAMS TO COLLABORATE AND TRANSFORM TRANSLATIONAL WORKFLOWS. OUR PROGRAMS WILL SIMPLIFY ACCESS TO RESOURCES, EMPHASIZE TEAM SCIENCE, OFFER JOINT ENRICHMENT PROGRAMS, AND ACCELERATE WORKFLOWS THROUGH IMPROVED EFFICIENCY AND STAKEHOLDER-INFORMED PERSPECTIVES. THESE INITIATIVES WILL BE IMPLEMENTED BY AN EXPERIENCED LEADERSHIP TEAM WITH AUTHORITY OVER THE RELEVANT ADMINISTRATIVE STRUCTURES, WHICH WILL EXPAND SYNERGIES IN CTS BETWEEN THE LARGEST UNIVERSITY SYSTEM IN HOUSTON WITH THE LEADING BIOMEDICAL RESEARCH INSTITUTION IN TEXAS.

MODIFIABLE DRIVERS OF EXPANSION AND MALIGNANT TRANSFORMATION FROM CLONAL HEMATOPOIESIS - PROJECT SUMMARY/ABSTRACT CLONAL HEMATOPOIESIS (CH) IS AN AGE-ASSOCIATED PRE-MALIGNANT CONDITION IN WHICH THE PROGENY OF HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) WITH SOMATIC MUTATIONS IN ABOUT 20 GENES DOMINATE PRODUCTION OF THE PERIPHERAL BLOOD. WHILE CH CAN PERSIST WITHOUT APPARENT HEALTH CONSEQUENCES FOR DECADES, IT IS ASSOCIATED WITH INCREASED RISK FOR HEMATOLOGIC MALIGNANCIES AS WELL AS ALL-CAUSE MORTALITY. EXTRINSIC CONDITIONS THAT FAVOR PARTICULAR CLONES MAY SEPARATE ASYMPTOMATIC CH CARRIERS FROM THOSE THAT PROGRESS TO DISEASE; YET, THE SPECIFIC RISK FACTORS THAT CAN BE MODIFIED TO INFLUENCE CH AND ITS SEQUELAE ARE LARGELY UNKNOWN. THE OVERALL GOAL OF THIS PROGRAM, WITH THREE INTERACTIVE PROJECTS AND TWO CORES, IS TO IDENTIFY MODIFIABLE RISK FACTORS OF CH-ASSOCIATED HSPC EXPANSION AND SUBSEQUENT MALIGNANT TRANSFORMATION, WITH A LONG-TERM VIEW TOWARD DEVELOPING CANCER PREVENTION STRATEGIES. A MAJOR FEATURE OF OUR PROGRAM IS THE USE OF NOVEL MOUSE MODELS TO MIMIC CH AND TEST MECHANISMS THAT DRIVE CLONE EXPANSION AND MALIGNANCY. IN ADDITION, OUR PROGRAM HARNESSES DATA FROM THE EXCEPTIONAL ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY – WHICH HAS FOLLOWED MORE THAN 9,500 DIVERSE PARTICIPANTS (27% BLACK, 55% FEMALE) OVER 30 YEARS – TO EVALUATE CH AND MALIGNANCY RISK IN OLDER ADULTS. PROJECT 1 MODELS CH IN MICE, WITH AN EMPHASIS ON HSPCS BEARING MUTATIONS IN EPIGENETIC REGULATORS (PARTICULARLY DNMT3A AND TET2), TO DETERMINE HOW INFLAMMATORY STRESS AND METABOLIC CHANGES PROMOTE EXPANSION, INCLUDING COOPERATION BETWEEN CLONES, AND MALIGNANT TRANSFORMATION. PROJECT 2 FOCUSES ON CH WITH DNA DAMAGE RESPONSE (DDR)-ASSOCIATED GENE MUTATIONS, AND HOW EXPOSURE TO GENOTOXIC STRESS FROM CHEMOTHERAPY AND SMOKING ENABLES CLONAL DOMINANCE AND MALIGNANT TRANSFORMATION IN MICE. BOTH PROJECTS 1 AND 2 EXPLORE POTENTIAL INTERVENTIONS TO SUPPRESS CLONE EXPANSION. PROJECT 3 ANALYZES THE CONTRIBUTION OF INFLAMMATION AND DNA DAMAGING EXPOSURES TO CLONAL EXPANSION AND MALIGNANT TRANSFORMATION IN THE ARIC COHORT, CAPITALIZING ON CLINICAL, PROTEOMIC, METHYLATION, WHOLE EXOME SEQUENCING, AND METABOLOMIC DATA ALREADY AVAILABLE. PROJECT 3 WILL ALSO PERFORM SINGLE CELL SEQUENCING TO DETERMINE CHANGES IN CH CLONAL CONTRIBUTION OVER TIME, INCLUDING CLONAL INTERACTIONS, AND THE EVOLUTION TO MALIGNANCY IN THE CONTEXT OF EXTERNAL STRESSORS. THE PROJECTS ARE HIGHLY INTERACTIVE, WITH PROJECTS 1 AND 2 ITERATIVELY TESTING THE CAUSAL AND MECHANISTIC INFLUENCE OF RISK FACTORS NOMINATED BY PRELIMINARY STUDIES AND BY PROJECT 3, AND PROJECT 3 PERFORMING ADDITIONAL ANALYSES TO VALIDATE FINDINGS GENERATED BY PROJECTS 1 AND 2. PROJECTS 1 AND 2 ARE MUTUALLY ENHANCED BY SHARED APPROACHES AND DATA. TOGETHER, ALL PROJECTS WILL DECONVOLUTE THE ROLE OF RISK FACTORS TO CH AND MALIGNANCY. THE PROGRAM IS SUPPORTED BY A SINGLE CELL SEQUENCING AND BIOINFORMATICS CORE AND AN ADMINISTRATIVE CORE. BY FOCUSING ON MODIFIABLE RISK FACTORS, WE CAN STRATIFY THE RISK OF HEMATOLOGIC MALIGNANCY TO INFORM CLINICAL GUIDANCE OF INDIVIDUALS WITH CH. OUR EXPERT TEAM COMBINES CLINICIANS AND SCIENTISTS WITH LONG TRACK RECORDS OF SUCCESSFUL COLLABORATION. TOGETHER WE WILL ADDRESS THIS CRITICAL PROBLEM FOR HUMAN HEALTH AND LONGEVITY.

SURVEILLANCE FOR VACCINE PREVENTABLE DISEASE IN CHILDREN

STRENGTHENING NATIONAL HIV/AIDS TRAINING SYSTEMS (SNATS) IN THE REPUBLIC OF UGAND

NEURONAL ANATOMY, CONNECTIVITY, AND PHENOTYPIC INNERVATION OF THE KNEE JOINT - PROJECT SUMMARY IDENTIFYING PATTERNS OF NEURONAL CONNECTIVITY IS CRITICAL FOR UNDERSTANDING FUNCTIONAL AND ANATOMICAL CIRCUITS THAT MEDIATE PAIN PERCEPTION. HOWEVER, KNOWLEDGE ABOUT THE TYPES AND DISTRIBUTION OF NEURONS IN JOINT TISSUES HAVE GENERALLY BEEN LIMITED TO TRADITIONAL 2-DIMENSION HISTOPATHOLOGICAL AND IMMUNOHISTOPATHOLOGICAL APPROACHES, AND LITTLE TO NO INFORMATION IS AVAILABLE ON CONNECTIVITY AND NEURONAL PHENOTYPES. NEW TECHNOLOGIES HAVE EMERGED THAT ALLOW FOR BOTH TRANS-SYNAPTIC CIRCUIT ANALYSIS AND PRECISE CONTROL OF NEURONAL FIRING, INCLUDING THE USE OF RETROGRADELY TRANSPORTED VIRAL VECTORS (I.E., PSEUDOTYPED RABIES VIRUS) AND HETEROLOGOUS RECEPTOR ACTIVATION. AT THE SAME TIME, 3-DIMENSIONAL VISUALIZATION OF NEURONAL AND VASCULAR PATTERNS HAVE BEEN ADVANCED BY TISSUE CLEARING TECHNIQUES IN CONJUNCTION WITH CELL TYPE SPECIFIC FLUORESCENT MARKERS GENERATED BY INTERCROSSING CELL TYPE SPECIFIC CRE RECOMBINASE MOUSE LINES WITH A VARIETY OF CONDITIONALLY ACTIVATED REPORTERS. FINALLY, THE ADVENT OF SINGLE CELL RNA SEQUENCING HAS ALLOWED FOR EXTENDING CELLULAR PHENOTYPING TO A MOLECULAR LEVEL THAT HAS NOT ONLY INCREASES ANALYTIC RESOLUTION, BUT ALSO THERAPEUTIC TARGETING WITH GREATER DISEASE SPECIFICITY THAN PREVIOUSLY POSSIBLE. THE DEVELOPMENT OF HIGH RESOLUTION SPATIAL TRANSCRIPTOMICS, I.E., MERFISH, ALLOWS FOR CORRELATION AND VALIDATION OF SCRNA-SEQ DATA. IN THIS CONTEXT, OSTEOARTHRITIS OF THE KNEE JOINT IS AN OPTIMAL MODEL FOR APPLYING THESE TOOLS AS ABUNDANT GENETIC AND SURGICAL MODELS ARE AVAILABLE FOR ORTHOGONAL VALIDATION OF FINDINGS. MOREOVER, IN THE PRECLINICAL CONTEXT, VARIOUS THERAPEUTIC APPROACHES INCLUDING GENE THERAPY HAVE BEEN SHOWN TO IMPACT PAIN MEASURES, AND AS SUCH, THEY CONSTITUTE AN IMPORTANT INTERVENTIONAL VALIDATION OF MOLECULAR CHANGES THAT ARE IDENTIFIED IN NEURONS IN THE DISEASE STATE. THE FACT THAT SOME OF THESE THERAPIES ARE NOW IN CLINICAL TRIAL ADDS TO THE POTENTIAL TRANSLATIONAL IMPACT OF THE PROPOSED PRECLINICAL FINDINGS HERE. ULTIMATELY, THE COMBINATION OF BOTH ANATOMIC, 3-D, AND MOLECULAR SIGNATURES WILL FACILITATE THE TRANSLATION INTO HUMAN TISSUES AND BIOPSIES, WHILE MAXIMIZING THE LIKELIHOOD OF RELEVANT NEW THERAPEUTIC TARGETS.

DNA SEQUENCING SUPPORT FOR THE EMERGE NETWORK

GENERAL CLINICAL RESEARCH CENTER

P30 - CORE GRANT FOR VISION RESEARCH

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLESCENTS, AND PREGNANT AND LACTATING WOMEN

MEDICAL SCIENTIST TRAINING PROGRAM

THE PURPOSE OF THE LEADR ACTIVITY IS TO PROVIDE EFFECTIVE DECENTRALIZED, DIFFERENTIATED, AND INTEGRATED FACILITY AND COMMUNITY SERVICES TO MAXIMIZE EQUITABLE ACCESS TO COMPREHENSIVE HIV, TB, AND COVID-19 INTERVENTIONS THROUGH A PRIMARY HEALTH CARE APPROACH TO ENSURE THAT CLIENTS HAVE ACCESS TO HOLISTIC SERVICES.

SEX HORMONE RECEOPTOR COMPONENTS AND THE CELL GENOME

CLINICAL SEQUENCING CORE FACILITY FOR THE UNDIAGNOSED DISEASES NETWORK

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

THE BCM TUMOR GENOME CHARACTERIZATION CENTER

MOLECULAR BASIS OF RCGG-MEDIATED NEURODEGENERATION

CENTER FOR REPRODUCTIVE BIOLOGICAL RESEARCH

FRAGILE X PREMUTATIONS, MECHANISMS AND MODIFIERS

3 D ELECTRON MICROSCOPY OF MACROMOLECULES

EPIGENOMICS DATA ANALYSIS AND COORDINATION CENTER AT BAYLOR COLLEGE OF MEDICINE

ENHANCING TRAINING FOR MINORITY BIOMEDICAL RESEARCHERS

STRUCTURAL STUDIES ON ROTAVIRUSES

MEDICAL SCIENTIST TRAINING PROGRAM

DEEP BRAIN STIMULATION FOR DEPRESSION USING DIRECTIONAL CURRENT STEERING AN INDIVIDUALIZED NETWORK TARGETING

A HUB FOR THE NUCLEAR RECEPTOR SIGNALING ATLAS1

G7-PDN (GULF 7- PEDIATRICS DISASTER CARE NETWORK) PEDIATRIC DISASTER CARE CENTER OF EXCELLENCE - THE FORMATION OF THE GULF 7 - PEDIATRIC DISASTER NETWORK (G7), LED BY TEXAS CHILDREN’S HOSPITAL AND BAYLOR COLLEGE OF MEDICINE (TCH/BCM), UNITES LEADING REGIONAL INSTITUTIONS WITH YEARS OF EXPERIENCE ACROSS THE CONTINUUM OF PEDIATRIC CARE. THIS CONSORTIUM ENCOMPASSES A DIVERSE SOCIO-GEOGRAPHIC LANDSCAPE WITH A RICH HISTORY OF PREPAREDNESS AND RESPONSE TO SOME OF THE NATION’S WORST DISASTERS. HURRICANES, STATE-WIDE POWER GRID FAILURES, AND THE PANDEMIC ARE JUST A FEW OF THE DISASTERS THAT HAVE SOLIDIFIED THE EXPERTISE OF PARTNERS WITHIN PEDIATRIC DISASTER PREPAREDNESS AND RESPONSE. G7 WILL EMPLOY ITS EXPANSIVE NETWORK OF SUBJECT MATTER EXPERTS IN LOCAL AND REGIONAL DISASTER PREPAREDNESS, CBRN, TRAUMA, BURNS, MENTAL AND BEHAVIORAL HEALTH, EMS, TELEMEDICINE, EDUCATION, MATERNAL AND FETAL MEDICINE, LAW, AND ETHICS TO IMPROVE PEDIATRIC DISASTER PREPAREDNESS OF THE GULF COAST STATES (TEXAS, LOUISIANA, MISSISSIPPI, ALABAMA AND FLORIDA), GEORGIA, AND PUERTO RICO. THE G7 CONSORTIUM ADAPTS EXPERTISE ALREADY ENGAGED IN WORK ON THE NATIONAL LEVEL INTO CENTERS THAT ARE INTEGRATED INTO PRE-EXISTING FEDERALLY-FUNDED ENTITIES: EMS FOR CHILDREN INNOVATIONS AND IMPROVEMENT CENTER; THE PEDIATRIC PANDEMIC NETWORK; THE REGIONAL DISASTER HEALTH RESPONSE SYSTEM; THE NATIONAL EMERGING SPECIAL PATHOGENS TRAINING AND EDUCATION CENTER; THE RADIATION INJURY TREATMENT NETWORK; HOSPITAL PREPAREDNESS PROGRAM RECIPIENTS; AND EXISTING PEDIATRIC DISASTER CARE CENTERS OF EXCELLENCE. OUR AIM IS TO ENSURE THAT OUR REGION CAN COMPREHENSIVELY RESPOND TO DISASTER EVENTS IMPACTING CHILD HEALTH. WE WILL EXPAND CAPABILITIES BY LEVERAGING THE ROBUST PREPAREDNESS EFFORTS ESTABLISHED BY OUR MEMBERS. THIS WILL ALLOW US TO DEVELOP AND DISSEMINATE DISASTER PREPAREDNESS AND RESPONSE BEST PRACTICES REGIONALLY.

DEVELOPING NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

FUNCTIONAL GENOMIC DISSECTION OF ALZHEIMER'S DISEASE IN HUMANS AND DROSOPHILA MODELS - SUMMARY ALZHEIMER’S DISEASE (AD) IS PROJECTED TO AFFECT 13 MILLION PEOPLE IN THE US BY 2050 AND REMAINS NEITHER CURABLE NOR PREVENTABLE. FOLLOWING REMARKABLE RECENT PROGRESS, THE GENOMIC ARCHITECTURE OF AD AND RELATED DEMENTIAS (ADRD) IS COMING INTO FOCUS. SIMILAR TO OTHER COMMON AND GENETICALLY COMPLEX DISORDERS, AD IS CHARACTERIZED BY SUBSTANTIAL LOCUS HETEROGENEITY AND POLYGENIC SUSCEPTIBILITY: RISK OR PROTECTIVE ALLELES ARE BEING IDENTIFIED IN MANY DISTINCT GENES, AND IN MOST INDIVIDUALS, A SUBSET OF COMMON AND RARE VARIANTS LIKELY INTERACT TO TRIGGER NEURODEGENERATION. THE CRITICAL NEXT STEPS INCLUDE CONFIRMATION OF THE RESPONSIBLE GENES, UNDERSTANDING THE FUNCTIONAL IMPACT OF DISEASE-ASSOCIATED VARIANTS, ELABORATION OF THE RELEVANT CELL TYPES AND PATHWAYS, AND DETERMINING HOW POLYGENIC INTERACTIONS MEDIATE DISEASE RISK. WE PROPOSE AN INTEGRATED COMPUTATIONAL AND TIERED EXPERIMENTAL VALIDATION STRATEGY TO ACCELERATE AD FUNCTIONAL GENOMICS, BUILDING ON ADVANCES FROM THE AD SEQUENCING PROJECT (ADSP) AND LEVERAGING POWERFUL TECHNOLOGIES AVAILABLE IN THE FRUIT FLY, DROSOPHILA MELANOGASTER. FIRST (AIM 1), LEVERAGING INFRASTRUCTURE DEVELOPED FOR THE CLINICAL GENOME RESOURCE AND ENCODE PROJECTS, WE WILL INTEGRATE ADSP RESULTS WITH OTHER HUMAN DATA, INCLUDING BRAIN TRANSCRIPTOME AND EPIGENOME PROFILES, PRIORITIZING GENES AND VARIANTS FOR EXPERIMENTAL FOLLOW-UP. NEXT (AIM 2), USING HIGH-THROUGHPUT DROSOPHILA SCREENING, WE WILL SYSTEMATICALLY MANIPULATE 2,000 CONSERVED, CANDIDATE AD GENES IN VIVO TO PINPOINT CAUSAL MODULATORS OF AGE-DEPENDENT NEURODEGENERATION, INCLUDING INTERACTIONS WITH TAU, ASS, AND OTHER PATHOLOGIC TRIGGERS. THIRD (AIM 3), FOR A SUBSET OF 200 PRIORITIZED GENE CANDIDATES, WE WILL GENERATE CUSTOMIZED DROSOPHILA STRAINS AND CHARACTERIZE CELL-TYPE EXPRESSION AND LOSS-OF-FUNCTION PHENOTYPES. LASTLY (AIM 4), FOR 50 HIGH-PRIORITY TARGETS, WE WILL EXPERIMENTALLY PROBE MECHANISMS IN-DEPTH, INCLUDING TESTING OF CELL-TYPE SPECIFIC REQUIREMENTS (NEURONS VS. GLIA) AND EXAMINING GENE-GENE INTERACTIONS THAT DEFINE RELEVANT PATHWAYS. WE WILL BROADLY SHARE ALL PROJECT DATA AND RESOURCES WITH THE RESEARCH COMMUNITY (AIM 5). OUR INTEGRATIVE, TIERED, CROSS-SPECIES STRATEGY PROMISES RAPID FUNCTIONAL ANNOTATION OF ADSP TARGETS USING POWERFUL, IN VIVO ASSAYS IN THE AGING NERVOUS SYSTEM OF DROSOPHILA, AND IS IDEALLY SUITED FOR RECIPROCAL CROSS-VALIDATION IN COMPLEMENTARY MAMMALIAN PRECLINICAL MODELS. ON A SCALE AND TIMEFRAME NOT CURRENTLY POSSIBLE IN OTHER MODEL SYSTEMS, OUR INNOVATIVE EXPERIMENTAL STRATEGY WILL TRANSCEND BARRIERS TO TRANSLATION OF HUMAN GENETIC DISCOVERIES AND CATALYZE BREAKTHROUGHS IN OUR UNDERSTANDING AD PATHOBIOLOGY.

TEXAS DEVELOPMENTAL CENTER FOR AIDS RESEARCH - PROJECT SUMMARY – TEXAS DEVELOPMENTAL CENTER FOR AIDS RESEARCH IN 2019, THE US ANNOUNCED A PLAN TO END THE HIV EPIDEMIC BY 2030. TO BE SUCCESSFUL, STRATEGIES THAT IMPROVE HIV PREVENTION AND HIV TREATMENT OUTCOMES ARE NEEDED. ONLY 56% OF PEOPLE WITH HIV (PWH) WERE VIRALLY SUPPRESSED IN 2018, A CRITICAL DETERMINANT OF HEALTH OUTCOMES AND TRANSMISSION RISK, AND 51% OF HIV DIAGNOSES IN 2018 WERE IN THE US SOUTH, DESPITE CONSTITUTING ONLY 38% OF THE POPULATION IN THE US. TEXAS IS THE SECOND MOST POPULOUS STATE IN THE US, BEHIND CALIFORNIA, WITH ABOUT 29 MILLION RESIDENTS, AND IS IN THE US SOUTH AS DEFINED BY CDC AND THE CENSUS BUREAU. UNFORTUNATELY, THIS LARGE TEXAS POPULATION, COUPLED WITH WEAKER PUBLIC HEALTH AND PREVENTION POLICIES AND FUNDING ACROSS THE US SOUTH, HAS A GROWING HIV POPULATION THAT LAGS IN CRITICAL HEALTH OUTCOMES. THERE IS AN URGENT NEED FOR MORE RESEARCH AND RESEARCH INFRASTRUCTURE TO COMBAT THE HIV EPIDEMIC IN THE US SOUTH AND SPECIFICALLY IN TEXAS TO BOTH CONTRIBUTE TO ENDING THE US HIV EPIDEMIC AND TO LEARN HOW TO BEST DO THAT IN RESOURCE CONSTRAINED AREAS OF THE US. WE THEREFORE WILL ESTABLISH A TEXAS DEVELOPMENTAL CENTER FOR AIDS RESEARCH (D-CFAR) TO SUPPORT THE OVERALL MISSION OF THE NATIONAL CFAR PROGRAM BY FACILITATING HIGH-PRIORITY HIV RESEARCH AND SUPPORTING THE EFFORT TO END THE HIV EPIDEMIC IN THE US. THREE INSTITUTIONS HAVE COLLABORATED TO PROPOSE THIS D-CFAR: BAYLOR COLLEGE OF MEDICINE IN HOUSTON, THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON AND THE TEXAS BIOMEDICAL RESEARCH INSTITUTE IN SAN ANTONIO. BASED UPON THE OUTSTANDING EXPERTISE OF ITS INVESTIGATORS, THE TEXAS D-CFAR WILL FOCUS ITS ACTIVITIES IN THE FIVE-YEAR FUNDING PERIOD ON THE RESEARCH THEME “ENDING HIV AND OPTIMIZING HIV HEALTH IN TEXAS.” TO ACCOMPLISH ITS GOALS, THE TEXAS D-CFAR WILL: 1) PROVIDE ORGANIZATIONAL AND FINANCIAL MANAGEMENT AND FACILITATE ACTIVITIES AND PROGRAMS THAT STRENGTHEN AND ENRICH THE D-CFAR RESEARCH AND INTELLECTUAL ENVIRONMENT; 2) SUPPORT TARGETED HIGH-PRIORITY INTERDISCIPLINARY PILOT RESEARCH PROJECTS, ASSIST IN RESPONDING TO NEW HIV-RELATED RESEARCH INITIATIVES, AND FACILITATE RESEARCH ON ENDING HIV AND IMPROVING HEALTH OF PWH IN TEXAS; AND 3) PROVIDE STATE-OF-THE-ART EXPERTISE, ADVICE, AND SERVICES TO FACILITATE THE RANGE OF HIV-RELATED RESEARCH FOR D-CFAR INVESTIGATORS. THE TEXAS D-CFAR WILL SUPPORT AN ADMINISTRATIVE CORE, A DEVELOPMENTAL CORE, A BASIC SCIENCE CORE AND A CLINICAL AND BIOSTATISTICS CORE TO MEET INVESTIGATOR NEEDS AND CATALYZE INNOVATIVE RESEARCH. THE SCIENTIFIC CORES WILL BUILD ON OUTSTANDING STRENGTHS IN VIROLOGY, NON-HUMAN PRIMATE RESOURCES, CLINICAL TRIALS RESEARCH AND BIOSTATISTICS. THE D-CFAR WILL ENGAGE A COMMUNITY ADVISORY BOARD AND INTERNAL AND EXTERNAL ADVISORY BOARDS FOR GUIDANCE. COUPLED WITH OUTSTANDING INSTITUTIONAL SUPPORT, THE D- CFAR WILL STIMULATE NEW RESEARCH AND COLLABORATIONS AMONG BASIC, TRANSLATIONAL, CLINICAL, HEALTH SERVICES AND PUBLIC HEALTH RESEARCHERS. THE D-CFAR WILL SIGNIFICANTLY ADVANCE KNOWLEDGE NEEDED TO END HIV AND IMPROVE THE HEALTH OF PWH IN TEXAS AND SIMILAR AREAS, TRAIN THE NEXT GENERATION OF SCIENTISTS, AND GROW INTO A FULL CFAR, THEREBY CONTRIBUTING TO ENDING THE HIV EPIDEMIC IN TEXAS, THE US SOUTH, AND BEYOND.

HOUSTON EDUCATION AND RESEARCH TRAINING PROGRAM FOR POST-DOCS

LOOK AHEAD: ACTION FOR HEALTH IN DIABETES

REGULATORY NETWORKS IN HUMAN EMBRYONIC STEM CELLS

RESEARCH TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLESCENTS, AND PREGNANT AND LACTATING WOMEN

DECODING ANTIBIOTIC-INDUCED SUSCEPTIBILITY TO CLOSTRIDIUM DIFFICILE INFECTION

NUCLEAR RECEPTORS AND THEIR COACTIVATORS AS MEDIATORS OF SYSTEMS METABOLISM

A NEW EXPERIMENTAL GENETIC MODEL OF EPILEPSY: SEIZURES AND ENHANCED COGNITION

BAYLOR INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTERS

MEDICAL GENETICS RESEARCH FELLOWSHIP PROGRAM

A SELECTIVE ANGIOGENESIS BLOCKER TO TREAT RETINOPATHY OF PREMATURITY

NOVEL MODEL SYSTEMS FOR THE STUDY OF CONE DISORDERS AND OTHER HERITABLE RETINAL DISEASES

ADAPTIVE DBS IN NON-MOTOR NEUROPSYCHIATRIC DISORDERS: REGULATING LIMBIC CIRCUIT IMBALANCE

BAYLOR COLLEGE OF MEDICINE INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER

COCAINE PHARMACOTHERAPY TARGETING DOPAMINE & GABA

CENTER FOR FUNCTIONAL ANALYSIS OF HUMAN UDN GENE HOMOLOGS IN DROSOPHILA AND ZEBRAFISH

REGULATION OF HEMATOPOIETIC PROGENITORS BY DE NOVO DNA METHYLATION

BASIS OF MUSCLE DYSFUNCTION IN MALIGNANT HYPERTHERMIA AND CENTRAL CORE DISEASE

A COMPREHENSIVE HUMAN CDNA LIBRARY FOR FUNCTIONAL GENE REPLACEMENT IN DROSOPHILA

REGULATION OF ROTAVIRUS REPLICATION

MATERNAL AND INFANT ENVIRONMENTAL HEALTH RISKSCAPE (MIEHR) RESEARCH CENTER

SOUTHWEST NATIONAL PEDIATRIC DEVICE CONSORTIUM

A MOUSE MODEL OF DNMT3A-ASSOCIATED HEMATOLOGIC MALIGNANCY

THE GUT MICROBIOME IN AUTISM

GENETIC EPIDEMIOLOGY OF GLIOMA INTERNATIONAL CONSORTIUM

MAPPING ALGORITHMIC STATE SPACE IN THE HUMAN BRAIN - ABSTRACT HUMANS HAVE A REMARKABLE ABILITY TO FLEXIBLY INTERACT WITH THE ENVIRONMENT. A COMPELLING DEMONSTRATION OF THIS COGNITIVE FLEXIBILITY IS OUR ABILITY TO RESPOND CORRECTLY TO NOVEL CONTEXTUAL SITUATIONS ON THE FIRST ATTEMPT, WITHOUT PRIOR REHEARSAL. WE REFER TO THIS ABILITY AS ‘AD HOC SELF-PROGRAMMING’: ‘AD HOC’ BECAUSE THESE NEW BEHAVIORAL REPERTOIRES ARE COBBLED TOGETHER ON THE FLY, BASED ON IMMEDIATE DEMAND, AND THEN DISCARDED WHEN NO LONGER NECESSARY; ‘SELF-PROGRAMMING’ BECAUSE THE BRAIN HAS TO CONFIGURE ITSELF APPROPRIATELY BASED ON TASK DEMANDS AND SOME COMBINATION OF PRIOR EXPERIENCE AND/OR INSTRUCTION. THE OVERALL GOAL OF OUR RESEARCH EFFORT IS TO UNDERSTAND THE NEUROPHYSIOLOGICAL AND COMPUTATIONAL BASIS FOR AD HOC SELF-PROGRAMMED BEHAVIOR. OUR PREVIOUS U01 PROJECT (NS 108923) FOCUSED ON HOW THESE PROGRAMS OF ACTION ARE INITIALLY CREATED. OUR RESULTS THUS FAR HAVE REVEALED TANTALIZING NOTIONS OF HOW THE BRAIN REPRESENTS THESE PROGRAMS AND NAVIGATES THROUGH THEM. IN THIS PROPOSAL, THEREFORE, WE FOCUS ON THE QUESTION OF HOW THESE MENTAL PROGRAMS ARE EXECUTED. BASED ON OUR PRELIMINARY FINDINGS AND CRITICAL CONCEPTUAL WORK, WE PROPOSE THAT THE MEDIAL TEMPORAL LOBE (MTL) AND VENTRAL PREFRONTAL CORTEX (VPFC) CREATES REPRESENTATIONS OF THE CRITICAL ELEMENTS OF THESE MENTAL PROGRAMS, INCLUDING CONCEPTS SUCH AS ‘RULES’ AND ‘LOCATIONS’, TO ALLOW FOR EFFECTIVE NAVIGATION THROUGH THE ALGORITHM. THESE DATA SUGGEST THE EXISTENCE OF AN ‘ALGORITHMIC STATE SPACE’ REPRESENTED IN MEDIAL TEMPORAL AND PREFRONTAL REGIONS. THIS PROPOSAL AIMS TO UNDERSTAND THE NEUROPHYSIOLOGICAL UNDERPINNINGS OF THIS ALGORITHMIC STATE SPACE IN HUMANS. BY STUDYING HUMANS, WE WILL PROFIT FROM OUR SPECIES’ POWERFUL CAPACITY FOR GENERALIZATION TO UNDERSTAND HOW SUCH STATE SPACES ARE CONSTRUCTED. WE THEREFORE LEVERAGE THE UNIQUE OPPORTUNITIES AVAILABLE IN HUMAN NEUROSCIENCE RESEARCH TO RECORD FROM SINGLE CELLS AND POPULATION-LEVEL SIGNALS, AS WELL AS TO USE INTRACRANIAL STIMULATION FOR CAUSAL TESTING, TO ADDRESS THIS CHALLENGING PROBLEM. IN AIM 1 WE STUDY THE BASIC REPRESENTATIONS OF ALGORITHMIC STATE SPACE USING A NOVEL BEHAVIORAL TASK THAT REQUIRES THE IMMEDIATE FORMATION OF UNIQUE PLANS OF ACTION. AIM 2 DIRECTLY COMPARES REPRESENTATIONS OF ALGORITHMIC STATE SPACE TO THAT OF PHYSICAL SPACE BY JUXTAPOSING BALANCED VERSIONS OF SPATIAL AND ALGORITHMIC TASKS IN A VIRTUAL REALITY (VR) ENVIRONMENT. FINALLY, IN AIM 3, WE TEST HYPOTHESES REGARDING INTERACTIONS BETWEEN VPFC AND MTL USING INTRACRANIAL STIMULATION.

THE PURPOSE OF THIS REQUISITION IS TO ISSUE A FIXED AMOUNT AWARD WITH BAYLOR LESOTHO EXPANDING HIV CLINICAL SERVICES IN LESOTHO.

MICROSCALED PROTEOGENOMICS FOR CANCER CLINICAL TRIALS

IMPROVING PREDICTION OF IDDM

HORMONAL REGULATION OF BREAST CANCER

FUNCTIONAL GENOMICS OF DICTYOSTELIUM

DEVELOPMENTAL AND PATHOLOGICAL EFFECTS OF PRESENILIN

COMPARISON OF SYMPTOM BURDEN/TOXICITY, NEUROCOGNITIVE CHANGE, AND FUNCTIONAL OUTCOMES IN PEDIATRIC BRAIN TUMOR PATIENTS TREATED WITH PROTON VS. PHOTON RADIOTHERAPY. - PROJECT SUMMARY MOST CHILDREN TREATED FOR CANCER IN THE US WILL ACHIEVE LONG-TERM SURVIVAL, AND SURVIVORSHIP PRESENTS UNIQUE CHALLENGES FOR THIS GROWING POPULATION. PEDIATRIC BRAIN TUMOR SURVIVORS, IN PARTICULAR, ARE AT RISK FOR NEUROCOGNITIVE IMPAIRMENTS, EDUCATIONAL DIFFICULTIES, SOCIAL PROBLEMS, AND MEDICAL DISABILITIES. CRANIAL RADIATION THERAPY IS AN ESSENTIAL LIFESAVING TREATMENT BUT IS ASSOCIATED WITH COGNITIVE DECLINE. PROTON BEAM RADIATION THERAPY (PBRT) IS ONE OF THE MOST PROMISING RECENT ADVANCES IN PEDIATRIC BRAIN TUMOR TREATMENT. THE PROPOSED MEDICAL ADVANTAGE OF PBRT LIES IN THE PRECISION OF RADIATION DELIVERY WITH PROTON BEAMS, DEPOSITING MAXIMUM DOSE TO CLINICAL TARGETS WHILE MINIMIZING RADIATION TO SURROUNDING TISSUES. BY REDUCING DOSE TO HEALTHY BRAIN TISSUE, PBRT MAY SPARE COGNITIVE FUNCTIONING AND REDUCE SYMPTOM BURDEN BETTER THAN CONVENTIONAL PHOTON OR X-RAY IRRADIATION (XRT) LEADING TO GREATER FUNCTIONAL INDEPENDENCE IN SURVIVORSHIP. USING A MODEL-BASED, ACCELERATED LONGITUDINAL COHORT COMPARISON DESIGN, WE WILL COMPARE SYMPTOM BURDEN/TOXICITY, NEUROCOGNITIVE CHANGE, AND FUNCTIONAL OUTCOMES AT MULTIPLE DATA POINTS FROM START OF RADIATION THROUGH LATE SURVIVORSHIP IN PATIENTS TREATED WITH PBRT VERSUS XRT. THE FOLLOWING AIMS ARE PROPOSED: (1) TO COMPARE SYMPTOM BURDEN AND TOXICITY BY RT TYPE IN PEDIATRIC BRAIN TUMOR PATIENTS AND SURVIVORS, (2) TO COMPARE CHANGE IN NEUROCOGNITIVE OUTCOMES OVER TIME BY RT TYPE, (3) TO COMPARE FUNCTIONAL OUTCOMES IN EARLY AND LATE SURVIVORSHIP BY RT TYPE, AND (4) TO EXAMINE RELATIONS AMONG SYMPTOM BURDEN/TOXICITY, NEUROCOGNITIVE FUNCTION, AND FUNCTIONAL OUTCOMES AS A FUNCTION OF RT TYPE. THIS PROPOSAL IS CONSISTENT WITH NCI’S OBJECTIVE TO “REDUCE THE LONG-TERM ADVERSE EFFECTS OF CANCER AND ITS TREATMENT” IN CHILDREN AND TO “IMPROVE THE QUALITY OF LIFE FOR CANCER PATIENTS, SURVIVORS, AND THEIR FAMILIES.” NEUROCOGNITIVE LATE EFFECTS LEAD TO SIGNIFICANT EDUCATIONAL, SOCIAL, AND OCCUPATIONAL LIMITATIONS FOR MANY SURVIVORS, GREATLY AFFECTING THEIR QUALITY OF LIFE AND FUNCTIONAL INDEPENDENCE LONG-TERM. RESEARCH IS NEEDED TO DETERMINE WHICH TREATMENTS ARE BEST ABLE TO LIMIT THE SUFFERING ASSOCIATED WITH SYMPTOM BURDEN AND POST- TREATMENT NEUROCOGNITIVE DECLINE. OUR RESULTS WILL HAVE CLINICAL VALUE, PROVIDING A TIMELY COMPARISON OF SYMPTOMS, NEUROCOGNITIVE CHANGES, AND FUNCTIONAL OUTCOMES BETWEEN PBRT AND XRT GROUPS THAT WILL GUIDE CLINICIANS AND FAMILIES ON THE RANGE OF OUTCOMES TO EXPECT AFTER PBRT.

FUNCTIONAL ANALYSIS OF ACTIVINS DURING DEVELOPMENT

MOLECULAR PATHOGENESIS STUDIES OF RETT SYNDROME

CODING AND PROCESSING OF ERROR SIGNALS IN INFERIOR OLIVARY-CEREBELLAR NETWORKS

MINORITY PDX DEVELOPMENT AND TRIAL CENTER: BAYLOR COLLEGE OF MEDICINE AND MD ANDERSON CANCER CENTER COLLABORATION ON MECHANISTIC STUDIES TO DISSECT AND COMBAT HEALTH DISPARITIES IN CANCER

RESEARCH TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLESCENTS, AND PREGNANT AND LACTATING WOMEN

PREVENTION OF HEPATOCELLULAR CARCINOMA RELATED TO METABOLIC SYNDROME - HEPATOCELLUAR CARCINOMA (HCC) IS THE FASTEST GROWING CAUSE OF CANCER DEATHS AMONG AMERICANS. IN THE PAST DECADE, THERE HAS BEEN AN EPIDEMIC INCREASE IN METABOLIC (DYSFUNCTION) ASSOCIATED FATTY LIVER DISEASE (MAFLD)-RELATED CIRRHOSIS AND HCC. MAFLD IS ESTIMATED TO AFFECT 1 BILLION INDIVIDUALS GLOBALLY AND IS PROJECTED TO BECOME THE LEADING CAUSE OF HCC IN THE NEXT 2 DECADES. THERE IS AN URGENT NEED TO DEVELOP EFFECTIVE STRATEGIES TO REDUCE HCC BURDEN IN THE GROWING MAFLD POPULATION. THE OVERALL GOAL OF THE PROGRAM PROJECT (PP) IS TO REDUCE THE BURDEN OF HCC- RELATED MORTALITY THROUGH BETTER UNDERSTANDING OF CONTEMPORARY RISK FACTORS (E.G., METABOLIC TRAITS AND BIOMARKERS) AND PROTECTIVE FACTORS (E.G., CHEMOPREVENTION, HCC SURVEILLANCE) OF HCC RELATED TO MAFLD. WE PROPOSE THREE HIGHLY INTEGRATED STUDIES. CENTRAL TO THIS PP IS LEVERAGING AND EXPANDING OUR MULTICITY, PROSPECTIVE COHORT OF PERSONS WITH MAFLD-RELATED CIRRHOSIS, THE TEXAS HCCC CONSORTIUM (THCCC) COHORT, WHICH WILL SERVE AS A RESOURCE FOR THE PROPOSED STUDIES. THE GOAL OF PROJECT 1 IS TO DEVELOP HCC RISK STRATIFICATION MODELS BASED ON PHENOTYPIC, METABOLIC, RADIOMIC AND GENETIC MARKERS OF METABOLIC DYSFUNCTION AMONG PATIENTS WITH CIRRHOSIS. WE PROPOSE THE ANALYSIS OF DATA AND BIOSPECIMENS FROM THE PROSPECTIVE THCCC COHORT OF >5000 PATIENTS WITH CIRRHOSIS (AND 350-400 INCIDENT HCC) TO DEVELOP A SUITE OF RISK SCORE ALGORITHMS) FOR PREDICTING THE RISK OF HCC AMONG PATIENTS WITH CIRRHOSIS. THE GOAL OF PROJECT 2 IS TO EVALUATE THE CHEMOPREVENTIVE EFFECTS AND POTENTIAL HARMS OF METFORMIN, STATINS OR GLITAZONES IN REDUCING THE RISK OF HCC IN INDIVIDUALS WITH MAFLD. WE PROPOSE A RETROSPECTIVE COHORT STUDY USING NATIONAL VA DATASETS OF >580,000 PATIENTS WITH MAFLD. WE WILL ALSO EXAMINE THE EFFECT OF GENETIC MARKERS ON THE CHEMOPREVENTIVE EFFECTS OF THESE MEDICATIONS IN PATIENTS WITH MAFLD CIRRHOSIS IN THCCC. THE GOAL OF PROJECT 3 IS TO EXAMINE COMPARATIVE COST-EFFECTIVENESS OF PREVENTION STRATEGIES IN MAFLD. WE WILL DEVELOP A MATHEMATICAL SIMULATION MODEL AND PERFORM COMPARATIVE ANALYSES OF BENEFITS VS. HARMS OF CHEMOPREVENTION AND HCC SURVEILLANCE IN INDIVIDUALS WITH MAFLD, AND OF USING PRECISION SURVEILLANCE/CHEMOPREVENTION USING HCC RISK STRATIFICATION WE PROPOSE A DATA & ANALYSIS CORE TO SUPPORT DATA MANAGEMENT, DATA HARMONIZATION, STATISTICAL ANALYSES AND WEB-BASED TOOLS; A BIOSPECIMEN AND BIOMARKER DEVELOPMENT CORE TO SUPPORT COLLECTION, PROCESSING, TRANSPORT AND STORAGE OF SERUM AND DNA SAMPLES FROM THCCC COHORT; AND CONDUCT BIOMARKER ASSAYS FOR THE PROJECTS, AND AN ADMINISTRATIVE CORE TO PROVIDE MANAGEMENT, COMMUNICATION AND COORDINATION AMONG PROJECTS, CORES, INVESTIGATORS AND STAFF.

BETA LACTAMASE MUTATIONS IN ANTIBIOTIC RESISTANCE

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLESCENTS, AND PREGNANT AND LACTATING WOMEN

PATHOGENESIS OF CONJUNCTIVAL SQUAMOUS METAPLASIA

TRAINING IN CELL AND GENE THERAPY

DIABETES ENDOCRINOLOGY RESEARCH CENTER

EXCITABILITY AND PLASTICITY IN DEVELOPING EPILEPTIC BRAIN

A NEW TARGET FOR CHROMATIN REMODELER DEFECTS IN CANCER

CLOSING -TB GAPS - FOR PEOPLE LIVING WITH HIV: TB GUIDANCE FOR ADAPTABLE PATIENT-CENTERED SERVICE

SMART POST-BACCALAUREATE PH.D PREP PROGRAM

PITX2 IN ATRIAL FIBRILLATION

FUNCTIONAL GENOMICS AND DEC-TEC TO IDENTIFY GERM CELL-SPECIFIC CONTRACEPTIVES

ENHANCING ATOH1 FUNCTION IN HAIR CELL REGENERATION

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

CAMKII REGULATION OF CARDIAC RYANODINE RECEPTORS IN ATRIAL FIBRILLATION

RBD RECOMBINANT PROTEIN-BASED SARS VACCINE FOR BIODEFENSE

PERSONALIZED FUNCTIONAL GENOMICS FOR MITOCHONDRIAL ENCEPHALOPATHY GENE DISCOVERY

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

DECODING THE IMPACT OF SEX DIFFERENCES ON ALZHEIMER'S DISEASE RISK - DECODING THE IMPACT OF SEX DIFFERENCES ON ALZHEIMER’S DISEASE RISK THE MOLECULAR BASIS AND GENETIC ARCHITECTURE OF ALZHEIMER’S DISEASE (AD) REMAIN POORLY DEFINED. SOLVING THESE PROBLEMS IS FURTHER COMPLICATED BY THE DIFFERENCES THAT EXIST BETWEEN MEN AND WOMEN WITH RESPECT TO THE PREVALENCE, ONSET, PROGRESSION AND COMORBIDITIES OF AD, SUGGESTING THAT SOME CONTRIBUTING GENETIC VARIANTS ARE SEX-SPECIFIC. SO FAR, MIXED-GENDER GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE LINKED OVER 100 LOCI WITH AD. THESE LOCI EXPLAIN MUCH OF THE POPULATION-ATTRIBUTABLE RISK BUT JUST A FRACTION OF HERITABILITY, AND WITH NO DISTINCTION BETWEEN MEN AND WOMEN. IT IS UNLIKELY THAT THIS HERITABILITY GAP WOULD IMPROVE JUST BY SPLITTING STUDIES BY SEX, HOWEVER, SINCE SEPARATE ANALYSES ON ABOUT HALF AS MANY PATIENTS WOULD BE LESS POWERFUL. RATHER, IN ORDER TO DESIGN EFFECTIVE SURVEILLANCE, SCREENING, PREVENTIVE, AND STRATIFICATION PROGRAMS TAILORED TO EACH SEX, THERE IS A CRITICAL NEED FOR MORE SENSITIVE AND ACCURATE METHODS, ABLE TO COMPUTE THE LINK BETWEEN GENETIC VARIANTS AND AD RISK SEPARATELY AND SPECIFICALLY IN MEN AND WOMEN. TO DO SO, WE PROPOSE AN INTEGRATIVE COMPUTATIONAL APPROACH THAT WILL BE VALIDATED BY EXPERIMENTAL AND TRANSLATIONAL STUDIES OF CANDIDATE GENES. RATHER THAN SEEK INDIVIDUAL VARIANTS, WE FOCUS INSTEAD ON GENES AND THEIR CODING REGIONS. IN ORDER TO INCREASE THE POWER OF OUR STUDIES, WE DEVELOPED AN UNBIASED EVOLUTION-BASED CONTINUOUS SCORE FOR THE FUNCTIONAL IMPACT OF ANY CODING VARIANT, FROM 0 (NEUTRAL) TO 1 (COMPLETE LOSS OF FUNCTION). USING THIS SCORING SYSTEM ADDS TO THE USUAL ANALYSES OF HUMAN VARIANTS A VAST NUMBER OF AMINO ACID MUTATION EXPERIMENTS ALREADY PERFORMED BY EVOLUTION OVER BILLIONS OF YEARS, WITH EACH MUTATION BEING TIED TO A FUNCTIONAL READOUT BASED ON THE CONTEXT OF ITS PHYLOGENETIC DIVERGENCE. WITH THIS SCORE, WE NOW PROPOSE TO IDENTIFY GENES THAT CARRY SIGNIFICANTLY MORE IMPACTFUL CODING VARIANTS IN AD WOMEN, OR AD MEN, COMPARED TO SEX-MATCHED CONTROLS. THE GAIN IN STATISTICAL POWER OF THIS APPROACH COMPARED TO GWAS HAS BEEN DEMONSTRATED IN PRELIMINARY DATA. IN AIM 1 WE PROPOSE TO DISCOVER SEX-SPECIFIC AD GENES ON MORE THAN 1000 ALZHEIMER’S DISEASE SEQUENCING PROJECT (ADSP) MEN AND 1400 ADSP WOMEN; AND IN AIM 2 TO DISCOVER SEX-SPECIFIC MODIFIERS OF APOE. AIM 3 WILL INCLUDE VALIDATION OF COMPUTATIONALLY-DERIVED CANDIDATE GENES IN HUMAN BRAIN TISSUE AND CEREBROSPINAL FLUID (CSF), AND THOROUGH EXPERIMENTAL CHARACTERIZATION IN AD ANIMAL-MODELS (MOUSE AND DROSOPHILA). TOGETHER, THIS COMBINATION OF NOVEL, INTEGRATIVE COMPUTATIONAL APPROACHES AND MULTI-MODEL SYSTEMS VALIDATION EXPERIMENTS WILL YIELD NEW BIOMARKERS THAT IMPROVE SEX-SPECIFIC RISK STRATIFICATION OF AD STATUS AND REVEAL DIFFERENCES IN DISEASE MECHANISMS BETWEEN WOMEN AND MEN THAT HIGHLIGHT POTENTIAL THERAPEUTIC TARGETS SPECIFIC TO EACH.

STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE

HEMATOLOGY TRAINING GRANT

RESEARCH TRAINING IN PEDIATRIC GASTROENTEROLOGY

THE PREVAIL-KIDS COMMON PROTOCOL - ABSTRACT PREVAIL-KIDS SITES HAVE IDEN5ED OPPORTUNI5ES TO RAPIDLY ACQUIRE AND SHARE SAMPLES AND CLINICAL DATA AMONG THEMSELVES, THUS CATALYZING THE PROCESS OF MUL5-SITE VALIDA5ON OF THEIR ONGOING DEVELOPMENTAL ASSAYS AND ALGORITHMS. VIA A SURVEY CONDUCTED IN APRIL 2023, THE SITES HAVE IDEN5ED THE MATRIX OF SHAREABLE/USABLE SAMPLES AND DATA AMONGST MEMBERS OF THE NETWORK. OVER 80% OF POSSIBLE EXCHANGES ARE GOING TO BE FRUI8UL. THE GOAL OF THIS SUPPLEMENTAL APPLICA5ON IS THEREFORE TO FACILITATE THE RAPID EXCHANGE OF DATA/SAMPLES BETWEEN THE 8 PREVAIL-KIDS SITES, SO THAT MUL5-SITE VALIDA5ON OF THEIR RESPEC5VE ASSAYS AND ALGORITHMS CAN PROCEED.

MISSION CONNECT MILD TBI TRANSLATIONAL RESEARCH CONSORTIUM

CLONAL HEMATOPOIESIS IN HUMANS: DETERMINANTS OF DEVELOPMENT AND PROGRESSION

MULTIDISCIPLINARY K12 UROLOGIC RESEARCH CAREER DEVELOPMENT PROGRAM AT BAYLOR

HIGH RESOLUTION MICROENDOSCOPY FOR THE MANAGEMENT OF ESOPHAGEAL NEOPLASIA

SURVIVORSHIP AND ACCESS TO CARE FOR LATINOS TO UNDERSTAND AND ADDRESS DISPARITIES (SALUD) - ABSTRACT PEDIATRIC CANCER SURVIVORS (PCS) EXPERIENCE AN EXCESS RISK OF ADVERSE OUTCOMES RELATED TO THEIR CANCER DIAGNOSIS AND THE TREATMENT THEY RECEIVE. THE ACCUMULATION AND SEVERITY OF THESE ACUTE AND CHRONIC HEALTH CONDITIONS BROADLY IMPACT PCS FUNCTIONING, QUALITY OF LIFE, AND HEALTH CARE RESOURCE UTILIZATION. CONSEQUENTLY, PCS ARE MORE LIKELY TO LIVE IN FINANCIAL HARDSHIP, HAVE LOWER EDUCATIONAL ATTAINMENT, BE UNEMPLOYED DUE TO POOR HEALTH, AND BE UNDER- OR UNINSURED COMPARED WITH THEIR AGE-BASED PEERS. LATINO PCS ARE AT PARTICULARLY HIGH RISK FOR HAVING A LOWER SOCIOECONOMIC STATUS (SES COMPARED WITH NON-LATINO PCS. THESE FACTORS CONTRIBUTE TO REDUCED ACCESS TO ROUTINE MEDICAL CARE, AND LOWER OVERALL SURVIVAL OF LATINO CHILDREN DIAGNOSED WITH CANCER. EXISTING AND WELL-ESTABLISHED PATIENT COHORTS OF PCS LARGELY INCLUDE LONG-TERM (AT LEAST 5 YEARS) SURVIVORS AND A RELATIVELY SMALL PROPORTION OF LATINO PCS, SO THAT THE OUTCOME DATA THAT INFORM OUR UNDERSTANDING OF RISK FOR CANCER TREATMENT LATE EFFECTS, AND THEREFORE OUR CLINICAL PRACTICE GUIDELINES, ARE LARGELY DERIVED FROM THE EXPERIENCES OF NHW PCS. THE OVER-ARCHING OBJECTIVE OF THIS PROPOSAL IS TO IDENTIFY AND COMPREHENSIVELY ASSESS ADVERSE OUTCOMES AMONG LATINO PCS THAT WILL INFORM CLINICAL GUIDELINES AND LAY THE FOUNDATION FOR EARLY, TARGETED INTERVENTIONS TO MITIGATE SUCH OUTCOMES IN THIS VULNERABLE AND GROWING POPULATION OF PCS. KEY TO THE SUCCESS OF OUR PROPOSAL IS THE PROSPECTIVE ESTABLISHMENT OF A LATINO PCS COHORT IN TEXAS THAT IS LINKED WITH GENOMIC AND GEOGRAPHIC DATA (UG3 PLANNING PHASE), WHICH WILL PERMIT ANALYSES OF THE INTERACTION BETWEEN ANCESTRY AND SES ON RISK FOR ADVERSE CANCER TREATMENT OUTCOMES DURING THE UH3 IMPLEMENTATION PHASE. THERE IS A SIGNIFICANT UNMET NEED TO COMPREHENSIVELY CHARACTERIZE THE SOCIOECONOMIC, PSYCHOSOCIAL, GENOMIC, AND METABOLOMIC RISK DETERMINANTS OF TREATMENT-RELATED TOXICITIES AND RELAPSE IN LATINO PCS IN THE CONTEXT OF KNOWN CLINICAL RISK FACTORS. IN ADDITION, AMONG UNDER-REPRESENTED MINORITIES THERE IS A CRITICAL NEED TO IDENTIFY FACILITATORS AND BARRIERS TO OBTAINING SURVIVORSHIP CARE. THEREFORE, UTILIZING EXISTING AND PROSPECTIVELY COLLECTED LONGITUDINAL DATA, WE WILL: (1) IDENTIFY DEMOGRAPHIC, CLINICAL, AND GENETIC/MOLECULAR DETERMINANTS OF TREATMENT-RELATED TOXICITIES AND THEIR ASSOCIATION WITH CHRONIC HEALTH CONDITIONS, PATIENT-REPORTED SYMPTOMS, AND NEUROCOGNITIVE/ PSYCHOLOGICAL AND FUNCTIONAL OUTCOMES IN LATINO PCS; (2) IDENTIFY DEMOGRAPHIC, CLINICAL, AND GENETIC/MOLECULAR DETERMINANTS OF THE EXCESS RISK OF CANCER RELAPSE/RECURRENCE IN A COHORT OF LATINO PCS; AND (3) DETERMINE LATINO PCS UNDERSTANDING OF RISK FOR LATE EFFECTS AND RATIONALE FOR SURVIVORSHIP CARE, AND IDENTIFY PERCEIVED FACILITATORS AND BARRIERS TO OBTAINING SURVIVORSHIP CARE. THIS PROPOSAL SYNERGIZES MULTIDISCIPLINARY EXPERTISE AND DATA COLLECTED FROM CLINICAL AND EPIDEMIOLOGICAL RESOURCES TO ESTABLISH A PROSPECTIVE, COMPREHENSIVE BIOBANK AND DATABASE INCLUSIVE OF A LARGE POPULATION OF LATINO PCS. OUR AIMS REPRESENT THE LARGEST ASSESSMENT TO DATE OF GENETIC AND SES CONTRIBUTORS TO OUTCOMES IN LATINO PCS, AN EFFORT THAT IS IMPERATIVE TO INFORM RISK ASSESSMENTS FOR ADVERSE OUTCOMES IN AN ETHNO-DIVERSE POPULATION, AS WELL AS POTENTIAL BARRIERS TO OBTAINING OPTIMAL SURVIVORSHIP CARE.

PEDIATRIC HIV/AIDS & INFECTION-RELATED MALIGNANCIES RESEARCH CONSORTIUM FOR SUB-SAHARAN AFRICA (PARCA)

THE MOLECULAR ARCHITECTURE OF AXONS IN HEALTH AND DISEASE - PROJECT SUMMARY ACTION POTENTIAL INITIATION AND PROPAGATION IN MYELINATED AXONS REQUIRES HIGH DENSITIES OF ION CHANNELS CLUSTERED AT AXON INITIAL SEGMENTS (AIS), NODES OF RANVIER, AND A ROBUST AXONAL CYTOSKELETON TO HELP AXONS RESIST MECHANICIAL INJURY. AIS ALSO FUNCTION TO MAINTAIN NEURONAL POLARITY AND REGULATE THE DISTINCTION BETWEEN AXONAL AND SOMATODENDRITIC DOMAINS. UNFORTUNATELY, DISRUPTION OF THESE DOMAINS AND THE CYTOSKELETON DURING DISEASE OR AFTER INJURY DRAMATICALLY IMPAIRS NERVOUS SYSTEM FUNCTION. FURTHERMORE, THE MOLECULAR MECHANISMS THAT CONTROL THE ASSEMBLY, FUNCTION, AND MAINTENANCE OF AIS, NODES, AND AXONAL CYTOSKELETON REMAIN POORLY UNDERSTOOD. SINCE ANY THERAPEUTIC APPROACH AIMED AT NERVOUS SYSTEM REPAIR OR REGENERATION MUST INCLUDE THE REASSEMBLY OR PRESERVATION OF AXONS, AIS AND NODES OF RANVIER, A DETAILED MECHANISTIC UNDERSTANDING OF THEIR STRUCTURE, MECHANISMS OF ASSEMBLY, AND COMPOSITION IS URGENTLY NEEDED. TO THIS END WE DEVELOPED PROTEOMIC APPROACHES TO PERFORM A MOLECULAR DISSECTION OF AIS AND NODES OF RANVIER; THESE EXPERIMENTS WILL YIELD AIS AND NODE 'INTERACTOMES.' TO DETERMINE THE FUNCTIONS OF IDENTIFIED PROTEINS WE WILL PERFORM RIGOROUS GAIN AND LOSS OF FUNCTION STUDIES USING MODERN MOLECULAR, IMAGING, GENETIC, AND ELECTROPHYSIOLOGICAL METHODS. BUILDING ON OUR PREVIOUS RESEARCH ACCOMPLISHMENTS AND OUR DISCOVERY THAT MECHANISMS OF NODE ASSEMBLY CONVERGE ON ANKYRIN AND SPECTRIN CYTOSKELETONS, WE WILL ALSO DETERMINE THE FUNCTIONS OF THESE ENIGMATIC, YET ESSENTIAL, CYTOSKELETAL PROTEINS USING CONDITIONAL KNOCKOUT MOUSE MODELS THAT WE HAVE DEVELOPED. TOGETHER, WE EXPECT THESE STUDIES TO REVEAL KEY MOLECULAR MECHANISMS RESPONSIBLE FOR THE ASSEMBLY, MAINTENANCE, AND FUNCTION OF AXONS. THESE DISCOVERIES MAY REVEAL TARGETS AND MECHANISMS THAT CAN BE USED FOR THERAPIES TO REPAIR OR PRESERVE AXON FUNCTION.

RISK STRATIFICATION FOR AND EARLY DETECTION OF LIVER CANCER

FUNCTIONAL DETERMINANTS IN G PROTEIN-COUPLED RECEPTORS

REGULATION OF ATROPHY-INDUCED PROGENITOR CELLS IN THE GASTRIC CORPUS

HARNESSING PROTEINS AS DRUGS: THE PROTECTOME OF CANCER- AND AGING-PREVENTION PROTEINS

MOLECULAR BASIS OF HUMAN VISUAL SYSTEM DISORDERS

VASCULAR MECHANISMS OF SECONDARY INJURY AFTER TBI

INTRACOCHLEAR ELECTROCHEMICAL GRADIENTS

A SYNTHETIC PLATFORM FOR NON-ANTIBIOTIC ERADICATION OF BACTERIAL INFECTIONS

THE ROLE OF INFLAMMASOME IN THE PATHOGENESIS OF ATRIAL FIBRILLATION

DECODE THE CHEMICAL LANGUAGE THAT ORCHESTRATES CELLULAR AND ORGANISMAL HOMEOSTASIS

TRANSLATION REGULATION BY ENTEROVIRUS PROTEINASE

HOUSTON AREA MOLECULAR BIOPHYSICS PROGRAM

MISSION CONNECT MILD TBI TRANSLATIONAL RESEARCH CONSORTIUM

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

GENETIC REPAIR OF FAMILIAL HYPERCHOLESTEROLEMIA

AN INTEGRATED ONE HEALTH APPROACH TO DETECT AND RESPOND TO EMERGING DISEASE THREATS IN HIGH-RISK REGIONS OF CENTRAL AMERICA

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

MAPPING THE DEVELOPMENTAL, GENETIC, AND FUNCTIONAL ORGANIZATION OF NORADRENERGIC RESPIRATORY NEURAL CIRCUITS

MOLECULAR PATHOGENESIS OF MYOTONIC DYSTROPHY

REGULATION OF DNA RECOMBINATION IN SACCHAROMYCES CEREVISIAE

A COMPREHENSIVE RESOURCE FOR MANIPULATING THE DROSOPHILA GENOME - PROJECT SUMMARY THE DROSOPHILA GENE DISRUPTION PROJECT (GDP), SINCE ITS FOUNDATION IN 2000, HAS PRODUCED A LARGE, PUBLICLY AVAILABLE LIBRARY OF INDIVIDUAL, SEQUENCE-MAPPED TRANSPOSABLE ELEMENT (TE) INSERTIONS THAT HAVE BECOME AN ESSENTIAL RESOURCE FOR FLY RESEARCH. GENERATING AND SEQUENCING 180,000 TES ALLOWED THE MOST USEFUL ~22,000 (LOCATED IN/NEAR 13,000 GENES) TO BE SELECTED AND DEPOSITED IN THE BLOOMINGTON DROSOPHILA STOCK CENTER. MORE THAN 750,000 GDP CULTURES HAVE BEEN DISTRIBUTED TO THOUSANDS OF LABS NATIONALLY AND INTERNATIONALLY, FACILITATING THE ANALYSIS OF THOUSANDS OF GENES. THE FEATURES OF THE TES DEVELOPED BY THE GDP, PARTICULARLY THE MIMIC TE, GREATLY ENHANCE THEIR VALUE AS THEY ALLOW CHARACTERIZATION OF GENE EXPRESSION, PROTEIN DISTRIBUTION, TISSUE SPECIFIC KNOCK DOWN, ISOLATION OF INTERACTING PROTEINS, ASSESSMENT OF THE FUNCTION OF HOMOLOGUES OF OTHER SPECIES AND OTHER SOPHISTICATED, STATE-OF-THE-ART MANIPULATIONS. THE FLEXIBILITY TO SWAP ANY DNA CASSETTE INTO EXISTING MIMIC TE SITES PROVIDES A GENETIC TOOLKIT THAT IS UNRIVALED, GREATLY ADVANCING THE FIELD OF FUNCTIONAL GENOMICS AND IMPACTING OUR UNDERSTANDING OF GENE FUNCTION ACROSS SPECIES. DURING THE PROPOSED BUDGET PERIOD, THE GDP WILL PROVIDE TOOLS TO ANALYZE GENE FUNCTION THAT WILL CONSTITUTE A NEW RESOURCE NOT ONLY TO TACKLE BASIC BIOLOGICAL QUESTIONS BUT ALSO MEDICAL QUESTIONS AIDING WITH THE DISCOVERY AND STUDY OF NEW HUMAN DISEASES AND THEIR UNDERLYING MECHANISMS. A CRITICAL PREREQUISITE FOR MODELING DISEASE IN DROSOPHILA IS THE ABILITY TO EXPRESS EACH OF THE 9,000 EVOLUTIONARILY CONSERVED HUMAN GENES IN THE ENDOGENOUS EXPRESSION PATTERN OF THEIR FLY ORTHOLOG. THIS CAN CURRENTLY BE ACHIEVED BY USING MIMIC AND THE SA-T2A-GAL4-POLYA CASSETTE (T2A-GAL4). WHEN INSERTED IN INTRONS BETWEEN TWO CODING EXONS, THIS CASSETTE IS HIGHLY MUTAGENIC AND PRODUCES A GAL4 THAT CAN BE USED TO DRIVE THE UAS-CDNA OF A FLY OR HUMAN HOMOLOG, FREQUENTLY RESCUING THE MUTANT PHENOTYPE AND ALLOWING DISEASE MODELING. HERE, WE PROPOSE TO EXPAND THE TAGGING OF MOST GENES THAT CAN BE TAGGED WITH THIS APPROACH. WE HAVE ALSO DEVELOPED A NEW STRATEGY TO PERMIT REPLACEMENT OF ALL GENES THAT DO NOT HAVE SUITABLE INTRONS FOR T2A-GAL4 INTEGRATION, WHICH CONSTITUTE ABOUT 45% OF ALL FLY GENES. THIS METHOD EXCHANGES THE GENE'S ENTIRE CODING REGIONS WITH A KOZAK CONSENSUS SEQUENCE FOLLOWED BY GAL4. WE PROPOSE TO TARGET 2,300 CURRENTLY UNTAGGED DROSOPHILA GENES USING THESE TWO STRATEGIES DEPENDING ON THE STRUCTURE OF THE LOCUS AND THE NATURE OF THE CASSETTE TO BE INSERTED. THE VAST MAJORITY OF THE GENES WILL BE TAGGED WITH GAL4 BECAUSE IT PERMITS NUMEROUS ELEGANT APPLICATIONS. THE RESULTING LINES WILL BE CHARACTERIZED GENETICALLY AND MOLECULARLY AND THE EXPRESSION PATTERN OF THE GENES WILL BE DOCUMENTED IN THIRD INSTAR LARVAL BRAINS. THE GENERATION AND DISTRIBUTION OF THESE REAGENTS IS HIGHLY APPRECIATED BY THE DROSOPHILA COMMUNITY AS SHOWN BY THE MANY LETTERS OF SUPPORT FROM LEADERS IN THE FLY COMMUNITY.

ALTERED MICROBIOME IN PANCREATITIS, DIABETES AND PANCREATIC CANCER

THE EFFECTIVENESS OF HIGH RESOLUTION MICROENDOSCOPY (HRME) IN HIGH GRADE INTRAEPITHELIAL LESIONS (HSIL) DIAGNOSIS FOR PEOPLE LIVING WITH HIV

MOLECULAR ENGINEERING OF NATURAL LIGHT-GATED CHLORIDE CHANNELS FOR OPTOGENETIC INHIBITION

GENETIC REGULATION OF INNER AND MIDDLE EAR DEVELOPMENT

CONSERVED FETAL EPIGENOMIC SIGNATURES IN A PRIMATE MODEL OF MATERNAL OBESITY

NATIONAL EMERGENCY MEDICAL SERVICES FOR CHILDREN (EMSC) RESOURCE CENTERS DEMONSTRATION CA

PREVENTION OF TRAUMA/HEMORRHAGIC SHOCK-INDUCED MORTALITY, APOPTOSIS, INFLAMMATION AND MITOCHONDRIAL DYSFUNCTION

COMBINATORIAL HELPER-DEPENDENT ADENOVIRAL GENE THERAPY FOR POST-TRAUMATIC OSTEOARTHRITIS

MOLECULAR EXCITABILITY IN THE CARDIOVASCULAR SYSTEM

RESEARCH AND RESEARCH EDUCATION TO IMPROVE THE NUTRITION OF INFANTS, CHILDREN, ADOLSECENTS, AND PREGNANT AND LACTATING WOMEN

MECHANISMS GOVERNING NUCLEAR FACTOR I GENE INDUCTION AND FUNCTION DURING THE INI

NONRECURRENT REARRANGEMENTS GENOME ARCHITECTURE AND NEURODEGENERATIVE DISEASE.

INTERVENTION STRATEGIES FOR NON-FOLATE RESPONSIVE NEURAL TUBE DEFECTS

MOLECULAR STUDIES OF SPINOCEREBELLAR ATAXIA TYPE 1

DATA MANAGEMENT AND RESOURCE REPOSITORY FOR THE EXRNA ATLAS PHASE II

LEVERAGING PASSIVE OBJECTIVE ASSESSMENT METHODS OF PRESCHOOLER'S MEDIA USE TO EXAMINE MULTIPLE PATHS OF INFLUENCE ON SLEEP, EXECUTIVE FUNCTION AND WEIGHT STATUS - TECHNOLOGY AND DIGITAL MEDIA (TDM), WHICH INCLUDES TV VIEWING, PLAYING COMPUTER GAMES, AND MOBILE DEVICE USE, IS COMMON AMONG PRESCHOOL AGED CHILDREN. MANY YOUNG CHILDREN EXCEED THE RECOMMENDED =1 HOUR/DAY OF PARENT SUPERVISED TDM USE AND THIS VARIES BY SEX AND RACE/ETHNICITY. THIS IS CONCERNING BECAUSE EXCESSIVE TDM USE HAS BEEN LINKED LESS DESIRED DEVELOPMENTAL AND HEALTH PROBLEMS. SOME OF THESE OUTCOMES, SUCH AS SLEEP, WEIGHT STATUS AND EXECUTIVE FUNCTIONING MAY BE INTERRELATED AND SHOULD BE EXAMINED TOGETHER IN ONE RESEARCH PROGRAM. HOWEVER, PAST STUDIES OF TDM USE AMONG YOUNG CHILDREN PRIMARILY RELIED ON PARENT REPORT OF CHILDREN’S TYPICAL USE OF TDM, RESULTING IN BOTH OVER- AND UNDER-REPORTING OF TDM USE. THE VALIDITY OF FINDINGS FROM THESE PAST STUDIES ARE THEREFORE QUESTIONED. FLASH-TV IS A NEW TECHNOLOGY DEVELOPED BY OUR TEAM TO PASSIVELY, OBJECTIVELY MEASURE CHILDREN’S VIEWING OF LARGE DIGITAL SCREENS, SUCH AS TVS OR VIDEO-GAME CONSOLES. IN THIS RESEARCH PROGRAM WE PROPOSE TO LEVERAGE FLASH-TV ALONG WITH NEW APPROACHES FOR MEASURING CHILDREN’S USE OF MOBILE DEVICES, TO ROBUSTLY ASSESS CHILDREN’S USE OF TDM ACROSS MULTIPLE PLATFORMS (TV, MOBILE DEVICES, AND VIDEOGAME CONSOLES). THIS WILL ALLOW US TO INVESTIGATE THE ROLE TDM USE HAS ON 1) HEALTH OUTCOMES (SLEEP AND CHILD WEIGHT STATUS) IN PROJECT 1; 2) DEVELOPMENT (EXECUTIVE FUNCTION) AND WEIGHT STATUS IN PROJECT 2, WHILE IDENTIFYING ANY PROTECTIVE ROLE PARENTAL SCAFFOLDING HAS ON CHILD TDM USE, AND 3) THE EFFECT OF TIMING OF TDM USE CLOSE TO BEDTIME ON CHILD SLEEP, CIRCADIAN RHYTHM, AND EXECUTIVE FUNCTION USING EXPERIMENTAL STUDIES IN PROJECT 3. THREE CORES WILL BE DEVELOPED TO PROVIDE SYNERGY ACROSS PROJECTS AND ALLOW FOR A COST EFFECTIVE APPROACH TO ACHIEVE THE AIMS OF ALL PROJECTS. AN ADMINISTRATIVE CORE WILL OVERSEE THE COMMUNICATION AND COORDINATION ACROSS PROJECTS. A DIGITAL ASSESSMENT CORE WILL OVERSEE THE PASSIVE AND OBJECTIVE ASSESSMENT OF TDM USE AND SLEEP AMONG CHILDREN ACROSS ALL THREE PROJECTS. THE BIOSTATISTICS AND DATABASE MANAGEMENT CORE WILL DEVELOP AND OVERSEE DATABASES, HARMONIZE VARIABLES, AND PROVIDE STATISTICAL SUPPORT FOR ALL THREE PROJECTS. A COHORT OF 4-YEAR OLD CHILDREN (N=200) AND THEIR PARENT WILL BE ESTABLISHED FOR THE OVERALL PROGRAM BY PROJECT 1 TO ASSESS THE CHILD’S TDM USE, WEIGHT STATUS, SLEEP, AND HOME ENVIRONMENT. THE COHORT WILL HAVE DATA COLLECTED OVER 10 DAYS AT TWO TIME-POINTS, 12 MONTHS APART. PROJECT 2 WILL LEVERAGE THE SAME COHORT AND MEASURE THE CHILD’S EXECUTIVE FUNCTION AND PARENT-CHILD INTERACTIONS DURING TDM USE USING ROBUST APPROACHES IN AN OBSERVATION LAB ACROSS THREE TIME POINTS (BASELINE, 6 MONTHS AND 12 MONTHS). A UNIQUE SAMPLE WILL BE RECRUITED TO PARTICIPATE IN THE EXPERIMENTAL STUDIES FOR PROJECT 3. FOR THE FIRST TIME, THESE NOVEL APPROACHES TO PASSIVELY AND OBJECTIVELY MEASURE CHILDREN’S TDM USE IN THEIR HOME ENVIRONMENT OVER MULTIPLE DAYS ALLOWS US TO ASSESS THE WITH-IN AND BETWEEN CHILD ASSOCIATION OF CHILDREN’S TDM USE ON CHILD HEALTH AND DEVELOPMENTAL OUTCOMES TO PROVIDE MORE ROBUST EVIDENCE TO INFORM FUTURE TDM GUIDELINES FOR CHILDREN.

NEW VULNERABILITIES IN MYC-DRIVEN BREAST CANCER

A HYPERSENSITIVE ER ALPHA MUTANT IN BREAST CANCER HORMONE RESISTANCE

EPIDEMIOLOGIC RESEARCH ON SCREENING FOR VESTIBULAR AND BALANCE DISORDERS

TRAINING PROGRAM IN CELL AND MOLECULAR BIOLOGY

IPGDAC, AN INTEGRATIVE PROTEOGENOMIC DATA ANALYSIS CENTER FOR CPTAC

SUPPORT AND DEVELOPMENT OF EMAN FOR ELECTRON MICROSCOPY IMAGE PROCESSING

MOLECULAR ANALYSIS OF UTERINE RECEPTIVITY