The Administrators Of The Tulane Educational Fund

TULANE NATIONAL PRIMATE RESEARCH CENTER

MENTORING RESEARCH EXCELLENCE IN AGING AND REGENERATIVE MEDICINE

TULANE NATIONAL PRIMATE RESEARCH CENTER, AIDS SPF BREEDING COLONY MAINTENANCE

TULANE COBRE FOR CLINICAL AND TRANSLATIONAL RESEARCH IN CARDIOMETABOLIC DISEASES

MAINTENANCE OF AN SPF MACAQUE BREEDING COLONY FOR AIDS RESEARCH

TRANS-OMICS INTEGRATION OF MULTI-OMICS STUDIES FOR MALE OSTEOPOROSIS

THERAPEUTIC TARGETING OF THE MYOFIBROBLAST IN FIBROTIC LUNG DISEASE

ESTROGENS, CARDIOMETABOLIC HEALTH, AND FEMALE COGNITIVE AGING - OVERALL SUMMARY LOSS OF OVARIAN FUNCTION AT MENOPAUSE IS HYPOTHESIZED TO BE A RISK FACTOR FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS. RESEARCH IN PRECLINICAL MODELS INDICATES THAT ESTROGENS ARE NEUROPROTECTIVE AND CAN POSITIVELY IMPACT THE COGNITIVE AGING TRAJECTORY. HOWEVER, CLINICAL DATA HAVE BEEN EQUIVOCAL AS TO THE BENEFITS OF MENOPAUSAL ESTROGEN THERAPY TO THE BRAIN AND COGNITION. VARIATION IN RESPONSE TO ESTROGEN THERAPY IN WOMEN SUGGESTS THAT PRE-EXISTING DISEASE SUCH AS HYPERTENSION AND METABOLIC SYNDROME CAN MODULATE MECHANISMS OF ESTROGEN ACTION. THESE ALTERATIONS MAY CONSEQUENTLY REDUCE OR REVERSE PROTECTIONS ESTROGENS PROVIDE AGAINST COGNITIVE DECLINE, ALZHEIMER’S DISEASE, AND RELATED DEMENTIAS. THE PROGRAM OBJECTIVE IS TO DETERMINE THE IMPACT OF CARDIOMETABOLIC STATUS ON THE ABILITY OF EXOGENOUSLY ADMINISTERED ESTROGENS TO BENEFIT THE BRAIN AND COGNITION IN AN AGING FEMALE RODENT MODEL. THE OVERALL HYPOTHESIS IS THAT ADMINISTRATION OF ESTROGENS IN AGING FEMALES WILL BENEFIT THE BRAIN AND COGNITION IF INITIATED IN HEALTHY SUBJECTS, BUT WILL PROVIDE NO BENEFITS IF INITIATED IN THE PRESENCE OF CARDIOMETABOLIC DISEASE. MECHANISMS BY WHICH THESE DIVERGENT EFFECTS OCCUR ARE HYPOTHESIZED TO INVOLVE BOTH ALTERATIONS IN MECHANISMS BY WHICH ESTROGENS ACT DIRECTLY ON BRAIN MEMORY SYSTEMS AND MECHANISMS BY WHICH ESTROGENS ACT ON CARDIOMETABOLIC SYSTEMS, WHICH IN TURN IMPACT BRAIN MEMORY SYSTEMS. EXPERIMENTS UNDER THE FOUR PROJECTS WILL TEST THIS HYPOTHESIS. PROJECT 1 WILL TEST THE HYPOTHESIS THAT CARDIOMETABOLIC DISEASE, DUE TO ASSOCIATED DYSFUNCTION OF THE UBIQUITIN/PROTEASOME SYSTEM, WILL DISRUPT THE ABILITY OF ESTROGENS TO REGULATE LEVELS OF ERA IN THE HIPPOCAMPUS, REGULATION THAT IS NECESSARY FOR MIDLIFE ESTRADIOL TREATMENT TO EXERT LASTING IMPACTS ON MEMORY. PROJECT 2 WILL TEST THE HYPOTHESIS THAT THE PRESENCE OF CARDIOMETABOLIC DISEASE IMPEDES ESTROGEN’S BENEFICIAL COGNITIVE EFFECTS BY BLUNTING NEUROVASCULAR COUPLING VIA ENDOTHELIAL NITRIC OXIDE SYNTHASE UNCOUPLING, THUS IMPAIRING THE LOCAL NETWORK ACTIVITY AND SYNAPTIC PLASTICITY REQUIRED TO PRESERVE FUNCTIONAL CORTICAL CIRCUITS AND THEREFORE FOR COGNITION. PROJECT 3 WILL TEST THE HYPOTHESIS THAT CARDIOVASCULAR DISEASE ALTERS THE ESTROGEN RECEPTOR PROFILE, ALTERING DOWNSTREAM MOLECULAR SIGNALING PATHWAYS AND ATTENUATING ITS PROTECTIVE VASCULAR EFFECTS AND SUBSEQUENT IMPACT ON COGNITION. PROJECT 4 WILL TEST THE HYPOTHESIS THAT INSULIN RESISTANCE CAUSED BY HIGH FAT DIET IMPAIRS DOWNSTREAM SIGNALING PATHWAYS NECESSARY FOR ESTRADIOL’S BENEFICIAL INFLUENCE ON CENTRAL REGULATION OF GLUCOSE HOMEOSTASIS, HIPPOCAMPAL LONG- TERM POTENTIATION, AND HIPPOCAMPUS-DEPENDENT COGNITIVE FUNCTION. THE ADMINISTRATIVE CORE WILL PROVIDE LEADERSHIP TO THE PROGRAM AND ENSURE INTEGRATION OF ALL PROGRAM COMPONENTS. THE CARDIOMETABOLIC AND HORMONES AND BEHAVIOR CORES WILL PROVIDE CRITICAL CONSISTENCIES IN MODELS AND PROCEDURES TO ENSURE SCIENTIFIC RIGOR AND REPRODUCIBILITY OF RESULTS ACROSS PROJECTS. RESULTS WILL IDENTIFY CONDITIONS UNDER WHICH ESTROGEN TREATMENT WILL (OR WILL NOT) CHANGE THE COGNITIVE AGING TRAJECTORY THAT COULD POTENTIALLY REDUCE OR DELAY AGE- RELATED COGNITIVE DISEASE INCLUDING ALZHEIMER’S DISEASE AND VASCULAR DEMENTIA.

COORDINATING CENTER FOR THE PEDIATRIC HIV/AIDS COHORT S*

I3C DECADE: DISPARITIES AND EQUITY IN CHILDHOOD CARDIOVASCULAR EXPOSURES AND ALZHEIMER'S DEMENTIA - SUMMARY RISK FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) REMAINS HIGHER IN BLACK POPULATIONS THAN IN OTHER RACE/ETHNIC GROUPS.THIS MAY BE DUE AT LEAST IN PART TO ACCUMULATED DISADVANTAGE WHICH ACCELERATES THE PROGRESSION OF CARDIOVASCULAR (CV) RISK FACTORS, THAT IN TURN MAY CONTRIBUTE TO THE DEVELOPMENT OF CLINICALLY SILENT ALZHEIMER’S PATHOLOGY AS EARLY AS MIDDLE AGE. OUR TEAM HAS DEMONSTRATED THAT EXPOSURE TO CV RISK FACTORS SUCH AS OBESITY, ELEVATED GLUCOSE, LIPIDS AND BLOOD PRESSURE CAN IMPACT THE VASCULAR SYSTEM BY CHILDHOOD AND EVEN IN UTERO. EARLY VASCULAR CHANGES, IN TURN, MAY CONTRIBUTE TO CHANGES IN BRAIN HEALTH DECADES LATER. DESPITE DOCUMENTED SOCIOECONOMIC AND GEOGRAPHIC DISADVANTAGES MORE OFTEN ENCOUNTERED BY BLACKS (IN, E.G., FOOD SECURITY, GREEN SPACES, EDUCATION QUALITY, POLLUTANTS) THAT PROMOTE CV HEALTH DISPARITIES IN CHILDHOOD, THERE IS LITTLE DATA EXAMINING SUCH INFLUENCES ON ALZHEIMER’S RELATED BRAIN HEALTH IN MIDLIFE OR LATER. THIS IS PRIMARILY DUE TO LIMITED PROSPECTIVELY COLLECTED, LIFE-COURSE DATA ON BLACKS. ADDRESSING THIS KNOWLEDGE GAP IS INCREASINGLY URGENT, AS MANY MORE BLACK AND WHITE CHILDREN WILL DEVELOP ADVERSE CV PROFILES NOW AS COMPARED TO PREVIOUS GENERATIONS. WE PROPOSE TO LEVERAGE THE SIGNIFICANT NIH INVESTMENT IN PROSPECTIVELY COLLECTED DATA, FROM BLACK AND WHITE MEN AND WOMEN PARTICIPATING IN THE BOGALUSA HEART STUDY (BHS), NHLBI GROWTH AND HEALTH STUDY (NGHS), AND PRINCETON LIPID RESEARCH STUDY (PLRS). THESE UNIQUE LIFE COURSE STUDIES HAVE A STRONG HISTORY OF COLLABORATION AND DATA HARMONIZATION FORMALIZED SINCE 2009 THROUGH THE INTERNATIONAL CHILDHOOD CV COHORT CONSORTIUM (I3C), WITH JOINT FOLLOW-UP OF CV EVENTS SINCE 2015. SHARED EXPOSURE DATA INCLUDE GEOGRAPHIC, SOCIOECONOMIC, AND CV RISK FACTORS IN CHILDHOOD (FROM AGES 3-19 YEARS), WITH 40+ YEARS OF FOLLOW-UP. MEASURING BRAIN HEALTH INDICATORS IN THESE COHORTS WILL ALLOW, FOR THE FIRST TIME, EXPLORATION OF THE IMPACT OF EARLY LIFE CV HEALTH DISPARITIES AND ANTECEDENT DISADVANTAGES ON MIDLIFE BRAIN HEALTH IN BLACKS AND WHITES. IN THE PROPOSED STUDY, DISPARITIES AND EQUITY IN CHILDHOOD CV EXPOSURE AND ALZHEIMER’S DEMENTIA (I3C DECADE), WE WILL COLLECT STRUCTURAL, FUNCTIONAL, COGNITIVE AND BLOOD-BASED INDICATORS OF ADRD-RELATED BRAIN HEALTH PROCESSES IN MID-LIFE (40-55 YEARS), A PERIOD WHEN THE SUBTLE IMPACTS OF SUBCLINICAL VASCULAR CHANGES ON BRAIN HEALTH FIRST BEGIN TO EMERGE, OFTEN SEVERAL DECADES BEFORE ADRD BECOME CLINICALLY EVIDENT. THE PIS OF THESE COHORT STUDIES WILL LEVERAGE THEIR ONGOING COLLABORATION TO BUILD AND SHARE A NOVEL DATA RESOURCE THAT ADVANCES OPEN SCIENCE IN EARLY LIFE RISK FACTORS, AND EXTENDS THAT EFFORT TO ADRD. THE IMPACT OF THIS WORK WILL BE TO INFORM STRATEGIES THAT MAY REDUCE ADRD HEALTH DISPARITIES BY IDENTIFYING AND INTERVENING AMONG BLACK AND WHITE BOYS AND GIRLS WHOSE CV BURDEN PLACES THEM AT INCREASED RISK OF ADRD DECADES LATER AND HAS THE POTENTIAL TO LEAD TO CHANGES IN PEDIATRIC CLINICAL PRACTICE GUIDELINES. THE PROPOSED I3C DECADE STUDY REPRESENTS A UNIQUE, AND ARGUABLY THE ONLY OPPORTUNITY TO INVESTIGATE THE INFLUENCE OF CHILDHOOD CV RISK AND DISPARITIES ON ADRD-RELATED BRAIN HEALTH IN THE CRITICAL PERIOD OF MIDLIFE.

CLINICAL CENTER FOR PROSPECTIVE COHORT STUDY OF CRI

NOLA SEED: A PROJECT TO IMPROVE & EXPAND NONTRADITIONAL EDUCATOR PATHWAYS

SCHOOL CHOICE POLICY RESEARCH CENTER: A NATIONAL RESEARCH PARTNERSHIP TO IMPROVE SCHOOL CHOICE FOR DISADVANTAGED STUDENTS

CURRENT CLINICAL APPROACHES LIKE INTRAOPERATIVE PATHOLOGY HAVE NOT SOLVED THE PERSISTENT PROBLEMOF INCOMPLETE TUMOR REMOVAL. SEVERAL TECHNOLOGIES HAVE BEEN TRIED OVER THE PAST 20 YEARS BUTTHERE IS CURRENTLY NO EXISTING TECHNOLOGY THAT CAN DELIVER THE TECHNICAL PERFORMANCE NEEDED TO FULLYADDRESS THIS PROBLEM AND SURVIVE IN THE WILD. IN THE MAGIC SCAN PROJECT WE WILL INTRODUCEKEY INNOVATIONS IN MICROSCOPY SAMPLE AUTOMATION CYBERINFRASTRUCTURE ML MODEL CO DESIGN ANDTRAINING ON PETASCALE DATA PRACTICAL RAPID ML MODEL DEPLOYMENT AND CANCER DETECTION ANDVISUALIZATION. WE WILL TAKE A HUMAN CENTERED APPROACH TO INNOVATION DESIGN AND DEVELOPMENTINVOLVING END USERS AND STAKEHOLDERS IN EVERY ASPECT OF THE PROJECT TO ACCOMPLISH TRUSTWORTHYPRACTICAL CAPABLE AND COST CONSCIOUS PRODUCT DESIGN THAT OPTIMIZES BENEFITS TO PHYSICIANS PAYERSAND PATIENTS.WE WILL DEVELOP THE WORLDS FASTEST HIGH RESOLUTION TISSUE SCANNER AND USE IT TO I AUTOMATICALLYPREPARE HANDLE AND SCAN THE COMPLETE SURFACE OF REMOVED CANCEROUS ORGANS AT 0.5 UM RESOLUTIONII DETECT THE PRESENCE OF ANY RESIDUAL CANCER CELLS AND III MAP THEIR LOCATION ON THE SPECIMENSURFACE FOR SURGEON VISUALIZATION IN THE OPERATING ROOM WITHIN 15 MINUTES. TWO COMPLEMENTARYCONCEPTS EACH REPRESENTING FUNDAMENTAL SCIENTIFIC AND TECHNICAL ADVANCES IN THEIR RESPECTIVEFIELDS COMPRISE OUR HUMAN CENTERED DESIGN. THE FIRST MAGIC SCAN MACHINE LEARNINGASSISTED GIGANTIC IMAGE CANCER MARGIN SCANNER COMBINES EXTREME FIELD OF VIEW OPTICALSECTIONINGAND SUPER RESOLUTION STRUCTURED ILLUMINATION MICROSCOPY OS SR SIM TO OBTAIN VERYHIGH SPEED VIRTUAL PATHOLOGY IMAGING OF CANCER TUMOR MARGIN SURFACES AT 2X THE RESOLUTION ALLOWEDBY DIFFRACTION MEETING THE PSI REQUIREMENT AND SATISFYING THE TA1 A BAA REQUIREMENTS OF AREACOVERAGE RESOLUTION AND CANCER VISUALIZATION WITHIN 10 MINUTES.TO ACCOMPLISH THE CANCER CLASSIFICATION GOALS OF AN END TO END SOLUTION IN LESS THAN OR EQUAL TO 10 MINUTES BOTHPRACTICALLY AND ECONOMICALLY WE PROPOSE THE COMPANION CONCEPT FASTMAP FAST ACCELERATEDSUPPORT FOR TRAINING MACHINE LEARNING MODELS ON PETASCALE DATA. FASTMAP IS A HUMANCENTEREDAPPROACH THAT ADDRESSES THE ITERATIVE NATURE OF THE CREATION EVALUATION PROCESS OF MLCANCER CLASSIFICATION MODELS BY IMPLEMENTING A HIGH PERFORMANCE COMPUTING CYBERINFRASTRUCTURECAPABLE OF DEVELOPING AND TRAINING NEW ACCURATE MODELS OVER PETASCALE DATA ON A SCALE OF DAYS.WE ADDRESS THIS CHALLENGE USING DATA MANAGEMENT AND PROCESSING TECHNIQUES DEVELOPED OVERALMOST TWO DECADES OF HIGH PERFORMANCE COMPUTING RESEARCH THAT ARE DEPLOYED IN THE LATESTEXASCALE COMPUTING ENVIRONMENTS. THIS APPROACH WILL BE COMPLEMENTED BY NOVEL STRATEGIES FORLIGHTNING FAST IMAGE PROCESSING AND ML INFERENCE AT THE EDGE PROCESSING TB OF DATA IN MINUTESWITHIN THE CONSTRAINTS OF RURAL HOSPITAL OPERATING ROOMS.VIA NINE MAJOR TASKS WE PROPOSE TO DEVELOP AN IMAGING SYSTEM THAT CAN I PROVIDE PATHOLOGYQUALITYIMAGES OVER 450 CM2 OF WET CAUTERIZED BULKY AND IRREGULAR FRESH TISSUE AT A 250 NM PIXELRESOLUTION AND II DELIVER AUTOMATED CANCER DETECTION AND LOCALIZATION ALL WITHIN 10 MINUTES USINGML MODELS TRAINED ON HUGE YET CHALLENGING DATASETS AND THAT CAN BE III PRACTICALLY AND RELATIVELYINEXPENSIVELY DEPLOYED IN COMPLEX OPERATING ROOM ENVIRONMENTS. IF SUCCESSFUL OUR WORK WOULDTRANSFORM CANCER SURGERY AS WE KNOW IT AND END THE WORRY OF INCOMPLETE TUMOR REMOVAL FOR EVERYAMERICAN FACING A CANCER OPERATION. THIS WOULD HAVE TREMENDOUS HEALTH ECONOMIC AND SOCIETALBENEFITS.

RISK FACTORS FOR CVD IN WOMEN

RESOURCES AND WORKFORCE DEVELOPMENT FOR THE TULANE REGIONAL BIOCONTAINMENT LABORATORY - THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC) IS ONE OF SEVEN NATIONAL PRIMATE RESEARCH CENTERS (NPRCS) DEDICATED TO CONDUCTING NONHUMAN PRIMATE (NHP) RESEARCH WITH THE GOAL OF IMPROVING HUMAN HEALTH. WITH A PRIMARY FOCUS ON INFECTIOUS DISEASE AND BIODEFENSE RESEARCH, THE TNPRC IS ONLY NPRC WITH A REGIONAL BIOCONTAINMENT LABORATORY (RBL) AT BIOSAFETY LEVEL 3 (BSL-3) FOR THE STUDY OF HIGH-CONSEQUENCE PATHOGENS, INCLUDING SELECT AGENTS AND TOXINS. THE TULANE UNIVERSITY RBL, WHICH CAME ONLINE IN JUNE 2010, HAS BEEN CRITICAL FOR ADVANCING RESEARCH AT THE TNPRC AND ACROSS THE REGION ON BIODEFENSE AGENTS AND EMERGING INFECTIOUS DISEASES, WITH A PRIMARY FOCUS ON IN VIVO STUDIES USING NHPS. SINCE ITS INCEPTION, SIGNIFICANT INFRASTRUCTURE PROJECTS HAVE BEEN COMPLETED TO CAPITALIZE ON THE PRESENCE OF THE RBL AND GROW AND DIVERSIFY RESEARCH AT THE TNPRC. IN RECENT YEARS, AND PARTICULARLY WITH THE ONSET OF THE COVID-19 PANDEMIC, THE TNPRC RBL HAS EXPANDED ITS CAPABILITIES AND CAPACITY TO ACCOMMODATE BSL-3-LEVEL EMERGING PATHOGEN AND BIODEFENSE RESEARCH. THE OVERARCHING GOAL OF THE PROPOSED PROJECT IS TO STRATEGICALLY ENHANCE AND FORTIFY BSL-3 RESEARCH CAPABILITIES WITHIN THE TNPRC RBL TO ENSURE THE LONG-TERM SUCCESS OF THIS PROGRAM IN SUPPORT OF INFECTIOUS DISEASE AND BIODEFENSE RESEARCH AND COUNTERMEASURE DEVELOPMENT. THIS WILL BE ACCOMPLISHED THROUGH THE FOLLOWING SPECIFIC AIMS: (1) ENSURE AGILITY OF THE TNPRC RBL RESPONSE TO EMERGING PUBLIC HEALTH CONCERNS AND THREATS BY LEVERAGING THE ROBUST RESEARCH INFRASTRUCTURE AND UNIQUE RESEARCH STRENGTHS OF THE TNPRC AND IMPLEMENTING EXCEPTIONAL PREVENTATIVE MAINTENANCE PROCESSES THAT ALLOW FOR BEST PRACTICES, QUALITY CONTROL, AND EXTENSIVE SAFETY OVERSIGHT FOR WORK WITH HIGH- CONSEQUENCE PATHOGENS. (2) PROVIDE FORMAL STRUCTURE FOR SHARING OF BEST PRACTICES FOR SAFETY, RESEARCH PROCEDURES AND FACILITIES MANAGEMENT WITH PARTNERS AND OTHER RBLS. (3) COORDINATE PRACTICES AND PROCEDURES ACROSS THE BIODEFENSE FACILITIES NETWORK TO LEVERAGE THE STRENGTHS OF ALL 12 RBLS; ENSURE EFFICIENT AND EFFECTIVE CROSS-TRAINING AND SHARING OF METHODOLOGIES, SOPS, AND BEST PRACTICES; AND COORDINATE AND ADVANCE INFECTIOUS DISEASE AND BIODEFENSE RESEARCH AND COUNTERMEASURE DEVELOPMENT NATION-WIDE.

BL3 NEUTRON LIFETIME APPARATUS -THE NEUTRON IS A BASIC CONSTITUENT OF ORDINARY MATTER AND THE MAJORITY OF THE EARTH'S MASS IS IN THE FORM OF NEUTRONS. WHEN FREED FROM THE CONFINES OF A STABLE ATOMIC NUCLEUS THE NEUTRON IS UNSTABLE; IT DECAYS INTO A PROTON, ELECTRON, AND ANTINEUTRINO WITH AN AVERAGE LIFETIME OF ABOUT FIFTEEN MINUTES. NEUTRON DECAY PLAYED AN IMPORTANT ROLE IN THE EARLY UNIVERSE; IT DETERMINED THE RELATIVE ABUNDANCES OF LIGHT ELEMENTS (HYDROGEN, HELIUM, LITHIUM, AND BERYLLIUM) AND THEIR ISOTOPES THAT WERE FORMED IN THE FIRST MINUTES AFTER THE BIG BANG. DUE TO ITS SIMPLICITY, NEUTRON DECAY IS AN IDEAL SYSTEM FOR STUDYING DETAILS OF THE MOST BASIC FORCES OF SUBATOMIC PHYSICS, IN PARTICULAR THE WEAK NUCLEAR FORCE. SUCH STUDIES IMPROVE OUR UNDERSTANDING OF NATURE AND MAY PROVIDE HINTS OF NEW FUNDAMENTAL PHYSICAL PHENOMENA YET TO BE DISCOVERED. THE NEUTRON LIFETIME HAS BEEN MEASURED WITH AN UNCERTAINTY OF LESS THAN ONE SECOND BY INDIVIDUAL EXPERIMENTS, BUT RESULTS FROM THE TWO MAIN EXPERIMENTAL METHODS, THE BEAM METHOD AND THE ULTRACOLD NEUTRON STORAGE METHOD, CURRENTLY DISAGREE BY MORE THAN EIGHT SECONDS. RESOLVING THIS DISCREPANCY IS A MATTER OF GREAT IMPORTANCE FOR NUCLEAR PHYSICS. THIS AWARD SUPPORTS THE DESIGN, CONSTRUCTION, AND TESTING OF A NEXT-GENERATION BEAM NEUTRON LIFETIME EXPERIMENT CALLED BL3. IT WILL EMPLOY NEW, POWERFUL TECHNICAL FEATURES TO ENABLE ITS GOALS OF RESOLVING THE DISCREPANCY AND PROVIDING A RELIABLE MEASUREMENT OF THE NEUTRON LIFETIME TO WELL BELOW ONE SECOND OF UNCERTAINTY. THE SCOPE OF THIS PROJECT IS TO DESIGN, CONSTRUCT, AND TEST THE BL3 APPARATUS, A NEW EXPERIMENT TO MEASURE THE NEUTRON LIFETIME USING THE BEAM METHOD. IT IS SIMILAR IN CONCEPT AND IMPROVES UPON PREVIOUS BEAM NEUTRON LIFETIME EXPERIMENTS. IT WILL EMPLOY A SIGNIFICANTLY LARGER SUPERCONDUCTING MAGNET TO ACCOMMODATE A LARGE AREA NEUTRON BEAM AND WILL INCORPORATE MANY TECHNICAL IMPROVEMENTS, SUCH AS MUCH HIGHER COUNTING STATISTICS, A MORE UNIFORM MAGNETIC FIELD IN THE TRAPPING REGION; A LARGE, SEGMENTED, ULTRATHIN WINDOW SILICON PROTON DETECTOR; AND A SOPHISTICATED NEUTRON TIME OF FLIGHT SPECTROMETER. BL3 HAS TWO SCIENTIFIC GOALS: 1) TO INVESTIGATE AND TEST SYSTEMATIC EFFECTS IN THE BEAM METHOD THAT MAY CONTRIBUTE TO THE 8.4 S (4 SIGMA) DISCREPANCY BETWEEN THE BEAM AND ULTRACOLD NEUTRON STORAGE EXPERIMENTS; AND 2) REDUCE THE TOTAL UNCERTAINTY OF THE NEUTRON LIFETIME BEAM METHOD TO LESS THAN 0.3 S. THE VALUE OF THE NEUTRON LIFETIME HAS IMPORTANT CONSEQUENCES IN NUCLEAR PHYSICS, PARTICLE PHYSICS, ASTROPHYSICS, AND COSMOLOGY. THIS PROJECT PROVIDES AN EXCELLENT OPPORTUNITY TO TRAIN UNDERGRADUATES, GRADUATE STUDENTS, AND POSTDOCS IN THE METHODS AND THEORY OF NEUTRON SCIENCE WHICH ARE APPLICABLE TO DIVERSE SCIENTIFIC STUDIES IN PHYSICS, CHEMISTRY, MATERIALS SCIENCE, AND BIOLOGY AT EXISTING AND EMERGING NEUTRON SOURCES AROUND THE WORLD. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

COMPILING EVIDENCE BASE FOR ORPHANS AND VULNERABLE CHILDREN

SOUTHERN CENTER FOR MATERNAL HEALTH EQUITY - THIS PROJECT WILL PROVIDE A STRONG PARADIGM FOR IMPLEMENTING MULTILEVEL PROGRAMS TO PREVENT MATERNAL COMPLICATIONS AND IMPROVE ACCESS TO CARE FOR BLACK BIRTHING PEOPLE, PREGNANCIES IN THE GULF SOUTH, AND THOSE LIVING IN MATERNITY CARE DESERTS, CONSISTENT WITH THE IMPROVE INITIATIVE’S GOAL OF REDUCING PREVENTABLE CAUSES OF MATERNAL DEATHS AND IMPROVING HEALTH FOR WOMEN BEFORE, DURING, AND AFTER DELIVERY.

TULANE UNIVERSITY COVID ANTIBODY AND IMMUNITY NETWORK (TUCAIN)

MENTORING RESEARCH EXCELLENCE IN AGING AND REGENERATIVE MEDICINE - AGING IS A BIOLOGICAL PROCESS THAT IS THE MAJOR RISK FACTOR FOR CHRONIC DISEASE AND DEGENERATION DURING THE LIFESPAN. HOWEVER, IT IS BEGINNING TO BE APPRECIATED THAT DISEASE AND DEGENERATION IMPINGE ON THE AGING PROCESS, IN SOMETHING AKIN TO A FEEDBACK LOOP, SUGGESTING THAT A BETTER KNOWLEDGE OF ONE CONTRIBUTES TO AN UNDERSTANDING OF THE OTHER. THIS NECESSITATES THAT DEVELOPMENT OF THERAPEUTIC INTERVENTIONS MUST ADDRESS THE DEGENERATIVE DISORDERS OF AGING, WHILE THE SEARCH FOR BROAD INTERVENTIONS THAT TARGET THE BIOLOGICAL AGING PROCESS ITSELF CONTINUES. THE AGENDA JUST DESCRIBED CALLS FOR THE CREATION AND NURTURING OF AN ENVIRONMENT IN WHICH MULTIDISCIPLINARY RESEARCH OF SUFFICIENT BREADTH IS FOCUSED ON KEY ELEMENTS OF AGING AND REGENERATION. AT THE SAME TIME, IT IS NECESSARY TO POPULATE THIS TRANSLATIONAL SPACE WITH TALENTED AND SUCCESSFUL INVESTIGATORS. OUR PHASE I AND II COBRE LAUNCHED AND FURTHER PROPELLED US IN THIS DIRECTION BY ALLOWING US TO SEED SEVERAL KEY RESEARCH TOPICS WITH AMBITIOUS JUNIOR INVESTIGATORS, WHO IN JUST NINE YEARS HAVE ADVANCED TO INDEPENDENTLY FUNDED STATUS WITH REMARKABLE SUCCESS. OUR TASK IS NOT YET DONE, HOWEVER, IF WE ARE TO MAINTAIN MOMENTUM AND A CRITICAL MASS OF INVESTIGATORS DEDICATED TO AGING AND REGENERATIVE MEDICINE. COBRE PHASE III WILL ALLOW US TO CONTINUE TO GROW OUR CADRE OF DEDICATED INVESTIGATORS THROUGH OUR PILOT PROJECTS AND BY ENRICHING THE RESEARCH ENVIRONMENT THROUGH OUR MENTORING AND TRAINING PROGRAMS, AS WELL AS TOPICAL SEMINARS. THESE EFFORTS WILL BE AIDED BY THE MAINTENANCE OF A STATE-OF-THE-ART GENOMICS, BIOINFORMATICS, AND MOLECULAR IMAGING CORE THAT HAS A SUSTAINING REVENUE BASE. OUR EMPHASIS IS ON MULTIPLYING THE OPPORTUNITIES FOR INTERACTIONS THAT WILL GENERATE COLLABORATIVE PROJECTS THAT ARE SYNERGISTIC AND COMPETITIVE FOR MULTICOMPONENT PROJECT GRANT FUNDING. OUR GOALS ARE TO: (1) CONTINUE TO EXPAND THE NUMBER OF AGING AND REGENERATION RESEARCH-ORIENTED, FUNDED INVESTIGATORS WITHIN OUR SCIENTIFIC COMMUNITY THROUGH OUR PILOT PROJECTS, WITH EMPHASIS ON COLLABORATIVE RESEARCH, AND TO PROVIDE A MENTORING PROGRAM FOR THESE RESEARCHERS AND OTHERS THAT SUPPORTS SUCCESSFUL CAREER DEVELOPMENT. (2) MAINTAIN OUR STATE-OF-THE-ART INFRASTRUCTURE TO PROVIDE SUSTAINABLE RESOURCES THAT CONTINUOUSLY ENHANCE THE COMPETITIVENESS OF OUR FACULTY FOR NATIONAL FUNDING, BY EXPANDING AND UPDATING THE SERVICES PERFORMED BY OUR GENOMICS, BIOINFORMATICS, AND MOLECULAR IMAGING CORE. (3) CEMENT THE POSITION OF THE TULANE CENTER FOR AGING AT THE FOREFRONT OF AGING AND REGENERATIVE MEDICINE BY GROWTH OF OUR THEMATIC, MULTIDISCIPLINARY RESEARCH FOCI TO FACILITATE SUCCESSFUL EXTRAMURALLY FUNDED COLLABORATIONS THAT WILL SUPPORT AND SUSTAIN THE CENTER. THIS EFFORT WILL BE SUPPORTED BY OUR RESEARCH WORKSHOPS, TRAINING AND CAREER DEVELOPMENT PROGRAMS, AND SEMINARS.

INSULIN-LIKE GROWTH FACTOR-1 AND ATHEROSCLEROSIS

DEMOGRAPHIC AND HEALTH DISPARITIES IN RECOVERY FROM HURRICANE KATRINA: KATRINA@10

TULANE BIRCWH

IMPACT OF TUBERCULOSIS ON THE DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM IN SIV-INFECTED INFANTS

COBRE IN SEX-BASED PRECISION MEDICINE - CRITICAL TO THE SUCCESS OF CLINICAL CARE AND TRANSLATIONAL SCIENCE IS AN AWARENESS BY CLINICIANS AND RESEARCHERS THAT DISEASES ARE CHARACTERIZED BY SEX AND GENDER DIFFERENCES IN EPIDEMIOLOGY, PATHOPHYSIOLOGY, MANIFESTATIONS, PROGRESSION, AND RESPONSE TO TREATMENT. HARNESSING THE BIOLOGICAL FORCES THAT DEFINE DISEASE MANIFESTATION AND SEVERITY IN ONE SEX COMPARED TO THE OTHER MAY HELP TRANSFORM ITS DIAGNOSIS AND TREATMENT. THEREFORE, SEX-BASED PRECISION MEDICINE (SPM) IS FUNDAMENTAL TO PRECISION MEDICINE THAT WILL BENEFIT WOMEN AND MEN. A TRANSDISCIPLINARY APPROACH IS NECESSARY TO UNDERSTAND THE COMPLEX INTERACTIONS BETWEEN GENES, HORMONES, ENVIRONMENT, SOCIAL FACTORS, AND DISEASE. THE PROPOSED TULANE CENTER OF BIOMEDICAL RESEARCH EXCELLENCE IN SEX-BASED PRECISION MEDICINE (COBRE IN SPM) WILL ADDRESS THIS CRITICAL BARRIER IN THE FIELD. THE OVERARCHING GOAL OF THE COBRE IN SPM IS TO 1) CREATE A TRANSDISCIPLINARY CENTER THAT WILL INVESTIGATE SEX AND GENDER FACTORS THAT INTERACT WITH OTHER DETERMINANTS OF HEALTH TO AFFECT BIOLOGY AND DISEASE, 2) PREPARE EARLY-STAGE AND NEW INVESTIGATORS (ESI/NI) FOR INDEPENDENT FEDERAL FUNDING, AND 3) ACHIEVE NATIONAL PROMINENCE. THE SPECIFIC AIMS OF THE COBRE ARE TO 1) CREATE A UNIVERSITY-WIDE CENTER THAT FOSTERS TRANSDISCIPLINARY COLLABORATIONS BETWEEN BASIC, CLINICAL, EPIDEMIOLOGICAL, AND SOCIAL SCIENCES TO STIMULATE INNOVATIVE RESEARCH AND DISCOVERIES ON THE ROLE OF SEX AND GENDER IN BIOLOGY, DISEASE, AND MEDICINE, 2) DEVELOP A CRITICAL MASS OF HIGHLY TRAINED INVESTIGATORS STUDYING SPM AND ENHANCE THEIR ABILITY TO COMPETE FOR EXTERNAL FUNDING THROUGH A STRONG MENTORING PROGRAM, 3) RECRUIT NEW INVESTIGATORS TO THE FIELD OF SPM RESEARCH BY ENGAGING THEM IN THE USE OF COBRE RESOURCES, AND 4) ESTABLISH AN INFRASTRUCTURE TO ADVANCE THE SCIENCE OF SPM AND IMPROVE HEALTH THROUGH AN INNOVATIVE ENRICHMENT PROGRAM THAT WILL TRAIN THE NEXT GENERATION OF HIGHLY QUALIFIED SPM INVESTIGATORS. TO ACCOMPLISH THESE AIMS, THE COBRE IN SPM WILL RELY ON THE FOLLOWING SPECIFIC STRATEGIES: AN ADMINISTRATIVE CORE TO COORDINATE AND SUPERVISE RESEARCH AND PILOT PROJECTS, SCIENTIFIC MENTORING AND CAREER DEVELOPMENT ACTIVITIES, AND ALL COMPONENTS OF THE COBRE. PROTECTED TIME AND RESEARCH SUPPORT FOR THREE RESEARCH PROJECT LEADERS (RPLS) TO ALLOW THEM TO ESTABLISH INDEPENDENT, FEDERALLY FUNDED RESEARCH PROGRAMS ON SPM. A STRUCTURED CAREER & MENTORING PLAN TO ASSIST ESI/NI IN ADVANCING THEIR INDEPENDENT RESEARCH AND BECOMING NIH-FUNDED INVESTIGATORS. A PILOT PROJECT PROGRAM TO PROVIDE SEED SUPPORT TO ESI/NI TO CATALYZE GROUNDBREAKING RESEARCH THAT WILL LEAD TO THE SUBMISSION OF SUCCESSFUL NIH R01S OR TO COBRE RESEARCH PROJECTS. AN SPM ENRICHMENT PROGRAM TO SUPPORT 1) A CURRICULUM HIGHLIGHTING THE IMPORTANCE OF SPM; 2) A BOOTCAMP THAT PROVIDES SKILL-BASED TRAINING TO INVESTIGATE SPM FOR ESI/NI AND ESTABLISHED SCIENTISTS; 3) AN SPM SEMINAR SERIES; AND 4) A WORKSHOP AND ANNUAL SYMPOSIUM THAT SHOWCASES ADVANCES IN SPM RESEARCH, BUILDS COLLABORATIVE NETWORKS, AND PROMOTES SPM RESEARCH BROADLY. AN SPM RESEARCH CORE TO SERVE RPLS AND PILOT PROJECT LEADERS AND PROVIDE STATISTICAL AND BIOINFORMATICS SUPPORT TO INVESTIGATORS STUDYING SEX AND GENDER FACTORS.

TNPRC REGIONAL BIOCONTAINMENT LABORATORY UPGRADE FOR CAPACITY BUILDING - PROJECT SUMMARY OVER ITS 57-YEAR HISTORY, THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC) HAS CONTINUED TO EVOLVE ITS CAPABILITIES TO SUPPORT LOCAL, REGIONAL, AND NATIONAL BIOMEDICAL RESEARCH BY EXPANDING IT CAMPUS INCLUDING THE REGIONAL BIOCONTAINMENT LAB (RBL) OPENING IN 2008. AS THE ONLY RBL OPERATING AT A NATIONAL PRIMATE RESEARCH CENTER, THE TNPRC HAS UNIQUE AND CRITICAL ASSETS THAT MUST MEET AND EXCEED THE REQUIREMENTS TO SAFELY ACCOMMODATE THE LEVEL OF RESEARCH OCCURRING WITHIN ITS WALLS. SEVERAL FACILITY UPGRADES, MODERNIZATION PROJECTS, AND LABORATORY ENHANCEMENTS ARE NECESSARY TO MEET THE EVER-INCREASING NEEDS OF THE SCIENTIFIC COMMUNITY FOR BSL-3 LEVEL RESEARCH ON BIODEFENSE PATHOGENS AND EMERGING INFECTIOUS DISEASES. IN THIS APPLICATION, WE PROPOSE UPGRADES TO EQUIPMENT AND AIR HANDLING SYSTEMS, RENOVATION OF LABORATORY SPACES, AND EXPANSION OF DECONTAMINATION CAPABILITIES. THE PROPOSED PROJECT OFFERS A COMPREHENSIVE AND STRATEGIC PACKAGE OF UPGRADES TO THE FACILITY THAT WILL ENHANCE RESEARCH SPACES AND ENSURE CONTINUITY OF SYSTEMS IN PLACE TO PROTECT THE SAFETY OF STAFF AND THE SURROUNDING COMMUNITY. COMPLETION OF THIS PROJECT WILL SIGNIFICANTLY ENHANCE OUR MISSION AS A NATIONAL PRIMATE RESEARCH CENTER, OPTIMIZE CAPABILITIES, AND PERMIT US TO RESPOND TO GROWING RESEARCH DEMANDS. MOST IMPORTANTLY, THESE UPGRADES AND ENHANCEMENTS WILL PROVIDE CRITICAL SUPPORT FOR LOCAL, STATE, REGIONAL, AND NATIONAL EFFORTS TO SUSTAIN BIODEFENSE PATHOGENS AND EMERGING INFECTIOUS DISEASES RESEARCH.

PROTECTING HIGHLY VULNERABLE CHILDREN-RESEARCH, MONITORING & QUALITY IMPROVEMENT ACTIVITY

SHELTERED OUTDOOR HOUSING EXPANSION FOR THE TNPRC SPF RHESUS MACAQUE BREEDING COLONY - PROJECT SUMMARY / ABSTRACT THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC) OF TULANE UNIVERSITY IS ONE OF SEVEN NATIONAL PRIMATE RESEARCH CENTERS (NPRC) SPONSORED BY THE NATIONAL INSTITUTES OF HEALTH. THE CENTER IS DEDICATED TO PROVIDING THE INFRASTRUCTURE AND SUPPORT FOR BASIC AND APPLIED RESEARCH EFFORTS TO ADVANCE SCIENTIFIC KNOWLEDGE AND IMPROVE HUMAN AND ANIMAL HEALTH AND WELL-BEING. THE NPRC PROGRAM PROVIDES RESOURCES AND OPPORTUNITIES FOR RESEARCH USING NONHUMAN PRIMATES (NHP) TO CORE FACULTY AND FACULTY AFFILIATED WITH OUTSIDE INSTITUTIONS. THE TNPRC SPECIFIC PATHOGEN FREE (SPF) RHESUS MACAQUE BREEDING COLONY IS AMONG THE LARGEST IN THE NPRC PROGRAM, WITH A CENSUS OF APPROXIMATELY 5,000. OVER THE PAST 5 YEARS, THE TNPRC SPF BREEDING COLONIES HAVE SUPPLIED 2,099 ANIMALS FOR RESEARCH PROGRAMS OF CORE AND AFFILIATE INVESTIGATORS ACROSS THE US. THERE CONTINUES TO BE HIGH NATIONAL DEMAND FOR SPF RHESUS MACAQUES WHICH CANNOT BE MET BY CURRENT NPRC BREEDING OPERATIONS. IN 2018, THE NIH SPONSORED THE NHP EVALUATION AND ANALYSIS PROJECT TO ENHANCE UNDERSTANDING OF THE DEMAND FOR AND SUPPLY OF NHP WITHIN THE US. KEY RECOMMENDATIONS MADE TO ENSURE THE ADEQUATE SUPPLY OF NHPS FOR BIOMEDICAL RESEARCH INCLUDED IMPROVING INFRASTRUCTURE AND PROVIDING SUPPORT FOR SPF NHP BREEDING COLONY EXPANSION. SINCE THE RESULTS OF THE 2018 REPORT WERE MADE PUBLIC, THE TNPRC HAS UNDERTAKEN ASSESSMENTS TO IDENTIFY THE NEEDS OF THE PROGRAM TO EXPAND ITS SPF RHESUS MACAQUE BREEDING COLONY. ALONG WITH FUNDING FROM THE NIH, THE TNPRC HAS COMMITTED FUNDS AND INITIATED PROJECTS TO: 1) IMPROVE THE BREEDING COLONY MANAGEMENT PROGRAM AND 2) EXPAND INFRASTRUCTURE TO MEET THE CURRENT AND PROJECTED FUTURE NATIONAL DEMAND. PRINCIPAL COMPONENTS OF THE LONG-TERM PLAN FOR INFRASTRUCTURE IMPROVEMENT ARE TO INCREASE THE NUMBER OF INDOOR/OUTDOOR HOUSING CONFIGURATIONS FOR ADDED PROTECTION OF NHP FROM INCLEMENT WEATHER AND COMPLEMENT THE EXISTING OUTDOOR NHP HOUSING ENCLOSURES. FUNDING IS REQUESTED TO CONSTRUCT INDOOR/OUTDOOR ENCLOSURES LOCATED ON THE BREEDING COLONY CAMPUS FOR THE PURPOSE OF HOUSING AND BREEDING SPF RHESUS MACAQUES. THIS PROJECT WILL ADD FACILITIES TO SUPPORT OUR COMMITMENT TO EXPAND PRODUCTION OF SPF RHESUS MACAQUES USED FOR NIH-ESTABLISHED PRIORITY RESEARCH AREAS AT THE TNPRC AND NATIONALLY. THE FACILITIES HAVE BEEN DESIGNED IN ALIGNMENT WITH OUR LONG-TERM INFRASTRUCTURE IMPROVEMENT PLAN TO ENHANCE PROTECTION OF ANIMALS, INCREASE HOUSING CAPACITY AND FLEXIBILITY, AND PROVIDE NOVEL AND PROVEN ENVIRONMENTAL ENHANCEMENT COMPONENTS. THE ANIMALS PRODUCED AS A RESULT OF THIS INFRASTRUCTURE IMPROVEMENT PROJECT WILL HELP ADDRESS THE NATIONAL SHORTAGE OF SPF MACAQUES.

STRUCTURE-BASED DESIGN OF NOVEL LASSA VIRUS GLYCOPROTEINS FOR VACCINE DEVELOPMENT

CD4_T-CELL_IMMUNITY_IN_THE_LUNG

DISSEMINATION AND IMPLEMENTATION OF THE SPRINT STUDY FINDINGS IN UNDERSERVED POPULATIONS

EFFECTIVENESS OF IMPLEMENTING AN INTENSIVE BLOOD PRESSURE REDUCTION INTERVENTION ON COGNITIVE DECLINE IN LOW-INCOME AND MINORITY HYPERTENSIVE PATIENTS - AFRICAN AMERICAN AND LOW-INCOME POPULATIONS BEAR A DISPROPORTIONATE BURDEN OF DEMENTIA AND HAVE BEEN UNDERREPRESENTED IN TRIALS OF COGNITIVE IMPAIRMENT. THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL (SPRINT) SHOWED THAT AN INTENSIVE BLOOD PRESSURE (BP) INTERVENTION (TARGET SYSTOLIC BP <120 MMHG) LOWERED THE RISK OF COGNITIVE IMPAIRMENT COMPARED TO A STANDARD BP INTERVENTION (SYSTOLIC BP TARGET <140 MMHG). THE NEXT IMPORTANT STEP IS TO DETERMINE HOW THE SUCCESSFUL SPRINT INTENSIVE BLOOD PRESSURE INTERVENTION CAN BE IMPLEMENTED IN A REAL-WORLD CLINIC SETTING TO PREVENT COGNITIVE DECLINE. THE OVERALL OBJECTIVE OF THE PROPOSED STUDY IS TO TEST A MULTIFACETED STRATEGY FOR IMPLEMENTING AN INTENSIVE BP INTERVENTION PROTOCOL ADAPTED FROM SPRINT TARGETING SYSTOLIC BP <120 MMHG ON COGNITIVE DECLINE IN RACIAL MINORITY AND LOW-INCOME HYPERTENSIVE PATIENTS IN RESOURCE-CONSTRAINED PRIMARY CARE PRACTICES IN LOUISIANA AND MISSISSIPPI. THE RE-AIM (REACH EFFECTIVENESS ADOPTION IMPLEMENTATION MAINTENANCE) FRAMEWORK HAS BEEN USED TO GUIDE THE DEVELOPMENT AND EVALUATION OF THE MULTIFACETED IMPLEMENTATION STRATEGY, INCLUDING PROTOCOL-BASED TREATMENT THAT EMPLOYS THE SPRINT STEPPED-CARE INTENSIVE BP MANAGEMENT ALGORITHM, DISSEMINATION OF SPRINT FINDINGS, SHARED- DECISION MAKING, TEAM-BASED COLLABORATIVE CARE, BP AUDIT AND FEEDBACK, HOME BP MONITORING, AND PATIENT HEALTH COACHING. BUILDING ON THE ONGOING IMPLEMENTATION OF MULTIFACETED PATIENT-CENTERED TREATMENT STRATEGIES FOR INTENSIVE BLOOD PRESSURE CONTROL (IMPACTS-BP) TRIAL, WE WILL COST-EFFECTIVELY CONDUCT A CLUSTER- RANDOMIZED TRIAL IN 36 FEDERALLY QUALIFIED HEALTH CENTER CLINICS THAT SERVE LOW-INCOME POPULATIONS IN LOUISIANA AND MISSISSIPPI. THE PRIMARY OUTCOME IN THE PROPOSED TRIAL IS THE NET DIFFERENCE IN MEAN CHANGE OF GLOBAL COGNITIVE COMPOSITE Z-SCORE OVER AN AVERAGE OF 42 MONTHS BETWEEN THE INTERVENTION AND ENHANCED USUAL CARE GROUPS. SECONDARY OUTCOMES INCLUDE NET DIFFERENCE IN MEAN CHANGE OF EXECUTIVE FUNCTION AND MEMORY COMPOSITE Z-SCORES, SYSTOLIC AND DIASTOLIC BP, ADVERSE EFFECTS, AND QUALITY OF LIFE. IMPLEMENTATION OUTCOMES, INCLUDING ACCEPTABILITY, ADAPTATION, ADOPTION, FEASIBILITY, FIDELITY, PENETRANCE, AND COST-EFFECTIVENESS, WILL ALSO BE COLLECTED AND USED TO IMPROVE INTERVENTION DELIVERY DURING THE TRIAL. THE PROPOSED TRIAL, WITH A SAMPLE SIZE OF 36 CLINICS (35 PATIENTS/CLINIC), HAS 85% STATISTICAL POWER TO DETECT A 0.30 OR HIGHER DIFFERENCE IN THE GLOBAL COGNITIVE COMPOSITE Z-SCORE AT A 2-SIDED SIGNIFICANCE LEVEL OF 0.05 ASSUMING 20% LOSS TO FOLLOW-UP AND AN INTRA-CLUSTER CORRELATION OF 0.05. IN A META-ANALYSIS OF 5 CLINICAL TRIALS, THE POOLED EFFECT SIZE WAS 0.35 (95% CI 0.32, 0.38) FOR THE GLOBAL COGNITIVE COMPOSITE Z-SCORE. THIS STUDY WILL GENERATE URGENTLY NEEDED DATA ON EFFECTIVE, ADOPTABLE, AND EQUITABLE INTERVENTION STRATEGIES TO REDUCE BLOOD PRESSURE-RELATED COGNITIVE DECLINE IN LOW-INCOME AND MINORITY POPULATIONS. IF PROVEN EFFECTIVE, THE IMPLEMENTATION STRATEGY FOR INTENSIVE BLOOD PRESSURE REDUCTION COULD BE ADAPTED AND SCALED UP IN DIVERSE PRIMARY CARE SETTINGS TO PREVENT COGNITIVE DECLINE AND CLINICAL DEMENTIA.

PUBLIC HEALTH TRAINING CENTERS

CENTER FOR YOUTH EQUITY (CYE) AT TULANE UNIVERSITY: A COMMUNITY-CENTERED APPROACH TO YOUTH VIOLENCE PREVENTION

PRECLINICAL EVALUATION OF A POTENT LASSA FEVER IMMUNOTHERAPEUTIC ANTIBODY COCKTAIL

NEUROGENIC INFLAMMATORY RESPONSE TO RSV

COMMUNITY HEALTH WORKER-LED CHURCH-BASED INTERVENTION FOR ELIMINATING CARDIOVASCULAR HEALTH DISPARITIES IN AFRICAN AMERICANS - PROJECT SUMMARY/ABSTRACT LOUISIANA RESIDENTS, ESPECIALLY AFRICAN AMERICANS, BEAR A DISPROPORTIONATELY HIGH BURDEN OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD). IN THE PROPOSED CLUSTER RANDOMIZED TRIAL, WE WILL TEST WHETHER A MULTIFACETED STRATEGY FOR IMPLEMENTING THE 2019 ACC/AHA GUIDELINE ON THE PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE WILL REDUCE CARDIOVASCULAR HEALTH DISPARITIES IN AFRICAN AMERICANS FROM 42 BLACK CHURCHES IN NEW ORLEANS AND BOGALUSA, LOUISIANA. THE PROPOSED STUDY WILL UTILIZE AN EFFECTIVENESS-IMPLEMENTATION HYBRID DESIGN TO 1). TEST THE EFFECTIVENESS OF A COMMUNITY HEALTH WORKER (CHW)-LED CHURCH-BASED MULTIFACETED IMPLEMENTATION STRATEGY FOR IMPROVING CARDIOVASCULAR HEALTH OVER 18 MONTHS AMONG AFRICAN AMERICANS AT HIGH RISK FOR ASCVD, AND 2). ASSESS THE IMPLEMENTATION OUTCOMES (ACCEPTABILITY, ADAPTATION, ADOPTION, FEASIBILITY, FIDELITY, PENETRANCE, COST- EFFECTIVENESS, AND SUSTAINABILITY) OF THE MULTIFACETED STRATEGY SIMULTANEOUSLY. THE RE-AIM FRAMEWORK HAS GUIDED THE DEVELOPMENT AND EVALUATION OF THE MULTIFACETED IMPLEMENTATION STRATEGY, WHICH INCLUDES CHW-LED HEALTH COACHING ON LIFESTYLE CHANGES AND MEDICATION ADHERENCE; CHURCH-BASED EXERCISE AND WEIGHT LOSS PROGRAMS; SELF-MONITORING OF PHYSICAL ACTIVITY, BLOOD PRESSURE (BP), AND GLUCOSE; AND PROVIDER EDUCATION AND ENGAGEMENT. THE PRIMARY EFFECTIVENESS OUTCOME IS THE DIFFERENCE IN THE PROPORTION OF PARTICIPANTS HAVING =4 IDEAL OR IMPROVED CARDIOVASCULAR HEALTH METRICS (CHMS), DEFINED AS A HEALTHY DIET SCORE OF 4-5 COMPONENTS OR INCREASE OF 2 COMPONENTS FROM BASELINE; 150 MINUTES/WEEK MODERATE- OR 75 MINUTES/WEEK VIGOROUS-INTENSITY PHYSICAL ACTIVITY OR A COMBINATION; NEVER SMOKING OR QUITTING =6 MONTHS AGO; BODY MASS INDEX <25 KG/M2 OR WEIGHT LOSS =10 POUNDS; A1C <7.0% (OR <8.0% WITH COMPLICATIONS); USE OF STATIN THERAPY AS APPROPRIATE; AND BP <130/80 MMHG OR SYSTOLIC BP REDUCED BY =10 MMHG. OUR STUDY HAS 90% STATISTICAL POWER TO DETECT AN ABSOLUTE DIFFERENCE OF 15% IN THE PRIMARY EFFECTIVENESS OUTCOME AT 18 MONTHS USING A 2-SIDED SIGNIFICANCE LEVEL OF 0.05. IN THE PLANNING PHASE, WE WILL WORK WITH STAKEHOLDERS TO ENSURE THE MULTIFACETED IMPLEMENTATION STRATEGY IS RESPONSIVE TO AFRICAN AMERICAN COMMUNITY NEEDS; WE WILL IDENTIFY 42 BLACK CHURCHES AS RESEARCH PARTNERS AND CONDUCT A HEALTH NEEDS ASSESSMENT; AND WE WILL DEVELOP THE STUDY PROTOCOL AND OBTAIN APPROVAL FROM THE NIH, DSMB, AND IRB. IN THE IMPLEMENTATION PHASE, WE WILL RECRUIT 1,050 AFRICAN AMERICAN PARTICIPANTS (25 PER CHURCH) AGED =40 YEARS WHO HAVE <4 IDEAL CHMS AND RANDOMLY ASSIGN 21 CHURCHES TO INTERVENTION AND 21 TO CONTROL; WE WILL IMPLEMENT THE MULTIFACETED INTERVENTION PROGRAM; WE WILL FOLLOW-UP PARTICIPANTS AND COLLECT DATA ON EFFECTIVENESS AND IMPLEMENTATION OUTCOMES AT 6, 12, AND 18 MONTHS; WE WILL EVALUATE THE SUSTAINABILITY OF THE INTERVENTION IN A 6-MONTH POST-INTERVENTION STUDY; AND WE WILL PERFORM INTENTION-TO-TREAT ANALYSES AND DISSEMINATE AND SCALE-UP THE PROVEN-EFFECTIVE IMPLEMENTATION STRATEGY. THE PROPOSED STUDY WILL GENERATE EVIDENCE ON THE EFFECTIVENESS, IMPLEMENTATION, AND SUSTAINABILITY OF THE MULTIFACETED INTERVENTION AIMED AT ELIMINATING CARDIOVASCULAR HEALTH DISPARITIES IN HIGH-BURDEN POPULATIONS IN THE US.

ROLE OF INTRACRINE ANGIOTENSIN II IN KIDNEY CELLS

NUTRIGENETICS AND NUTRIGENOMICS FOR PRECISION WEIGHT-LOSS DIET INTERVENTIONS

ROLE OF ESTROGEN RECEPTORS IN PANCREATIC BETA-CELL SURVIVAL AND INSULIN SECRETION

IMMUNOPATHOGENESIS IN FUNGAL ASTHMA

INTERCELLULAR COMMUNICATION AND OOCYTE POLARITY

NSF CONVERGENCE ACCELERATOR TRACK E: GLASS RECYCLING TO RESTORE THE COAST -PEOPLE RELY ON COASTAL RESOURCES FOR FOOD, WATER, AND ENERGY. HOWEVER, EXTRACTION OF THESE NATURAL RESOURCES OVER THE LAST CENTURY HAS LED TO POLLUTION AND COASTAL LAND LOSS. THIS PROJECT AIMS TO CONVERT RECYCLED GLASS BACK INTO ITS ORIGINAL FORM, SAND, TO SUPPORT COASTAL RESTORATION, PRESERVATION, AND RESILIENCY. THE RECOAST TEAM CONSISTS OF OVER TWENTY SCIENTISTS AND ENGINEERS CONDUCTING EXTENSIVE REGIONAL ECONOMIC, SOCIAL, CULTURAL, AND ENVIRONMENTAL RESEARCH TO CREATE LONG-TERM, SUSTAINABLE SOLUTIONS FOR GLASS RECYCLING AND LAND PRESERVATION THROUGHOUT THE UNITED STATES. TO TAILOR THESE SOLUTIONS TO MEET THE NEEDS OF THE COMMUNITY, THE RECOAST TEAM HAS CONDUCTED INTERVIEWS WITH RESIDENTS, GOVERNMENT ORGANIZATIONS, LOCAL BUSINESS OWNERS, NON-PROFIT ORGANIZATIONS, AND STUDENTS. FROM THESE INTERACTIONS, THE RECOAST TEAM HAS FORMED PARTNERSHIPS WITH ORGANIZATIONS LIKE THE POINTE AU CHIEN INDIGENOUS TRIBE, THE PONTCHARTRAIN CONSERVANCY (WHICH FOCUSES ON ENVIRONMENTAL SUSTAINABILITY AND STEWARDSHIP THROUGH SCIENTIFIC RESEARCH, EDUCATION, AND ADVOCACY), THE LOWER 9TH WARD CENTER FOR SUSTAINABLE ENGAGEMENT AND DEVELOPMENT, HOME BY HAND (WHICH BUILDS AFFORDABLE HOUSING WITH PROPER WATER MANAGEMENT SYSTEMS FOR LOW-INCOME RESIDENTS), AND MANY OTHERS. OVER THE NEXT TWO YEARS, THE RECOAST TEAM WILL ADAPT THE LESSONS LEARNED FROM THEIR WORK IN SOUTHEAST LOUISIANA TO OTHER ENVIRONMENTS, INCLUDING THE FLORIDA AND TEXAS COASTS AND ISLAND NATIONS. WE RELY ON COASTAL RESOURCES FOR FOOD, WATER, AND ENERGY. HOWEVER, A CENTURY OF EXTRACTING THESE NATURAL RESOURCES HAS LED TO POLLUTION AND COASTAL EROSION. PROTECTING AND RESTORING OUR COASTS WHILE CONTINUING TO SUPPORT THE ECONOMIES OF COASTAL COMMUNITIES HAS NEVER BEEN MORE URGENT. IN THE PHASE I PARTNERSHIP BETWEEN GLASS RECYCLING STARTUP COMPANY GLASS HALF FULL AND UNIVERSITY RESEARCHERS IN CHEMICAL ENGINEERING, CIVIL & ENVIRONMENTAL ENGINEERING, RIVER & COASTAL ENGINEERING, AND ECOLOGY & EVOLUTIONARY BIOLOGY, THE TEAM: (I) ESTABLISHED THE MATERIAL AND ECOLOGICAL SAFETY OF THE RECYCLED GLASS SAND PRODUCT, (II) FORMED COMMUNITY PARTNERSHIPS FOR MULTIPLE DEMONSTRATION SITES IN SOUTHEAST LOUISIANA, (III) EVALUATED VALUE-ADDED PRODUCTS FOR TRANSLATION-READINESS, AND (IV) BROADENED PARTICIPATION THROUGH OUTREACH TO INDIGENOUS COMMUNITIES, INTERDISCIPLINARY STUDENT TRAINING, AND STUDENT SERVICE-LEARNING PROJECTS. IN PHASE II, THE TEAM PROPOSES TO (I) CARRY OUT PLANNED RESTORATION PROJECTS, WHICH WE EXPECT TO ATTRACT INVESTMENT IN GLASS RECYCLING AND COASTAL RESTORATION TO SUSTAIN A BLUE ECONOMY NETWORK IN LOUISIANA BEYOND THE LIFE OF THE PROJECT, (II) BRING VALUE-ADDED PRODUCTS TO TRANSLATION-READINESS (TRL 6-7), (III) CONDUCT TECHNO-ECONOMIC, LIFECYCLE, AND MULTI-CRITERIA DECISION ANALYSES TO SUPPORT THE ECONOMIC AND ENVIRONMENTAL CASES FOR OUR PROPOSED BLUE ECONOMY NETWORK, (IV) EXTEND LESSONS LEARNED FROM LOUISIANA COASTAL MARSHES TO OTHER ECOSYSTEMS, AND (V) EXPAND THEIR BROADENING PARTICIPATION EFFORTS TO INCLUDE RESIDENTS OF NEW ORLEANS? LOWER NINTH WARD, A PREDOMINANTLY AFRICAN AMERICAN NEIGHBORHOOD SUBJECTED TO DECADES OF ENVIRONMENTAL RACISM, PROVIDE OPPORTUNITIES FOR CITIZEN SCIENCE, AND REDOUBLE K-12 OUTREACH EFFORTS AS SCHOOLS BEGIN RE-OPENING TO CAMPUS VISITORS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

ROLE OF IL-15 IN THE PATHOGENSIS OF EOSINOPHILIC ESOPHAGITIS

CELL-CONTACT MEDIATED MECHANISMS ASSEMBLING SYNAPSES

IMPROVED THERAPEUTICS AND DIAGNOSTICS FOR PNEUMOCYSTIS PNEUMONIA

MECHANISMS OF INNATE IMMUNE DYSFUNCTION IN SIV/MALARIA CO-INFECTION IN PREGNANCY - PROJECT SUMMARY/ABSTRACT HIV REMAINS ONE OF THE WORLD’S MOST DEVASTATING DISEASES, WITH MORE THAN 38 MILLION PEOPLE LIVING WITH HIV (PLWH) AND AN ADDITIONAL 1.7 MILLION NEW INFECTIONS PER YEAR. MOREOVER, IN 2019, INFECTION WITH MALARIA WAS REPORTED TO HAVE REACHED 229 MILLION CASES WORLDWIDE AND CAUSED OVER 409,000 DEATHS. ALTHOUGH ADVANCES HAVE BEEN MADE IN REDUCING THE INCIDENCE OF BOTH HIV AND MALARIA, THE RISK OF INFECTION WITH EITHER DISEASE IS STILL GREAT, ESPECIALLY IN RESOURCE-LIMITED COUNTRIES. IMPORTANTLY, THE GEOGRAPHICAL OVERLAP IN ENDEMIC HIV AND MALARIA CONSTITUTES A HIGH RISK FOR CO-INFECTION, FUELING TRANSMISSION AND PATHOGENESIS OF BOTH DISEASES. THE BURDENS OF HIV AND MALARIA ARE PARTICULARLY ELEVATED IN PREGNANT WOMEN, LEADING TO INCREASED RISK OF POOR BIRTH OUTCOMES AND MATERNAL AND INFANT MORTALITY. NOTABLY, MALARIA IN PREGNANCY (MIP) IN WOMEN LIVING WITH HIV (WLH) RESULTS IN EVEN GREATER RISK OF ADVERSE OUTCOMES AND THE TREATMENTS CURRENTLY AVAILABLE FOR MIP HAVE ONLY SHOWN LIMITED SUCCESS IN WLH. THEREFORE, OUR LONG-TERM GOAL IS TO IDENTIFY KEY FACTORS IN MIP IMMUNOPATHOGENESIS TO AID IN DEVELOPMENT OF NEW THERAPEUTICS THAT CAN SAFELY AND EFFECTIVELY REDUCE MATERNAL AND FETAL MORBIDITY AND MORTALITY IN WLH. THE OVERALL OBJECTIVES FOR THIS APPLICATION ARE TO (1) DISSECT THE PATHOGENIC OUTCOMES OF P. FRAGILE INFECTION IN SIV+ PREGNANT RHESUS MACAQUES (RMS) AND (2) MECHANISTICALLY ELUCIDATE THE ROLE OF NEUTROPHILS AND INNATE LYMPHOID CELLS (ILCS) IN DECIDUAL INFLAMMATION DURING SIV/P. FRAGILE CO-INFECTION. OUR CENTRAL HYPOTHESIS IS THAT P. FRAGILE AND SIV CO-INFECTION OF PREGNANT RMS WILL RESULT IN GREATER PLACENTAL PARASITEMIA AND DYSFUNCTION THAT ASSOCIATES WITH HIGHER LEVELS OF DECIDUAL NEUTROPHIL ACCUMULATION AND ILC ACTIVATION, AS COMPARED TO MONO-INFECTED OR HEALTHY RMS. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY OF NEUTROPHILS AND ILCS IN PLACENTAL DYSFUNCTION WILL PROMOTE SUBSEQUENT, TARGETED STUDIES TO LEVERAGE OUR FINDINGS TO DEVELOP NOVEL INTERVENTIONS TO TREAT MIP IN WLH. THE CENTRAL HYPOTHESIS WILL BE TESTED BY PURSUING THREE SPECIFIC AIMS: 1) TO IDENTIFY KEY PATHOGENIC CONSEQUENCES OF P. FRAGILE INFECTION AND THE IMPACT OF SIV CO-INFECTION DURING PREGNANCY; 2) TO DEFINE THE ROLE OF NEUTROPHILS IN PERIPHERAL AND DECIDUAL INFLAMMATION DURING CO-INFECTION OF PREGNANT RMS; AND 3) TO DETERMINE THE ROLE OF ILCS IN REGULATING PERIPHERAL AND DECIDUAL INFLAMMATION IN CO-INFECTED PREGNANT RMS. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT FOCUSES ON USING A HIGHLY TRANSLATIONAL ANIMAL MODEL TO OPEN NEW SCIENTIFIC HORIZONS ON KEY ALTERATIONS IN INNATE IMMUNE FUNCTION THAT DRIVE POOR MATERNAL AND FETAL OUTCOMES IN SIV AND P. FRAGILE CO- INFECTION, WHICH CLOSELY PARALLELS THE DYNAMICS OF HIV AND P. FALCIPARUM INFECTION. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT IS EXPECTED TO PROVIDE A STRONG, EVIDENCE-BASED FOUNDATION FOR FUTURE PRE-CLINICAL STUDIES OF THE BIOLOGICAL MECHANISMS OF MIP IN WLH. ULTIMATELY, THESE STUDIES WILL PROVIDE NEW OPPORTUNITIES TO DEVELOP THERAPIES AND PREVENTION STRATEGIES TO REDUCE MORBIDITY AND MORTALITY DUE TO MALARIA IN HIGHLY VULNERABLE WLH.

OBESITY GENES, ENERGY REGULATION IN RESPONSE TO WEIGHT-LOSS DIETS

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

PSYCHOSOCIAL FACTORS AND LUPUS DISEASE PROGRESSION AMONG AFRICAN AMERICAN WOMEN

ROLE OF RHCMV IN SHAPING THE SIV PROVIRAL LANDSCAPE - PROJECT SUMMARY/ABSTRACT THE MAIN OBSTACLE TO CURING HIV-1 INFECTION IS A RESERVOIR THAT CONSISTS OF RESTING MEMORY CD4 T CELLS WHOSE GENOMES CONTAIN INDUCIBLE AND REPLICATION-COMPETENT HIV-1 PROVIRUSES. DECAY OF THE RESERVOIR IS SLOW AND REQUIRES LIFELONG ANTIRETROVIRAL THERAPY (ART). IT HAS BECOME INCREASINGLY CLEAR THAT THE PREDOMINANT MECHANISM SUSTAINING HIV-1 PERSISTENCE DURING ART IS THE PHYSIOLOGIC PROLIFERATION OF LATENT-INFECTED MEMORY CD4 T CELLS. INFECTED CD4 T CELLS CAN PROLIFERATE WITHOUT PRODUCING VIRUS, THE RESULT OF WHICH WILL LEAD TO DAUGHTER CELLS HARBORING EXPANDED HIV-1 PROVIRAL CLONES THAT SHARE IDENTICAL SEQUENCE AND HOST INTEGRATION SITES. THE RATE OF EXPANSION AMONG DISTINCT PROVIRAL CLONES IN THIS SETTING HOWEVER IS NOT EQUAL. IN SOME INDIVIDUALS, UPWARDS OF 30% OF PROVIRUSES SAMPLED CAN BELONG TO POPULATIONS THAT ARE HIGHLY CLONALLY EXPANDED, A MECHANISM CONSISTENT WITH CLONAL PROLIFERATION BY ANTIGEN ENCOUNTER. ESTABLISHING A LINK BETWEEN PARTICULAR ANTIGENS AND THE DEGREE TO WHICH THEY INDEPENDENTLY CONTRIBUTE TO HIV PERSISTENCE, HOWEVER, IS AN UNRESOLVED QUESTION. CYTOMEGALOVIRUS (CMV) IS A LATENT BETAHERPESVIRUS THAT WHILE ASYMPTOMATIC IN IMMUNOCOMPETENT HOSTS, PERSISTENTLY STIMULATES THE MEMORY T CELL POOL. PERSONS LIVING WITH HIV ARE NEAR UNIVERSALLY COINFECTED WITH CMV. IN THIS PROJECT, WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM OF INVESTIGATORS TO DIRECTLY ASSESS THE DEGREE TO WHICH CHRONIC ANTIGENIC STIMULATION BY CMV (I) PROMOTES PROLIFERATION OF THE MEMORY CD4 T CELL POOL (II) CONTRIBUTES TO CLONAL DIVERSITY AND SIZE OF THE HIV- 1 RESERVOIR DURING ART AND (III) IMPACTS THE TIME TO VIRAL RECRUDESCENCE WHEN ART IS INTERRUPTED. SPECIFICALLY, WE WILL UTILIZE THE WELL-ESTABLISHED MODEL OF ART-TREATED SIV-INFECTED RHESUS MACAQUES TO EXAMINE THESE QUESTIONS BY A DUAL APPROACH. THE FIRST WILL EXPLOIT AVAILABILITY OF PATHOGEN-FREE, RHESUS CMV (RHCMV)-NAÏVE RHESUS MACAQUES (RMS) TO COMPARE SIV RESERVOIR DYNAMICS IN THE PRESENCE OR ABSENCE OF CMV. THE SECOND WILL ASSESS MEASURES OF SIV PERSISTENCE WHEN CMV REPLICATION IS BLOCKED PHARMACOLOGICALLY WITH ANTIVIRAL CIDOFOVIR. CRITICAL TO OUR AIMS ARE THAT WE WILL INTERROGATE SIV PROVIRAL DNA AT MULTIPLE LONGITUDINAL TIMEPOINTS, IN MULTIPLE TISSUES, AND WITH SEVERAL ASSAYS THAT INFORM BOTH QUANTITATIVE AND QUALITATIVE ASPECTS OF THE SIV RESERVOIR. WE BELIEVE THAT THE COMPREHENSIVE, HIGHLY SYNERGISTIC, AND RIGOROUSLY CONTROLLED STUDIES WE PROPOSE WILL (I) IDENTIFY AN IMMUNODOMINANT TARGET THAT PROMOTES TURNOVER OF MEMORY CD4 T CELLS DURING ART AND BY EXTENSION, PERSISTENCE OF THE HIV-1 RESERVOIR AND (II) PROVIDE A RATIONALE TO EMPLOY RECENT WELL-TOLERATED FDA-APPROVED CMV ANTIVIRALS AS A MEANS TO ACCELERATE HIV-1 CLEARANCE.

TARGETING OF SIV MACROPHAGE RESERVOIRS IN THE CNS BY CSF1R INHIBITION

WEIGHT-LOSS DIET INTERVENTION ON CARDIOMETABOLIC FACTORS OF GUT MICROBIOTA

REFINING TRICHOMONAS VAGINALIS TREATMENT IN WOMEN AND MEN. - ABSTRACT TRICHOMONAS VAGINALIS IS ESTIMATED TO BE THE MOST COMMON NON-VIRAL SEXUALLY TRANSMITTED INFECTION (STI). IT CAUSES CONSIDERABLE AND COSTLY PERINATAL/REPRODUCTIVE MORBIDITY, DISPROPORTIONATELY AFFECTS PERSONS OF COLOR, AND CAN AMPLIFY HIV TRANSMISSION. AFTER OUR TWO TRIALS FOUND MULTI-DOSE ORAL METRONIDAZOLE (MTZ) TO BE SUPERIOR TO SINGLE-DOSE 2 G ORAL MTZ, THE CENTERS FOR DISEASE CONTROL AND PREVENTION NOW RECOMMENDS MULTI-DOSE MTZ AS THE TREATMENT OF CHOICE FOR T. VAGINALIS IN ALL WOMEN. SINCE NEITHER TRIAL INCLUDED MEN AND THERE IS A PAUCITY OF DATA IN MEN, SINGLE-DOSE 2 G ORAL MTZ STANDS AS THE RECOMMENDED TREATMENT FOR MEN. IN BOTH FEMALE TRIALS, HOWEVER, EVEN THOUGH MULTI-DOSE ORAL MTZ WAS FOUND TO BE SUPERIOR TO SINGLE-DOSE MTZ, MULTI- DOSE MTZ STILL HAD UNACCEPTABLY HIGH RATES OF BREAKTHROUGH INFECTION (9%-11%). WITH APPROXIMATELY 2.6 MILLION CASES OF T. VAGINALIS PER YEAR IN THE UNITED STATES, OVER 280,000 PERSONS/YEAR ARE ESTIMATED TO BE INSUFFICIENTLY TREATED WITH MULTI-DOSE ORAL MTZ. THUS, THERE IS A CRITICAL NEED TO REFINE T. VAGINALIS TREATMENT. SINGLE-DOSE 2 G ORAL SECNIDAZOLE (SEC), A NEXT GENERATION 5-NITROIMIDAZOLE, MAY BE A GOOD OPTION. OUR RECENT TRIAL FOUND THAT SINGLE-DOSE 2 G ORAL SEC WAS SUPERIOR TO PLACEBO IN T. VAGINALIS-INFECTED WOMEN. ORAL SEC HAS MULTIPLE BENEFITS COMPARED TO MULTI-DOSE ORAL MTZ INCLUDING A LONGER HALF-LIFE AND IMPROVED TOLERABILITY. SINGLE-DOSE SEC POSES LESS BURDEN ON THE PATIENT AND CAN TREAT BACTERIAL VAGINOSIS, A COMMON COMORBIDITY AMONG WOMEN WITH T. VAGINALIS. ON THE OTHER HAND, MTZ IS FAR LESS COSTLY AND CAN BE GIVEN DURING PREGNANCY/LACTATION. THE OVERALL GOALS OF THIS MULTI-CENTERED, RANDOMIZED TRIAL ARE TO EXAMINE THE EFFECTIVENESS AND COST-EFFECTIVENESS OF ORAL MULTI-DOSE MTZ COMPARED TO SINGLE-DOSE ORAL SEC INBOTH WOMEN AND MEN WITH T. VAGINALIS. AIM 1. TO EXAMINE THE OPTIMAL TREATMENT FOR T. VAGINALIS INFECTION IN WOMEN AND MEN. THIS WILL BE DONE BY CONDUCTING AN OPEN-LABEL, RANDOMIZED, MULTI-CENTERED, PARALLEL PHASE IV CLINICAL TRIAL COMPARING ORAL MULTI-DOSE MTZ (500 MG BID FOR 7 DAYS) TO SINGLE-DOSE ORAL 2 G SEC FOR THE TREATMENT OF T. VAGINALIS IN WOMEN AND MEN. THE TEST-OF-CURE (TOC) VISIT WILL BE 4 WEEKS (± 1 WEEK) AFTER COMPLETION OF TREATMENT. WE HYPOTHESIZE THAT T. VAGINALIS REPEAT INFECTION RATES AT TOC WILL BE 1.75 LOWER IN THE SINGLE-DOSE 2 G ORAL SEC ARM VERSUS THE MULTI- DOSE ORAL MTZ ARM. AIM 2 TO COMPARE THE COST EFFECTIVENESS OF MULTI-DOSE ORAL MTZ VERSUS SINGLE-DOSE ORAL SEC FOR THE TREATMENT OF T. VAGINALIS INFECTION. WE WILL COMPARE THE DIRECT AND INDIRECT COSTS OF TREATMENT USING EITHER ARM, TAKING INTO CONSIDERATION THE REPRODUCTIVE AND PERINATAL OUTCOMES ASSOCIATED WITH T. VAGINALIS INFECTION AS WELL AS INCREASED RISK FOR HIV-ACQUISITION. WE HYPOTHESIZE THE SINGLE-DOSE SEC WILL HAVE HIGHER INITIAL COST BUT WILL BE MORE COST EFFECTIVE COMPARED TO MULTI-DOSE MTZ, LARGELY DUE TO LOWER BREAKTHROUGH RATES. DATA FROM THESE AIMS WILL FILL CRITICAL GAPS IN THE LITERATURE AND PROVIDE DATA ON REFINING THE TREATMENT OF T. VAGINALIS AMONG WOMEN AND MEN, WITH THE LONG-TERM GOAL OF REDUCING HEALTH DISPARITIES ATTRIBUTABLE TO THIS COMMON INFECTION.

VACCINATION WITH INVARIANT MHC-II-LINKED ACCESSORY ANTIGENS FOR PROTECTION FROM HIV INFECTION

NOVEL STRATEGIES FOR ELIMINATING HIV RESERVOIRS IN LYMPHOID TISSUES

INDOOR-OUTDOOR HOUSING EXPANSION OF THE TNPRC SPF MACAQUE BREEDING COLONY TO SUPPORT HIV/AIDS-RELATED RESEARCH - PROJECT SUMMARY / ABSTRACT THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC) AT TULANE UNIVERSITY IS ONE OF SEVEN NATIONAL PRIMATE RESEARCH CENTERS (NPRCS) WITH FUNDING FROM THE NATIONAL INSTITUTES OF HEALTH (NIH). DEDICATED TO ADVANCING SCIENTIFIC KNOWLEDGE AND IMPROVING HUMAN AND ANIMAL HEALTH, THE TNPRC PROVIDES CRITICAL INFRASTRUCTURE AND SUPPORT FOR BOTH BASIC AND APPLIED RESEARCH. ITS SPECIFIC PATHOGEN-FREE (SPF) RHESUS MACAQUE BREEDING COLONY, THE LARGEST IN THE NPRC PROGRAM, HAS A CENSUS OF OVER 4500 ANIMALS. THE TNPRC HIV/AIDS RESEARCH PROGRAM IS THE CENTER’S LARGEST, WITH 2404 NHPS ASSIGNED TO NIH-FUNDED HIV/AIDS-RELATED STUDIES OVER THE PAST DECADE (63% OF TOTAL ASSIGNED NHPS). THE NIH-SPONSORED 2018 NHP EVALUATION AND ANALYSIS PROJECT HIGHLIGHTED THE IMPORTANCE OF ENHANCING INFRASTRUCTURE AND EXPANDING BREEDING COLONIES TO MEET THE DEMAND FOR NHP IN BIOMEDICAL RESEARCH. THIS CONCERN WAS ECHOED IN THE 2023 NIH-COMMISSIONED INDEPENDENT NATIONAL ACADEMIES OF SCIENCES, ENGINEERING, AND MEDICINE (NASEM) CONSENSUS STUDY REPORT ON NONHUMAN PRIMATE MODELS IN BIOMEDICAL RESEARCH: STATE OF THE SCIENCE AND FUTURE NEEDS, WHICH EMPHASIZED THE CRITICAL ROLE OF NHP RESOURCES IN ADDRESSING PUBLIC HEALTH EMERGENCIES IN THE UNITED STATES AND ADVANCING BIOMEDICAL RESEARCH. THE NASEM REPORT CALLED FOR PRIORITIZING THE EXPANSION OF DOMESTIC NHP BREEDING PROGRAMS TO ADDRESS THE INCREASING SHORTAGE OF THESE VITAL RESOURCES. IN RESPONSE, THE TNPRC, ALONGSIDE NIH FUNDING, HAS INVESTED IN INITIATIVES TO IMPROVE BREEDING COLONY MANAGEMENT AND EXPAND INFRASTRUCTURE TO MEET CURRENT AND FUTURE DEMANDS. A KEY COMPONENT OF THE TNPRC’S LONG-TERM INFRASTRUCTURE IMPROVEMENT PLAN IS THE CONSTRUCTION OF ADDITIONAL INDOOR/OUTDOOR HOUSING FACILITIES. THESE ENCLOSURES WILL ENHANCE ANIMAL PROTECTION, INCREASE GROUP HOUSING FLEXIBILITY AND CAPACITY, AND INCORPORATE INNOVATIVE ENVIRONMENTAL ENRICHMENT STRATEGIES. THE PROPOSED PROJECT, DESIGNED TO ALIGN WITH THESE OBJECTIVES, WILL CONSTRUCT INDOOR/OUTDOOR ENCLOSURES TO HOUSE AND BREED SPF RHESUS MACAQUES ON THE TNPRC BREEDING COLONY CAMPUS. THE PROPOSED PROJECT WILL ENSURE THAT THE TNPRC REMAINS AT THE FOREFRONT OF ADVANCING HIV-AIDS RESEARCH AND SUPPORTING NIH-ESTABLISHED PUBLIC HEALTH PRIORITIES (HIV/AIDS-RELATED RESEARCH) BY ENSURING A STABLE SUPPLY OF SPF RHESUS MACAQUES, BOTH AT THE TNPRC AND ACROSS THE UNITED STATES.

SPF RHESUS MACAQUE BREEDING COLONY EXPANSION TO SUPPORT HIV/AIDS-RELATED RESEARCH - PROJECT SUMMARY / ABSTRACT THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC) OF TULANE UNIVERSITY IS ONE OF SEVEN NATIONAL PRIMATE RESEARCH CENTERS (NPRC) SPONSORED BY THE NATIONAL INSTITUTES OF HEALTH (NIH). THE TNPRC IS DEDICATED TO PROVIDING INFRASTRUCTURE AND SUPPORT FOR BASIC AND APPLIED RESEARCH TO ADVANCE SCIENTIFIC KNOWLEDGE AND IMPROVE HUMAN AND ANIMAL HEALTH AND WELL-BEING. THE TNPRC SPECIFIC PATHOGEN-FREE (SPF) RHESUS MACAQUE BREEDING COLONY IS AMONG THE LARGEST IN THE NPRC PROGRAM, WITH A CENSUS NEARING 5000, AND THE TNPRC AIDS RESEARCH PROGRAM IS THE LARGEST RESEARCH PROGRAM AT THE CENTER. TNPRC’S SPF BREEDING COLONY SERVES AS A NATIONAL RESOURCE FOR NIH-FUNDED INVESTIGATORS AND HAS SUPPLIED 2155 ANIMALS FOR RESEARCH PROGRAMS ACROSS THE US IN THE PAST FIVE YEARS, WITH THE VAST MAJORITY ASSIGNED TO AIDS-RELATED STUDIES. CURRENT NPRC BREEDING OPERATIONS CANNOT MEET THE CONTINUED HIGH NATIONAL DEMAND FOR SPF RHESUS MACAQUES. THE NIH-SPONSORED 2018 NHP EVALUATION AND ANALYSIS PROJECT, DESIGNED TO ENHANCE UNDERSTANDING OF THE DEMAND FOR AND SUPPLY OF NONHUMAN PRIMATES (NHPS) WITHIN THE US, NOTED THAT IMPROVING INFRASTRUCTURE AND PROVIDING SUPPORT FOR EXPANSION OF NHP BREEDING COLONIES IS NECESSARY TO ENSURE ADEQUATE SUPPLY OF NHPS FOR BIOMEDICAL RESEARCH. THE 2023 NIH- COMMISSIONED INDEPENDENT NATIONAL ACADEMIES OF SCIENCES, ENGINEERING, AND MEDICINE (NASEM) CONSENSUS STUDY REPORT ON NONHUMAN PRIMATE MODELS IN BIOMEDICAL RESEARCH: STATE OF THE SCIENCE AND FUTURE NEEDS RECOGNIZED THE WORSENING SHORTAGE OF NHP RESOURCES FOR NIH-SPONSORED RESEARCH AND EMPHASIZED THE IMPORTANCE OF NHP RESEARCH RESOURCES IN RESPONDING TO US PUBLIC HEALTH EMERGENCIES AND ADVANCING BIOMEDICAL RESEARCH. THE NASEM REPORT CONCLUDED THAT THE US NEEDS TO PRIORITIZE EXPANSION OF DOMESTIC NHP BREEDING PROGRAMS. ALONG WITH FUNDING FROM THE NIH, THE TNPRC HAS COMMITTED FUNDS AND INITIATED PROJECTS TO 1) IMPROVE THE BREEDING COLONY MANAGEMENT PROGRAM AND 2) EXPAND INFRASTRUCTURE TO MEET THE CURRENT AND PROJECTED NATIONAL DEMAND. A PRIMARY COMPONENT OF THE LONG-TERM INFRASTRUCTURE IMPROVEMENT PLAN IS TO INCREASE THE NUMBER OF INDOOR/OUTDOOR HOUSING FACILITIES THAT WILL PROVIDE ADDITIONAL PROTECTION FROM INCLEMENT WEATHER AND COMPLEMENT EXISTING OUTDOOR NHP HOUSING ENCLOSURES. THE PROPOSED PROJECT WILL CONSTRUCT INDOOR/OUTDOOR ENCLOSURES TO HOUSE AND BREED SPF RHESUS MACAQUES ON THE TNPRC BREEDING COLONY CAMPUS AND PROVIDE INFRASTRUCTURE FOR CURRENT AND FUTURE EXPANSION. THESE FACILITIES WILL SUPPORT OUR COMMITMENT TO EXPAND PRODUCTION OF SPF RHESUS MACAQUES TO BE USED FOR NIH-ESTABLISHED PRIORITY RESEARCH AREAS (AIDS-RELATED RESEARCH) AT THE TNPRC AND NATIONALLY. THE FACILITIES HAVE BEEN DESIGNED IN ALIGNMENT WITH OUR LONG-TERM INFRASTRUCTURE IMPROVEMENT PLAN TO ENHANCE PROTECTION OF ANIMALS, INCREASE OVERALL GROUP HOUSING FLEXIBILITY AND CAPACITY, AND PROVIDE NOVEL AND PROVEN ENVIRONMENTAL ENHANCEMENT. THE ANIMALS PRODUCED AS A RESULT OF THIS INFRASTRUCTURE IMPROVEMENT PROJECT WILL HELP ADDRESS THE NATIONAL SHORTAGE OF SPF MACAQUES.

ADMINISTRATIVE SUPPLEMENT REQUEST TO LIFESPAN CARDIOVASCULAR RISK EXPOSURES AND ALZHEIMER-RELATED BRAIN HEALTH

INHIBITING PERIODONTITIS BY TARGETING CATHEPSIN K AND ATTENUATING TLR SIGNALING

DIRECT QUANTITATION OF THE CIRCULATING MTB-PEPTIDOME FOR PEDIATRIC TB MANAGEMENT

MATERNAL AND CHILD HEALTH PUBLIC HEALTH TRAINING PROGRAM

QUALIFICATION OF CIRCULATING MTB ANTIGENS FOR RAPID TB DIAGNOSIS AND TREATMENT MONITORING

INITIATION OF IMMUNE RESPONSES TO SARS COV2 IN THE ORAL CAVITY AND UPPER AIRWAY - ABSTRACT INFECTION WITH SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2) CAUSES CORONAVIRUS DISEASE 2019 (COVID-19), A LIFE-THREATENING ILLNESS WITH MULTI-SYSTEM INVOLVEMENT IN A SUBSET OF INFECTED INDIVIDUALS. ORAL AND NASOPHARYNGEAL (NP) EPITHELIAL CELLS EXPRESS THE SARS-COV-2 RECEPTOR ACE2, AND INFECTION OF THE ORAL/NASOPHARYNGEAL CAVITY (ONP) IS LIKELY AN OBLIGATE STEP IN THE DEVELOPMENT OF COVID-19. IMMUNE RESPONSES FIRST GENERATED IN THE ONP ARE ALMOST CERTAINLY CRUCIAL FOR VIRAL CLEARANCE BUT MAY ALSO PLAY A CENTRAL ROLE IN THE DEVELOPMENT OF HYPERINFLAMMATORY INJURY OBSERVED IN MANY INFECTED INDIVIDUALS. WE HAVE USED SINGLE CELL (SC)- RNA SEQUENCING FROM A RACIALLY DIVERSE PROSPECTIVE COHORT OF COVID-19 PATIENTS TO IDENTIFY DISTINCT SUBSETS OF CILIATED EPITHELIAL CELLS WITHIN THE NP THAT ARE DIRECT TARGETS FOR SARS-COV-2 INFECTION AND HAVE DESCRIBED INNATE ANTI-VIRAL RESPONSES GENERATED BY THOSE CELLS WITHIN BOTH DIRECTLY INFECTED AS WELL AS NON-INFECTED BYSTANDER CELLS. INTERESTINGLY THIS ANALYSIS DEMONSTRATES THAT INCREASED MORTALITY IS LINKED TO BLUNTED ANTI-VIRAL GENE RESPONSE IN THE NP, SUGGESTING THAT A SUCCESSFUL INNATE RESPONSE TO VIRAL INFECTION IN THE NOSE IS A CRITICAL COMPONENT OF A SUCCESSFUL ANTI-VIRAL RESPONSE. IN ADDITION TO THE NOSE, THERE IS STRONG EVIDENCE THAT SARS-COV-2 CAN INFECT THE ORAL EPITHELIUM. WHILE THERE ARE SEVERAL ANATOMIC SITES WITHIN THE MOUTH THAT ARE LIKELY INVOLVED IN ANTI-VIRAL RESPONSES, THE GINGIVAL SULCUS IS A UNIQUE IMMUNOLOGICALLY ACTIVE LOCATION THAT IS CRUCIAL FOR MAINTAINING ORAL HEALTH. THE GINGIVAL EPITHELIUM EXPRESSES BOTH THE SARS-COV-2 RECEPTOR ACE2 AS WELL AS THE HOST PROTEASE TMPRSS2 NECESSARY FOR VIRAL ENTRY, BUT EXHIBITS IMPORTANT IMMUNOLOGICAL DIFFERENCES COMPARED TO THE NASAL EPITHELIUM INCLUDING A BIAS TOWARDS IL-17 ASSOCIATED NEUTROPHIL RESPONSES. THUS, OUR OVERALL HYPOTHESIS IS THAT IDENTIFYING AND ENHANCING SUCCESSFUL INNATE AND ADAPTIVE CELLULAR IMMUNE RESPONSES OF THE NASAL AND GINGIVAL EPITHELIUM WILL LEAD TO NOVEL THERAPEUTIC AVENUES FOR COVID-19. TO ADDRESS THIS HYPOTHESIS, PROPOSE THE FOLLOWING AIMS: 1. STRATIFY CELL STATES AND VIRAL DYNAMICS ACROSS MUCOSAL SURFACES FOLLOWING SARS-COV-2 INFECTION AND VACCINATION; 2. COMPARE MEMORY T CELL RESPONSES WITHIN THE NOSE AND GINGIVA THAT ARE ASSOCIATED WITH SUCCESSFUL OR PATHOGENIC RESPONSES TO SARS-COV-2; AND 3. CHARACTERIZE THE REGULATION OF HOST INNATE IMMUNE DEFENSE MECHANISMS THAT ARE ESSENTIAL TO LIMIT PROPAGATION OF SARS-COV-2 INFECTION WITHIN ONP EPITHELIAL CELLS. TO ACCOMPLISH THESE AIMS, WE WILL ANALYZE HUMAN ONP SAMPLES FROM INDIVIDUALS WITH COVID- 19, RECOVERED FROM COVID-19, AND VACCINATED FOR COVID-19 USING SC-RNA-SEQ, FLOW CYTOMETRY, AND OTHER MOLECULAR BIOLOGY TECHNIQUES. AT COMPLETION, THE PROJECT WILL DEFINE THE PROTECTIVE INNATE AND ADAPTIVE IMMUNE MECHANISMS OPERATING IN THE ONP OF PATIENTS INFECTED WITH SARS-COV-2, IMPROVE OUR OVERALL UNDERSTANDING OF VIRAL INDUCED IMMUNITY IN THE ONP, AND PROVIDE INSIGHT INTO HOW THESE PATHWAYS INFLUENCE DISEASE PATHOGENESIS.

SUPPLEMENTAL FUNDING REQUEST FOR RF1 AG062309 EARLY LIFE GLYCEMIC STATUS AND ALZHEIMER'S DISEASE NEUROIMAGING MARKERS IN MIDDLE AGE: THE BOGALUSA HEART STUDY

MTB AND HIV/SIV ANTIGEN PEPTIDE SIGNATURES AS BLOOD BIOMARKERS TO DETECT EARLY INFECTION TO ACTIVE DISEASE IN YOUNG CHILDREN AND NHP - ABSTRACT ONE MILLION CHILDREN DEVELOP TB ANNUALLY; BUT CURRENT TB DIAGNOSTICS EXHIBIT POOR PERFORMANCE IN CHILDREN, AND THE VAST MAJORITY (96%) OF THE 205,000 CHILDREN WHO DIE OF TB-RELATED CAUSES EACH YEAR DO NOT RECEIVE TREATMENT. SUCH CHILDREN OFTEN PRESENT WITH NON-SPECIFIC SYMPTOMS AND PAUCIBACILLARY TB – PARTICULARLY THOSE CO-INFECTED WITH HIV – AND ARE NOT DIAGNOSED, AND MAY THEN PROGRESS TO DISSEMINATED OR EXTRAPULMONARY TB CASES THAT CAN RAPIDLY PROGRESS IN THE ABSENCE OF APPROPRIATE TREATMENT. IN YOUNG CHILDREN, DIFFICULTY OBTAINING SPUTUM SAMPLES USED BY MOST FRONT-LINE TB DIAGNOSTICS REDUCES THE ABILITY TO ACCURATELY DIAGNOSE TB AND MONITOR ITS RESPONSE TO TREATMENT. THUS, NON-SPUTUM-BASED DIAGNOSTICS ARE URGENTLY NEEDED TO ADDRESS THIS PROBLEM, BUT CURRENT VERSIONS OF SUCH ASSAYS EITHER DEMONSTRATE POOR SENSITIVITY FOR ACTIVE TB OR CANNOT DIFFERENTIATE ACTIVE DISEASE FROM LATENT TB INFECTION OR ACCURATELY MONITOR TREATMENT RESPONSES. WE HAVE REPORTED THAT DETECTION OF VIRULENCE FACTORS SECRETED BY MYCOBACTERIAL TUBERCULOSIS (MTB) IN SERUM CAN DIAGNOSE ALL FORMS OF TB IN CHILDREN (PULMONARY AND EXTRAPULMONARY TB), INCLUDING PAUCIBACILLARY AND HIV- ASSOCIATED TB CASES. WE HAVE RECENTLY SHOWN THAT MULTIPLEX DETECTION OF HIV- AND MTB-DERIVED PROTIENS IN SERUM CAN SENSITIVELY DIAGNOSE HIV AND TB IN YOUNG CHILDREN, AND SIMULTANEOUSLY MONITOR THEIR RESPONSE TO HIV AND TB TREATMENT. THIS IS A CRITICAL ISSUE FOR THOSE AT HIGHEST RISK FOR MORTALITY; VERY YOUNG CHILDREN WHO MAY BE EXPOSED AND/OR INFECTED WITH BOTH PATHOGENS WHILE BREASTFEEDING, DURING THE FIRST TWO YEARS OF LIFE. BASED ON OUR SUCCESS IN IDENTIFYING PATHOGEN-SPECIFIC PEPTIDE BIOMARKERS AND DEVELOPING CORRESPONDING DIAGNOSTIC ASSAYS, WE PROPOSE TO DEVELOP A MULTIPLEX HIV AND TB ASSAY FOR IMPROVED DETECTION AND MONITORING OF HIV VIRAL LOAD AND ALL STAGES OF TB, FROM EARLY INFECTION TO ACTIVE TB DISEASE, IN YOUNG CHILDREN SUSPECTED HIV AND TB INFECTIONS OR HIV/TB CO-INFECTIONS. WE PROPOSE TO ACHIEVE THIS GOAL THROUGH THE PURSUIT OF THREE INTERLINKED SPECIFIC AIMS WHERE WE WILL: 1) ESTABLISH AN ASSAY FOR MULTIPLEX QUANTIFICATION OF SERUM LEVELS OF TB-DERIVED FACTORS ASSOCIATED WITH EACH STAGE OF TB DEVELOPMENT, FROM EARLY INFECTION TO ACTIVE TB DISEASE IN AN INFANT NON-HUMAN PRIMATE TB MODEL THAT CLOSELY RECAPITULATES THE PATHOLOGY OF HIV AND TB INFECTION AND CO-INFECTION; 2) DEVELOP A PREDICTIVE MODEL BASED ON CORRELATIONS BETWEEN TB STAGE MARKERS, IMMUNE RESPONSES AND TB PATHOLOGY IN THIS DISEASE MODEL; AND 3) CONDUCT A MULTI-CENTER VALIDATION OF THIS MULTIPLEX ASSAY TO DIAGNOSE HIV INFECTION AND LATENT TB INFECTIONS AND EARLY AND ACTIVE TB DISEASE IN HIV-EXPOSED PEDIATRIC COHORTS WITH CAREFULLY ANNOTATED CLINICAL, RADIOLOGICAL AND BACTERIOLOGICAL DATA. EMPLOYING A NON-HUMAN PRIMATE MODEL OF HIV/TB CO-INFECTION AND QUANTITATIVE PROTEOMICS WILL ALLOW US TO IDENTIFY TB-ASSOCIATED CHANGES CORRESPONDING TO SYMPTOM DEVELOPMENT AND IMMUNE CHANGES ASSOCIATED WITH DISEASE PROGRESSION THAT COULD NOT FEASIBLY BE DETECTED USING HUMAN COHORTS. THE COMPREHENSIVE EVALUATION OF OUR ASSAY IN MULTIPLE WELL-CHARACTERIZED PEDIATRIC COHORTS WILL FACILLITATE THE RAPID TRANSLATION OF THESE BIOMARKERS INTO PRACTICE AND THE DEVELOPMENT OF OUR PORTABLE DEVICE-BASED ASSAY.

ERADICATION OF LATENT SIV FROM THE CNS

INVESTIGATION OF HUMAN DNA POLYMERASE EPSILON VARIANTS

GAMMA DELTA T CELL AND MICROBIAL MODULATION TO TARGET CHRONIC SIV-ASSOCIATED INFLAMMATION - PROJECT SUMMARY GUT DYSFUNCTION, DYSBIOSIS, AND RESIDUAL INFLAMMATION ARE MAJOR FACTORS CONTRIBUTING TO THE HIGH PREVALENCE OF COMORBIDITIES SUCH AS METABOLIC, CARDIOVASCULAR, KIDNEY, AND LIVER DISEASES IN PEOPLE LIVING WITH HIV UNDER ANTIRETROVIRAL THERAPY (ART). HOWEVER, THE IMMUNE MECHANISMS UNDERLYING THE PROCESS OF GUT DYSFUNCTION AND PERSISTENT INFLAMMATION IN THE SETTING OF LONG-TERM VIRAL SUPPRESSION WITH ART REMAIN POORLY UNDERSTOOD. WE HAVE RECENTLY REPORTED IN THE NONHUMAN PRIMATE MODEL OF HIV WITH ART THAT FOLLOWING INITIAL RESOLUTION OF CIRCULATING LEAKY GUT BIOMARKERS DURING EARLY ART, DYSREGULATION OF IL-17/IL-22 FUNCTIONS OF INTESTINAL GAMMA DELTA (D) T CELLS ARE CORRELATED WITH RESURGENCE OF INTESTINAL EPITHELIAL BARRIER DAMAGE (IEBD) AND SYSTEMIC INFLAMMATION DURING LONG-TERM ART. FURTHER, INTESTINAL VD2T CELL FREQUENCIES SIGNIFICANTLY CORRELATED WITH THE LOSS OF SPECIFIC GUT MICROBIAL SPECIES DURING LONG-TERM ART. BASED ON THIS, WE PROPOSE TO TEST THE HYPOTHESIS THAT SPECIFIC DYSREGULATION OF THE IL-17/IL-22 PATHWAY IN DT CELLS, PARTICULARLY THE VD2 SUBSET, CONTRIBUTES TO BREAKDOWN OF THE GUT EPITHELIAL BARRIER, RESULTING IN MICROBIAL TRANSLOCATION (MT) AND SYSTEMIC INFLAMMATION DURING CHRONIC TREATED HIV INFECTION. HERE, WE PROPOSE TO ASSESS THE ROLE OF VD2 DT CELLS IN THE REPAIR AND MAINTENANCE OF GUT HOMEOSTASIS THROUGH A DIRECT IN VIVO INTERVENTION. WE WILL EVALUATE THE EFFECT OF IN VIVO VD2T-STIMULATION AND EXPANSION ON IEBD, MT, AND INFLAMMATION IN LONG-TERM ART SUPPRESSED SIV-INFECTION VIA TREATMENT WITH THE AMINOBISPHOSPHONATE DRUG, ZOLEDRONATE (ZOL) IN COMBINATION WITH IL-2 AND IL-15 CYTOKINES. SECOND, WE PROPOSE TO TEST THE HYPOTHESIS THAT MODULATION OF GUT MICROBIOME DURING CHRONIC SIV+ART WITH MICROBIAL SUPPLEMENTATION COMBINED WITH IN VIVO VD2T CELL STIMULATION WILL HAVE A SYNERGISTIC EFFECT ON IMPROVING GUT BARRIER FUNCTIONS. WE WILL ADMINISTER FECAL MICROBIAL TRANSPLANT (FMT) SUPPLEMENTED WITH ANTI-INFLAMMATORY BACTERIAL SPECIES, WITH/WITHOUT ZOL TREATMENT TO ASSESS NORMALIZATION OF SYSTEMIC INFLAMMATORY MARKERS AND GUT IMMUNE FUNCTIONS IN FMT-ONLY VS. FMT WITH IMMUNOMODULATION. FINALLY, WE WILL DETERMINE THE MECHANISMS BY WHICH DT CELLS AND MICROBIOME MODULATE INTESTINAL EPITHELIAL HOMEOSTASIS DURING LONG-TERM TREATED SIV INFECTION. WE WILL LONGITUDINALLY ASSESS THE TRANSCRIPTIONAL AND FUNCTIONAL SIGNATURES OF INTESTINAL IL-17/IL-22 PRODUCING CELLS AND EVALUATE EPITHELIAL BARRIER FUNCTIONS IN PRECISELY TIMED GUT BIOPSIES AND IN VITRO COCULTURE ASSAYS TO IDENTIFY NOVEL CELLULAR/MOLECULAR MECHANISMS INVOLVED. BY EXPLORING THE BENEFICIAL EFFECTS OF COMBINED IMMUNE/MICROBIOME MODULATION ON EPITHELIAL BARRIER-PROTECTIVE FUNCTION AND SYSTEMIC INFLAMMATION, THIS STUDY WILL HAVE THE CRITICAL IMPACT OF OPENING NEW AVENUES FOR THE CONTINUED DEVELOPMENT OF COMBINATORIAL APPROACHES TO TARGET ENTEROPATHY AND CHRONIC INFLAMMATION IN PEOPLE LIVING WITH HIV.

STUDY OF ANP RECEPTOR: GENE TARGETING AND EXPRESSION

MECHANISMS OF PROBIOTICS IN ALCOHOLIC LIVER DISEASE

THE ROLE OF L5, L11 AND L23 IN THE MDM2-P53 FEEDBACK REGULATION

EVALUATION OF MEMORY RESPONSES AND BIOMARKERS FROM A PHASE IENTEROTOXIGENIC ESCHERICHIA COLI (ETEC) INTRAMUSCULAR SUBUNITVACCINE WITH DMLT ADJUVANT - ENTEROTOXIGENIC E. COLI (ETEC) IS A MAJOR CAUSE OF BACTERIAL INFECTIOUS DIARRHEA IN CHILDREN, TRAVELERS AND DEPLOYED MILITARY PERSONNEL IN RISK AREAS. AS SUCH, DEVELOPMENT OF A VACCINE WOULD BE ADVANTAGEOUS FOR PUBLIC HEALTH. ONE STRATEGY IS TO USE SUBUNITS OF COLONIZATION FACTORS COMBINED WITH TOXOIDS OF HEAT-LABILE TOXIN (LT). RECENTLY, A FIRST-IN-HUMANS SAFETY AND IMMUNOGENICITY PHASE 1 VACCINE TRIAL (NCT03404674) WAS CONDUCTED. WITH DOSE- ESCALATING INTRAMUSCULAR DELIVERY OF CS6-SUBUNIT ANTIGEN CSSBA COMBINED WITH LT-R192G/L211A (DMLT). NO SERIOUS ADVERSE EVENTS WERE REPORTED AND WE OBSERVED STRONG HUMORAL IMMUNOGENICITY IN SEVERAL COHORTS, NOTABLY RELATED TO DMLT DOSE. YET A COMPLETE ANALYSIS OF CLINICAL TRIAL SAMPLES, INCLUDING HUMORAL AND CELLULAR MEMORY IS LACKING. AS THIS VACCINE TRIAL INDICATES, DMLT IS NOT ONLY AN LT TOXOID BUT ALSO A POTENT ADJUVANT THAT STIMULATES IMMUNITY TO CO-DELIVERED ANTIGENS; HOWEVER, THERE IS A GAP IN OUR UNDERSTANDING OF MOLECULAR MECHANISMS RESPONSIBLE FOR INITIATING VACCINATION OUTCOMES WITH ANTIGENS CO-DELIVERED WITH DMLT. THE OBJECTIVE OF THIS PROPOSAL IS TO EXPAND ANALYSIS ON SERUM AND PBMC SAMPLES FROM AN ETEC PHASE 1 CLINICAL TRIAL AND TO DEFINE THE KEY BIOMARKERS AND MOLECULAR MECHANISMS DIRECTING VACCINE OUTCOMES. IN THE PROPOSED STUDIES WE AIM TO EXPLORE (1) HOW VACCINATION DOSES MODULATED DEVELOPMENT OF MEMORY, LONGEVITY AND DIVERSITY OF THE HUMORAL RESPONSE; (2) HOW VACCINATION ALTERED DEVELOPMENT OF DURABLE CELLULAR IMMUNITY; (3) WHETHER EARLY SIGNALING EVENTS CAN SERVE AS BIOMARKERS OF IMMUNITY; AND (4) WHAT MOLECULAR MECHANISMS DURING IMMUNIZATION SHAPE VACCINATION OUTCOMES. TO DO SO WE WILL ANALYZE OUR STORED CLINICAL TRIAL SAMPLES AND PERFORM A NUMBER OF SOPHISTICATED ANALYSES, INCLUDING TRANSCRIPTIONAL AND METABOLOMICS ASSAYS USING SAMPLES FROM A RELATED ETEC PHASE 2B VACCINE- EFFICACY TRAIL TO DEFINE SIGNATURES OF VACCINE INDUCED PROTECTION WHICH WE WILL THEN VALIDATE USING THE PHASE 1 TRIAL SAMPLES. IN ADDITION, WE WILL VALIDATE FINDINGS WITH CELLULAR ANALYSES AND MOUSE MODELS. THESE FINDINGS WILL HELP WITH THE DEVELOPMENT OF AN ETEC VACCINE FOR HUMAN USE BY PARENTERAL ROUTE AND ALSO PROVIDE MECHANISTIC INSIGHT INTO KEY EVENTS DIRECTING VACCINATION OUTCOMES.

A MECHANISTIC TRIAL OF DIETARY SODIUM REDUCTION ON VASCULAR STRUCTURE AND FUNCTION IN AFRICAN AMERICANS - PROJECT SUMMARY HIGH DIETARY SODIUM INTAKE INCREASES RISK OF CARDIOVASCULAR DISEASE (CVD) INDEPENDENT OF ESTABLISHED RISK FACTORS, INCLUDING BLOOD PRESSURE (BP). NON-BP MEDIATED MECHANISMS UNDERLYING THE INCREASED RISK OF CVD ASSOCIATED WITH DIETARY SODIUM INTAKE ARE NOT WELL UNDERSTOOD, BUT OBSERVATIONAL STUDIES SUGGEST DIRECT TARGET ORGAN DAMAGE IN THE HEART AND VASCULATURE MIGHT PLAY AN IMPORTANT ROLE. LITTLE EVIDENCE EXISTS FROM RANDOMIZED CONTROLLED TRIALS (RCTS) ON TARGET ORGAN EFFECTS OF DIETARY SODIUM REDUCTION, AND THE NATIONAL ACADEMY OF MEDICINE HAS RECOMMENDED FUTURE RESEARCH TO “TEST THE EFFECTS OF DIFFERENT SODIUM INTAKE LEVELS ON ENDOTHELIAL AND VASCULAR FUNCTION” IN ORDER TO “TO BETTER CHARACTERIZE THE RELATIONSHIP BETWEEN SODIUM INTAKE AND CHRONIC DISEASE”. FURTHER, NO RCTS HAVE BEEN POWERED TO TEST THE EFFECT OF DIETARY SODIUM REDUCTION ON SUBCLINICAL CARDIOVASCULAR STRUCTURE AND FUNCTION IN AFRICAN AMERICANS, WHO ARE MORE SENSITIVE TO DIETARY SODIUM INTAKE AND AT HIGHER RISK FOR CVD. THE OVERALL OBJECTIVE OF THE PROPOSED MECHANISTIC TRIAL IS TO TEST THE EFFECT OF DIETARY SODIUM REDUCTION ON CARDIAC AND VASCULAR STRUCTURE AND FUNCTION. SPECIFICALLY, THE PROPOSED TRIAL WILL TEST WHETHER DIETARY SODIUM REDUCTION (TARGETING A DIETARY SODIUM INTAKE OF <2,300 MG/DAY) WILL IMPROVE LEFT VENTRICULAR MASS INDEX (LVMI), LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN (LVGLS), CAROTID-FEMORAL PULSE WAVE VELOCITY (CFPWV), AND FLOW-MEDIATED DILATION (FMD) COMPARED TO USUAL INTAKE. ADDITIONALLY, WE WILL TEST WHETHER THIS EFFECT IS INDEPENDENT FROM BP REDUCTION. WE WILL RECRUIT 240 AFRICAN AMERICANS WITH ELEVATED BP OR HYPERTENSION FROM THE GREATER NEW ORLEANS AREA AND RANDOMLY ASSIGN THEM TO A DIETITIAN-LED BEHAVIORAL INTERVENTION AIMED AT DECREASING DIETARY SODIUM INTAKE TO <2,300 MG/DAY FOR 12 MONTHS OR TO A USUAL DIET. STUDY OUTCOMES, INCLUDING CARDIAC MAGNETIC RESONANCE IMAGING (CMR)-DETERMINED LVMI AND LVGLS, CFPWV, AND FMD, WILL BE MEASURED AT BASELINE, 6-MONTH, AND 12-MONTH CLINIC VISITS USING STANDARDIZED PROTOCOLS WITH STRINGENT QUALITY CONTROL. THESE OUTCOMES ARE VALIDATED BIOMARKERS FOR TARGET ORGAN DAMAGE AND PREDICT THE RISK OF CLINICAL CVD EVENTS. IN PRIMARY ANALYSES, THE EFFECT OF SODIUM REDUCTION ON EACH SUBCLINICAL CVD ENDPOINT WILL BE COMPARED BETWEEN THE SODIUM REDUCTION AND USUAL DIET GROUPS ACCORDING TO THE INTENTION-TO- TREAT PRINCIPLE WITHOUT ADJUSTING FOR COVARIATES. IN SECONDARY ANALYSES, CHANGES IN AMBULATORY AND CLINICAL BP WILL BE ADJUSTED TO ASSESS THE BP-INDEPENDENT EFFECT OF DIETARY SODIUM REDUCTION ON EACH SUBCLINICAL CVD ENDPOINT. THE PROPOSED TRIAL HAS 85% STATISTICAL POWER TO DETECT A CLINICALLY SIGNIFICANT DIFFERENCE IN CHANGES OF THE FOUR CO-PRIMARY OUTCOMES (10 G/M2 IN LVMI, 1.3% IN LVGLS, 0.9 M/S IN CFPWV, AND 1.1% IN FMD) OVER 12 MONTHS BETWEEN THE TWO GROUPS AT A 2-SIDED SIGNIFICANCE LEVEL OF 0.0125 (0.05/4). THIS STUDY IS THE FIRST RCT TO TEST THE EFFECT OF DIETARY SODIUM REDUCTION ON SUBCLINICAL CVD ENDPOINTS IN AFRICAN AMERICANS. FINDINGS FROM THIS TRIAL WILL FILL THE KNOWLEDGE GAP OF THE UNDERLYING MECHANISMS OF DIETARY SODIUM INTAKE ON CVD RISK AND PROVIDE FURTHER EVIDENCE ON SODIUM REDUCTION FOR CVD PREVENTION.

SUPPORTING TAILORED ADAPTIVE CHANGE AND REINFORCEMENT FOR MEDICATION ADHERENCE PROGRAM (STAR-MAP): RANDOMIZED TRIAL OF A NOVEL APPROACH TO IMPROVE ADHERENCE IN OLDER HYPERTENSIVE WOMEN AND MEN - PROJECT SUMMARY THERE IS A FUNDAMENTAL GAP IN THE AVAILABILITY OF INTERVENTIONS THAT 1) SUSTAINABLY IMPROVE ADHERENCE TO PRE- SCRIBED BLOOD PRESSURE (BP) MEDICATIONS, 2) IDENTIFY UNDERLYING BEHAVIOR CHANGE MECHANISMS, AND 3) DEMON- STRATE EFFICACY BY SEX AND RACE IN OLDER ADULTS. ACCORDINGLY, INTERVENTIONS TO IMPROVE ADHERENCE AND BP CONTROL REMAIN MINIMALLY EFFECTIVE. THE LONG-TERM GOAL IS TO IMPROVE MEDICATION ADHERENCE, BP CONTROL, AND HEALTHY AGING IN OLDER HYPERTENSIVE ADULTS. THE OVERALL OBJECTIVE FOR THIS R01 APPLICATION IS TO DETERMINE THE EFFICACY OF THE SUPPORTING TAILORED ADAPTIVE CHANGE AND REINFORCEMENT FOR MEDICATION ADHERENCE PROGRAM (STAR- MAP), WHICH INTEGRATES THE TRANSFORMATIVE OVERCOMING IMMUNITY-TO-CHANGE (OITC) HEALTH COACHING PROCESS, ON IMPROVING ADHERENCE, BP CONTROL, AND QUALITY OF LIFE (QOL). THE OITC APPROACH THAT HAS PROVEN USEFUL IN OTHER ARENAS WAS SUCCESSFULLY APPLIED TO BP MANAGEMENT IN THE RESEARCH TEAM'S RECENT PILOT STUDY. BASED ON THIS PRIOR WORK, THE CENTRAL HYPOTHESIS IS THAT STAR-MAP, DESIGNED TO HELP NONADHERENT OLDER HYPERTENSIVE ADULTS TO IDENTIFY AND ALTER IMPLICIT ATTITUDES THAT HINDER MEDICATION ADHERENCE, WILL CHANGE MINDSETS AND IM- PROVE DAILY TAKING OF PRESCRIBED MEDICATIONS, LEADING TO LOWERED BP AND BETTER QOL. THE RATIONALE FOR THE PRO- POSED STUDY IS THAT DEMONSTRATION OF THE EFFICACY OF STAR-MAP WOULD PROVIDE NEW OPPORTUNITIES TO OVERTURN NONADHERENT BEHAVIOR AND IMPROVE BP CONTROL AND HEALTHY AGING FOR THE GROWING POPULATION OF OLDER ADULTS WITH HYPERTENSION, OVERALL AND IN SEX AND RACE SUBGROUPS. THE CENTRAL HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: (1) DETERMINE THE EFFICACY, UNDERLYING MECHANISM, AND SUSTAINABILITY OF THE STAR-MAP INTERVEN- TION, AIMED AT IMPROVING MEDICATION-TAKING BEHAVIOR, ON MEDICATION ADHERENCE AND CLINICAL OUTCOMES; AND (2) EXPLORE THE EFFICACY OF STAR-MAP IN SEX AND RACE SUBGROUPS. UNDER THE FIRST AIM, A RANDOMIZED CONTROLLED TRIAL WILL BE CONDUCTED IN 402 NONADHERENT (PROPORTION OF DAYS COVERED (PDC) <0.8) ADULTS =65 YEARS WITH UN- CONTROLLED BP (201 PER ARM – INTERVENTION VERSUS USUAL CARE; 50% WOMEN; 50% BLACK) AND FULLY INSURED BY BLUE CROSS BLUE SHIELD OF LOUISIANA. THE STUDY WILL HAVE 90% STATISTICAL POWER TO DETECT A 15% DIFFERENCE AT 12 MONTHS IN THE PROPORTION OF PARTICIPANTS WITH PDC =0.8 BETWEEN THOSE RANDOMIZED TO INTERVENTION VERSUS USUAL CARE WITH ATTENTION CONTROL. UNDER THE SECOND AIM, EFFICACY OF STAR-MAP IN SEX AND RACE SUBGROUPS WILL BE EXPLORED. THE APPROACH IS INNOVATIVE BECAUSE IT WILL BE THE FIRST LARGE CLINICAL TRIAL TO RIGOROUSLY TEST A NEW INTERVENTION THAT TARGETS NEGATIVE IMPLICIT ATTITUDES TOWARD MEDICATIONS WITH A GOAL TO IMPROVE ADHERENCE, BP CONTROL, AND QOL. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL REPRESENT AN IMPORTANT STEP IN A CONTIN- UUM OF RESEARCH THAT IS EXPECTED TO LEAD TO AN EFFICACIOUS, SCALABLE INTERVENTION (WITH DATA ON THE UNDERLYING BEHAVIOR CHANGE MECHANISM). FINALLY, THE RESULTS ARE EXPECTED TO PROVIDE NEW INSIGHTS ON AN UNDERAPPRECIATED PSYCHOLOGICAL MECHANISM (I.E., IMPLICIT ATTITUDES) OF NONADHERENCE THAT COULD BE USEFUL FOR IMPROVING THE EFFEC- TIVENESS OF OTHER MEDICATION ADHERENCE INTERVENTIONS.

USING PARENTERAL COMBINATION ADJUVANTS TO INDUCE PAN-MUCOSAL CELLULAR AND HUMORAL IMMUNITY - PROJECT SUMMARY MOST PATHOGENS ENTER THE BODY AT MUCOSAL SURFACES, YET, TO DATE, THE MAJORITY OF LICENSED VACCINES ARE INJECTED PARENTERALLY, PREDOMINANTLY INTRAMUSCULARLY. WHILE EXCELLENT AT ELICITING SYSTEMIC IMMUNITY, THEY DO NOT ALWAYS INDUCE THE REQUIRED MUCOSAL IMMUNE RESPONSES. THIS HIGHLIGHTS A GAP IN OUR UNDERSTANDING OF HOW NON-MUCOSAL IMMUNIZATION MIGHT BE MANIPULATED TO ELICIT MUCOSAL IMMUNE RESPONSES AND HOW SUCH KNOWLEDGE COULD BE EXPLOITED TO CREATE BETTER VACCINES AGAINST MUCOSAL PATHOGENS. DEFINING THE ROLE THAT ADJUVANTS PLAY IN THIS RESPONSE IS KEY TO DEVELOPING SUCH VACCINES; HOWEVER, THE MECHANISMS THAT DICTATE ADJUVANT DRIVEN MUCOSAL ANTIBODY AND CELLULAR IMMUNE RESPONSES ARE NOT WELL UNDERSTOOD. OUR PUBLISHED WORK AND PRELIMINARY EXPERIMENTS USING MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I (MHCI) AND II (MHCII) AND B CELL TETRAMERS TO EXAMINE MUCOSAL IMMUNE RESPONSES AFTER INTRADERMAL IMMUNIZATION WITH A NOVEL DETOXIFIED BACTERIAL ADP- RIBOSYLATING ENTEROTOXIN, CALLED DMLT, DEMONSTRATE THAT WE CAN RETARGET THE ENDOGENOUS T AND B CELL IMMUNE RESPONSES TO THE LUNG, INTESTINAL MUCOSA, AND FEMALE REPRODUCTIVE TRACT (FRT). WHEN DMLT IS COMBINED WITH A SAFE, BACTERIAL-DERIVED OUTER MEMBRANE VESICLE (OMV) ADJUVANT, CD4 T CELL NUMBERS AND VACCINE-SPECIFIC ANTIBODIES AND B CELLS ARE EVEN FURTHER INCREASED. SIMULTANEOUSLY, OMV ADJUVANT INDUCES SIGNIFICANT EXPANSION OF VACCINE-SPECIFIC CD8 T CELLS. FURTHERMORE, IMMUNIZATION WITH DMLT- OR OMV-ADJUVANTED VACCINES ELICITS PROTECTION AGAINST BACTERIAL INFECTIONS IN THE LUNG AND GUT. THESE RESULTS LEAD US TO HYPOTHESIZE THAT INTRADERMAL IMMUNIZATION WITH COMBINED DMLT PLUS OMVS WILL DRIVE ANTIGEN-SPECIFIC B CELLS AND T CELLS TO THE MUCOSA AND ENHANCE VACCINE PROTECTION AGAINST MUCOSAL PATHOGENS. WE PROPOSE TO: 1) DETERMINE HOW INTRADERMAL IMMUNIZATION WITH DMLT COMBINED WITH OMV ADJUVANT DIRECTS 1) T CELLS AND 2) B CELLS TO MUCOSAL TISSUE AND WHETHER THESE CELLS ARE BONA FIDE TISSUE RESIDENT MEMORY CELLS. IN PARALLEL, WE WILL 3) EXAMINE IF IMMUNIZATION WITH DMLT-OMV ADJUVANTED VACCINES IS PROTECTIVE AGAINST MUCOSAL VIRAL AND BACTERIAL INFECTIONS IN THE LUNG, GUT AND FRT. THIS INVESTIGATION WILL PROVIDE NOVEL INSIGHTS INTO HOW ADJUVANTS REGULATE IMMUNITY AT THE MUCOSA AND ALLOW US TO GUIDE THE RESPONSE IN FAVOR OF PATHOGEN ELIMINATION.

PEROXYNITRITE IS A MOLECULAR DETERMINANT OF IMPAIRED MICROVASCULAR ENERGETICS IN ALZHEIMER'S DISEASE - SUMMARY BRAIN MICROVESSELS (BMVS) PLAY AN IMPORTANT ROLE IN THE NEUROVASCULAR COUPLING (NVC). MITOCHONDRIA ARE ENERGY SENSORS OF CELLS AND IMPAIRED MITOCHONDRIAL RESPIRATORY FUNCTION INITIATE CRITICAL SIGNALING DETRIMENTAL TO NVC LEADING TO IMPAIRED COGNITIVE FUNCTION ASSOCIATED WITH ALZHEIMER'S DISEASE (AD). OUR RECENT TECHNOLOGICAL BREAKTHROUGH UTILIZING AGILENT SEAHORSE XFE EXTRACELLULAR FLUX ANALYZER DEVELOPED A MITOCHONDRIAL RESPIRATION ASSAY IN BMVS. USING THIS NOVEL METHOD, WE OBSERVED AGE-DEPENDENT IMPAIRMENT OF MITOCHONDRIAL RESPIRATION AND BIOENERGETICS IN BMVS FROM MALE AND FEMALE C57BL/6 MICE. NOTABLY, WE FOUND THAT BMVS FROM APP NL-G-F KNOCK-IN MODEL OF AD DISPLAY IMPAIRED MITOCHONDRIAL RESPIRATION AND ACCELERATED SENESCENCE. FURTHERMORE, WE OBSERVED THAT YOUNG AND AGED FEMALE MICE DISPLAY SEX-DEPENDENT DIFFERENCES IN MICROVASCULAR ENERGETICS RELATED TO THE RELATIVE CONTRIBUTION OF OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS TO OVERALL ENERGY PRODUCTION. FINALLY, WE FOUND THAT PEROXYNITRITE SCAVENGER (FETMPYP) TREATMENT ENHANCED NON-MITOCHONDRIAL RESPIRATION YOUNG FEMALE MICE BUT ENHANCED PROTON LEAK IN YOUNG MALE MICE INDICATING THAT THE DIFFERENTIAL PEROXYNITRITE ACTIVITY IS SEX-DEPENDENT. THEREFORE, WE HYPOTHESIZE THAT PEROXYNITRITE DIFFERENTIALLY REGULATES MICROVASCULAR MITOCHONDRIAL FUNCTION SEX-DEPENDENTLY AND IS THE MOLECULAR DETERMINANT OF EXAGGERATED AGE-RELATED IMPAIRMENT OF NVC AND COGNITIVE FUNCTION IN AD. WE WILL EMPLOY MALE AND FEMALE AD AND C57BL/6 MICE OF 8 MONTHS AND 20 MONTHS AGE. AIM 1 WILL DETERMINE THE SEX DEPENDENT DIFFERENTIAL IMPACT OF PEROXYNITRITE ON THE BIOENERGETICS AND ENZYME ACTIVITIES (KREBS CYCLE, GLYCOLYSIS, AND ANTIOXIDANTS) IN BMVS EX VIVO. AIM 2 WILL DETERMINE THE SEX DEPENDENT DIFFERENTIAL IMPACT OF PEROXYNITRITE ON IN VIVO NVC RESPONSES TO WHISKER DEFLECTIONS BY TWO-PHOTON EXCITATION MICROSCOPY IN AWAKE MICE. AIM 3 WILL DETERMINE THE SEX DEPENDENT DIFFERENTIAL IMPACT OF FETMPYP ON COGNITIVE FUNCTION BY ASSESSING WHISKER-DEPENDENT PERCEPTUAL LEARNING USING THE NOVEL TEXTURE DISCRIMINATION TASK. THE RESULTS OF THIS PROPOSAL WOULD CHALLENGE THE EXISTING DOGMA AND WILL DEMONSTRATE THE SEX-SPECIFIC PHYSIOLOGICAL ROLE OF PEROXYNITRITE IN REGULATING THE MICROVASCULAR BIOENERGETICS AND NEUROVASCULAR UNIT. FURTHERMORE, OUR RESULTS WILL FIRMLY ESTABLISH MICROVASCULAR PEROXYNITRITE AS A POTENTIAL THERAPEUTIC TARGET IN SEX- DEPENDENT VULNERABILITY AND SEVERITY OF AD AND OTHER NEURODEGENERATIVE DISEASES.

CPLA2, COX-2 AND PPAR-GAMMA IN CHOLANGIOCARCINOMA

PLACE MATTERS - ADAPTABLE SOLUTIONS TO VIOLENCE AT THE COMMUNITY LEVEL

EARLY PREVENTION INTERVENTIONS TOWARDS ART-FREE PEDIATRIC HIV REMISSION - PRINCIPAL INVESTIGATORS (LAST, FIRST, MIDDLE): XU, HUANBIN PROJECT SUMMARY/ABSTRACT: DESPITE REMARKABLE ADVANCES IN PREVENTION OF VERTICAL HIV-1 TRANSMISSION, HOWEVER, THERE IS LITTLE DATA TO GUIDE THE OPTIMAL EARLY TREATMENT REGIMENS IN VULNERABLE NEONATES WITH HIGH RISK OF MTCT. CURRENT RECOMMENDED ANTIRETROVIRAL REGIMENS FOR CHILDREN ARE EXTRAPOLATED FROM CLINICAL TRIAL IN ADULTS. MOST RECENTLY, OUR STUDIES SHOW THAT A SHORT-TERM COMBINED ART (CART) INCORPORATING AN INTEGRASE STRAND TRANSFER INHIBITOR (INSTI), INITIATED AT 3 DAYS POST INFECTION (DPI) BUT NOT ONE DAY BEYOND, CAN RAPIDLY SUPPRESS VIREMIA TO UNDETECTABLE LEVELS IN NEONATES, AND A PROLONGED 9-MONTH-EARLY INTERVENTION OF THIS REGIMEN RESULTS IN SUSTAINED VIROLOGIC REMISSION IN 4 OF 5 INFANTS FOR MORE THAN 2.5 YEARS AFTER TREATMENT CESSATION. SURPRISINGLY, OUR FURTHER PRELIMINARY DATA SHOWED THAT DELAYING TREATMENT (E.G., NEWBORN MACAQUES INOCULATED WITH SIV/SHIV AD8 AND CART INITIATED AT 5DPI) OR TREATING OLDER INFANTS (E.G., 1.5-MONTH OLD INFANT MACAQUES EXPOSED TO SIV WITH CART INITIATED AT 3DPI) DRASTICALLY ALTERED THE OUTCOMES AFTER INTERRUPTION OF THE SAME 9-MONTH-EARLY INTERVENTION, AS INDICATED BY VIRAL REBOUND IN 4/5 AND 3/3 ANIMALS, RESPECTIVELY. THESE FINDINGS SUGGEST THAT OUTCOME OF PEDIATRIC SUSTAINED VIROLOGIC REMISSION APPEARS TO BE VERY SENSITIVE TO THE AGE OF INFANTS (E.G., NEWBORN VERSUS INFANTS) AND THE TIMING (E.G., PROVIRAL RESERVOIR SEEDING?) OF INTERVENTION INITIATION, YET THE EXACT MECHANISMS OF VIRAL REMISSION REMAIN ELUSIVE. NEW ANTIVIRALS ARE ALSO EMERGING AND A ONCE-MONTHLY ANALOG OF DTG CALLED CABOTEGRAVIR (CAB) SHOWS EVEN GREATER POTENTIAL FOR PREVENTING HIV ACQUISITION AND REPLICATION IN RECENT ADULT CLINICAL TRIALS, YET ITS EFFICACY AND SAFETY IN PEDIATRIC HIV THERAPY HAVE NOT BEEN EXAMINED. GIVEN NEWBORN NEONATES LACK WELL-ORGANIZED LYMPHOID TISSUES (SANCTUARY SITES FOR ANTIRETROVIRALS PENETRATION AND VIRAL RESERVOIRS) WHILE POSSESSING MORE DYNAMIC AND REGENERATIVE CAPACITY THAN AN ADULT, PROPHYLACTIC INTERVENTION IN INFANTS MAY BE UNIQUE IN THAT IT MAY HAVE MORE EFFECTIVE ANTIVIRAL ACTIVITY FOR ART-FREE HIV REMISSION, RESULTING IN MORE REPLENISHMENT OF KEY IMMUNE CELLS AND NORMAL DEVELOPMENT OF THE IMMUNE SYSTEM. IN THIS PROPOSAL, WE HYPOTHESIZE THAT EARLY PREVENTION INTERVENTIONS, BASED ON APPROPRIATE INITIAL TIMING, DURATION AND INSTI COMBINATION, COULD EFFECTIVELY BLOCK VIRAL GENOME INTEGRATION AND COMPLETELY ELIMINATE EARLY VIRAL RESERVOIRS, RESULTING IN A SUSTAINED STATE OF ART-FREE VIROLOGIC REMISSION IN INFANTS EXPOSED TO OR INFECTED WITH HIV, AND SUBSEQUENTLY, NORMAL IMMUNE DEVELOPMENT THROUGHOUT INFANCY. UTILIZING THE PEDIATRIC NHP MODEL OF HIV, OUR OVERARCHING OBJECTIVE IS ADDRESS: SA1, THE IMPACT OF PROVIRAL RESERVOIRS ON PROPHYLACTIC INTERVENTION OUTCOMES IN INFANTS WHILE ASSESSING THE EFFICACY AND SAFETY OF CABOTEGRAVIR IN A PRECLINICAL TRIAL; SA2, THE OPTIMUM PREVENTION INTERVENTION STRATEGY FOR ACHIEVING PEDIATRIC HIV REMISSION, AND; SA3, THE PHARMACOKINETICS AND IMMUNOLOGICAL ALTERATIONS OF ART IN THE UNIQUE INFANT PRIMATE HOST. OVERALL, THESE STUDIES WILL PROVIDE INSIGHT INTO THE OPTIMAL PREVENTION INTERVENTION THAT ACHIEVES A SUSTAINED STATE OF ART-FREE VIROLOGIC REMISSION FOR INFANTS EXPOSED TO OR INFECTED WITH HIV AT BIRTH, WHICH WILL HAVE SIGNIFICANT TRANSLATIONAL SIGNIFICANCE TOWARDS THE TREATMENT OF HIV INFECTION OF INFANTS IN GENERAL.

SHORT-TERM ESTRADIOL USE IN MIDDLE-AGE: IMPLICATIONS FOR FEMALE COGNITIVE AGING

MECHANISMS OF ALTERED GASTROINTESTINAL DYSFUNCTION

ELUCIDATING THE MEASUREMENT OF TELOMERES: DEVELOPMENT OF A TRANSDISCIPLINARY, HIGH-IMPACT TELOMERE RESEARCH NETWORK

BIOLOGY OF INNATE IL-22 DURING LUNG FUNGAL INFECTION

LONGITUDINAL FOLLOW-UP OF BRIEF PARENTING INTERVENTIONS TO REDUCE RISK OF CHILD PHYSICAL MALTREATMENT IN A SELECTED POPULATION

A NANOPORE BIOSENSOR FOR LEVELING MTB ANTIGENS IN BLOOD - TUBERCULOSIS (TB) IS A GLOBAL HEALTH THREAT BUT CAN BE DIFFICULT TO DIAGNOSE AND MANAGE DUE TO THE SUB-OPTIMAL PERFORMANCE AND NON-QUANTITATIVE NATURE OF FRONTLINE DIAGNOSTIC ASSAYS, WHICH REQUIRE SPUTUM OR TISSUE BIOPSIES AND EXHIBIT REDUCED PERFORMANCE WHEN APPLIED TO DIAGNOSE PAUCIBACILLARY OR EXTRAPULMONARY TB CASES. THERE IS AN UNMET NEED FOR A RAPID, NON-SPUTUM-BASED ASSAY THAT CAN SENSITIVELY DIAGNOSE ACTIVE TB AND MEASURE TREATMENT RESPONSES IN CLINICALLY DIVERSE POPULATIONS. WE HAVE PREVIOUSLY REPORTED THAT SERUM LEVELS OF TWO PEPTIDES DERIVED FROM THE MYCOBACTERIUM TUBERCULOSIS (MTB) VIRULENCE FACTORS CFP-10 AND ESAT-6 CAN ACT AS SPECIFIC BIOMARKERS OF ACTIVE TB AND, USING A MASS SPECTROMETRY (MS) ASSAY, VALIDATED THEIR DIAGNOSTIC PERFORMANCE IN RELEVANT COHORTS OF ADULTS AND CHILDREN. THIS INCLUDED HIV+/HIV-, PULMONARY / EXTRAPULMONARY, AND CULTURE-POSITIVE / NEGATIVE TB CASES, AS WELL AS THOSE WITH LATENT TB AND NONTUBERCULOUS MYCOBACTERIA INFECTIONS. THIS MS ASSAY HAD SIMILAR DIAGNOSTIC SENSITIVITY (88.6 VS 88.2%) AND SPECIFICITY (93.8 VS 97.2%) IN ADULTS AND CHILDREN AND EXCEEDED THE REPORTED PERFORMANCE OF FRONTLINE TESTS IN COMPARABLE POPULATIONS. SERUM MTB ANTIGEN LEVELS WERE ALSO INFORMATIVE IN MONITORING ANTI-TB TREATMENT RESPONSES. HOWEVER, THIS MS ASSAY IS NOT SUITABLE FOR USE IN RESOURCE LIMITED SETTINGS. THE PROPOSED STUDIES WILL THEREFORE REFINE AND EVALUATE THE PERFORMANCE OF A PROTEIN-BASED NANOPORE BIOSENSOR ASSAY TO DIAGNOSE ACTIVE TB CASES USING THE SAME SERUM BIOMARKERS. THIS SYSTEM IS EASY TO OPERATE, HAS LOW FABRICATION AND INSTRUMENT COSTS, AND CAN PERFORM HIGH- THROUGHPUT AND ULTRA-SENSITIVE MEASUREMENTS OF SPECIFIC MTB-DERIVED PEPTIDES. ITS ROBUST NATURE AND PORTABILITY ALSO ALLOW ITS USE IN RESOURCE-LIMITED AREAS SUBJECT TO HIGH TB PREVALENCE. OUR RESULTS SHOW THAT A NANOPORE ASSAY CAN ACCURATELY DETECT CFP-10 AND ESAT-6 PEPTIDES, AND THIS DATA HAS SIGNIFICANT DIAGNOSTIC PROMISE. BASED ON THESE FINDINGS, WE PROPOSE THAT THE PORTABLE PROTEIN NANOPORE BIOSENSOR ASSAY THAT WILL BE ANALYZED IN THESE STUDIES CAN IMPROVE TB DIAGNOSIS IN ADULTS AND CHILDREN, PARTICULARLY IN RESOURCE-LIMITED AREAS WITH HIGH TB PREVALENCE. WE WILL UTILIZE THIS SYSTEM TO MEASURE SERUM LEVELS OF MTB ANTIGEN-DERIVED PEPTIDE BIOMARKERS IN ORDER TO: (1) DEVELOP A SENSITIVE AND ROBUST NANOPORE-BASED TB DIAGNOSTIC ASSAY; (2) VALIDATE THIS ASSAY IN WELL-ORGANIZED COHORTS, CONTAINING PATIENTS WITH PULMONARY AND EXTRAPULMONARY TB CASES; AND (3) EVALUATE HOW SERUM LEVELS OF MTB ANTIGENS CHANGE IN ADULT PTB CASES IN DURING ANTI-TB THERAPY. GIVEN THE SUCCESS OF THESE PROOF-OF-CONCEPT STUDIES, THE LONG-TERM GOAL OF THE PROPOSED RESEARCH PROGRAM IS TO BUILD PROTOTYPE DEVICES FOR LARGE-SCALE ON-SITE CLINICAL VALIDATION STUDIES IN HIGH TB BURDEN REGIONS, AND TO MODIFY AND EXTEND THIS SYSTEM TO DETECT OTHER DISEASE BIOMARKERS. THIS RESEARCH PROGRAM SHOULD HASTEN THE TRANSLATION OF A PROMISING BIOSENSOR PLATFORM INTO A PRACTICAL ASSAY SUITABLE FOR RAPID TRANSLATION TO CLINICAL APPLICATIONS FOR DISEASE DIAGNOSIS.

CHUKKA AUCHAFFI' NATANA: THE WEAVING HEALTHY FAMILIES PROGRAM TO PROMOTE WELLNESS AND RESILIENCE AND PREVENT ALCOHOL AND OTHER DRUG ABUSE AND VIOLENCE

A NEW APPROACH TO CONTROLLING CHLAMYDIA TRANSMISSION IN YOUNG PEOPLE

DECODING METHYLATION MEDIATED EPIGENOMIC CONTRIBUTIONS TO MALE OSTEOPOROSIS

ROLE OF COMPLEMENT ACTIVATION IN SEVERE COVID-19 - PROJECT SUMMARY/ABSTRACT: IN RESPONSE TO NOTICE OF SPECIAL INTEREST (NOSI): COMPLEMENT IN BASIC IMMUNOLOGY (CIBI), WE PROPOSE TO EXAMINE THE CAUSATIVE EFFECT OF COMPLEMENTS IN THE PATHOGENESIS OF SEVERE COVID-19. THE COMPLEMENT SYSTEM IS ACTIVATED VIA ONE OF THREE PATHWAYS—CLASSICAL, ALTERNATIVE, AND MANNOSE-BINDING LECTIN (MBL)—WHICH CONVERGE AT C3 CLEAVAGE, LEADING TO THE FORMATION OF C3 AND C5 CONVERTASES AND CONCLUDING WITH ASSEMBLY OF THE MEMBRANE ATTACK COMPLEX (MAC). MAC IS A CYTOLYTIC MACROMOLECULAR PORE THAT CAN INSERT INTO HOST CELL MEMBRANES UNDER PATHOLOGICAL CONDITIONS. EXTENSIVE EVIDENCE OBTAINED FROM OTHERS AND US INDICATES THAT THE COMPLEMENT (C) SYSTEM, IN PARTICULAR MAC, MAY PARTICIPATE IN MEDIATING ENDOTHELIAL DAMAGE, ACTIVATING THE COAGULATION PATHWAY AND PLATELETS, AND CAUSING MULTIPLE ORGAN DAMAGE LEADING TO SEVERE COVID-19. HOWEVER, THE CAUSATIVE ROLES OF C AND MAC IN SEVERE COVID-19 HAVE NOT BEEN EXPERIMENTALLY INVESTIGATED. THE PROPOSED STUDIES WILL UTILIZE OUR NEWLY DEVELOPED STATE-OF-THE-ART TOOLS TO BLOCK OR MODIFY THE C ACTIVATION PRODUCTS TO INVESTIGATE THE ROLE OF C IN ENDOTHELIAL CELL DAMAGE, PLATELET ACTIVATION, AND THROMBOSIS FORMATION SEEN IN SEVERE COVID-19, INCLUDING THERAPEUTIC PARADIGMS. TO ADDRESS OUR NEEDS, WE HAVE ESTABLISHED AND CHARACTERIZED AN ANIMAL MODEL OF SEVERE COVID- 19 USING SARS-COV-2-INFECTED K18-HACE2 MICE. THE MICE DEVELOP ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS), PROGRESSIVE WEIGHT LOSS, AND MORTALITY AT 7 DAYS THAT IS ASSOCIATED WITH SEVERE INTERSTITIAL INFLAMMATION, PERIVASCULAR INFLAMMATION, PLATELET ACTIVATION, AND THROMBOSIS IN THE LUNGS. WE ALSO OBSERVE (I) ENDOTHELIAL CELL (EC) DYSFUNCTION OF THE ALVEOLAR SEPTA; (II) INCREASED VASCULAR PERMEABILITY ASSOCIATED WITH THE EXTENSIVE ACTIVATION OF IMMUNE CELLS (E.G., LUNG MACROPHAGE CELLS); AND (III) INCREASED C3 AND MAC DEPOSITION IN PULMONARY VASCULATURE. IN ADDITION, SINGLE-CELL RNASEQ SHOWS C ACTIVATION AND COAGULATION IN THE LUNGS OF THIS SEVERE COVID-19 MODEL. THESE RESULTS HAVE PROMPTED US TO HYPOTHESIZE THAT THE C IN GENERAL, AND MAC IN PARTICULAR, SIGNIFICANTLY CONTRIBUTE TO THE EC DAMAGE, PLATELET ACTIVATION, AND THROMBOSIS FORMATION SEEN IN SEVERE CASES OF COVID-19. AIM 1 WILL INVESTIGATE WHETHER THE INHIBITION OF C ACTIVATION AND MAC FORMATION WILL REDUCE EC DAMAGE AND PLATELET AND COAGULATION PATHWAY ACTIVATION IN SARS-COV-2-INFECTED K18 MICE. AIM 2 WILL TEST THE HYPOTHESIS THAT THE RESTRICTION OF MAC FORMATION WILL PROTECT AGAINST EC DAMAGE AND ACTIVATION OF THE MYELOID CELLS, LEADING TO REDUCED PLATELET AND COAGULATION ACTIVATION IN SARS-COV-2-INFECTED K18 MICE. AIM 3 WILL INVESTIGATE THE ROLE OF C IN THE PATHOGENESIS OF SAR-COV-2 INFECTION IN A CLINICALLY RELEVANT PARADIGM AND EVALUATE SITE-TARGETED C INHIBITION AS A TREATMENT FOR COVID-19. HELP US BETTER UNDERSTAND THE ROLE OF C ACTIVATION AND THE MAC IN PATHOGENESIS OF SEVERE COVID-19, OPEN A NEW AVENUE TO PREVENT AND TREAT COVID-19, AND FOSTER THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES INVOLVING MODULATION OF THE C SYSTEM.

CANDIDA MEDIATED PROTECTION AGAINST POLYMICROBIAL SEPSIS

REGULATION OF OCULAR ANGIOGENESIS BY MICRORNAS

NON-INFERIORITY TRIAL OF A THERAPEUTIC VACCINE AGAINST CHAGAS DISEASE IN NATURALLY-INFECTED RHESUS MACAQUES - PROJECT SUMMARY NON-INFERIORITY TRIAL OF A THERAPEUTIC VACCINE AGAINST CHAGAS DISEASE IN NATURALLY- INFECTED RHESUS MACAQUES CHAGAS DISEASE IS A MAJOR VECTOR BORNE PARASITIC DISEASE CAUSE BY THE PROTOZOAN PARASITE TRYPANOSOMA CRUZI, WITH OVER 6 MILLION CASES IN THE AMERICAS. CHRONIC CHAGASIC CARDIOMYOPATHY (CCC) IS THE MOST COMMON AND LIFE-THREATHENING MANIFESTATION OF CHAGAS DISEASE. THERE IS A CRITICAL NEED TO DEVELOP NEW TREATMENTS FOR CHAGASIC PATIENTS, AND VACCINES WOULD REPRESENT A VERY COST-EFFECTIVE ALTERNATIVE TO DRUG THERAPY. PREVENTIVE AND THERAPEUTIC VACCINES HAVE SHOWN PROMISE IN MOUSE AND DOG MODELS, IN PARTICULAR WITH VACCINES BASED ON TSA-1 AND TC24 PARASITE ANTIGENS. THEREFORE, OUR LONG-TERM GOAL IS TO DEVELOP A HUMAN VACCINE, TO IMPROVE THE PREVENTION AND CONTROL OF CHAGAS DISEASE, AND WE HAVE ESTABLISHED A FIRST PUBLIC-PRIVATE CONSORTIUM TO REACH THIS GOAL. THE OVERALL OBJECTIVE OF THE PROJECT IS TO EVALUATE THE SAFETY AND EFFICACY OF A THERAPEUTIC VACCINE AGAINST T. CRUZI IN NON-HUMAN PRIMATES BY PERFORMING A NON- INFERIORITY TRIAL IN NATURALLY INFECTED RHESUS MACAQUES. CHAGASIC MACAQUES WILL BE RANDOMLY ASSIGNED TO TREATMENTS BASED ON (A) OUR THERAPEUTIC VACCINE ALONE, (B) THERAPEUTIC VACCINATION PLUS SUBPATENT BENZNIDAZOLE (BZN) TREATMENT, FOR A NON- INFERIORITY COMPARISON WITH (C) THE STANDARD BZN DRUG TREATMENT (COMPARATOR ARM). WE WILL USE BLOOD PARASITIC LOAD MEASURED BY QPCR, IMMEDIATELY (MONTH 3) AND 10 MONTHS AFTER TREATMENT AS A PRIMARY EFFICACY OUTCOME, AS IN SEVERAL CURRENT CLINICAL TRIALS. WE WILL TEST THE HYPOTHESIS THAT THERAPEUTIC VACCINATION (ALONE OR COMBINED WITH BZN) IS NON- INFERIOR TO CONVENTIONAL BZN TREATMENT, IMMEDIATELY AND 10 MONTHS AFTER TREATMENT. WE WILL ALSO MONITOR CARDIAC FUNCTION THROUGH ELECTROCARDIOGRAPHIC AND ECHOGRAPHIC RECORDINGS AS A SECONDARY OUTCOME, TO TEST THE HYPOTHESIS THAT CARDIAC FUNCTION CAN BE PRESERVED BY THERAPEUTIC VACCINATION. FINALLY, WE WILL IDENTIFY THE IMMUNE CORRELATES AND BIOMARKERS FOR DISEASE PROGRESSION AND RESPONSE TO TREATMENTS BY ASSOCIATING CANDIDATE MOLECULES WITH CARDIAC FUNCTION AND PARASITE BURDEN. UPON COMPLETION OF THESE STUDIES, WE EXPECT TO IDENTIFY A LEADING VACCINE CANDIDATE FOR FUTURE CLINICAL TRIALS, WHICH WILL LEAD TO IMPROVED PATIENT CARE AND CONTROL OF CHAGAS DISEASE.

DIAGNOSTIC INNOVATIONS FOR PEDIATRIC TUBERCULOSIS IN BOLIVIA - PEDIATRIC TUBERCULOSIS (TB) CONTINUES TO POSE DIAGNOSTIC CHALLENGES IN LOW- AND MIDDLE-INCOME COUNTRIES WITH HIGH RATES OF TB DISEASE, DUE TO THE WELL-DESCRIBED IMPACT OF PAUCIBACILLARY DISEASE IN CHILDREN, AND CURRENT TB CULTURE AND POLYMERASE-CHAIN REACTION TESTS ARE OF LIMITED USEFULNESS DUE TO COST, RESTRICTED AVAILABILITY, AND POOR SENSITIVITY IN SPECIMENS AVAILABLE FROM YOUNGER CHILDREN. OUR TEAM OF EXPERTS FROM TULANE, JOHNS HOPKINS UNIVERSITY, UNIVERSIDAD PERUANA CAYETANO HEREDIA, AND ASOCIACION BENEFICA PRISMA HAVE CONFRONTED ALL OF THESE CHALLENGES THROUGH MORE THAN 25 YEARS OF COLLABORATION IN PERU AND BOLIVIA. OUR GOAL IS TO DIRECTLY ADDRESS THE CHALLENGES OF TB IN CHILDREN BY EVALUATING A NEW DIAGNOSTIC APPROACH DEVELOPED BY MPI TONY HU AT TULANE UNIVERSITY USING A CRISPR-MEDIATED TB ASSAY (CRISPR-TB) OPTIMIZED TO DETECT CIRCULATING MYCOBACTERIUM TUBERCULOSIS CELL-FREE DNA (MTB-CFDNA), AND USED TO ANALYZE CRYOPRESERVED SERUM IN PILOT STUDIES FROM ADULTS AND CHILDREN WITH PRESUMPTIVE TB, THEIR ASYMPTOMATIC HOUSEHOLD CONTACTS, AND A COHORT OF SYMPTOMATIC CHILDREN LIVING WITH HIV (CLHIV) AT HIGH RISK FOR TB. RESULTS FROM SYMPTOMATIC ADULT COHORTS YIELDED A POOLED SENSITIVITY OF 93%; SPECIFICITY OF 93%; POSITIVE PREDICTIVE VALUE OF 95%; AND NEGATIVE PREDICTIVE VALUE OF 92%. IN LIMITED PILOT STUDIES IN CLHIV CRISPR-TBD RESULTS ACCURATELY IDENTIFIED ALL CONFIRMED TB (13/13) AND MOST CHILDREN WITH UNCONFIRMED TB (80%; 52/65). WE PROPOSE TO ENROLL 200 PRESUMPTIVE TB CASES AND AN EQUAL NUMBER OF WELL CONTROL SUBJECTS IN EACH OF 2 STUDY POPULATIONS (TEST POPULATION AND VALIDATION POPULATION) IDENTIFIED THROUGH CLINICS ASSOCIATED WITH THE “DR. MARIO ORTIZ SUAREZ” CHILDREN'S HOSPITAL IN SANTA CRUZ, BOLIVIA. WE WILL DETERMINE THE DISTRIBUTION OF CFDNA CONCENTRATIONS IN PERIPHERAL BLOOD IN A “TEST POPULATION” COMPOSED OF TWO AGE-BASED GROUPS OF CHILDREN (2 MONTHS-6 YEARS, 7-14 YEARS) WITH RESPIRATORY DISEASE GROUPED BY LIKELIHOOD OF TB BASED ON THE NIH CONSENSUS CASE DEFINITIONS (CONFIRMED TB, UNCONFIRMED TB, AND UNLIKELY TB) AND IN AGE-MATCHED CONTROLS GROUPED BY PRESENCE OF LATENT TB INFECTION (LTBI), WITH CFDNA MEASURED SERIALLY IN TIME AMONG TB CASES RECEIVING ANTIBIOTIC THERAPY. WE WILL ALSO VALIDATE STANDARD RANGES OF QUANTITATIVE CFDNA ESTABLISHED FOR CLINICAL SUBGROUPS OF CHILDREN WITH TB DISEASE OR LTBI IN AN INDEPENDENT VALIDATION COHORT. AN ADDITIONAL AIM WILL DETERMINE THE CORRELATION BETWEEN QUANTITATIVE CFDNA AND QUANTITATIVE IMAGING-BASED TB SCORES BASED ON EVIDENCE OF DISEASE IN THE LUNG, THE PRIMARY TARGET ORGAN IN TB DISEASE, BY (1) CHEST RADIOGRAPH, MEASURED BY COMPUTER-AIDED ANALYSIS USING THE CAD4TB V7 SYSTEM, AND BY (2) LUNG ULTRASOUND, PERFORMED WITH A PORTABLE/LOW-COST PROBE ASSISTED BY MACHINE LEARNING ALGORITHMS FOR AUTOMATIC INTERPRETATION. THESE BIOMARKERS WILL BE TESTED AS POTENTIAL COFACTORS THAT MAY BE COMBINED WITH CFDNA LEVELS IN PERIPHERAL BLOOD, TO IMPROVE THE DETECTION OF TB DISEASE IN CHILDREN. THE RESULTS OF THIS STUDY WILL BE THE FIRST STEP IN A PROCESS TO FIND A PATH TO ALLOW DETECTION OF THE MANY “UNCONFIRMED” TB CASES AND IDEALLY MAKE THE DIAGNOSIS OF PEDIATRIC TB IN REACH FOR LOW RESOURCE SETTINGS WHERE IT IS SO CRITICALLY NEEDED.

IMPACT OF HIV/SIV INFECTION ON PANETH AND INTESTINAL STEM CELL INTERACTION

DIGITAL NANOPLASMONIC QUANTIFICATION OF TUMOR-DERIVED EXTRACELLULAR VESICLES IN PLASMA MICROSAMPLES

VU-MOZAMBIQUE COLLABORATIVE RESEARCH ETHICS EDUCATION PROGRAM

TULANE-XAVIER MINORITY TRAINING IN INTERNATIONAL HEALTH

A NOVEL RESEARCH INFRASTRUCTURE ENABLING LIFE-COURSE STUDIES OF HEALTHY AGING

INTERPLAY BETWEEN 14-3-3GAMMA AND MDMX IN REGULATING THE P53 PATHWAY

ANGIOPOIETIN-2 SIGNALING TARGETED THERAPEUTICS FOR ARTERIOVENOUS MALFORMATIONS - PROJECT SUMMARY HEREDITARY HEMORRHAGIC TELANGIECTASIA (HHT) IS A VASCULAR GENETIC DISORDER CHARACTERIZED BY ENLARGED, LEAKY SMALL VESSELS (TELANGIECTASIAS) AND INAPPROPRIATE, FRAGILE CONNECTIONS BETWEEN ARTERIES AND VEINS CALLED ARTERIOVENOUS MALFORMATIONS (AVMS). HHT PATIENTS DEVELOP AVMS IN A SPECIFIC SUBSET OF MAJOR ORGANS, WHICH CAN RUPTURE CAUSING SEVERE HEMORRHAGE AND ANEMIA, AS WELL AS ANEURYSMS, STROKE AND EVEN DEATH. CAUSES OF HHT ARE LINKED TO THE TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING PATHWAY, WITH OVER 90% OF PATIENTS EXHIBITING HETEROZYGOUS LOSS-OF-FUNCTION MUTATIONS IN THE ACTIVIN RECEPTOR-LIKE KINASE 1 (ACVRL1/ALK1) OR ENDOGLIN (ENG) CO-RECEPTORS, OR THE DOWNSTREAM TRANSCRIPTION FACTOR, SMAD-RELATED PROTEIN 4 (SMAD4). DESPITE KNOWING THE CAUSATIVE MUTATIONS, A SIGNIFICANT GAP REMAINS IN OUR UNDERSTANDING OF THE IMMEDIATE TGF-BETA DOWNSTREAM SIGNALING COMPONENTS RESPONSIBLE FOR HHT PATHOLOGIES. FURTHERMORE, NO CURE IS CURRENTLY AVAILABLE FOR HHT. WE HAVE FOUND THAT DIRECTLY DOWNSTREAM OF ALK1, ENG AND SMAD4 LOSS-OF-FUNCTION, THE ANGIOGENIC FACTOR AND ANTAGONISTIC LIGAND TO THE TIE2 RECEPTOR, ANGIOPOIETIN-2 (ANGPT2/ANG2), IS TRANSCRIPTIONALLY ELEVATED TO TRIGGER HHT VASCULAR PATHOLOGIES; ANG2 NEUTRALIZATION EFFICIENTLY REDUCED AVM PATHOLOGY IN TWO HHT MOUSE MODELS. IN ADDITION, LOSS OF ALK1 SIGNALING LED TO A ROBUST AND CONSISTENT TRANSCRIPTIONAL AND SIGNALING INHIBITION OF TEK/TIE2. TOGETHER, THESE OBSERVATIONS STRONGLY SUPPORT THE WORKING MODEL THAT ANG2 IS ELEVATED AND TIE2 SIGNALING IS REPRESSED DURING THE PATHOGENIC PROCESS OF AVM DEVELOPMENT IN HHT. MOREOVER, THE METABOLIC PI3K/AKT/MTOR PATHWAY IS DEREGULATED IN HHT TO SUSTAIN AVM DEVELOPMENT, HOWEVER ITS CONNECTION TO ANG2 PRO-AVM SIGNALS IS UNCLEAR. USING MOUSE MODELS OF THE DIFFERENT GENETIC FORMS OF HHT AND PRIMARY ENDOTHELIAL CELLS (ECS), WE HAVE OBTAINED STRONG PILOT DATA INDICATING THAT ANG2-TIE2 DEREGULATIONS, WORKING IN CONCERT WITH ENHANCED FOXO1 TRANSCRIPTIONAL ACTIVITY AND SEQUENTIAL OVERACTIVATION OF THE MTOR PATHWAY VIA CXCR4 CHEMOKINE SIGNALING, DRIVE HHT PHENOTYPES. THE CENTRAL OBJECTIVE OF THIS APPLICATION IS TO ANSWER 3 FUNDAMENTAL QUESTIONS: 1) HOW DOES ANG2 ELEVATION AND TIE2 SIGNALING REPRESSION DIRECT AVM PATHOGENESIS, 2) WHAT IS THE MECHANISM BY WHICH MTOR OVERACTIVATION IS CONTROLLED BY ANG2-TIE2 SIGNALING DEREGULATIONS AND 3) ARE APPROACHES TARGETING ANG2 AND THE NEWLY IDENTIFIED ANG2-REGULATED PATHOGENIC SIGNALING CASCADE UNIVERSALLY EFFECTIVE IN TREATING HHT VASCULAR PATHOLOGIES? WE WILL ADDRESS THESE TOPICS BY TESTING THE FOLLOWING SPECIFIC AIMS: 1) ASSESS ANG2 AND TIE2 SIGNALING DEREGULATIONS IN THE MOST PHYSIOLOGICALLY AFFECTED ORGANS AND DETERMINE IF ANG2 INHIBITION UNIVERSALLY BLOCKS VASCULAR PATHOLOGIES IN HHT MOUSE MODELS; 2) DETERMINE FOXO1 CONTRIBUTIONS TO ANG2 AND CXCR4 ELEVATIONS AND HHT VASCULAR PATHOLOGIES; AND 3) TEST IF TGF-BETA-TIE2- FOXO1-MEDIATED CXCR4 ELEVATIONS DRIVE MTOR ACTIVATION. THESE STUDIES WILL ADVANCE OUR MECHANISTIC UNDERSTANDING OF AVM PATHOGENESIS AND UNCOVER NEW POTENTIAL TARGETS FOR TREATING OF HHT.

MOLECULAR MO SULFIDE CLUSTERS FOR H2-EVOLUTION: SURFACE IMMOBILIZATION AND WATER SOLUBILITY,COMPOSITION-FUNCTION RELATIONSHIPS, AND PROBES OF MECHANISM

STRESS PLASTICITY OF CRH NEURONS

IMPACT OF CHRONIC PRENATAL THC EXPOSURE ON SIV-ASSOCIATED INFLAMMATION AND IMPAIRMENTS IN PLACENTAL AND FETAL DEVELOPMENT - PROJECT SUMMARY/ABSTRACT HIV REMAINS A MAJOR PUBLIC HEALTH CONCERN, PARTICULARLY AMONG PREGNANT INDIVIDUALS. EVEN WITH SUPPRESSIVE ANTIRETROVIRAL THERAPY (ART), PREGNANT PEOPLE WITH HIV (PWH) HAVE SIGNIFICANTLY GREATER RISK OF MATERNAL MORTALITY AND ADVERSE PREGNANCY OUTCOMES AS COMPARED TO PREGNANT PEOPLE WITHOUT HIV. THIS RISK HAS BEEN LINKED WITH PLACENTAL INFLAMMATION AND VASCULAR MALPERFUSION, WHICH CAN LEAD TO PLACENTAL DYSFUNCTION AND CAUSE ADVERSE FETAL DEVELOPMENT. ADDITIONALLY, IN UTERO EXPOSURE TO MATERNAL INFLAMMATION, A HALLMARK OF HIV INFECTION THAT PERSISTS DESPITE ART, CONTRIBUTES TO POOR FETAL AND INFANT IMMUNITY AND INFLUENCES SHORT- AND LONG-TERM OFFSPRING HEALTH. THUS, DEFINING THE UNDERLYING PATHWAYS AND EFFECTS OF MATERNAL AND PLACENTAL INFLAMMATION AND PLACENTAL DYSFUNCTION TO INFORM DEVELOPMENT OF THERAPIES TO MITIGATE ADVERSE PREGNANCY OUTCOMES IN PWH IS CRUCIAL. CANNABIS IS THE MOST COMMONLY USED FEDERALLY ILLICIT SUBSTANCE AMONG PREGNANT PWH AND, INDEPENDENT OF CONCURRENT HIV INFECTION, IS ASSOCIATED WITH INCREASED PREGNANCY COMPLICATIONS (E.G., PRETERM BIRTH, STILLBIRTH) AND NEGATIVE IMPACTS ON OFFSPRING HEALTH AND DEVELOPMENT. ALTHOUGH THE CURRENT LITERATURE SUGGESTS A LIKELY ADDITIVE ADVERSE EFFECT OF CANNABIS USE ON PREGNANCY AND FETAL OUTCOMES AMONG PWH, THERE IS INSUFFICIENT EVIDENCE TO VALIDATE THIS THEORY. THIS GAP IN KNOWLEDGE IS DUE IN PART TO 1) THE PRACTICAL AND ETHICAL CONSTRAINTS OF CONDUCTING IN VIVO OR EX VIVO STUDIES AMONG PREGNANT PWH TO EXAMINE THE BIOLOGICAL MECHANISMS BY WHICH THC IMPACTS PREGNANCY OUTCOMES; 2) THE INABILITY TO SERIALLY SAMPLE CRITICAL TISSUE SITES (E.G., LYMPH NODES, AMNIOTIC FLUID) IN PREGNANT PWH; AND 3) THE PAUCITY OF RELEVANT PRECLINICAL MODELS THAT HAVE STRONG TRANSLATION TO HUMAN HEALTH. OUR CENTRAL HYPOTHESIS IS THAT CHRONIC PRENATAL THC EXPOSURE IN ART-TREATED SIV-INFECTED RHESUS MACAQUES WILL RESULT IN DISRUPTIONS IN VIRAL CONTROL, HAVE AN ADDITIVE NEGATIVE IMPACT ON PLACENTAL INSUFFICIENCY AND VASCULAR DYSREGULATION, AND RESULT IN ADVERSE FETAL DEVELOPMENT THAT ARE ALL PRIMARILY MEDIATED BY IMMUNE DYSFUNCTION. TO TEST THIS HYPOTHESIS, WE WILL LEVERAGE OUR TRANSLATIONAL, FIRST-IN-KIND RHESUS MACAQUE MODEL OF CHRONIC (I.E., DAILY) EDIBLE THC USE AND ART-TREATED SIV INFECTION, LONGITUDINAL BIOLOGICAL SAMPLING AND ADVANCED IN VIVO IMAGING. OUR COMPREHENSIVE ASSESSMENTS AT THE MATERNAL, PLACENTAL, AND FETAL LEVELS AND IN-DEPTH DATA ANALYSIS STRATEGY WILL PROVIDE MUCH NEEDED INFORMATION OF THE IMPACT OF THC DURING ART-TREATED SIV INFECTION ON MATERNAL SIV- ASSOCIATED IMMUNOPATHOLOGY AND VIRAL DYNAMICS (AIM 1), PLACENTAL DEVELOPMENT AND FUNCTION (AIM 2), AND FETAL DEVELOPMENT (AIM 3) THAT WOULD BE IMPOSSIBLE TO STUDY IN HUMANS. THIS STUDY WILL ALSO GENERATE A UNIQUE, COMPREHENSIVE RHESUS MACAQUE TISSUE BANK OF BIOLOGICAL SAMPLES AVAILABLE TO ALL RESEARCHERS FOR FUTURE STUDIES. WITH THE CONTINUED AND CONCERNING RISE IN PRENATAL CANNABIS USE BY PWH, THIS IS A NECESSARY AND IMPACTFUL FIRST STEP TO GENERATE CRITICALLY NEEDED INFORMATION ON THE EFFECTS OF COMBINED THC EXPOSURE, ART TREATMENT, AND SIV INFECTION ON MATERNAL, PLACENTAL, AND FETAL OUTCOMES TO GUIDE HEALTHCARE PROVIDERS ON PREGNANCY MANAGEMENT TO IMPROVE FUTURE MATERNAL AND OFFSPRING HEALTH.

TRAUMA-INFORMED APPROACHES TO IMPROVE SCHOOL SAFETY

DEVELOPMENT OF IMPROVED SEROLOGICAL DIAGNOSTIC AND PARASITE GENOTYPING TOOLS FOR CONGENITAL CHAGAS DISEASE

INTESTINE FXR ACTIVATION BY LGG-DERIVED NANOPARTICLES IN ALCOHOL-ASSOCIATED LIVER DISEASE - NUMEROUS STUDIES HAVE REPORTED THE EFFICACY OF PROBIOTICS FOR ALCOHOL ASSOCIATED LIVER DISEASE (ALD). THIS REFLECTS A STRONG INTEREST AMONG THE SCIENTIFIC AND MEDICAL COMMUNITIES IN IDENTIFYING ALTERNATIVE OR ADJUNCTIVE APPROACHES FOR ALD, FOR WHICH THERE IS NO CURRENT EFFECTIVE OR WIDELY ACCEPTED THERAPEUTIC OPTION. HOWEVER, IN DEPTH MOLECULAR KNOWLEDGE ON HOW PROBIOTICS RENDER THEIR EFFECTS IS LACKING. PATIENTS WITH ALD OFTEN EXHIBIT MANIFESTATIONS OF CHOLESTASIS, A LIVER PATHOLOGY DEFINED BY ACCUMULATION OF HEPATIC BILE ACIDS (BAS), WHICH ARE TOXIC AND ARE AN IMPORTANT CAUSATIVE FACTOR IN HEPATOCYTE DEATH AND LIVER INJURY IN ALD. EXCESS HEPATIC BA CONCENTRATION IS PARTIALLY A RESULT OF INCREASED BA DE NOVO SYNTHESIS. WE HAVE IDENTIFIED A MIRNA (MIR194) THAT IS OVEREXPRESSED IN THE INTESTINAL EPITHELIAL CELLS IN MICE FED ALCOHOL. MMIR194 SUPPRESSES A NUCLEAR RECEPTOR FXR THAT IS ACTIVATED BY BAS AND REGULATES INTESTINE-DERIVED HORMONE, FGF15, EXPRESSION, WHICH PLAYS A MAJOR ROLE IN MAINTAINING HEPATIC BA HOMEOSTASIS BY SUPPRESSING BA SYNTHESIS VIA DOWN-REGULATION OF CYP7A1. WHILE THE BA ACTIVATION OF FXR IS WELL-STUDIED, HOW FXR IS REGULATED TRANSCRIPTIONALLY IS LESS CLEAR. OUR PRELIMINARY DATA SHOWED THAT PROBIOTIC LACTOBACILLUS RHAMNOSUS GG-DERIVED NANOPARTICLES (LDNPS) ADMINISTRATION REDUCED INTESTINAL MIR194 AND INCREASED FXR AND FGF15 EXPRESSION, AND DECREASED HEPATIC BAS AND FATTY LIVER IN MICE WITH ALD. WE HYPOTHESIZE THAT ALCOHOL SUPPRESSES BOTH THE TRANSCRIPTIONAL EXPRESSION AND LIGAND-MEDIATED ACTIVATION OF FXR IN THE INTESTINE THROUGH UPREGULATING MIR194 AND DISTURBING GUT-MICROBIOME-BA TRANSFORMATION, RESPECTIVELY, WHICH LEAD TO THE INCREASES IN HEPATIC DE NOVO BA SYNTHESIS, LIPOGENESIS AND ALD AND THAT LDNP SUPPLEMENTATION CAN DIMINISH ALCOHOL-INDUCED INCREASES IN BA SYNTHESIS AND LIPOGENESIS AND ATTENUATE ALD THROUGH SUPPRESSING INTESTINAL MIR194 EXPRESSION AND REGULATING GUT MICROBIOME BA TRANSFORMATION. THE FOLLOWING SPECIFIC AIMS WILL BE PURSUED TO TEST THIS HYPOTHESIS: AIM 1. DETERMINE THE ROLE OF INTESTINAL MIR194 IN THE ALCOHOL-INDUCED DYSREGULATION OF LIVER BA SYNTHESIS AND LIPOGENESIS. AIM 2. DETERMINE THE ROLE OF LDNPS IN THE REGULATION OF INTESTINAL MIR194-FXR-FGF15 SIGNALING IN ALD. AIM 3. DETERMINE WHETHER LDNP TREATMENT ALTERS GUT MICROBIOTA AND BA PROFILE THAT CONTRIBUTE TO FXR ACTIVATION IN ALD. AIM 4. EVALUATE THE INTESTINAL MIR194 AND FXR ACTIVITY IN PATIENTS WITH AH. IN SUMMARY, THE PROPOSED STUDY REPRESENTS THE FIRST MOLECULAR STUDY ON HOW INTESTINAL MIRNA REGULATES LIVER BA HOMEOSTASIS AND HOW A PROBIOTIC PRODUCT TARGETS INTESTINAL MIRNA194-FXR-FGF15 SINGLING IN ALD. THE RESULTS OBTAINED FROM THIS STUDY MAY LEAD TO IMPROVED MANAGEMENT OF ALD.

MITOCHONDRIAL STRUCTURE AND FUNCTION IN CEREBRAL ARTERIES DURING DIABETES AND ISCHEMIC STRESS

PROMOTING COLOR BRAVE CONVERSATIONS IN FAMILIES: A PUBLIC HEALTH STRATEGY TO ADVANCE RACIAL EQUITY - PROJECT SUMMARY/ABSTRACT RESEARCH ON RACIAL SOCIALIZATION PRACTICES HAS BEEN PRIMARILY CONDUCTED IN FAMILIES OF COLOR, AND PREVAILING MODELS HAVE BEEN DEVELOPED AROUND RACIAL IDENTITY DEVELOPMENT AMONG NON-WHITE CHILDREN. THERE IS A PAUCITY OF RESEARCH ON HOW WE CAN LEVERAGE RACIAL SOCIALIZATION PRACTICES IN FAMILIES, AND IN PARTICULAR WHITE FAMILIES, TO PROMOTE CRITICAL UNDERSTANDINGS ABOUT RACE, RACISM, AND ANTI-RACISM AMONG CHILDREN—AS A MEANS TO REDUCE RACIAL BIAS, ENCOURAGE PROSOCIAL BEHAVIORS AND RACIAL EMPATHY, AND IMPROVE SOCIAL/EMOTIONAL WELL-BEING AMONG CHILDREN, INCLUDING POSITIVE PEER RELATIONSHIPS AND INTERACTIONS. THERE IS LIMITED SCIENTIFIC RESEARCH ON THE ROLE THAT PARENTS CAN HAVE IN PREVENTING RACISM AND DEVELOPING ANTI-RACIST CHILDREN. THIS PROJECT IS INNOVATIVE BY SHIFTING THE TYPICAL PARADIGM OF INTERVENING ON RACISM, WHICH HAS MOSTLY BEEN ON HOW FAMILIES OF COLOR BUFFER THEIR CHILDREN FROM RACIST EXPERIENCES; FOR INSTANCE, THROUGH RACIAL SOCIALIZATION PRACTICES TO INSTILL POSITIVE SELF-CONCEPT, AND PREPARATION FOR RACIAL DISCRIMINATION. WE POSIT THAT AN ALTERNATIVE APPROACH— ONE THAT IS GROUNDED IN INTERVENING ON FAMILIES TO PREVENT THE PERPETRATION OF RACISM—IS WARRANTED. WE PROPOSE RECRUITING A NATIONAL SAMPLE OF PARENTS AND THEIR K-2ND GRADE CHILDREN. QUALITATIVE DATA FROM FOCUS GROUPS WILL ENHANCE THE SCIENTIFIC BASIS FOR OUR INTERVENTION PROGRAM—A MULTI-MODULE APP THAT GUIDES PARENTS IN HAVING “COLOR BRAVE” (AS OPPOSED TO COLORBLIND) CONVERSATIONS WITH THEIR CHILDREN. WE TEST THE INTERVENTION USING A RIGOROUS RANDOMIZED ATTENTION/WAIT-LIST CONTROLLED TRIAL DESIGN. THE DESIGN OF THE INTERVENTION IS BASED ON RESEARCH INDICATING THAT AMONG CHILDREN, POSITIVE INTERGROUP CONTACT WITH OUTGROUP MEMBERS, INCLUDING VICARIOUS ENGAGEMENT, CAN PREVENT OR REDUCE ANTI-OUTGROUP BIAS, IN PARTICULAR, WHEN CONTACT IS BASED ON COMMON GOALS, COOPERATION RATHER THAN COMPETITION, AND SUPPORTED BY EXTERNAL AUTHORITIES. WE COLLECT A BROAD RANGE OF MEASURES USING MIXED-METHODS, THROUGH ONE-ONE-ONE INTERVIEWS WITH PARENTS AND CHILDREN AND DYADIC INTERVIEWS. ADAPTING THE INTERVENTION FOR DELIVERY VIA A DOWNLOADABLE APP FACILITATES SCALABILITY RESULTING IN GREATER POTENTIAL TO HAVE WIDE SOCIAL IMPACT. THIS WORK EXPANDS THE SCOPE OF THE SCIENCE ON HOW RACIAL SOCIALIZATION PRACTICES CAN INCREASE RACIAL EMPATHY, INCLUDING AMONG WHITE CHILDREN. THIS PROJECT AIMS TO REDUCE THE PERPETRATION OF RACISM, WHICH IS A DOCUMENTED SOCIETAL AND HEALTH HAZARD EXPERIENCED BY CHILDREN OF COLOR. IT ALSO AIMS TO ENHANCE SUPPORT FOR ANTI-RACIST PRACTICES AND POLICIES AIMED AT ACHIEVING HEALTH AND SOCIAL EQUITY. THE EVENTUAL GOAL OF THIS RESEARCH IS TO CONTRIBUTE TO THE CULTIVATION AND MOBILIZATION OF ANTI-RACIST PARTNERS, AND TO HELP DEVELOP A CONCERTED EFFORT TO DISMANTLE RACISM AND RACIST STRUCTURES. THIS INTERVENTION MAY BE PART OF A BROADER, COMPREHENSIVE INTERGENERATIONAL AND SOCIETAL EFFORT TO ELIMINATE RACISM AND ADDRESS ITS CONSEQUENCES.

TESTING NOVEL MICROBICIDE CANDIDATES IN SUSTAINED RELEASE FORMULATIONS

INVESTIGATING THE ROLE AND THE THERAPEUTIC POTENTIAL OF PERLECAN IN EXPERIMENTAL VASCULAR DEMENTIA - ABSTRACT VASCULAR DEMENTIA (VAD) IS THE SECOND LEADING CAUSE OF DEMENTIA BEHIND ALZHEIMER’S DISEASE, BUT ITS PATHOGENESIS IS POORLY UNDERSTOOD. CEREBRAL BLOOD VESSELS UNDERGO AGE-RELATED DEGENERATIVE CHANGES RESULTING IN BLOOD-BRAIN BARRIER (BBB) DISRUPTION AND HYPOPERFUSION, LEADING TO NEURODEGENERATION AND COGNITIVE DECLINE. PERICYTES (PC) ARE KEY COMPONENTS OF THE BBB WHOSE BEHAVIOR IS REGULATED BY EXTRACELLULAR MATRIX COMPONENTS SUCH AS THE HEPARAN SULFATE PROTEOGLYCAN, PERLECAN. WE HYPOTHESIZE THAT AGE-RELATED OVEREXPRESSION OF CEREBROVASCULAR PERLECAN, COUPLED WITH REDUCED PROTEOLYTIC ACTIVITY OF THE CYSTEINE PROTEASE CATHEPSIN B, WHICH PROCESSES PERLECAN INTO A NEUROPROTECTIVE LAMININ GLOBULAR DOMAIN 3 (LG3) PEPTIDE, PLAYS A CENTRAL PATHOLOGICAL ROLE IN VAD, BY REDUCING PC COVERAGE OF BLOOD VESSELS, LEADING TO DIMINISHED BBB INTEGRITY. FIRST, CEREBRAL BLOOD VESSELS IN AGED MICE SHOW INCREASED PERLECAN EXPRESSION THAT CORRELATES WITH BBB DISRUPTION AND REDUCED PC COVERAGE. SECOND, YOUNG MICE EXPOSED TO CHRONIC MILD HYPOXIA (CMH; 8% O2 FOR 4 DAYS) DISPLAY SIMILAR INCREASED PERLECAN EXPRESSION THAT CORRELATES CLOSELY WITH REDUCED PC COVERAGE AND BBB DISRUPTION. THIRD, PERLECAN INHIBITS PC PROLIFERATION AND MIGRATION IN VITRO, IN KEEPING WITH SIMILAR EFFECTS DESCRIBED FOR SMOOTH MUSCLE CELLS, IN WHICH INHIBITORY EFFECTS ARE LOST WITH REMOVAL OF HEPARAN SULFATE (HS) SIDE CHAINS. FOURTH, CEREBROVASCULAR PERLECAN EXPRESSION CHRONICALLY INCREASED IN THE BRAIN AFTER ISCHEMIC STROKE. FIFTH, PERLECAN IS INCREASED IN CONDITIONS WITH ABNORMAL BRAIN VASCULATURE INCLUDING ARTERIOVENOUS MALFORMATION. SIXTH, THE ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) DEFICIENT MOUSE MODEL OF VAD DISPLAY REDUCED PC COVERAGE AND BBB DAMAGE; OUR PRELIMINARY DATA SHOW THESE MICE HAVE INCREASED BRAIN PERLECAN AND REDUCED CATHEPSIN B, WITH PROGRESSION TO VAD. SEVENTH, OUR PRELIMINARY DATA SHOWS CATHEPSIN B KO MICE EXPRESS SIGNIFICANTLY MORE BRAIN PERLECAN AND LESS PC COVERAGE, SUPPORTING THE ROLE OF CATHEPSIN B IN PERLECAN PROCESSING AND PERLECAN’S ROLE IN PC COVERAGE. THEREFORE, WE HYPOTHESIZE THAT THE FULLY INTACT PERLECAN MOLECULE AND ITS LG3 FRAGMENT, AS REGULATED BY CATHEPSIN B PROTEOLYSIS, HAVE OPPOSING DELETERIOUS AND BENEFICIAL EFFECTS, RESPECTIVELY, ON VASCULAR HEALTH AND INTEGRITY IN CEREBROVASCULAR DISEASES SUCH AS VAD. SPECIFICALLY, WE HYPOTHESIZE THAT (I) IN RESPONSE TO AGING +/- HYPOXIA OR DIMINISHED ENOS, UPREGULATION OF CEREBROVASCULAR PERLECAN IN ASSOCIATION WITH DECREASED CATHEPSIN B ACTIVITY, AND THEREBY LESS LG3, LEADS TO REDUCED PC COVERAGE AND BBB DISRUPTION, CULMINATING IN NEURODEGENERATION AND COGNITIVE DECLINE, AND (II) PERLECAN LG3 ‘REPLACEMENT THERAPY’ MAY PREVENT OR MITIGATE THIS PROCESS. TO TEST THIS HYPOTHESIS WE PROPOSE TO: 1, DETERMINE HOW AGE AND SEX INFLUENCE LEVELS OF FULL-LENGTH PERLECAN (AND ITS HS MODIFICATION), THE LG3 FRAGMENT, AND CATHEPSIN B IN THE ENOS- DEFICIENT AND CMH MOUSE MODELS OF SPONTANEOUS VAD, 2, DEFINE THE MOLECULAR BASIS OF THE POSITIVE (INTEGRIN BINDING SITES) AND NEGATIVE (HS SIDE CHAINS) EFFECTS OF PERLECAN AND LG3 ON PC BEHAVIOR, AND 3, DETERMINE THE THERAPEUTIC POTENTIAL OF LG3 IN THE ENOS-DEFICIENT AND CMH MOUSE MODELS OF SPONTANEOUS VAD.

A SPHINGOMYELIN HYDROLASE REGULATES THE LATE STAGES OF HIV ASSEMBLY AND BUDDING - ABSTRACT HIV ASSEMBLY OCCURS AT THE PLASMA MEMBRANE WITHIN SPECIALIZED MEMBRANE MICRODOMAINS (COMMONLY KNOWN AS LIPID RATS) THAT EXHIBIT REDUCED LATERAL MOBILITY OWING TO AN ENRICHMENT OF SATURATED LIPIDS INCLUDING PIP2, CERAMIDE, SPHINGOMYELIN, AND STEROLS. THE HIV-1 GAG PRECURSOR PROTEIN TARGETS TO THE INNER LEAFLET OF THESE PLASMA MEMBRANE MICRODOMAINS AND REGULATES ESSENTIAL EVENTS REQUIRED FOR VIRION ASSEMBLY AND BUDDING. HOWEVER, THE MECHANISMS BY WHICH GAG REGULATES THE FORMATION OF THESE MICRODOMAINS AND THE ROLE FOR THESE MICRODOMAINS IN VIRAL ASSEMBLY IS CURRENTLY UNKNOWN. HERE WE PROVIDE THE FIRST EVIDENCE THAT GAG CO-LOCALIZES WITH THE SPHINGOMYELIN HYDROLASE NSMASE2 (WHICH CATALYZES THE FORMATION OF CERAMIDE FROM SPHINGOMYELIN), AND THAT NSMASE2 IS A CRITICAL REGULATOR OF HIV REPLICATION. IN PRELIMINARY EXPERIMENTS WE DISCOVERED THAT THIS ENZYME IS REQUIRED FOR THE SUCCESSFUL COMPLETION OF THE LATE STAGES OF HIV ASSEMBLY AND MATURATION. PHARMACOLOGICAL INHIBITION OR GENETIC DELETION OF NSMASE2 PREVENTED THE PROCESSING OF GAG AND RESULTED IN THE PRODUCTION OF IRREGULARLY SHAPED IMMATURE NON-INFECTIOUS VIRIONS. IN HUMANIZED HIV INFECTED MICE, INHIBITION OF NSMASE2 PRODUCED A LINEAR DECREASE OF VIRAL LOADS TO BELOW DETECTABLE LIMITS IN THE MAJORITY OF ANIMALS TESTED. MORE IMPORTANTLY, ANIMALS WHO ACHIEVED VIRAL LOADS BELOW DETECTABLE LIMITS WITH TREATMENT, DID NOT EXHIBIT VIRAL REBOUND WHEN DRUG ADMINISTRATION WAS DISCONTINUED. THE FINDINGS FROM THESE STUDIES WILL INCREASE OUR BASIC UNDERSTANDING OF THE VIRAL REPLICATION CYCLE BY DESCRIBING FOR THE FIRST TIME A ROLE FOR NSMASE2 AND CERAMIDE IN HIV REPLICATION.

INNATE IMMUNE MEMORY PROMOTES NEURAL DAMAGE IN THE ART SUPPRESSED HIV INFECTED BRAIN - ABSTRACT THE WIDESPREAD USE OF ANTIRETROVIRAL THERAPY (ART) IN DEVELOPED COUNTRIES HAS MODIFIED HIV INFECTION FROM A TERMINAL ILLNESS TO WHAT IS NOW LARGELY A MANAGEABLE CHRONIC INFECTION. EVEN WHEN HIV REPLICATION IS SUPPRESSED WITH ART, PEOPLE INFECTED WITH HIV PRESENT WITH A CHRONIC INFLAMMATORY STATE THAT IS THOUGHT TO CONTRIBUTE TO THE DEVELOPMENT OF NEUROLOGIC AND PSYCHIATRIC CO-MORBID CONDITIONS. A GROWING BODY OF EVIDENCE IS IMPLICATING THE INNATE IMMUNE SYSTEM WITH SENSITIZATION OF THE BRAIN TO NEUROLOGICAL DAMAGE ASSOCIATED WITH HIV INFECTION AND OTHER NEURODEGENERATIVE CONDITIONS. THIS NON-RESOLVING INFLAMMATORY/IMMUNE RESPONSE SENSITIZES AND PRIMES THE BRAIN FOR ANY SUBSEQUENT INFLAMMATORY EVENT, AND IS THOUGHT TO BE A FORM OF INNATE IMMUNE MEMORY IN WHICH MICROGLIA ADAPT THEIR PHENOTYPE DEPENDING ON THE STIMULUS THEY ARE EXPOSED TO, AND THE FREQUENCY WITH WHICH THEY ARE EXPOSED TO THAT STIMULUS. THIS ADAPTATION IS A FORM OF INNATE IMMUNE MEMORY THAT CAN BE ASSOCIATED WITH LONG-LASTING MOLECULAR REPROGRAMMING THAT CAN EITHER ENHANCE OR SUPPRESS THE MICROGLIAL RESPONSE TO SUBSEQUENT STIMULI. THE IMPACT OF HIV INFECTION, AND ART ON MICROGLIAL REPROGRAMMING IS UNKNOWN. HERE WE HAVE IDENTIFIED THE SPHINGOMYELIN HYDROLASE NEUTRAL SPHINGOMYELINASE2 (NSMASE2) GENERATED CERAMIDE AS A CRITICAL REGULATOR OF THE INNATE IMMUNE RESPONSE TO ART SUPPRESSED HIV INFECTION.

CEREBRAL MICROVASCULAR BIOENERGETICS AND NEUROVASCULAR COUPLING

SYNAPTIC MECHANISMS OF AUDITORY INFORMATION PROCESSING

ADDICTION MEDICINE FELLOWSHIP

ESTIMATED TOTAL FUNDS REFER TO THE FUNDS AVAILABLE FOR CASH GRANTS WHILE ESTIMATED NUMBER OF GRANTS EQUALS TOTAL OF ALL AMERICORPS VISTA PROJECTS, TH

EXAMINING THE FUNCTION OF BIOLOGICAL SEX SPECIFIC GENES: THE NLGN4S

RENAL MACROPHAGE BIOLOGY - PROJECT SUMMARY/ABSTRACT RENAL MACROPHAGES (RMS) ARE MYELOID CELLS RESIDING IN RENAL TISSUE THAT FULFILL SPECIFIC RENAL FUNCTIONS INCLUDING HOMEOSTASIS, IMMUNE SURVEILLANCE, AND REPAIR. RMS ACCOUNT FOR ABOUT 50% OF TOTAL CD45+ LEUKOCYTES IN MOUSE KIDNEYS AND ARE ALSO FOUND IN LARGE NUMBERS IN THE HUMAN KIDNEY. THEY CONSIST OF EMBRYO-DERIVED (EMRMS) AND BONE MARROW (BM)-DERIVED RMS (BMRMS). RECENTLY, IDE, ET AL. FOUND THAT YOLK-SAC-DERIVED RENAL MACROPHAGES (YSRMS)[5] CONTRIBUTE A VERY SMALL PORTION OF RMS AT BIRTH, BUT PROGRESSIVELY EXPAND IN NUMBER WITH AGE AND BECOME A MAJOR CONTRIBUTOR TO THE RM POPULATION IN OLDER MICE. THE MACROPHAGES’ NICHE IN TISSUES SUCH AS BRAIN, LIVER, AND LUNG MAY DETERMINE THE SPECIFIC FUNCTIONS OF THE TISSUE MACROPHAGES (TMS). ONLY A SMALL NUMBER OF THE NICHE SIGNALS HAVE BEEN DESCRIBED FOR THESE TMS, AND THE SPECIFIC MOLECULAR MECHANISM UNDERLYING RM REGENERATION HAS NOT BEEN STUDIED. UNDERSTANDING THE MECHANISMS OF THE RM NICHES WILL BE CRITICAL TO THE DEVELOPMENT OF THERAPEUTICS FOR KIDNEY DISEASES THAT BLOCK OR INDUCE SPECIFIC SIGNALING PATHWAYS. HOW RM NICHES IMPACT RM LONGEVITY, FATE, DYNAMICS, AND IMMUNE METABOLIC RESPONSES REMAINS UNCLEAR. TO ADDRESS THESE QUESTIONS, WE HAVE APPLIED A RECENTLY GENERATED CRE INDUCED-HUMAN CD59 TRANSGENIC LINE (IHCD59) TO TRACE RM LINEAGE AND DETERMINE THE INTRINSIC PROPERTIES OF RMS OF BM OR EMBRYONIC ORIGINS. WE FIND THAT RMS ARE MAINLY DERIVED FROM FETAL LIVER MONOCYTES BEFORE BIRTH, BUT SELF-MAINTAIN THROUGH ADULTHOOD WITH CONTRIBUTIONS FROM PERIPHERAL MONOCYTES. AT A STEADY STATE, DEFICIENCY OF CX3CR1, BUT NOT OF CCR2, SIGNIFICANTLY REDUCES THE NUMBER OF RMS, BUT NOT MICROGLIA, FROM BIRTH THROUGH ADULTHOOD. OUR PRELIMINARY RESULTS SUGGEST THE CX3CR1/CX3CL1 AXIS IS INDISPENSABLE FOR SPECIFIC REGENERATION AND MAINTENANCE OF RMS. ALTHOUGH THE ROLE OF CX3CR1/CX3CL1 IN THE PROGRESSION OF VARIOUS DISEASES IN TISSUES (INCLUDING KIDNEY TISSUE) HAS BEEN RECOGNIZED FOR MANY YEARS, ITS CRITICAL ROLE IN THIS NICHE SIGNALING FOR RMS OF BM, EMBRYONIC, AND YOLK-SAC ORIGINS HAS NOT BEEN STUDIED. FRACTALKINE/CX3CL1 EXISTS AS A MEMBRANE- ANCHORED MOLECULE AS WELL AS IN SOLUBLE FORM, EACH MEDIATING DIFFERENT BIOLOGICAL ACTIVITIES. HOWEVER, THE ROLES FOR THESE TWO TYPES OF CX3CL1 IN RM REGENERATION AND MAINTENANCE REMAIN UNKNOWN. THEREFORE, WE PROPOSE TO EXAMINE OUR WORKING HYPOTHESIS THAT THE CX3CL1 SIGNALING PATHWAY IS CRITICAL FOR CX3CR1+RM LONGEVITY, FATE, DYNAMICS, AND IMMUNE METABOLIC RESPONSES UNDER NORMAL (AIM 1) AND PATHOLOGICAL CONDITIONS (AIM 2). IN AIM 3, WE WILL EXAMINE THE CELLULAR AND MOLECULAR MECHANISMS BY WHICH THE CX3CR1/CX3CL1 AXIS CONTRIBUTES SPECIFICALLY TO RM REGENERATION AND MAINTENANCE. SUCCESSFUL COMPLETION OF THESE AIMS WILL ADVANCE OUR UNDERSTANDING OF TISSUE MACROPHAGE BIOLOGY, AND SPECIFICALLY OF RMS WHICH WILL ALLOW FOR IMPROVED DESIGN AND DEVELOPMENT OF THERAPEUTICS FOR KIDNEY DISEASE THAT BLOCK OR INDUCE SPECIFIC SIGNALING PATHWAYS.

ROLE OF PROXIMAL TUBULE NHE3 IN ANGIOTENSIN II-INDUCED HYPERTENSION

MECHANISTIC BASIS OF THE ROLE OF CBX3 IN NEGATIVELY REGULATING OSTEOCLAST DIFFERENTIATION THROUGH EPIGENETIC MODIFICATION

RESEARCH TRAINING IN EXPERIMENTAL MEDICINE AND PATHOLOGY

NEURAL CIRCUITS REGULATING FLIGHT AND PANIC BEHAVIOR.

COMPUTATIONAL TOOLS FOR TOP DOWN MASS SPECTROMETRY BASED PROTEOFORM IDENTIFICATION AND PROTEOGENOMICS

EPIGENETIC MECHANISMS OF BILIARY EPITHELIAL NEOPLASIA

EXPLORATORY RESEARCH ON HIV CONTRIBUTION TO HEART AND LUNG COMORBIDITIES

PERFORIN 2 CONTROLS UNCONVENTIONAL CYTOKINE RELEASE FROM MUCOSAL APC - PERFORIN 2 CONTROLS UNCONVENTIONAL CYTOKINE RELEASE FROM MUCOSAL APC PROJECT SUMMARY HOW PROFESSIONAL ANTIGEN PRESENTING CELL (APC) POPULATIONS FOCALLY DELIVER CYTOKINES TO T CELLS FOR SHAPING THE PRO-INFLAMMATORY VS. ANTI-INFLAMMATORY STATUS OF MUCOSAL TISSUE REMAINS INCOMPLETELY UNDERSTOOD. IN PARTICULAR, CYTOKINES THAT LACK N-TERMINAL PEPTIDE SEQUENCE SUCH AS THE IL-1 FAMILY CYTOKINE IL-33 CAN'T ACCESS CONVENTIONAL PROTEIN SECRETION PATHWAYS, WHICH HAS LED TO THE PREVAILING VIEW THAT CELL DEATH IS RESPONSIBLE FOR IL-33 RELEASE. THIS PROJECT IS BUILT UPON AN EXCITING SET OF PRELIMINARY DATA DEMONSTRATING THAT MUCOSAL CONVENTIONAL DENDRITIC CELL (CDC) SUBSETS, IN BOTH HUMANS AND MICE, EXPRESS THE TRANSMEMBRANE PORE-FORMING PROTEIN PERFORIN-2, WHICH AT LEAST IN MICE, FACILITATES IL-33 SECRETION. WHILE IN HUMAN CDC, WE FIND PERFORIN-2 EXPRESSION PRIMARILY IN AN INTERFERON REGULATORY FACTOR 4 (IRF4) SUBSET INDICATING THE CDC2 LINEAGE, IN MOUSE CDC, WE FIND PERFORIN-2 IN THE CD103+ CDC1 SUBSET KNOWN TO EXPRESS THE TRANSCRIPTION FACTORS IRF8 AND BATF3. IRRESPECTIVE OF THIS LINEAGE DISTINCTION, BOTH HUMAN AND MOUSE CD11C+ CELLS IN THE RESPIRATORY MUCOSA CONTAIN CYTOPLASMIC IL-33 PROTEIN. OUR DATA DEMONSTRATE THAT INHIBITION OF PERFORIN-2 ACTIVITY PREVENTS IL-33 RELEASE FROM CDC AND INHIBITS THE PROLIFERATIVE EXPANSION OF A POORLY UNDERSTOOD ST2+GATA3+FOXP3+TREG SUBSET. GIVEN THAT PERFORIN-2 HAS BEEN SHOWN TO ALSO REGULATE TYPE 1 IFN SIGNALING THROUGH CONTROLLING IFNAR RESPONSIVENESS, WE PROPOSE AN IMPORTANT REGULATORY MECHANISM EXISTS IN HUMANS AND MICE THAT IS DEPENDENT UPON MUCOSAL APC THAT EXPRESS PERFORIN-2. THIS PROJECT TESTS THE CENTRAL HYPOTHESIS THAT APC REQUIRE PERFORIN-2 AS AN INDUCIBLE PLASMA MEMBRANE CONDUIT FOR UNCONVENTIONAL CYTOKINE DELIVERY AT THE MUCOSAL INTERFACE. THREE SPECIFIC AIMS (SA) WILL BE INVESTIGATED. SA1 WILL DETERMINE WHETHER PERFORIN-2+ APC PREDICT TREG SUBSET ABUNDANCE IN SINONASAL MUCOSA AND DEFINE THE TRANSCRIPTIONAL LANDSCAPE OF PERFORIN-2+ APC. SA2 WILL DEFINE THE PERFORIN-2 DOMAINS REQUIRED FOR IL-33 RELEASE, THE DIVERSITY OF PERFORIN-2-DEPENDENT SECRETED MOLECULES, AND THE REQUISITE INTRACELLULAR TRAFFICKING MACHINERY RESPONSIBLE FOR PERFORIN-2 PLASMA MEMBRANE LOCALIZATION DURING APC-T CELL INTERACTIONS. SA3 WILL DIRECTLY TEST WHETHER CDC1 AND/OR CDC2 SUBSETS PREFERENTIALLY USE PERFORIN-2 FOR DRIVING PATHOGEN-SPECIFIC T CELL RESPONSES IN MOUSE MODELS OF RESPIRATORY VIRUS OR HELMINTH INFECTION. TAKEN TOGETHER, THIS MIST PROJECT STANDS TO UNCOVER A NEW PARADIGM FOR UNDERSTANDING HOW CDC INSTRUCT IMMUNITY WITHIN THE RESPIRATORY MUCOSA.

SHORT-COURSE BENZNIDAZOLE TREATMENT TO REDUCE TRYPANOSOMA CRUZI PARASITIC LOAD IN WOMEN OF REPRODUCTIVE AGE: A NON-INFERIORITYRANDOMIZED CONTROLLED TRIAL

INVESTIGATING THE ROLE AND THERAPEUTIC POTENTIAL OF THE ALPHA5BETA1 INTEGRIN IN RISK FACTORS FOR COVID-19-ASSOCIATED COGNITIVE IMPAIRMENT - ABSTRACT RAPIDLY EMERGING EVIDENCE HAS CHARACTERIZED THE ASSOCIATION BETWEEN VASCULAR DEMENTIA (VAD) AND INCREASED COVID-19 INCIDENCE, MORBIDITY, AND POST-COVID COGNITIVE DECLINE. WE THEORIZE THAT BRAIN VASCULAR PATHOLOGY IN VAD AND ADDITIONAL PATHOPHYSIOLOGIC FEATURES SUCH AS BLOOD-BRAIN BARRIER (BBB) DISRUPTION AND REDUCED CEREBRAL BLOOD FLOW MAY DIRECTLY CONTRIBUTE TO BOTH VAD AND COVID-19. SEVERAL LINES OF EVIDENCE SUPPORT THIS HYPOTHESIS. FIRST, WE HAVE DEMONSTRATED THAT SARS-COV-2 BINDS TO THE VASCULAR INTEGRIN A5SS1 RECEPTOR TO INFECT CELLS, THE SAME RECEPTOR WE HAVE ALSO LINKED TO BBB DISRUPTION IN BRAIN ISCHEMIA (STROKE) MODELS AND CHRONIC BILATERAL CAROTID ARTERY STENOSIS (BCAS), WHICH MODELS PATHOPHYSIOLOGICAL ASPECTS OF VAD SUCH AS REDUCED CEREBRAL BLOOD FLOW, BBB DISRUPTION, NEUROINFLAMMATION, WHITE MATTER DAMAGE, AND COGNITIVE DECLINE. SECOND, INTEGRIN A5SS1 IS SUBSTANTIALLY UPREGULATED IN AN AGE-DEPENDENT FASHION (AGED>YOUNG) IN THE BRAIN VASCULATURE AFTER STROKE AND BCAS, AND INHIBITION OF THIS RECEPTOR WITH THE CLINICALLY-VALIDATED INTEGRIN A5SS1 PENTAPEPTIDE INHIBITOR ATN-161 LESSENS BBB DISRUPTION AND COGNITIVE IMPAIRMENT IN THESE MODELS. THIRD, SARS-COV-2 INFECTION ALSO INCREASES INTEGRIN A5SS1 EXPRESSION IN VIVO AND DISRUPTS THE BBB. FORTH, PRELIMINARY RESULTS SUGGEST THAT SARS-COV-2 INFECTION AFTER BCAS FURTHER INCREASES MORBIDITY VS. BCAS OR INFECTION ALONE AND ACCELERATES BRAIN VASCULAR INTEGRIN A5SS1 UPREGULATION. FIFTH, ATN-161 INHIBITS SARS-COV-2 INFECTION IN VITRO AND IN VIVO AND PREVENTS SARS- COV-2-INDUCED INCREASED EXPRESSION OF A5SS1 INTEGRIN. FINALLY, ALTHOUGH ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) IS THE CANONICAL RECEPTOR FOR VIRAL ENTRY (INTERNALIZATION AND FUSION) INTO HOST CELLS, ITS ECTODOMAIN BINDS THE VIRAL SPIKE PROTEIN (S-PROTEIN) ON THE SURFACE TO FACILITATE VIRUS ATTACHMENT AND ACCESS INTO HOST CELLS THROUGH RECEPTOR-MEDIATED ENDOCYTOSIS USING AN RGD MOTIF. AS MANY CELL-SURFACE INTEGRINS ALSO BIND RGD, WE AND OTHERS HAVE PROVIDED COMPELLING EVIDENCE THAT INTEGRINS ARE CO-RECEPTORS OF THE VIRUS. ADDITIONALLY, WE HAVE SHOWN THAT TALIN-DEPENDENT INTEGRIN ACTIVATION IS REQUIRED FOR SARS-COV-2 INFECTIVITY. CONSISTENT WITH OUR RESULTS, PREVIOUS STUDIES HAVE SHOWN THAT A5SS1 AND ACE2 ENGAGE IN SIGNALING CROSSTALK LIKELY DRIVEN BY MUTUAL INTERACTION AT THEIR CYTOPLASMIC TAILS. BUILDING ON THESE FINDINGS, WE HYPOTHESIZE THAT (I) INTEGRIN A5SS1 PLAYS AN IMPORTANT AGE-DEPENDENT PATHOGENIC ROLE IN THE ASSOCIATION BETWEEN SARS-COV-2 INFECTION AND VAD BY WORSENING PRE-EXISTING VAD AFTER COVID-19, (II) ATN-161 TREATMENT BEFORE, DURING, OR AFTER COVID-19 INFECTION WILL STABILIZE BBB INTEGRITY TO IMPROVE COVID-19 NEUROCOGNITIVE OUTCOMES IN THE CONTEXT OF PRE-EXISTING VASCULAR DEMENTIA, AND (III) INTEGRIN A5SS1 SIGNALING REGULATES INFECTIVITY, AND ITS UPREGULATION POTENTIATES DYSREGULATION OF THE BBB. TO INVESTIGATE THESE HYPOTHESES, WE PROPOSE TO 1). DEMONSTRATE THAT EXPERIMENTAL VAD WORSENS COVID-19 MORBIDITY AND SUBSEQUENT COGNITIVE DECLINE, 2). DETERMINE THE THERAPEUTIC POTENTIAL OF INTEGRIN A5SS1 INHIBITION IN IMPROVING VAD POST-COVID MORBIDITY AND COGNITIVE DECLINE, 3). DETERMINE THE SIGNALING MECHANISM OF INTEGRIN A5SS1 REQUIRED FOR SARS-COV-2 PRODUCTIVE INFECTION AND DYSREGULATION OF CELL BARRIER FUNCTION.

BRAIN CIRCUITS INVOLVED IN THE SYMPATHETIC CONTROL OF THE LIVER

COALITION FOR COMPASSIONATE SCHOOLS - THE COALITION FOR COMPASSIONATE SCHOOLS (C2S) DRAWS UPON LONG-STANDING LOCAL PARTNERSHIPS BETWEEN CITY AGENCIES, THE NCTSN PROJECT FLEUR-DE-LIS, TULANE UNIVERSITY, AND COMMUNITY ORGANIZATIONS TO SUPPORT TRANSFORMATIVE CHANGE IN NEW ORLEANS SCHOOLS THROUGH THE IMPLEMENTATION AND SUSTAINMENT OF A HEALING-CENTERED, MULTITIERED TRAUMA-INFORMED SCHOOLS SERVICE APPROACH TO IMPROVE THE PSYCHOLOGICAL, BEHAVIORAL, AND EDUCATIONAL OUTCOMES OF YOUTH EXPOSED TO TRAUMA AND TO PREVENT NEW EXPOSURE IN SCHOOLS. THE C2S WILL ADDRESS CRITICAL GAPS IN THE TRAUMA-INFORMED SCHOOLS SERVICE APPROACH BY INTEGRATING SOCIAL JUSTICE AND RACIAL EQUITY INTO OUR TRAINING CONTENT, TOOLS, AND IMPLEMENTATION STRATEGIES; EMPLOYING A MULTI-YEAR STRATEGY GROUNDED IN IMPLEMENTATION SCIENCE TO INCREASE THE CAPACITY OF THE K-8 EDUCATION WORKFORCE IN THE TIS-SA; AND EXPANDING OUR APPROACH INTO AFTERSCHOOL PROGRAMS AND OTHER YOUTH SERVICE SYSTEMS. WE WILL PARTNER WITH THE NCTSN CENTER FOR SAFE SUPPORTIVE SCHOOLS (MARYLAND) AND THE NCTSN CULLEN CENTER (OHIO) TO DISSEMINATE AND REPLICATE OUR IMPLEMENTATION MODEL, FILLING THE NEED FOR A SCHOOLS-FOCUSED NCTSN CATEGORY II CENTER IN THE SOUTHERN/CENTRAL REGION OF THE US. OUR GOALS ARE TO: 1) INCREASE THE CAPACITY OF NEW ORLEANS K-8 PUBLIC SCHOOLS TO IMPLEMENT AND SUSTAIN A TIS-SA TO IMPROVE OUTCOMES FOR YOUTH EXPOSED TO TRAUMA AND PREVENT NEW EXPOSURE IN SCHOOLS; 2) EXPAND IMPLEMENTATION OF TIS-SA TO AFTERSCHOOL PROGRAMS AND COORDINATE TRAINING AND CONSULTATION ACROSS SERVICE SYSTEMS TO SUPPORT SERVICE PROVIDERS AND YOUTH AFFECTED BY TRAUMATIC EVENTS; AND 3) DEVELOP ADDITIONAL PRODUCTS TO SUPPORT A TIS-SA AND PROVIDE TRAINING, CONSULTATION, AND IMPLEMENTATION SUPPORT FOR THE REPLICATION AND DISSEMINATION OF OUR TIS-SA TO SCHOOLS ACROSS THE COUNTRY.

LOUISIANA EXPERIMENT TO ADDRESS DIABETES: ZERO-DOLLAR COPAYMENT (LEAD-ZDC) FOR IMPROVING DISEASE MANAGEMENT

A SEEK, TEST, AND TREAT INTERVENTION TO REDUCE CHLAMYDIA TRACHOMATIS DISPARITIES IN BLACK YOUTH LIVING IN THE DEEP SOUTH - CHLAMYDIA TRACHOMATIS (CT) IS THE MOST COMMON REPORTABLE SEXUALLY TRANSMITTED INFECTION IN THE UNITED STATES THAT CAUSES SEVERE AND COSTLY MORBIDITY. BLACK YOUTH ARE DISPROPORTIONATELY IMPACTED, WITH CT RATES 7.5 TIMES HIGHER THAN THE RATES AMONG NON-BLACK YOUTH. IN OVER TWO DECADES OF CT SCREENING IN YOUNG WOMEN, POPULATION-BASED RATES OF CT HAVE DECLINED FOR WHITE YOUTH BUT NOT FOR BLACK YOUTH, AND CLINIC-BASED CT SCREENING IS ACCESSED LESS FREQUENTLY THAN RECOMMENDED BY BLACK WOMEN, INDICATING THAT A DIFFERENT APPROACH IS NEEDED, PARTICULARLY WHEN CONSIDERING STRUCTURAL RACISM AND MEDICAL MISTRUST. WE POSIT THAT A COMMUNITY- BASED, SEEK, TEST, AND TREAT APPROACH IS REQUIRED. CHECK IT (NICHD/NIAID R01HD086794) WAS A SEEK, TEST, AND TREAT BUNDLED NETWORK APPROACH TO REDUCING CHLAMYDIA DISPARITIES THAT WAS DESIGNED FOR YOUNG BLACK MEN. IN 33.5 MONTHS OF RECRUITMENT, WE SCREENED 1907 MEN AND FOUND A 10.6% CT POSITIVITY RATE. WE FOUND THAT SCREENING MEN REDUCED THE RATE IN WOMEN BY AN AVERAGE OF 2.1 PERCENTAGE POINTS COMPARED TO SYNTHETIC CONTROL SITES; FOR EVERY 5 MEN SCREENED, 1 INFECTION IN WOMEN WAS AVERTED; AND THAT THE PROGRAM COSTS WERE $5,468 PER QALY GAINED. THE STUDY GOAL IS TO FURTHER ADAPT AND REFINE CHECK IT, A SEEK, TEST, AND TREAT COMMUNITY-BASED CT PREVENTION PROGRAM AIMED TO REDUCE DISPARITIES AMONG BLACK YOUTH IN THE UNITED STATES. WE WILL ACHIEVE THIS IN THREE AIMS: AIM 1. TO ADAPT AND REFINE CHECK IT – USING THE ADAPT-ITT FRAMEWORK47 AND IN COLLABORATION WITH OUR INTENDED POPULATION, CONTENT EXPERTS, AND COMMUNITY PARTNERS, WE WILL MAKE FIVE ADAPTATIONS TO THE PROGRAM: INCLUSION OF WOMEN, USE OF DOXYCYCLINE, ADDITION OF A HOME COLLECTION OPTION, REFINEMENT OF INCENTIVIZED PEER REFERRAL, AND EXTRAGENITAL SELF-COLLECTION IN THE FIRST YEAR AND THEN READAPT AS NEEDED IN THE THIRD YEAR. WE WILL CONDUCT INTERRUPTED TIME SERIES ANALYSIS & HYPOTHESIZE THAT THESE ADAPTATIONS WILL INCREASE ENROLLMENT. AIM 2. TO DETERMINE EFFICACY AND COST-EFFECTIVENESS OF THE ADAPTED CHECK IT– AFTER ADAPTATIONS AND IMPLEMENTATION AMONG BLACK YOUTH IN NEW ORLEANS (N=2322), USING MEDICAID DATA, WE WILL COMPARE NEW ORLEANS (INTERVENTION) TO SYNTHETIC CONTROLS TO EXAMINE THE ADAPTED PROGRAM'S IMPACT ON WOMEN'S CT RATES.48 WE WILL ALSO USE TIME-MOTION ANALYSIS TO EXAMINE THE COST- EFFECTIVENESS,34 HYPOTHESIZING THAT INCLUSION OF BOTH MEN AND WOMEN IS COST EFFECTIVE AND WILL LOGARITHMICALLY REDUCE THE RATES OF CT INFECTION IN WOMEN. AIM 3. TO EXAMINE THE FEASIBILITY/UTILITY OF CT/GC EXTRAGENITAL AND SYPHILIS/HIV TESTING – PARTICIPANTS WILL BE OFFERED EXTRAGENITAL SPECIMEN SELF-COLLECTION & SYPHILIS/HIV TESTING. WE HYPOTHESIZE THAT >80% WILL ACCEPT TO DO EXTRAGENITAL TESTING AND THAT SYPHILIS/HIV RATES WILL EXCEED THE NATIONAL AVERAGE. TO BREAK DOWN HEALTH DISPARITIES, IT IS ESSENTIAL TO GO TO THE COMMUNITIES OF THOSE IMPACTED. IF SUCCESSFUL, CHECK IT II CAN SERVE AS A MODEL FOR OTHER SITES ULTIMATELY REDUCING CT DISPARITIES ON A BROADER BASIS. CHECK IT II COULD ALSO SERVE AS A MODEL FOR OTHER STI INTERVENTIONS IN THIS POPULATION SUCH AS DOXY PREP OR VACCINES.

UNDERSTANDING THE ROLE OF THE CEREBRAL MICROVASCULATURE IN BRAIN AGING - PROJECT SUMMARY/ABSTRACT AGING IS ONE OF THE MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF CEREBROVASCULAR, CARDIOVASCULAR, AND NEURODEGENERATIVE DISEASES, CONTRIBUTING TO LONG-TERM DISABILITY AND MORTALITY IN THE ELDERLY. AGING- ASSOCIATED PROGRESSIVE STRUCTURAL AND FUNCTIONAL DECLINE OF VASCULAR CELLS LEAD TO VASCULAR DYSFUNCTION SUCH AS DECREASED CEREBRAL BLOOD FLOW. WHILE THE VASCULATURE IS ONE OF THE MOST IMPORTANT TARGETS OF AGING, IT IS NOT CLEAR WHETHER ACCUMULATING VASCULAR PATHOLOGIES OR AGING DRIVES VASCULAR DYSFUNCTION. THE OVERALL LONG-TERM GOAL OF THIS PROJECT IS TO ELUCIDATE AGING, AND BRAIN HYPOPERFUSION-ASSOCIATED TEMPORAL CHANGES IN THE CEREBRAL VASCULATURE. WE WILL TEST THE HYPOTHESIS THAT BRAIN HYPOPERFUSION EXACERBATES AGING-ASSOCIATED COMPROMISED BLOOD-BRAIN-BARRIER INTEGRITY FACILITATED BY MITOCHONDRIAL DYSFUNCTION. TO TEST OUR OVERALL HYPOTHESIS, WE PROPOSED TWO SPECIFIC AIMS. WE WILL USE YOUNG AND OLD, MALE, AND FEMALE MITO-DENDRA2 EXPRESSING AND WILD TYPE MICE IN THE PROPOSED STUDIES. BILATERAL COMMON CAROTID ARTERY STENOSIS (BCAS) WILL BE USED TO MIMIC CEREBRAL HYPOPERFUSION. THE THERAPEUTIC POTENTIAL OF VASCULAR MITOCHONDRIA WILL BE TESTED USING A MITOCHONDRIA TARGETED TETRAPEPTIDE. TWO-PHOTON MICROSCOPY WILL BE USED TO DETERMINE HOW HYPOPERFUSION EXACERBATES AGING-ASSOCIATED BBB DYSFUNCTION IN VIVO, TO MAP THE BRAIN VASCULATURE, AND VASCULAR MITOCHONDRIAL DYNAMICS REAL TIME. OUR STUDIES WILL BE COMPLEMENTED WITH IMMUNOFLUORESCENCE STUDIES, DISCOVERY-BASED PROTEOMICS APPROACH, AND WESTERN BLOT. THE PROPOSED RESEARCH WILL REVEAL HOW AGING AND CEREBRAL HYPOPERFUSION AFFECT ENDOTHELIAL MITOCHONDRIA, AND WILL ELUCIDATE MECHANISMS THAT MIGHT CONTRIBUTE TO AGING-RELATED PATHOLOGIES SUCH AS ALZHEIMER’S DISEASE.

HEALTH AND PUBLIC SAFETY WORKFORCE RESILIENCY TRAINING PROGRAM

SHORT-TERM ESTRADIOL USE IN MIDDLE-AGE: IMPLICATIONS FOR FEMALE COGNITIVE AGING

REPRODUCTIVE HISTORY AND LATER-LIFE BRAIN HEALTH: THE BOGALUSA HEART STUDY - EVEN AFTER ACCOUNTING FOR LONGEVITY, WOMEN ARE AT HIGHER RISK FOR ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD), AND DISEASE PROGRESSION AND UNDERLYING MOLECULAR MECHANISMS DIFFER BY SEX. THE METABOLIC EXPOSURES OF REPRODUCTION ARE ONE POTENTIAL BIOLOGICAL DRIVER OF SEX DIFFERENCES. PREGNANCY HAS STRONG EFFECTS ON METABOLISM: HIGH PARITY IS ASSOCIATED WITH LATER-LIFE DIABETES RISK, DUE POSSIBLY TO PERSISTENT ALTERATIONS IN GLUCOSE HOMEOSTASIS AND ACTIVITY, WHILE BREASTFEEDING IS PROTECTIVE AGAINST METABOLIC RISK. BECAUSE INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS ARE RISK FACTORS FOR AD, IT IS PLAUSIBLE THAT THESE REPRODUCTION-RELATED METABOLIC EXPOSURES CONTRIBUTE TO AD RISK AMONG WOMEN. HOWEVER, IT IS UNKNOWN WHETHER THESE EXPOSURES ARE IMPORTANT PREDICTERS OR MODIFIERS OF RISK OF COGNITIVE DECLINE AND AD AND WHETHER SUCH COGNITIVE CHANGES ARE DRIVEN BY AD-RELATED NEUROBIOLOGICAL SUBSTRATES INCLUDING CEREBRAL AMYLOID. THE BOGALUSA HEART STUDY IS A STUDY OF CARDIOVASCULAR HEALTH STARTING IN CHILDHOOD IN A BIRACIAL (65% WHITE, 35% BLACK) COHORT. SUBSTUDIES INCLUDE BOGALUSA BABIES, WHICH INTERVIEWED 1803 WOMEN ABOUT THEIR REPRODUCTIVE HISTORIES, AND AN ONGOING STUDY OF CHILDHOOD AND EARLY ADULTHOOD GLYCEMIC CONTROL AND MIDLIFE COGNITION, BRAIN STRUCTURE, AND BRAIN FUNCTION. IN THIS PROJECT, WE BUILD ON THIS PROTOCOL, PROVIDING A COMBINED SAMPLE OF 950 WOMEN WITH COGNITIVE MEASURES, 450 WITH MRI AND 275 WITH PET SCANS. THE OVERALL OBJECTIVE IS TO ASSESS THE RELATIONSHIP AMONG REPRODUCTIVE HISTORY, LIFETIME METABOLIC EXPOSURES, AND MIDLIFE COGNITION AND BRAIN FUNCTION, AS MEASURED BY AD-RELEVANT INSTRUMENTS AND MARKERS. THE OVERALL HYPOTHESIS IS THAT PREGNANCY-RELATED METABOLIC EXPOSURES WILL BE ASSOCIATED WITH LATER-LIFE BRAIN HEALTH EVEN AFTER CONTROL FOR PRE-PREGNANCY METABOLIC EXPOSURES (GLUCOSE AND INSULIN RESISTANCE), AND THAT THESE EFFECTS WILL BE PARTIALLY MEDIATED BY METABOLIC EXPOSURES POST- PREGNANCY. THE HYPOTHESIS WILL BE TESTED THROUGH THE FOLLOWING SPECIFIC AIMS: 1) EXAMINE REPRODUCTIVE HISTORY AS A PREDICTOR OF MIDLIFE COGNITION AND COGNITIVE DECLINE; 2) EXAMINE REPRODUCTIVE HISTORY AS A PREDICTOR OF BRAIN STRUCTURAL AND FUNCTIONAL OUTCOMES; AND 3) EXAMINE REPRODUCTIVE HISTORY AS A PREDICTOR OF AD- AND METABOLISM- RELATED MOLECULAR SUBSTRATES OF COGNITION. PRELIMINARY DATA SHOWED WORSE COGNITION ASSOCIATED WITH NULLIPARITY, LACK OF HISTORY OF BREASTFEEDING, AND WORSE EARLY-LIFE GLUCOSE LEVELS, ESPECIALLY AMONG WOMEN. THEREFORE, THE HYPOTHESES ARE THAT NULLIPARITY, SHORTER/NO HISTORY OF LACTATION, HIGHER BIRTHWEIGHT, AND HIGHER GESTATIONAL WEIGHT GAIN WILL BE ASSOCIATED WITH WORSE SCORES ON A STANDARDIZED NEUROCOGNITIVE BATTERY AND GREATER COGNITIVE DECLINE; LOWER GRAY MATTER VOLUME AND GREATER WHITE MATTER HYPERINTENSITY VOLUME ON 3T BRAIN MRI, AND LOWER FMRI ACTIVATION TO A STROOP TASK; AND HIGHER BURDEN OF CEREBRAL AMYLOID ON 18F-FLORBETAPIR PET AND CEREBRAL GLUCOSE HYPERMETABOLISM ON 18F-FLUORODEOXYGLUCOSE PET. THIS STUDY IS UNIQUELY SITUATED TO PROVIDE CRITICAL NEW INFORMATION THAT COULD HELP IDENTIFY TREATMENTS AND INTERVENTIONS THAT MAY BLOCK THE EFFECTS OF METABOLIC OR ENDOCRINE DYSFUNCTION ON THE BRAIN, AND ADD IMPETUS TO IMPROVING HEALTH IN EARLY ADULTHOOD TO PREVENT AD.

IN VIVO BIOLOGY OF MAMMALIAN L1 RETROTRANSPOSITION - PROJECT SUMMARY LONG INTERSPERSED NUCLEAR ELEMENTS (LINES) ARE A CLASS OF RETROTRANSPOSABLE ELEMENTS THAT CONTINUALLY MUTATE GENOMES, INCLUDING MAMMALIAN GENOMES. THE CURRENTLY ACTIVE FAMILY OF LINES IN MAMMALS IS CALLED LINE-1 (L1). THERE ARE HUNDREDS OF THOUSANDS OF COPIES OF L1 IN MAMMALIAN GENOMES, AND UNCHECKED EXPRESSION OF THIS ELEMENT IN HUMANS AND/OR MODEL ORGANISMS IS ASSOCIATED WITH VARIOUS ABNORMAL STATES, SUCH AS CANCER, INFERTILITY, AGING AND NEUROLOGIC DISEASE. WE DO NOT KNOW WHETHER L1 PLAYS A CAUSATIVE ROLE IN THESE DISORDERS, PARTLY BECAUSE OUR KNOWLEDGE OF L1 BIOLOGY IN VIVO IS RUDIMENTARY, WHICH HAS LIMITED OUR ABILITY TO EXPERIMENTALLY MANIPULATE ENDOGENOUS L1 ACTIVITY IN A SPECIFIC MANNER. ALTHOUGH A NUMBER OF CELLULAR HOST FACTORS THAT CAN ALTER L1 RETROTRANSPOSITION HAVE BEEN IDENTIFIED FROM BIOCHEMICAL PULLDOWNS AND GENETIC SCREENS IN IMMORTALIZED CELL LINES, THE IN VIVO BIOLOGICAL RELEVANCE OF THESE FACTORS IN THE EVOLUTIONARILY RELEVANT GERM CELLS IS UNCLEAR. PREVIOUSLY OUR LAB DISCOVERED THAT THE ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT (ESCRT) PLAYS A CRITICAL ROLE FOR PRODUCTIVE LINE RETROTRANSPOSITION IN BOTH YEAST AND HUMAN TISSUE CULTURE. THIS PROPOSAL WILL USE MOUSE GENETICS TO EXAMINE WHETHER ESCRT IS USED FOR L1 INTRACELLULAR TRAFFICKING AND RETROTRANSPOSITION IN THE MALE GERM LINE, AND WHETHER DISRUPTION OF THE ESCRT/L1 INTERACTION CAN ALLEVIATE GERM LINE DEFECTS FOUND IN A MOUSE MODELS OF INFERTILITY. TO THIS END, WE WILL UTILIZE BOTH WILD TYPE MICE AND MICE WITH KNOWN INCREASES IN L1 EXPRESSION IN THE GERMLINE. MICE DELETED IN THE GENE FOR MAELSTROM (MAEL-/-) HAVE MASSIVE OVEREXPRESSION OF L1, ARREST IN MEIOTIC PROPHASE I, AND ARE MALE STERILE. MAELSTROM IS INVOLVED IN THE BIOGENESIS OF SMALL RNAS IN THE GERM LINE, CALLED PIRNAS, AND SIMILAR TRANSPOSON/INFERTILITY DEFECTS ARE SEEN WHEN RELATED PIRNA BIOGENESIS GENES (E.G. MOV10L1) ARE KNOCKED OUT IN MICE. IT IS CURRENTLY UNKNOWN WHETHER L1 IS A DRIVING FACTOR OF INFERTILITY IN THESE MICE. TO REDUCE L1 ACTIVITY, WE WILL INTRODUCE AN ALIX KNOCKOUT ALLELE (ALIX IS A COMPONENT OF THE ESCRT COMPLEX). IN AIM 1 WE WILL EVALUATE GERM LINE L1 RNP LOCALIZATION, REGULATION, AND RETROTRANSPOSITION WHEN THE L1/ESCRT INTERACTION IS DISRUPTED. IN AIM 2 WE WILL DETERMINE THE CONTRIBUTION OF L1 OVEREXPRESSION TO GERM CELL PHENOTYPES IN MICE. THIS PROJECT WILL PROVIDE VALUABLE INSIGHT INTO WHETHER ESCRT ENABLES L1 RNP TRAFFICKING IN THE GERM LINE. THE PROPOSED WORK WILL ALSO SHED LIGHT ON WHETHER EXCESS L1 RETROTRANSPOSITION IS A DRIVING FACTOR RESPONSIBLE FOR INFERTILITY IN PIRNA PATHWAY MUTANTS. BECAUSE L1 AND THE PIRNA PATHWAY ARE CONSERVED IN HUMANS, AND MUTATIONS IN PIRNA PATHWAY GENES HAVE BEEN ASSOCIATED WITH HUMAN INFERTILITY, WE EXPECT THAT THIS WORK WILL FORM THE BASIS FOR FUTURE STUDY ON THE RELATION BETWEEN TRANSPOSON REGULATION AND SOME CASES OF HUMAN MALE INFERTILITY.

ENVIRONMENTAL INFLUENCES ON URBAN SCHISTOSOMIASIS TRANSMISSION AND ELIMINATION

ELICITING ESTROGEN'S PROTECTIVE VASCULAR EFFECTS

MULTIPLEXED DETECTION OF CELL-FREE M. TUBERCULOSIS DNA AND ITS DRUG-RESISTANT VARIANTS IN BLOOD - ABSTRACT EVERY YEAR 10 MILLION PEOPLE FALL ILL WITH TUBERCULOSIS (TB) AND 1.5 MILLION PEOPLE DIE FROM TB – MAKING IT THE LEADING CAUSE OF DEATH FROM INFECTIOUS DISEASE – BUT TB CAN BE DIFFICULT TO DIAGNOSE. EXTENDED M. TUBERCULOSIS (MTB) CULTURES ARE STILL OFTEN USED FOR DIAGNOSIS. PCR-BASED ASSAYS (E.G. XPERT MTB/RIF) THAT DETECT TB DNA CAN PROVIDE MORE RAPID RESULTS, BUT REQUIRE SPECIAL EQUIPMENT AND, LIKE MTB CULTURE, EXHIBIT REDUCED SENSITIVITY WHEN EMPLOYED TO ANALYZE SPUTUM FROM INDIVIDUALS WITH EXTRAPULMONARY TB OR COMPROMISED IMMUNE SYSTEMS. BLOOD-BASED TB ASSAYS SHOULD DETECT ALL FORMS OF TB, BUT CURRENT TESTS ANALYZE THE IMMUNE RESPONSE TO MTB ANTIGENS AND CANNOT DISTINGUISH ACTIVE AND LATENT TB. SENSITIVE DETECTION OF MTB-DERIVED CELL-FREE DNA (CFDNA) IN THE CIRCULATION, HOWEVER, REPRESENTS A POTENTIAL NEW MEANS FOR ENHANCED TB DIAGNOSIS. CIRCULATING CFDNA IS RAPIDLY DEGRADED AFTER ITS RELEASE AND DISEASE-ASSOCIATED CFDNA LEVELS IN BLOOD CAN RAPIDLY CHANGE IN RESPONSE TO PATHOLOGIC CHANGES AND PHYSIOLOGIC RESPONSES. THIS SHORT HALF-LIFE CAN ENABLE “REAL-TIME” CFDNA ANALYSES REQUIRED FOR ACCURATE EVALUATION OF THE CURRENT STATUS OF ACTIVE MTB INFECTIONS AND RAPID GRANULAR EVALUATION OF MTB TREATMENT RESPONSES. HOWEVER, THE LIMIT OF DETECTION (LOD) OF CURRENT PCR-BASED ASSAYS ARE NOT SUFFICIENT TO RELIABLY DETECT MTB CFDNA IN BLOOD. WE HAVE ESTABLISHED A CRISPR-CAS12A-BASED DETECTION SYSTEM THAT CAN ULTRA-SENSITIVELY DETECT TRACE AMOUNT OF SARS-COV-2 RNA IN BLOOD TO DIAGNOSE COVID-19, PREDICT DISEASE SEVERITY, AND EVALUATE INFECTION RESOLUTION. WE HAVE ADAPTED THIS APPROACH TO DEVELOP A BLOOD-BASED MULTIPLEXED CRISPR-MEDIATED TB DIAGNOSIS (CRISPR-TBD) ASSAY THAT CAN DETECT CIRCULATING MTB CFDNA, INCLUDING SNPS RESPONSIBLE FOR DRUG-RESISTANT TB. OUR PRELIMINARY DATA FROM LONGITUDINAL SERUM SAMPLES OF PATIENTS UNDERGOING TB TREATMENT PROVIDE STRONG PROOF-OF-PRINCIPLE EVIDENCE FOR THE CLINICAL UTILITY OF THIS PLATFORM. WE HAVE ADAPTED THIS APPROACH TO A PAPER STRIP-BASED POINT OF CARE (POC) CRISPR-TBD DETECTION PLATFORM SUITABLE FOR USE IN RESOURCE-LIMITED REGIONS WITH HIGH TB BURDEN, WITHOUT DECREASING ASSAY SENSITIVITY. WE NOW PROPOSE TO: 1) SYSTEMATICALLY OPTIMIZE ALL CRISPR-TBD PAPER STRIP ASSAY STEPS TO IMPROVE QUANTITATIVE DETECTION OF MTB-CFDNA IN POC SETTINGS; 2) EVALUATE THE PERFORMANCE OF THIS POC ASSAY TO DIAGNOSE PULMONARY AND EXTRAPULMONARY TB AND TO IDENTIFY DRUG-SENSITIVE AND -RESISTANT TB CASES; 3) QUANTIFY MTB-CFDNA CHANGES IN SERUM DURING TB TREATMENT AS A MEASURE OF TREATMENT EFFICACY OR FAILURE AND FOR EARLY DETECTION OF NASCENT DRUG RESISTANCE; AND 4) IN-FIELD VALIDATE THE DIAGNOSTIC PERFORMANCE OF THIS POC ASSAY IN AN INDEPENDENT TB PATIENT COHORT WHEN PERFORMED IN A CLINICAL LABORATORY IN A HIGH ENDEMIC TB REGION AND EVALUATE IN PARALLEL THE PERFORMANCE OUR PREDICTIVE MTB-CFDNA MODEL FOR TB TREATMENT.

TARGETING MATRIX STIFFNESS IN LUNG FIBROSIS ASSOCIATED WITH AGING

CD4+ T CELL IMMUNITY IN THE RESPIRATORY TRACT - ABSTRACT PNEUMONIA REMAINS THE #1 KILLER OF CHILDREN IN THE WORLD AND IS A LEADING CAUSE OF MORBIDITY AND MORTALITY IN CHILDREN IN THE US AND THE #8 CAUSE OF MORTALITY IN ADULTS. OUR LABORATORY HAS MADE SEMINAL INSIGHTS IN MECHANISMS UNDERLYING HOST DEFENSE AGAINST EXTRACELLUAR PATHOGENS – PARTICULARLY IN THE AREA OF TYPE 17 CYTOKINES –IL-17 AND IL-22, AND TISSUE RESIDENT MEMORY CD4+ T CELLS. USING MURINE AND PRIMATE RESPIRATORY TRACT SAMPLES WE WILL ASSESS THE METABOLIC REQUIREMENT OF LUNG AND NASAL TRM CELLS AND INVESTIGATE IF ANTIGEN EXPOSURE IS REQUIRED FOR LUNG TERM SURVIVAL. WE HAVE PREVIOUSLY SHOWN THESE CELLS OCCUPY A UNIQUE SUBMUCOSAL NICHE AND REQUIRE IL-17RC SIGNALING IN FIBROBLASTS FOR FUNCTION. WE WILL DETERMINE IF THERE ARE FEEDBACK LOOPS BETWEEN FIBROBLASTS AND T CELL TO MAINTAIN THESE CELLS AND IF LUNG TRM CELLS EPIGENETICALLY MODIFY LUNG FIBROBLAST POPULATIONS. THE RESEARCH PROPOSED UNDER THIS R35 WILL SHED NEW LIGHT ON PULMONARY HOST DEFENSES THAT CAN BE EXPLOITED TO REDUCE THE GLOBAL BURDEN OF PNEUMONIA MORTALITY AND MORBIDITY.

USING COMBINATION ADJUVANTS TO DIRECT AND CONTROL IMMUNE RESPONSES AT THE INTESTINAL MUCOSA

CBF? MEDIATES ARTICULAR CARTILAGE REGENERATION AND REPAIR IN AGING

PROGRAMMED SPLICING DERANGEMENT AS NEW EBV HOST CELL SHUT-OFF MECHANISM - THE EPSTEIN BARR VIRUS IS A DNA TUMOR VIRUS THAT IS ASSOCIATED WITH HUMAN PATHOLOGIES INCLUDING HODGKIN'S LYMPHOMA, NON-HODGKIN'S LYMPHOMA, STOMACH CANCER, NASOPHARYNGEAL CARCINOMA AND AUTOIMMUNE DISEASES. EBV IS PARTICULARLY PROBLEMATIC IN THE HIV/AIDS POPULATION WHERE EBV ASSOCIATED LYMPHOMAS ARE ESPECIALLY PREVALENT. WHILE MORE THAN 90% OF THE WORLD'S POPULATION CARRIES EBV, THE VIRUS TYPICALLY EXISTS IN A “LATENT” STATE WITH LITTLE IMPACT ON THE HOST. IN RESPONSE TO CERTAIN STIMULI OR LOCAL MICROENVIRONMENTAL CUES, HOWEVER, EBV ENTERS THE VIRAL LYTIC REPLICATION PROGRAM, LEADING TO VIRAL SPREAD BOTH WITHIN AND BETWEEN HOSTS. DESPITE THE KNOWN ROLE OF VIRAL LATENCY PROTEINS IN EBV ASSOCIATED CANCERS, THERE ARE WELL-ESTABLISHED LINKS BETWEEN ELEVATED LYTIC REPLICATION AND THE ONSET OF EBV ASSOCIATED CANCERS. FURTHER, GENERAL ELEVATION OF EBV LYTIC REPLICATION IS OBSERVED IN THE CONTEXT OF HIV CO-INFECTION (+ OR – ART), LIKELY CONTRIBUTING TO THE INCREASED SUSCEPTIBILITY OF HIV INFECTED INDIVIDUALS TO EBV ASSOCIATED LYMPHOMAS AND AUTOIMMUNE DISEASES. WITH MINIMAL GENETIC CONTENT, VIRUSES ARE HIGHLY DEPENDENT ON HOST CELL RESOURCES FOR THEIR REPLICATION AND THEY ELICIT EXTENSIVE ALTERATIONS OF HOST CELL METABOLIC PROCESSES TO FACILITATE EFFICIENT VIRUS REPLICATION. ONE OF THE MOST CONSERVED AND WELL STUDIED VIRUS-HOST INTERACTIONS IN HERPESVIRUS REPLICATION IS “HOST SHUT OFF” WHERE VIRUS ENCODED FACTORS DEGRADE HOST CELL RNAS DESTINED FOR TRANSLATION, FREEING UP TRANSLATION RESOURCES FOR DEDICATED PRODUCTION OF HIGH AMOUNTS OF VIRAL STRUCTURAL PROTEINS. RECENTLY, THE GLAUNSINGER LAB SHOWED THAT DESPITE INDUCING GLOBAL POL III ACTIVATION OF HOST B2 SINE ELEMENTS, THE MURINE -HERPESVIRUS, MHV68, INHIBITS HOST POL II TRANSCRIPTION AS A SECOND ARM OF HOST SHUT OFF, FURTHER PROMOTING PREFERENTIAL VIRAL PROTEIN SYNTHESIS. USING EBV REACTIVATION MODELS THAT FACILITATE INTERROGATION OF TRANSCRIPTOME CHANGES IN PURE REACTIVATING CELL POPULATIONS, WE HAVE GAINED INSIGHTS INTO REMARKABLE AND UNEXPECTED INTERACTIONS BETWEEN EBV AND THE HOST CELL TRANSCRIPTOME. UNLIKE MHV68, WE FOUND THAT EBV SUSTAINS CELL POL II GENE EXPRESSION AT CANONICAL PROMOTERS DURING LYTIC REPLICATION AND STRIKINGLY, CAUSES TRANSCRIPTION AT >10,000 NEW POL II INITIATION SITES ACROSS THE CELL GENOME. WHILE THE REASON FOR THE BROAD INDUCTION OF PREDOMINANTLY NON-CODING POL II (EBV) OR POL III (MHV68) TRANSCRIPTION ACROSS HOST GENOMES IS UNCLEAR, IT COULD RELATE TO SOME ROLE IN REMODELING NUCLEAR STRUCTURE OR REDISTRIBUTION OF NUCLEAR RESOURCES. OUR STUDIES ALSO REVEALED THAT EBV REACTIVATION INDUCES WIDESPREAD, NONCANONICAL EXON SKIPPING, THE EXTENT OF WHICH SURPASSES THE DEGREE OF EXON SKIPPING OBSERVED UPON SEVERE DEPLETION OF MOST SPLICEOSOME COMPONENTS. PRELIMINARY ANALYSIS OF KSHV REACTIVATION SIMILARLY REVEALED WIDESPREAD INDUCTION OF EXON SKIPPING INDICATING THAT SPLICING DISRUPTION IS NOT UNIQUE TO EBV. PREVIOUS STUDIES HAVE SHOWN THAT EXON SKIPPING CAN CAUSE EITHER NUCLEAR RETENTION OR CYTOPLASMIC NUCLEOLYTIC DEGRADATION BY THE CELLULAR NONSENSE MEDIATED RNA DECAY (NMD) PATHWAY; AND WE SHOW THAT NEARLY 50% OF EXON SKIPPING EVENTS OBSERVED DURING REACTIVATION ARE NMD CANDIDATES. WE HYPOTHESIZE THAT EBV (AND KSHV) LYTIC REPLICATION INDUCES EXTENSIVE NON-CANONICAL EXON SKIPPING OF CELL TRANSCRIPTS RESULTING IN EITHER NUCLEAR RETENTION OR DEGRADATION THROUGH THE CYTOPLASMIC NMD PATHWAY AS A SECOND, NEW ARM OF HOST SHUT OFF. WHILE CLASSIC HOST SHUT OFF HAS BEEN STUDIED FOR MANY YEARS, HOW SPECIFICITY FOR CELL TRANSCRIPTS IS ACHIEVED HAS BEEN LARGELY ENIGMATIC. NOTABLY, HERPESVIRAL LYTIC GENES EXHIBIT A REMARKABLY CONSISTENT FEATURE OF BEING PRIMARILY MONO-EXONIC (I.E. UNSPLICED). WE HYPOTHESIZE THAT SPLICING DERANGEMENT IS A NEW ARM OF HOST SHUT OFF THAT FACILITATES SELECTIVE TARGETING OF SPLICED CELL TRANSCRIPTS TO FREE UP RESOURCES FOR HIGH-LEVEL PRODUCTION OF VIRAL PROTEINS. IN THIS PROP

THE ROLE OF VIRAL EXPOSURE AND AGE IN ALZHEIMER'S DISEASE PROGRESSION - CURRENTLY AFFLICTING MORE THAN 6.2 MILLION AMERICANS, ALZHEIMER’S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE CONDITION THAT RESULTS FROM PATHOLOGICAL BRAIN AGING AND IS THE MOST COMMON CAUSE OF COGNITIVE DYSFUNCTION AMONG OLDER ADULTS. THE LACK OF COMPREHENSIVE UNDERSTANDING REGARDING DRIVERS OF AD INITIATION AND PROGRESSION REPRESENTS A CRITICAL BARRIER TO PROGRESS FOR THE FIELD AND HAS CONTRIBUTED TO THE CURRENT LACK OF VIABLE TREATMENT OPTIONS. PATHOGENS ARE EMERGING AS A POTENTIAL CONTRIBUTOR TO THE ETIOLOGY OF AD. NEUROLOGICAL MANIFESTATIONS AND AD-ASSOCIATED PHENOTYPES FOLLOWING ACUTE INFECTION WITH A VARIETY OF PATHOGENS HAVE BEEN WELL DOCUMENTED. THE LONG-TERM CONSEQUENCES OF REPEATED INFECTION ARE INADEQUATELY STUDIED, THOUGH EMERGING EPIDEMIOLOGICAL AND PRECLINICAL EVIDENCE SUGGESTS THAT A HIGHER LIFETIME INFECTION BURDEN IMPAIRS COGNITION, ESPECIALLY AMONG ORGANISMS CARRYING AD GENETIC RISK. THAT PATHOGENS IMPACT CELLULAR METABOLISM MAY REPRESENT A KEY AD-RELATED MECHANISM BY WHICH INFECTION ACCELERATES AD PROGRESSION. WHAT REMAINS UNKNOWN IS 1) WHETHER A HIGHER LIFETIME EXPOSURE FREQUENCY TO PATHOGENS, ESPECIALLY THOSE THAT HAVE LIMITED NEURONAL TROPISM, CAN PROMOTE AN AD PHENOTYPE, 2) HOW ADVANCED AGE MAY POTENTIATE THIS RISK, AND 3) THE EXTENT TO WHICH ALTERED METABOLISM, DUE TO INFECTION, CONTRIBUTES TO THESE EFFECTS. DETERMINATION OF HOW REPEATED VIRAL EXPOSURE INFLUENCES AD NEUROPATHOLOGICAL DEVELOPMENT AND COGNITIVE IMPAIRMENT AS A FUNCTION OF AGE IS A CRITICAL NEED FOR THE FIELD. OUR PRELIMINARY DATA DEMONSTRATES THAT INTERMITTENT INFECTION INDUCES ALTERED METABOLIC PHENOTYPES IN BRAIN MICROVASCULAR ENDOTHELIAL CELLS (BMVEC) AND CORRELATES WITH REDUCED COGNITIVE FUNCTION. WE OBSERVE SIGNIFICANT DECREASES IN MARKERS ASSOCIATED WITH MITOCHONDRIAL FUNCTION IN INFECTED MICE. WE WILL LEVERAGE AN AGING MURINE MODEL WITH REPEATED EXPOSURE TO VIRUSES, TO DETECT CHANGES TO METABOLIC PATHWAYS IN THE BLOOD BRAIN BARRIER AND HOW THIS CORRELATES TO COGNITIVE ABILITY. AIM 1 WILL ADDRESS IF REPEATED VIRAL EXPOSURE ACCELERATES AGE-ASSOCIATED MITOCHONDRIAL DYSFUNCTION OF CELLS IN THE BLOOD BRAIN BARRIER, CONTRIBUTING TO AD PROGRESSION. AIM 2 WILL DEFINE HOW VOLTAGE DEPENDENT ANION CHANNEL 1 MECHANISTICALLY ALTERS MITOCHONDRIAL FUNCTION IN BMVEC WITH AGE. AIM 3, DEFINES HOW VIRUSES IMPACTS BLOOD BRAIN BARRIER PERMEABILITY AS A FUNCTION OF AGE, ACCELERATING AD PROGRESSION. THE OUTCOME OF THESE STUDIES WILL CONTRIBUTE CRUCIAL UNDERSTANDING OF HOW PATHOGEN EXPOSURE INFLUENCES AD PROGRESSION AND COGNITIVE FUNCTION. THIS PROJECT COULD POTENTIALLY REVEALING NOVEL THERAPEUTIC OR PREVENTATIVE TARGETS TO PREVENT AD PROGRESSION, OFFERING HOPE TO MILLIONS OF PATIENTS AND THEIR CAREGIVERS.

TARGETING MECHANISMS OF IMMUNE EVASION IN CHEMOTHERAPY-INDUCED SENESCENT CELLS - PROJECT SUMMARY/ABSTRACT BREAST TUMORS ARE RARELY ERADICATED BY CHEMOTHERAPY. RESIDUAL DISEASE EXISTS FOR 2 REASONS: THE TUMOR CELLS 1) AVOID DEATH FROM APOPTOSIS, MITOTIC CATASTROPHE, AND NUTRIENT DEPRIVATION; 2) AVOID IMMUNE CLEARANCE. OUR PREVIOUS RESEARCH HAS ESTABLISHED THAT BY ACTIVATING P53-MEDIATED PROGRAMS OF ARREST AND SENESCENCE, TUMOR CELLS AVOID DEATH BY MITOTIC CATASTROPHE, APOPTOSIS, AND NUTRIENT DEPRIVATION. WE SHOWED CHEMOTHERAPY TREATED BREAST CANCER PATIENTS WITH P53 WILD TYPE TUMORS HAVE DISMAL SURVIVAL COMPARED TO PATIENTS WITH P53 MUTANT TUMORS. SENESCENT CELLS PROMOTE RELAPSE BY THEIR PRODUCTION OF CYTOKINES AND CHEMOKINES (TERMED THE SENESCENCE ASSOCIATED SECRETORY PHENOTYPE, OR SASP). THE WEAKNESS OF PRIOR RESEARCH HAS BEEN A FAILURE TO IDENTIFY HOW THE TREATED, SENESCENT TUMOR CELLS AVOID IMMUNE CLEARANCE. IN THIS PROPOSAL, WE PRESENT COMPELLING PRELIMINARY DATA ADDRESSING THIS WEAKNESS, AND PLANS TO FULLY CHARACTERIZE AND INVESTIGATE POTENTIAL THERAPEUTIC AVENUES THAT TARGET THE EVASION OF CELL DEATH, THUS FACILITATING IMMUNE CLEARANCE AND IMPROVING SURVIVAL. IN PRELIMINARY DATA, WE IDENTIFY A REMARKABLE UPREGULATION OF PD-L1 IN THE PERSISTING RESIDUAL DISEASE LIKELY MEDIATED THROUGH INTERACTIONS WITH STROMAL CELLS, AND EXPRESSION IS MAINTAINED IN THE RELAPSE, SUGGESTING A STRONG SELECTIVE PRESSURE. THE GOAL OF THIS PROJECT IS TO IDENTIFY MECHANISMS AND DEVELOP STRATEGIES TO TARGET IMMUNE EVASION SPECIFICALLY IN TUMOR CELLS THAT HAVE SURVIVED CHEMOTHERAPY BY ENTERING SENESCENCE. HYPOTHESIS: STROMAL INTERFERON GAMMA (IFN) INDUCES PD-L1 IN A SPECIFIC SUBSET OF CELLS IN A CHEMOTHERAPY- TREATED, SENESCENT TUMOR. THESE PERSISTING, SENESCENT TUMOR CELLS CAN BE TARGETED USING A NOVEL STRATEGY THAT COMBINES SENOLYTIC DRUGS TO INDUCE IMMUNOGENIC CELL DEATH FOLLOWED BY IMMUNE CHECKPOINT INHIBITORS. IN AIM 1 WE WILL USE MOUSE MAMMARY TUMOR MODELS TO DETERMINE IF PD-L1 EXPRESSING TUMOR CELLS HAVE GREATER RELAPSE POTENTIAL THAN CELLS WITHIN THE SAME TREATED TUMOR THAT DO NOT EXPRESS PD-L1, AND HOW EACH RESPONDS TO RETREATMENT. WE WILL CHARACTERIZE GENE EXPRESSION DIFFERENCES IN CELLS THAT EXPRESS PD-L1 VS. THOSE THAT DO NOT. IN AIM 2 WE WILL IDENTIFY THE FACTORS IN VIVO THAT ARE REQUIRED FOR PD-L1 UPREGULATION ON SENESCENT TUMOR CELLS. WE WILL TRANSPLANT MAMMARY TUMORS INTO SYNGENEIC MICE THAT LACK SPECIFIC IMMUNE COMPONENTS SUCH AS T CELLS, TREAT WITH CHEMOTHERAPY, AND DETERMINE CHANGES IN PD-L1 EXPRESSION AND IMMUNE CONTEXTURE. IN AIM 3, PRELIMINARY DATA SHOW ONLY ONE THIRD OF SENESCENT MOUSE MAMMARY TUMORS RESPONDED TO ANTI-PD-L1 THERAPY FOLLOWING CHEMOTHERAPY. WE WILL TEST IF INDUCING IMMUNOGENIC CELL DEATH WITH BH3 MIMETIC DRUGS WE HAVE SHOWN TO HAVE SENOLYTIC ACTIVITY CAN IMPROVE THE RESPONSE TO IMMUNE CHECKPOINT INHIBITORS. IN AIM 4, WE WILL USE MULTIPLEX IMMUNOHISTOCHEMISTRY STAINING OF HUMAN BREAST CANCER SPECIMENS PRE AND POST CHEMOTHERAPY TO DETERMINE IF PD-L1 EXPRESSION IS INDUCED IN SENESCENT TUMORS.

NEURO-IMMUNE MECHANISMS AGAINST SKIN-PENETRATING HELMINTHS - NEURO-IMMUNE MECHANISMS AGAINST SKIN-PENETRATING HELMINTHS SUMMARY DIVERSE HELMINTH SPECIES ESTABLISH HOST INFECTION THROUGH DIRECT SKIN PENETRATION, BUT THE MECHANISMS OF CUTANEOUS IMMUNITY ARE POORLY UNDERSTOOD. CURIOUSLY, PERCUTANEOUS INFECTION OF OVER 250 MILLION PEOPLE WITH THE WATER-BORNE BLOOD FLUKE SCHISTOSOMA MANSONI OFTEN GOES UNNOTICED AND MOST OF THESE INDIVIDUALS EXPERIENCE FREQUENT RE-INFECTION DUE TO POOR IMMUNE RESPONSES TO SKIN-PENETRATING LARVAE. WHETHER A MECHANISTIC LINK EXISTS BETWEEN IMPAIRED PROTECTIVE IMMUNITY AND FAILURE OF SKIN AFFERENT NEURONS TO RELEASE IMMUNOSTIMULATORY FACTORS IS A MAJOR GAP IN OUR CURRENT UNDERSTANDING OF HOST IMMUNITY. MOREOVER, THE ROLE OF THE ALARMIN CYTOKINE INTERLEUKIN 33 (IL-33) IN DRIVING HOST RESISTANCE OR SUSCEPTIBILITY TO SKIN PENETRATION BY HELMINTH LARVAE HAS NOT BEEN TESTED. OUR DATA REVEAL THAT PRE-EMPTIVE ACTIVATION OF MOUSE SKIN-AFFERENTS DRIVES INNATE RESISTANCE TO PARASITE INVASION ACCOMPANIED BY THE RECRUITMENT OF INTERLEUKIN (IL)-17-PRODUCING CD4 AND GD T CELL SUBSETS, AND INFLAMMATORY MONOCYTES. SURPRISINGLY, SKIN NEURON ACTIVATION ALSO RAPIDLY DEPLETES IL-33 IN TISSUE MACROPHAGES AND TYPE 2 CONVENTIONAL DENDRITIC CELLS (CDC2), BUT NOT SKIN FIBROBLASTS. INDEED, MICE WITH A GENETIC DELETION OF IL-33 ONLY IN CD11C+ MYELOID ANTIGEN PRESENTING CELLS (APC) PHENOCOPY HOST IMMUNE RESPONSES IN WILD-TYPE MICE WITH ACTIVATED SKIN-SENSORY NEURONS. THIS PROJECT SEEKS TO IDENTIFY THE SPECIFIC NEURON SUBSETS AND THE SOLUBLE MEDIATORS THEY RELEASE THAT DRIVE HOST RESISTANCE AND DISCERN WHETHER SUCH PROTECTION REQUIRES LOSS OF MYELOID-SPECIFIC IL-33. ONE OF THE KEY IMMUNOREGULATORY NEUROPEPTIDES RELEASED BY SKIN AFFERENTS IS CALCITONIN GENE-RELATED PEPTIDE (CGRP) AND OUR DATA SHOW THAT CGRP ADMINISTRATION RESULTS IN MYELOID APC- INTRINSIC LOSS OF IL-33 THROUGH UNKNOWN MECHANISM(S). THEREFORE, OUR CENTRAL HYPOTHESIS THAT ITCH-RESPONSIVE SKIN NEURONS INITIATE HOST RESISTANCE TO SKIN PENETRATING HELMINTHS VIA CGRP-MEDIATED REDUCTION OF MYELOID-SPECIFIC IL-33, WHICH INITIATES PRODUCTION OF IL-17-PROMOTING CYTOKINES FROM SKIN MACROPHAGE AND CDC SUBSETS. THE TWO SPECIFIC AIMS OF THIS PROPOSAL ARE TO: (1) IDENTIFY THE NEURON SUBSETS NECESSARY AND SUFFICIENT FOR SKIN RESISTANCE TO HELMINTH INFECTION AND (2) DETERMINE HOW CGRP CAUSES DECREASE IN MYELOID- SPECIFIC IL-33 AND HOST RESISTANCE TO PARASITE INVASION. SUCCESSFUL COMPLETION OF THIS PROJECT DESIGNED TO UNDERSTAND HOW SENSORY NEURON-APC INTERACTIONS CONTROL HOST PROTECTION AND IL-33 EXPRESSION STANDS TO PROVIDE KEY INSIGHT(S) FOR DEVELOPING PREVENTATIVE MEASURES AGAINST HELMINTH SKIN PENETRATION IN HUMANS, WHICH DO NOT CURRENTLY EXIST.

EVALUATING THE ASSOCIATION BETWEEN CARDIOMETABOLIC HEALTH OVER THE LIFESPAN AND VERTEBRAL STRENGTH - ABSTRACT FRAGILITY FRACTURES ARE A SUBSTANTIAL PUBLIC HEALTH PROBLEM IN OLDER ADULTS IN THE UNITED STATES (US), WITH VERTEBRAL FRACTURES BEING THE MOST PREVALENT FRACTURE TYPE. CARDIOMETABOLIC DISORDERS (E.G., HYPERTENSION, TYPE 2 DIABETES MELLITUS, ABDOMINAL OBESITY, AND HYPERLIPIDEMIA) HAVE BEEN ASSOCIATED WITH LOWER BONE STRENGTH, BONE MINERAL DENSITY (BMD), AND HIGHER FRACTURE RISK. ALTHOUGH SEVERAL EPIDEMIOLOGIC STUDIES HAVE EVALUATED THE ROLE OF CARDIOMETABOLIC HEALTH ON VERTEBRAL FRACTURES, BY NOT ACCOUNTING FOR THE CLUSTERING OF CARDIOMETABOLIC CONDITIONS, MANY OF THE STUDY FINDINGS ARE LIMITED. LARGE STUDIES WITH THE ABILITY TO ADJUST FOR MULTIPLE CARDIOMETABOLIC CONDITIONS ARE NEEDED TO PROVIDE INFORMATION ON THE FULL EFFECT OF CARDIOMETABOLIC CONDITIONS ON VERTEBRAL HEALTH, INCLUDING BMD AND STRENGTH. STUDIES EVALUATING MOLECULAR MECHANISMS OF CARDIOMETABOLIC CONDITIONS ON VERTEBRAL HEALTH ALSO HAVE STUDY DESIGN LIMITATIONS, INCLUDING THE LACK OF ADJUSTMENT FOR CLUSTERING OF OTHER CARDIOMETABOLIC CONDITIONS AND/OR BIOMARKERS, AND CROSS-SECTIONAL EVALUATIONS WHERE EITHER THE CARDIOMETABOLIC EXPOSURES AND/OR BONE HEALTH DATA ARE ASSESSED AT A SINGLE TIME POINT. THE LACK OF LONGITUDINAL DATA LIMITS OUR ABILITY TO UNDERSTAND HOW CARDIOMETABOLIC HEALTH IS RELATED TO VERTEBRAL HEALTH. LASTLY, ADVANCES IN COMPUTED TOMOGRAPHY (CT) TECHNOLOGY HAS ALLOWED FOR BONE MASS AND STRENGTH MEASUREMENTS. BIOMECHANICAL CT (BCT) ANALYSIS HAS ALLOWED RESEARCHERS TO OBTAIN VALIDATED BONE MASS AND STRENGTH ON CT IMAGES OBTAINED FOR OTHER CLINICAL INDICATIONS, OPENING THE INVESTIGATION OF THE ROLE OF CARDIOMETABOLIC DISORDERS ON VERTEBRAL HEALTH IN INDIVIDUALS WHO DO NOT ROUTINELY RECEIVE DXA IMAGING (I.E. WOMEN OF COLOR AND MEN). THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS (CARDIA) STUDY HAS FOLLOWED 5,115 BLACK AND WHITE MALE AND FEMALE ADULTS AGED 18-30 YEARS AT BASELINE FOR 35 YEARS. THE PROPOSED STUDY WILL BUILD ON CARDIA’S PREVIOUSLY COLLECTED CARDIOMETABOLIC DISEASE AND BIOMARKER DATA. IT WILL ALSO ADD VERTEBRAL STRENGTH DATA THROUGH BCT ANALYSIS OF YEAR 25 AND 35 ABDOMINAL CT SCANS. OUR AIMS ARE TO: 1) EVALUATE THE ASSOCIATION BETWEEN CARDIOMETABOLIC DISEASE PATTERNS AND VERTEBRAL HEALTH, 2) DETERMINE THE ROLE OF CARDIOMETABOLIC BIOMARKERS ON VERTEBRAL HEALTH, AND 3) IDENTIFY CARDIOMETABOLIC HEALTH FACTORS THAT PREDICT 10-YEAR CHANGES IN VERTEBRAL HEALTH. OUR OVERALL GOAL IS TO PROVIDE UNBIASED AND LONGITUDINAL ESTIMATES OF THE ASSOCIATION BETWEEN CARDIOMETABOLIC HEALTH AND VERTEBRAL HEALTH, AND TO EXPLORE THE POTENTIAL BIOLOGIC MECHANISMS OF THESE ASSOCIATIONS. DETERMINING HOW CARDIOMETABOLIC DISEASE PATTERNS AND BIOMARKERS, AT CLINICAL OR SUBCLINICAL LEVELS, IMPACT VERTEBRAL BONE HEALTH IS HIGHLY DESIRABLE AND CAN LEAD TO CHANGES IN FRACTURE SCREENING PROTOCOLS IN THIS HIGH RISK POPULATION.

THE IMPACT OF LINE-1 RETROTRANSPOSONS ON LIFE SPAN, SASP, AND TELOMERES IN VIVO

CHARACTERIZATION AND FUNCTIONAL ASSESSMENT OF A NOVEL POPULATION OF WNT/BETA-CATENIN DRIVEN ADOPOCYTES. - PROJECT SUMMARY/ABSTRACT OBESITY, CAUSED BY THE INCREASE IN SIZE AND THE AMOUNT OF FAT CELLS (ADIPOCYTES), IS BECOMING A WORLDWIDE PANDEMIC, PRODUCING A HUGE PUBLIC HEALTH PROBLEM DUE TO THE ASSOCIATED RISK WITH DEVELOPING OTHER DISEASES. IN MAMMALS, THE ADIPOSE/FAT TISSUE IS COMPOSED OF CLASSIC WHITE ADIPOSE TISSUE (WAT) AND BROWN ADIPOSE TISSUE (BAT), WITH WAT SERVING FOR ENERGY STORAGE AND BAT FOR ENERGY DISSIPATION TO PRODUCE HEAT. A THIRD TYPE OF ADIPOCYTES EXISTS, KNOWN AS BEIGE ADIPOCYTES THAT ARE TRANSIENTLY GENERATED IN WA T DEPOTS IN RESPONSE TO ENVIRONMENTAL STIMULATIONS. BAT/BEIGE FATS ARE THE ESTABLISHED THERMOGENIC TISSUES THAT PLAY AN ESSENTIAL ROLE IN HUMAN ENERGY HOMEOSTASIS AND THEREFORE IN PROTECTION OF OBESITY-RELATED METABOLIC DISORDERS. WHILE WHITE ADIPOCYTES AND BROWN ADIPOCYTES DIFFERENTIATE FROM PRECURSORS WITH DISTINCT ORIGINS, IT IS THE CONSENSUS THAT WNT/SS- CATENIN SIGNALING IMPOSES NEGATIVE EFFECTS ON ADIPOGENESIS BY INHIBITING ADIPOGENIC DIFFERENTIATION. ALTHOUGH SOME STUDIES HAVE IMPLICATED THE REQUIREMENT OF WNT SIGNALING AND ITS COMPONENTS IN ADIPOGENESIS AND PROPER FUNCTIONS OF ADIPOSE TISSUES, DIRECT EVIDENCE IS LACKING, LEAVING A CRITICAL KNOWLEDGE GAP AS IF WNT SIGNALING PLAYS A DIRECT AND CRUCIAL ROLE IN ADIPOGENESIS. IN OUR PRELIMINARY STUDIES, WE HAVE SURPRISINGLY DISCOVERED THE EXISTENCE OF A POPULATION OF WNT/SS-CATENIN SIGNALING DRIVEN ADIPOCYTES, NAMED AS WNT+ ADIPOCYTES, IN VARIOUS FAT DEPOTS INCLUDING BONE MARROW IN MICE FROM EMBRYONIC STAGE TO ADULTHOOD. USING WNT+ ADIPOCYTES INDUCED FROM SVF CELLS IN VITRO, WE FURTHER SHOWED THE REQUIREMENT OF THE LIGAND- AND RECEPTOR-INDEPENDENT WNT/SS-CATENIN SIGNALING, WHICH APPEARED TO DEPEND ON ACTIVE AKT/MTOR SIGNALING, IN ADIPOCYTE MATURATION. OUR SCRNA-SEQ AND SCATAC- SEQ ANALYSES HAVE DISTINGUISHED THIS NOVEL POPULATION OF ADIPOCYTES FROM THE CLASSIC ADIPOCYTES AT MOLECULAR AND GENOMIC LEVELS. WE ALSO FOUND THAT THESE ADIPOCYTES EXHIBIT POTENTIALLY HIGH METABOLIC AND THERMOGENIC PROPERTIES, BEING ABLE TO CONVERT/TRANSDIFFERENTIATE INTO BEIGE ADIPOCYTES IN RESPONSE TO COLD STRESS, AND BEING IMPLICATED IN SYSTEMIC ENERGY HOMEOSTASIS. BASED ON THESE PRELIMINARY RESULTS, WE HYPOTHESIZE THAT A NOVEL POPULATION OF WNT/SS-CATENIN SIGNALING DRIVEN ADIPOCYTES IS WIDELY PRESENT IN VARIOUS FAT DEPOTS AND PLAYS CRUCIAL FUNCTION IN REGULATING WHOLE BODY METABOLIC HOMEOSTASIS. IN THIS PROPOSAL, TWO SPECIFIC AIMS ARE PROPOSED TO TEST THIS HYPOTHESIS RIGOROUSLY: 1) TO CHARACTERIZE ENDOGENOUS WNT+ ADIPOCYTES AND TO INVESTIGATE THE FUNCTIONAL MECHANISM OF THE INTRACELLULAR WNT/SS-CATENIN SIGNALING IN ADIPOGENESIS; 2) TO DETERMINE THE IN VIVO FUNCTION OF WNT+ ADIPOCYTES IN REGULATING WHOLE-BODY METABOLISM IN FETAL/NEONATAL AND ADULT STAGE. OVERALL, WE WILL DEFINE THE IDENTITY AT CELLULAR, MOLECULAR, AND GENOMIC LEVELS OF A NOVEL POPULATION OF WNT/SS-CATENIN DRIVEN ADIPOCYTES THAT EXIST IN VARIOUS FAT DEPOTS AND EXHIBIT POTENTIALLY HIGH METABOLIC AND THERMOGENIC PROPERTIES. WE WILL ALSO ASSESS OVERALL IMPACTS OF THIS POPULATION OF ADIPOCYTES ON ADIPOSE TISSUE FUNCTION, WHOLE-BODY METABOLIC HOMEOSTASIS, AND PROTECTION OF OBESITY. THE PROPOSAL WILL ALSO ADDRESS THE FUNCTIONAL MECHANISM AND IDENTIFY DIRECT TARGETS OF THE AKT/MTOR SIGNALING DEPENDENT INTRACELLULAR WNT/SS-CATENIN SIGNALING DURING ADIPOGENESIS IN THIS POPULATION OF ADIPOCYTES. RESULTS OBTAINED FROM PROPOSED STUDIES WILL REVEAL THE ORIGIN, RECRUITMENT, ACTIVATION, MOLECULAR REGULATION, AND FUNCTION OF A UNIQUE POPULATION OF THERMOGENIC ADIPOCYTES, PROVIDING NOVEL KNOWLEDGE TO THE BIOLOGY OF ADIPOCYTES AS WELL AS SOLID FOUNDATION FOR FUTURE APPLICATION OF THIS POPULATION OF ADIPOCYTES IN THE THERAPY OF OBESITY.

PRIMARY CARE TRAINING AND ENHANCEMENT - RESIDENCY TRAINING IN MENTAL AND BEHAVIORAL HEALTH

PURPOSE:THE PURPOSE OF THIS GRANT IS TO PROVIDE EQUIPMENT FOR A NEW STATE OF THE ART MICRO/NANOFABRICATION CLEANROOM FACILITY IN SPACE SET ASIDE WITHIN THE NEW STEVEN & JANN PAUL SCIENCE AND ENGINEERING RESEARCH BUILDING (PAUL HALL) AT TULANE UNIVERSITY.ACTIVITIES TO BE PERFORMED:THE EQUIPMENT WILL HELP TRAIN STUDENTS AND STAFF WHO WILL BECOME KEY MEMBERS OF THE WORKFORCE FOR THE SEMICONDUCTOR AND NANOTECHNOLOGY INDUSTRY. THE NEW EQUIPMENT WILL ALLOW THE FACILITY TO SERVE APPROXIMATELY 20 LOCAL NEW ORLEANS PRINCIPAL INVESTIGATORS AND THEIR RESEARCH GROUPS, 120 RESEARCH, STAFF, GRADUATE, AND UNDERGRADUATE STUDENT RESEARCHERS.IN ADDITION, THE PROJECT WILL ENABLE AND SUPPORT NEW AND EXISTING NANOTECHNOLOGY COLLABORATIONS AMONGST REGIONAL UNIVERSITIES, START-UPS AND SMALL COMPANIES, IN A BROAD RANGE OF APPLICATIONS INCLUDING ENERGY AND QUANTUM TECHNOLOGIES, MICROSENSORS, AND BIOMEDICAL DEVICES.EXPECTED OUTCOMES:THE NEW INSTRUMENTS WILL INCREASE THE CAPABILITIES OF THE MICRO/NANOFABRICATION CLEANROOM FACILITY AT STEVEN & JANN PAUL SCIENCE AND ENGINEERING RESEARCH BUILDING AT TULANE UNIVERSITY, AND PROVIDE TRAINING OPPORTUNITIES FOR ABOUT 30 MORE STUDENTS EACH YEAR VIA COURSEWORK, CAPSTONE PROJECTS, AND OTHER HANDS-ON MICRO/NANOFABRICATION TEACHING AND OUTREACH.INTENDED BENEFICIARIES:MICRO/NANOFABRICATION CLEANROOM FACILITY AT STEVEN & JANN PAUL SCIENCE AND ENGINEERING RESEARCH BUILDING (PAUL HALL), OF TULANE UNIVERSITY, RESEARCHERS AT TULANE, XAVIER UNIVERSITY OF LOUISIANA, AND THE UNIVERSITY OF NEW ORLEANS. MEMBERS OF THE CONSORTIUM FOR INNOVATION IN MANUFACTURING AND MATERIALS CORE USER FACILITY (CUR), A NETWORK OF ADVANCED MANUFACTURING AND METROLOGY CENTERS THAT EXIST AT LOUISIANA STATE UNIVERSITY, LOUISIANA TECH, THE UNIVERSITY OF LOUISIANA, AND TULANE UNIVERSITY.SUBRECIPIENT ACTIVITIES:THE RECIPIENT DOES NOT INTEND TO SUBAWARD FUNDS.

PURPOSE: TITLE: SOUTHWEST LOUISIANA AND CENTRAL ACADIANA RESILIENT FUTURE RECIPIENT: BYWATER INSTITUTE, TULANE UNIVERSITY PROJECT TYPE: REGIONAL COLLABORATIVE BUILDING AND STRATEGY DEVELOPMENT (TRACK ONE) FUNDING AMOUNT: $1,998,800 CONGRESSIONAL DISTRICT: LA-02 SUMMARY: TO DEVELOP A COORDINATED VISION AND SUSTAINABLE RESILIENCE-FOCUSED ACTION PLAN FOR LOUISIANAS SOUTHWEST AND CENTRAL ACADIANA, THIS PROJECT WILL USE A MULTI-PRONGED APPROACH FOR COMMUNITY-BASED REGIONAL PLANNING AND GOVERNANCE. ACTIVITIES INCLUDE ANALYZING EXISTING PLANS; CHARACTERIZING CLIMATE RISK; DEFINING BEST PRACTICES; PRIORITIZING POTENTIAL PROJECTS; EVALUATING POLICIES; AND DEVELOPING ENGINEERING REPORTS TO MOVE PRIORITIZED PROJECTS TOWARD IMPLEMENTATION. TO MEET FUTURE NEEDS, THE PROJECT WILL SET UP A REGIONAL COLLABORATIVE THAT OFFERS CONTINUED COORDINATION, IMPLEMENTATION, EVALUATION, AS WELL AS SUSTAINED KNOWLEDGE AND RESOURCE SHARING. THIS FUNDING SUPPORTS FOUNDATIONAL BUILDING BLOCKS NEEDED FOR LONG-TERM SUCCESS, FILLING IN TECHNICAL AND DATA-RELATED INFORMATION GAPS; HELPING COMMUNITIES IDENTIFY AND USE APPROPRIATE DATA AND TOOLS; STRENGTHENING COORDINATION BETWEEN GOVERNMENTS AT ALL SCALES, INCLUDING TRIBAL; ASSESSING THE ROBUSTNESS OF EXISTING RESILIENCE PROJECTS, POLICIES, AND PROGRAMS; AND EVALUATING EQUITY IMPACTS.

THE ROLE OF UBE3A IN GLIOPATHIC SEIZURES

STATE SOCIAL POLICY INTERVENTIONS FOR MATERNAL HEALTH - PROJECT SUMMARY POVERTY IS THE MOST WIDELY STUDIED FUNDAMENTAL DETERMINANT OF MATERNAL MENTAL HEALTH, MORBIDITY, MORTALITY, AND INEQUITIES IN THE U.S. AND WORLDWIDE. LOW ABSOLUTE AND RELATIVE INCOME AND LOW SOCIOECONOMIC STATUS ARE ASSOCIATED WITH FINANCIAL HARDSHIP, FOOD AND HOUSING INSECURITY, DISCRIMINATION, LIMITED HEALTHCARE ACCESS, OTHER SOCIAL STRESSORS, AND SUBSEQUENT DEPRESSION DURING THE PRECONCEPTION, PERINATAL, POSTPARTUM, AND PARENTING YEARS; EFFECTS ARE DISPROPORTIONATELY ADVERSE FOR RACIAL AND ETHNIC MINORITY, RURAL-RESIDING, AND OTHER STRUCTURALLY DISADVANTAGED GROUPS OF WOMEN. PUBLIC POLICIES THAT SHAPE THE SOCIAL CONDITIONS IN WHICH WOMEN LIVE, NOTABLY THOSE THAT ASSURE ECONOMIC RESOURCES AND SUPPORTS DURING THE EARLY CHILDBEARING YEARS, CAN SET LIFE-LONG TRAJECTORIES OF MATERNAL AND CHILD WELLBEING. THUS, ECONOMIC SECURITY LAWS HAVE STRONG POTENTIAL AS PUBLIC HEALTH INTERVENTIONS FOR WOMEN’S MENTAL HEALTH AND HEALTH EQUITY; YET THE MOST TIMELY AND PROMISING STATE-LEVEL LAWS WITHIN THE DYNAMIC, COMPLEX POLICY LANDSCAPE OVER THE LAST TWO DECADES HAVE NOT BEEN COLLECTIVELY OR RIGOROUSLY EVALUATED. THE GOAL OF THIS R01 IS TO EMPIRICALLY TEST THE EFFECTS OF SIX STATE-LEVEL ECONOMIC SECURITY POLICIES TARGETING LOW-INCOME WOMEN ON MATERNAL MENTAL HEALTH OUTCOMES AND DISPARITIES ACROSS THE U.S. OVER THE LAST 20 YEARS. WE FOCUS ON PAID FAMILY LEAVE, PAID MEDICAL LEAVE, CHILD CARE AND DEVELOPMENT FUND, EARNED INCOME TAX CREDITS, MINIMUM WAGE, AND TEMPORARY ASSISTANCE FOR NEEDY FAMILIES. FIRST, WE WILL USE OUR TEAM’S VALIDATED NOVEL LEGAL MEASUREMENT, ANALYSIS, AND MAPPING METHODS TO CONDUCT A DETAILED STATE- YEAR-LEVEL POLICY SURVEILLANCE STUDY OF THE SIX ECONOMIC POLICIES ACROSS ALL 50 STATES AND WASHINGTON D.C. FROM 2000 TO 2023. SECOND, WE WILL ESTIMATE THE INDEPENDENT EFFECTS OF EACH ECONOMIC SECURITY POLICY (AND SPECIFIC DIMENSIONS OF EACH POLICY) ON A RANGE OF MENTAL HEALTH INDICATORS SPANNING THE PRECONCEPTION, PERINATAL, POSTPARTUM, AND PARENTING PERIODS AMONG U.S. WOMEN AGES 18 TO 45. WE WILL USE A RIGOROUS QUASI- EXPERIMENTAL APPROACH (DIFFERENCE-IN-DIFFERENCES), EXPLOITING STATE-YEAR-LEVEL POLICY VARIATION AND SIX DIFFERENT POPULATION DATASETS, TO PROVIDE CAUSAL ESTIMATES AND MAXIMIZE STATISTICAL POWER. WE WILL EXAMINE DIFFERENCES IN POLICY EFFECTS BY RACE, ETHNICITY, SOCIOECONOMIC STATUS, RURALITY/URBANICITY, AND AGE. THIRD, WE WILL USE INTERACTION ANALYSES TO TEST WHETHER COMBINATIONS OF ECONOMIC SECURITY POLICIES HAVE GREATER IMPACT THAN EACH ALONE AND DETERMINE WHICH POLICY COMBINATIONS HAVE THE GREATEST EFFECTS ON MATERNAL MENTAL HEALTH OUTCOMES AND FOR WHICH GROUPS. FOURTH, WE WILL USE MEDIATION ANALYSIS TO TEST WHETHER ECONOMIC OUTCOMES, HEALTH CARE ACCESS, PSYCHOSOCIAL AND BEHAVIORAL OUTCOMES, AND SOCIAL STRESSORS ARE MECHANISMS LINKING THE ECONOMIC POLICIES TO HEALTH. THIS RESEARCH WILL SUBSTANTIALLY ADVANCE OUR UNDERSTANDING OF HOW SOCIAL POLICIES CAN BE OPTIMALLY USED FOR POPULATION MATERNAL HEALTH PROMOTION. FINDINGS WILL GUIDE POLICYMAKERS TOWARD EVIDENCE- BASED POLICY INTERVENTIONS AT A CRITICAL TIME IN U.S. HISTORY WHEN PUBLIC HEALTH CRISES OF MENTAL HEALTH MORBIDITY, MATERNAL MORTALITY, AND POVERTY ARE COLLIDING FOR CHILDBEARING WOMEN OF STRUCTURAL DISADVANTAGE.

HUMAN MICROPHYSIOLOGICAL MODEL OF AFFERENT NOCICEPTIVE SIGNALING - PROJECT SUMMARY THE MANAGEMENT OF PAIN—BOTH ACUTE AND CHRONIC—CAN BE A FRUSTRATINGLY FUTILE ENDEAVOR FOR BOTH PATIENTS AND CLINICIANS. DESPERATE ATTEMPTS AT TREATMENT WITH OPIOIDS AND OTHER NARCOTICS HAS LED TO A HEARTBREAKING AND CALAMITOUS EPIDEMIC OF ADDICTION TO PRESCRIPTION PAINKILLERS. THIS EPIDEMIC HAS PROMPTED FEDERAL AGENCIES AND THE PHARMACEUTICAL INDUSTRY TO WORK TOWARD THE IDENTIFICATION OF THE NEXT GENERATION OF ANALGESICS. UNFORTUNATELY, THERE ARE FEW ADEQUATE MODEL SYSTEMS CURRENTLY IN USE TO ENABLE RAPID SCREENING OF THE ANALGESIC PROPERTIES OF DRUG CANDIDATES. THERE IS AN ACUTE NEED FOR NEXT-GENERATION NEURAL MICROPHYSIOLOGICAL SYSTEMS THAT ARE USEFUL FOR IDENTIFYING DRUG CANDIDATES FOR PROBLEMS SUCH AS PAIN. MOST CURRENT MICROPHYSIOGICAL MODELS OF THE NERVOUS SYSTEM TEND TOWARD TWO CATEGORIES: ORGANOIDS AND MICROFLUIDIC/ MICROELECTRODE CHIPS. WE POSTULATE THAT THE UNIQUE COMPLEXITY AND STRUCTURE OF THE NERVOUS SYSTEM DEMAND AN INTEGRATED APPROACH IN ORDER TO REALIZE DESIGNS OF NEURAL MICROPHYSIOLOGICAL SYSTEMS THAT CAN BEGIN TO ACCOUNT FOR THE BASIC PHYSIOLOGICAL UNITS THAT ASSEMBLE TO PRODUCE EMERGENT BEHAVIORS OF THE NERVOUS SYSTEM. WE PROPOSE TO DEVELOP A HUMAN CELL-BASED MODEL OF THE AFFERENT PAIN PATHWAY IN THE DORSAL HORN OF THE SPINAL CORD. OUR APPROACH IS INNOVATIVE BECAUSE IT UTILIZES NOVEL HUMAN PLURIPOTENT STEM CELL (HPSC)-DERIVED PHENOTYPES IN A MODEL THAT COMBINES THE 3D NATURE OF ORGANOID CULTURE WITH THE STRUCTURAL AND ORGANIZATIONAL SPECIFICITY OF MICROFABRICATED SYSTEMS, ALL ON AN INTEGRATED, CUSTOM 3D MICROELECTRODE ARRAY. THE RESULTING CULTURE PLATFORM WILL BE THE ONLY AVAILABLE HUMAN MODEL OF THE DORSAL HORN AFFERENT CIRCUIT. THE OBJECTIVES OF THE PROPOSAL WILL BE MET IN TWO PHASES. IN THE FIRST, WE WILL ESTABLISH THE FEASIBILITY OF A PHYSIOLOGICALLY RELEVANT, HUMAN, 3D MODEL OF THE AFFERENT PAIN PATHWAY THAT WILL BE USEFUL FOR EVALUATION OF CANDIDATE ANALGESIC DRUGS. IN THE SECOND PHASE, WE WILL THEN IMPROVE THE PHYSIOLOGICAL RELEVANCE OF THE SYSTEM BY PROMOTING NEURAL NETWORK MATURATION BEFORE THEN DEMONSTRATING THE SYSTEM’ UTILITY IN MODELING ADVERSE EFFECTS OF OPIOIDS AND SCREENING A LIBRARY OF COMPOUNDS TO VALIDATE THE MODEL. COMPLETION OF THE OBJECTIVE WILL ESTABLISH NOVEL PROTOCOLS FOR DERIVING DORSAL HORN NEURONS FROM HPSCS AND CREATE THE FIRST HUMAN MICROPHYSIOLOGICAL MODEL OF THE SPINAL CORD DORSAL HORN AFFERENT SENSORY PATHWAY.

FUNCTIONS OF DUCTAL- AND STROMAL-ASSOCIATED MACROPHAGES IN THE MAMMARY GLAND - PROJECT SUMMARY TISSUE RESIDENT MACROPHAGE FUNCTION HAS EMERGED AS A CRITICAL COMPONENT CONTROLLING THE BALANCE BETWEEN ORGAN HEALTH AND DISEASE. IN THE MAMMARY GLAND, MACROPHAGES ARE CLOSELY ASSOCIATED WITH THE DUCTAL EPITHELIUM AND HAVE IMPORTANT PHAGOCYTOTIC ROLES TO MAINTAIN TISSUE HOMEOSTASIS. RECENT STUDIES FROM OUR LABORATORY AND OTHERS REVEALED DISTINCT DUCTAL- AND STROMAL-ASSOCIATED TISSUE RESIDENT MACROPHAGES THAT CONTRIBUTE TO MAINTAINING THE DEVELOPING DUCTAL STRUCTURES. HOWEVER, THE IMPORTANT MACROPHAGE-DERIVED FACTORS THAT REGULATE MAMMARY GLAND DEVELOPMENT AND THE MECHANISMS BY WHICH THESE DISTINCT MACROPHAGE POPULATIONS MAINTAIN THE HOMEOSTATIC STATE ARE POORLY UNDERSTOOD. THE OVERALL GOAL OF THESE STUDIES IS TO DEFINE THE FUNCTIONS AND MECHANISMS BY WHICH TISSUE RESIDENT MACROPHAGES CONTRIBUTE TO DUCTAL REMODELING THROUGHOUT DISTINCT STAGES OF MAMMARY GLAND DEVELOPMENT. OUR PRELIMINARY STUDIES IDENTIFY TRANSCRIPTIONAL PROFILES OF DISTINCT MACROPHAGE POPULATIONS IN THE MAMMARY GLANDS OF ADULT MICE. WE SHOW THAT TWO KEY FACTORS, CEBPB AND GAS6, ARE HIGHLY EXPRESSED IN DUCTAL- AND STROMAL-ASSOCIATED MACROPHAGES, RESPECTIVELY, PROVIDING POTENTIAL MECHANISMS FOR MACROPHAGE FUNCTION IN MAMMARY GLAND DEVELOPMENT. GENETIC ABLATION OF THESE FACTORS RESULTS IN ALTERATIONS IN THE MAMMARY GLAND DURING KEY DEVELOPMENTAL WINDOWS. WE HYPOTHESIZE THAT C/EBPB AND GAS6 ARE CRUCIAL EFFECTOR MOLECULES THAT DRIVE DISTINCT FUNCTIONS OF DUCTAL AND STROMAL MACROPHAGES, RESPECTIVELY, DURING KEY STAGES OF MAMMARY GLAND DEVELOPMENT. IN AIM 1, WE WILL CHARACTERIZE MACROPHAGE HETEROGENEITY THROUGHOUT POSTNATAL DEVELOPMENT AND DETERMINE THE FUNCTIONS OF DISTINCT MACROPHAGE POPULATIONS IN MAMMARY GLAND DEVELOPMENT. IN AIM 2, THE MECHANISMS OF HOW C/EBPB-INDUCED FACTORS IN DUCTAL MACROPHAGES ALTER STEM CELL EXPANSION WILL BE DETERMINED. IN AIM 3, GAS6-DEPENDENT MECHANISMS OF COLLAGEN HOMEOSTASIS BY STROMAL MACROPHAGES WILL BE DETERMINED. IMPACT: THROUGHOUT MAMMARY GLAND DEVELOPMENT, THERE ARE CRITICAL WINDOWS THAT ARE HIGHLY SUSCEPTIBLE TO MUTAGENIC EVENTS. ALTHOUGH MACROPHAGES HAVE BEEN WELL-STUDIED DURING TUMOR PROGRESSION AND METASTASIS, THE MECHANISMS DRIVING TISSUE RESIDENT MACROPHAGE FUNCTION DURING THESE KEY STAGES OF DEVELOPMENT ARE NOT KNOWN. UNDERSTANDING THESE MECHANISMS WILL ADVANCE OUR UNDERSTANDING OF HOW TISSUE RESIDENT MACROPHAGES IMPACT MAMMARY TISSUE HOMEOSTASIS, AND PROVIDE INSIGHT INTO HOW DISRUPTED TISSUE HOMEOSTASIS LEADS TO DISEASE, SUCH AS TUMORIGENESIS.

IMMUNOTHERAPY OF KPC INFECTION

DEVELOPMENT OF NOVEL ADJUVANTS LTA AND LTA1

TRPV4 REGULATION OF LYMPHATIC VASCULAR FUNCTION: IMPLICATIONS IN METABOLIC SYNDROME - PROJECT SUMMARY A MAJOR FUNCTION OF THE LYMPHATIC SYSTEM IS FLUID TRANSPORT, WHICH IS CRITICAL FOR FLUID HOMEOSTASIS, LIPID TRANSPORT AND METABOLISM, AND THE TRANSPORT OF IMMUNE CELLS AND PRO-INFLAMMATORY MOLECULES. LYMPHATIC VESSELS CONTRACT SPONTANEOUSLY TO PUMP FLUID, WHILE INTRALUMINAL ONE-WAY VALVES ENSURE NET FORWARD FLOW. OUR GROUP AND OTHERS HAVE SHOWN THAT OBESITY AND METABOLIC SYNDROME CAN CAUSE DIFFERENT FORMS OF LYMPHATIC VASCULAR DYSFUNCTION. IN FACT, THIS CONNECTION IS A DYSFUNCTION- AND DISEASE-PROMOTING FEEDBACK LOOP, AS LYMPHATIC DYSFUNCTION ALSO CONTRIBUTES TO OBESITY. THIS SUGGESTS PHARMACOLOGICAL IMPROVEMENT OF LYMPHATIC FUNCTION AS A POTENTIAL THERAPEUTIC ALTERNATIVE IN OBESITY AND METABOLIC SYNDROME. RELEVANT TO THIS PROPOSAL, TRANSIENT RECEPTOR POTENTIAL VANILLOID 4 (TRPV4) CHANNELS ARE KEY REGULATORS OF VASCULAR FUNCTION, AND THEIR ACTIVITY IS DYSREGULATED IN VARIOUS INFLAMMATORY DISEASES, INCLUDING OBESITY AND METABOLIC SYNDROME; HOWEVER, THE ROLE OF TRPV4 CHANNELS IN REGULATING LYMPHATIC VASCULAR FUNCTION IN HEALTH AND DISEASE REMAINS UNEXPLORED. OUR PRELIMINARY STUDIES SHOW THAT OVERACTIVITY OF TRPV4 CHANNELS IN A VARIETY OF CELL TYPES WITHIN AND AROUND THE LYMPHATIC WALL IS DETRIMENTAL TO DIFFERENT ASPECTS OF THE FUNCTION OF THE LYMPHATIC VASCULATURE, INCLUDING IMPAIRMENT OF CONTRACTILITY AND COMPROMISED BARRIER FUNCTION. IMPORTANTLY, PARTIAL DEFICIENCY OF TRPV4 CHANNELS IN THE LYMPHATIC ENDOTHELIUM PREVENTED SIGNIFICANT IMPAIRMENT OF LYMPHATIC FUNCTION UPON STIMULATION OF TRPV4 CHANNELS. TRPV4 CHANNELS HAVE ALSO BEEN IMPLICATED IN REGULATORY MECHANISMS OF TISSUE FIBROSIS VIA ACTIVATION OF THE PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1) LEADING TO REMODELING OF THE EXTRACELLULAR MATRIX. PAI-1 IS AN IMPORTANT BIOMARKER FOR DISEASE, FIBROSIS, AND INFLAMMATION. WE RECENTLY SHOWED THAT PAI-1 IS SIGNIFICANTLY INCREASED IN THE LYMPHATIC VASCULATURE OF DIET-INDUCED OBESE MICE; AND GLOBALLY DEFICIENT PAI-1 MICE ARE SIGNIFICANTLY PROTECTED AGAINST DIET-INDUCED OBESITY AND METABOLIC DYSFUNCTION; HOWEVER, THE UNDERLYING MECHANISMS REMAIN UNKNOWN. IN LINE WITH THE EMERGING SIGNIFICANT ROLE OF THE LYMPHATIC SYSTEM IN LIPID METABOLISM, WE HYPOTHESIZE THAT, IN OBESITY AND METABOLIC SYNDROME, INCREASED PAI-1 CAN BE A KEY MODULATOR OF TRPV4 OVERACTIVITY, AND THIS IS DETRIMENTAL FOR LYMPHATIC VASCULAR FUNCTION, WHICH RECIPROCALLY EXACERBATES OBESITY. WE PROPOSE EVALUATING PAI-1 AS A LONG-TERM THERAPEUTIC ALTERNATIVE FOR DIRECT OR INDIRECT MODULATION OF TRPV4 ACTIVITY. WE ANTICIPATE THAT REDUCING INFLAMMATION AND FIBROSIS VIA PAI-1 INHIBITION WILL DECREASE DIRECT ACTIVATION OF TRPV4 CHANNELS IN TWO WAYS, 1) BY DECREASING INFLAMMATORY MOLECULES; AND 2) BY REDUCING STIFFENING OF THE EXTRACELLULAR MATRIX, AND THEREFORE DECREASING STRETCH-MEDIATED ACTIVATION. AS IMPORTANT REGULATORS OF INFLAMMATORY RESPONSES, DUAL TARGETING OF TRPV4 AND PAI-1 MAY OFFER SYNERGISTIC THERAPEUTIC BENEFITS, TO BE EVALUATED IN THIS PROPOSAL. THIS PROJECT WILL PROVIDE FUNDAMENTAL INFORMATION ABOUT TRPV4 CHANNELS IN THE REGULATION OF LYMPHATIC VASCULAR FUNCTION AND WILL IDENTIFY THE ROLE OF LYMPHATIC TRPV4 CHANNELS IN OBESITY AND METABOLIC SYNDROME.

GPR4 IN BLOOD BRAIN BARRIER DYSFUNCTION IN BRAIN ISCHEMIA - ABSTRACT BRAIN MICROVASCULAR ENDOTHELIAL CELLS (BMEC), TIGHTLY CONNECTED THROUGH TIGHT JUNCTIONS AND ADHESIONS JUNCTIONS, PROVIDE THE STRUCTURAL BASIS FOR THE BLOOD-BRAIN BARRIER (BBB). IN BOTH HUMAN PATIENTS AND ANIMAL MODELS, BBB DISRUPTION EXHIBITS POSITIVE CORRELATION WITH STROKE OUTCOME. DISCOVERING NOVEL MECHANISMS TO PROTECT ENDOTHELIAL BARRIER INTEGRITY WILL PROVIDE IMPORTANT INSIGHTS INTO BETTER THERAPEUTIC TARGETING OF ISCHEMIA-REPERFUSION-INDUCED NEURONAL INJURY. ONE PREVALENT PROCESS IN BRAIN ISCHEMIA IS THE PROLONGED REDUCTION OF BRAIN PH, WHICH IMPLICATES PROTONS AS AN IMPORTANT EXTRACELLULAR SIGNAL. IN PREVIOUS STUDIES, MOST EMPHASIS ON BRAIN PROTON SIGNALING HAS BEEN ON ITS ROLE IN NEURONS. IN CONTRAST, FEW STUDIES HAVE ASSESSED WHETHER ACIDOSIS ALTERS BLOOD-BRAIN BARRIER INTEGRITY, WHICH IS ONE IMPORTANT CONTRIBUTOR TO ISCHEMIA-INDUCED NEURONAL INJURY. THIS APPLICATION WILL FOCUS ON GPR4, A PROTON-SENSITIVE G PROTEIN-COUPLED RECEPTOR WHICH EXHIBITS ABUNDANT EXPRESSION IN BMEC. USING A COMBINATION OF IN VIVO AND IN VITRO MODELS, THE PROPOSED RESEARCH WILL DETERMINE WHETHER GPR4 MEDIATES ACID SIGNALING IN BMEC, AND IDENTIFY ITS DOWNSTREAM MEDIATOR IN ACIDOTIC AND ISCHEMIC CONDITIONS. WITH GENETIC MANIPULATION AND PHARMACOLOGICAL INTERVENTIONS, WE WILL DETERMINE WHETHER DELETING OR INHIBITING GPR4 SPECIFICALLY IN ENDOTHELIAL CELLS ATTENUATES ISCHEMIA-INDUCED BMEC DYSFUNCTION AND PROTECTS THE BRAIN FROM ISCHEMIA-INDUCED NEURONAL INJURY. TO BETTER UNDERSTAND THE MECHANISM, THE RESEARCH WILL ANALYZE DOWNSTREAM SIGNALING AND PERFORM UNBIASED ANALYSIS OF TRANSCRIPTOME CHANGES FROM ACUTELY ISOLATED BMEC. LASTLY, THIS STUDY WILL USE THE LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY APPROACH TO DETERMINE THE PHARMACOKINETICS OF A GPR4 INHIBITOR IN BRAIN AND BLOOD TISSUE. ONCE SUCCESSFULLY ACCOMPLISHED, THE STUDY WILL OFFER GPR4 INHIBITION AS A NOVEL NEUROPROTECTIVE APPROACH TO ALLEVIATE ISCHEMIA-INDUCED BRAIN INJURY.

PROYECTO TARIKI: IMPLEMENTATION SCIENCE FOR COMMUNITY-MOBILIZED RISK REDUCTION OF DENGUE - ABSTRACT THERE IS SCIENTIFIC CONSENSUS THAT THERE ARE EFFECTIVE TOOLS AND STRATEGIES TO CONTROL DENGUE, BUT PROGRAM FAILURES ARE LINKED TO IMPROPER IMPLEMENTATION. THIS PROJECT BRINGS TOGETHER RESEARCHERS WITH >23 YEARS OF EXPERIENCE IN COMMUNITY-BASED EPIDEMIOLOGICAL DENGUE RESEARCH IN IQUITOS, IMPLEMENTATION SCIENCE, AND A TEAM THAT SUCCESSFULLY DEVELOPED AND IMPLEMENTED A SOFTWARE PLATFORM DENGUECHAT, IN NICARAGUA AND PARAGUAY, THAT MOBILIZED COMMUNITIES TO CONTROL MOSQUITO PRODUCING CONTAINERS IN THEIR OWN HOMES. OUR PROJECT DIRECTLY ADDRESSES PAST IMPLEMENTATION FAILURES BY USING IMPLEMENTATION SCIENCE THEORIES, MODELS, AND FRAMEWORKS (INSPIRE, CFIR), DENGUE EPIDEMIOLOGY AND ENTOMOLOGY EXPERTISE, INFRASTRUCTURE AND RELATIONSHIPS DEVELOPED IN IQUITOS AND LIMA, AND ADDRESSES THREE PROGRAMMATIC GAPS IDENTIFIED IN IQUITOS AND INCORPORATES KEY LESSONS LEARNED FROM THE COVID PANDEMIC (DIFFERENTIAL RESPONSE TO CHANGING RISK LEVEL), TO DEVELOP, IMPLEMENT AND EVALUATE “PROYECTO TARIKI” – AN INTEGRATED DENGUE RISK REDUCTION PROGRAM. TARIKI WILL: (1) MOBILIZE COMMUNITY MEMBERS TO TAKE CONTROL MEASURES IN THEIR OWN HOMES, (2) ENHANCE SURVEILLANCE OF DISEASE VECTORS AND FEBRILE CASE OUTBREAKS, (3) IMPROVE TRIAGE AND MANAGEMENT OF CASES, (4) TARGET AND DEPLOY EFFECTIVE RESPONSES DURING PERIODS OF HIGH TRANSMISSION, (5) PROMOTE BI-DIRECTIONAL DATA EXCHANGE BETWEEN COMMUNITY RESIDENTS, HEALTH CARE PROVIDERS AND AUTHORITIES, AND OTHER STAKEHOLDERS, AND (6) SUPPORT GOVERNMENT PROGRAMS THROUGH COMMUNITY ENGAGEMENT AND TRAINING AND IMPLEMENTATION ON PRAGMATIC EVALUATION PROTOCOLS. WE WILL CONDUCT KEY-INFORMANT INTERVIEWS AND FOCUS GROUP DISCUSSIONS WITH HEALTH AND COMMUNITY STAKEHOLDERS TO UNDERSTAND THE SYSTEM PROBLEMS AND ESTABLISH A FIXED-GROUP OF STAKEHOLDERS CALLED THE ‘TARIKI CHAMPIONS’ (AIM 1). WE WILL ALSO ADAPT THE PROVEN DENGUECHAT APPLICATION TO IQUITOS AND EXPAND THE PLATFORM TO INCLUDE FEVER SURVEILLANCE; DENGUECHAT PLUS WILL BE THE CORNERSTONE OF THE TARIKI PROGRAM. TARIKI CHAMPIONS WILL PARTICIPATE IN GROUP MODEL BUILDING (GMB) WORKSHOPS THROUGHOUT THE 5-YEAR PROJECT TO FIND LEVERAGE WITHIN THE SYSTEM TO PLAN, IMPLEMENT, AND MONITOR AND EVALUATE TARIKI USING MIXED METHODS BASED ON RE-AIM METRICS FOCUSED ON EPIDEMIOLOGICAL, ENTOMOLOGICAL, AND COST OUTCOMES (AIMS 1 AND 2). IN YEAR 3, AFTER REVIEWING ALL DATA USING THE CFIR DOMAINS (INCLUDING PROGRAM CHARACTERISTICS, COSTS, AND PROCESSES), THE RMOH WILL TAKE OVER MANAGEMENT OF TARIKI AND SCALE UP PROGRAM ACTIVITIES ACROSS THE CITY OF IQUITOS (AIM 3), CONTINUING TO MONITOR THE PROGRAM THROUGH RE-AIM METRICS AND PRAGMATIC EVALUATIONS. WE HYPOTHESIZE THAT TARIKI WILL REDUCE RISK FOR DENGUE BY IMPROVING COMMUNITY MOBILIZATION FOR CONTROL, INCREASING COMMUNITY SURVEILLANCE FOR FEBRILE ILLNESS AND CASE MANAGEMENT, AND IMPLEMENTING PRAGMATIC PROTOCOLS FOR INTERVENTION EVALUATION.

HUMAN PAPILLOMAVIRUS IN HIV ASSOCIATED LUNG CANCERS - SUMMARY IN RECENT YEARS, THE INCIDENCE OF AIDS-DEFINING CANCERS HAS DRAMATICALLY DECREASED DUE TO THE HAART THERAPY. IN CONTRAST, THE INCIDENCE OF THE NON-AIDS-DEFINING CANCERS (NADC), ESPECIALLY LUNG CANCER (LC) HAS RISEN BY MORE THAN 3 FOLD. IN THE U.S., LC HAS BECOME THE MOST COMMON NADC WITH AN INCIDENCE RATE OF 204 CASES PER 100,000 PERSON-YEARS. LC IS ALSO THE MOST COMMON NADC CAUSE OF DEATH AND ACCOUNTS FOR 21% OF CANCER- RELATED DEATH IN THE HIV(+) POPULATION. ALTHOUGH SMOKING IS A KEY RISK FACTOR FOR HIV ASSOCIATED LCS, HIV(+) INDIVIDUALS STILL HAVE A 3-FOLD INCREASED LC RISK AFTER CONTROLLING FOR SMOKING STATUS, INDICATING THAT OTHER FACTORS ARE RESPONSIBLE FOR THIS INCREASED INCIDENCE. UNLIKE OTHER COMMON HIV ASSOCIATED CANCERS SUCH AS CERVICAL CANCER, NON-HODGKIN'S LYMPHOMA, AND KAPOSI'S SARCOMA, HIV ASSOCIATED LCS DO NOT HAVE A KNOWN VIRAL ETIOLOGY. TO DISCOVER ANY POTENTIAL ONCOPATHOGEN FOR HIV ASSOCIATED LCS, WE HAVE UTILIZED OUR NEXT- GENERATION-SEQUENCING-BASED PARSES PIPELINE TO INTERROGATE MORE THAN 1,000 LC RNA-SEQ DATA SETS. WE DISCOVERED THAT HUMAN PAPILLOMAVIRUS (HPV) IS CAUSALLY ASSOCIATED WITH LCS IN THE HIV(+) POPULATION. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO DETERMINE THE INVOLVEMENT OF HPV IN HIV ASSOCIATED LCS USING OUR WELL- ESTABLISHED SEQUENCING BASED INFORMATICS APPROACHES AS WELL AS NEWLY CREATED HPV(+) HIV ASSOCIATED LC MODEL SYSTEMS. WE WILL FIRST EXAMINE THE HYPOTHESIS THAT THERE IS A CAUSAL ASSOCIATION BETWEEN HPV AND LCS IN THE HIV(+) POPULATION BUT NOT IN THE GENERAL POPULATION. IN ADDITION, WE WILL TEST THE HYPOTHESIS THAT HPV PROMOTES LUNG ONCOGENESIS BY ENHANCING THE ESTROGEN-MEDIATED GROWTH SIGNALING AND EXPRESSING VIRAL E5/E6/E7/HPV-CIRC-880-408 ONCOGENES IN THE HIV(+) INDIVIDUALS. WE WILL ELUCIDATE THE CRITICAL ROLES OF HPV ONCOGENE PRODUCTS INCLUDING A NOVEL VIRAL CIRCULAR RNA AND ESTROGEN-MEDIATED GROWTH SIGNALING AND IMMUNE- EVASION IN HIV ASSOCIATED LUNG CARCINOGENESIS. WE WILL SIMULTANEOUSLY EXAMINE AN IMPORTANT CONCEPT OF BEING ABLE TO PRECISELY TREAT HPV(+) HIV ASSOCIATED LCS WITH ANTI-ESTROGEN AND/OR ANTI-HPV REGIMENS IN THE ERA OF PERSONALIZED MEDICINE. FURTHER, BY DETERMINING THE HPV ETIOLOGY, OUR WORK MAY HELP PREVENT LCS BY PROMOTING HPV VACCINATION FOR BOTH SEXES. TOGETHER, COMPLETION OF THE RESEARCH WILL ADD CONCEPTUALLY TO OUR UNDERSTANDING OF HIV ASSOCIATED LCS AND PROVIDE POTENTIALLY UNIQUE THERAPEUTIC OPPORTUNITIES AND ULTIMATELY BENEFIT A SUBSET OF HIV(+) LC PATIENTS.

INTEGRATION OF FMRI IMAGING, GENOMICS, NETWORK AND BIOLOGICAL KNOWLEDGE

MECHANISTIC REGULATION OF AMMONIA METABOLISM IN AEDES AEGYPTI MOSQUITOES

PERIODONTITIS AS A COMORBIDITY IN SIV INFECTION AND ANTIRETROVIRAL THERAPY - ABSTRACT THE TWO MAJOR ORAL DISEASES OF MANKIND ARE CHRONIC INFECTIONS THAT RESULT IN DENTAL CARIES AND PERIODONTITIS. THERE IS EVIDENCE OF SPECIFIC DYNAMICS OF ALTERATIONS IN COMMENSAL AND PATHOGENIC BACTERIA RELATED TO PERIODONTITIS WITHIN THE NORMAL POPULATION THAT APPEARS TO DIFFER WITH AGING AND IN DIABETES. IT IS UNCLEAR, HOWEVER, HOW HIV-1 INFECTION AND CURRENT MANAGEMENT WITH ANTIRETROVIRAL DRUGS MAY AFFECT THE MICROBIOME AND DISEASE. IT IS ALSO UNCLEAR HOW DIFFERENCES IN THIS ORAL MICROBIAL ECOLOGY AND SYSTEMIC VIRAL ENVIRONMENT TOGETHER WITH HOST RESPONSES CONTRIBUTE TO THE DESTRUCTION OF THE PERIODONTIUM. SINCE CHARACTERISTICS OF THE IMMUNE SYSTEM REPERTOIRE ARE CRITICAL FOR MAINTAINING GENERAL HEALTH, CONGENITAL OR ACQUIRED DISRUPTORS OF DEVELOPMENT OF NORMAL IMMUNE FUNCTIONS ARE REFLECTED IN ALTERED MICROBIOTA ACROSS BODY NICHES WITHIN THE POPULATION. WHILE EXTENSIVE LITERATURE HAS BEEN ACQUIRED OVER THE LAST 3+ DECADES ON THE FEATURES OF THE ORAL MICROBIAL BIOFILMS IN HEALTH AND PERIODONTITIS, THESE HAVE PRIMARILY BEEN REPORTED FROM CROSS-SECTIONAL STUDIES IN ADULTS WITH CHRONIC PERIODONTITIS. THE INTERACTION OF A MICROBIAL DYBIOSIS AND DYSREGULATED RESPONSE IN PERIODONTITIS COINCIDENT WITH HIV-1 INFECTION AND RESPONSE TO ANTIRETROVIRAL THERAPY (ART) REMAINS UNKNOWN. THIS PROPOSAL ENGAGES A MULTI-DISCIPLINARY AND MULTI-INSTITUTIONAL COLLABORATIVE APPROACH FOR THE DETERMINATION OF THE INTERACTION OF THE CHRONIC ORAL INFECTION AND INFLAMMATORY DISEASE, PERIODONTITIS, WITH THE COURSE AND CHARACTERISTICS OF SIV INFECTIONS AND RESPONSE TO ART. THE STUDY WILL USE A NONHUMAN PRIMATE MODEL OF LIGATURE-INDUCED PERIODONTITIS, WHICH IS A WELL-ESTABLISHED MODEL OF ORAL INFECTION, INFLAMMATION, AND MUCOSAL DISEASE, IN MACACA MULATTA. THE EXPERIMENTAL DESIGN WILL ADDRESS SPECIFIC KNOWLEDGE GAPS ABOUT THE INTERACTION OF THE CHRONIC INFECTION AND DYSREGULATED IMMUNE RESPONSES OF PERIODONTITIS WITH THE IMMUNOLOGICAL AND BIOLOGIC CHANGES OCCURRING WITH SIV INFECTION, INCLUDING: (I) PERIODONTITIS EFFECTS ON THE VIREMIA AND CD4+ LEVELS FROM SIV INFECTION; (II) SIV EFFECTS ON THE ORAL MICROBIOME AND SALIVARY AND SERUM RESPONSES; AND (III) INTERACTION OF PERIODONTITIS ON ART EFFICACY. OUR OVER-ARCHING HYPOTHESIS IS THAT “PERIODONTITIS AND AGE WILL SYNERGIZE TO NEGATIVELY IMPACT PARAMETERS OF SIV INFECTION AND WILL DELETERIOUSLY AFFECT THE EFFICACY OF ART IN MANAGING THE SIV INFECTION.” OUR PROPOSED STUDIES WILL BE EXAMINED IN THREE SPECIFIC AIMS: SPECIFIC AIM 1: TO DELINEATE AGE EFFECTS ON THE ORAL MICROBIOME AND TARGETED SALIVARY BIOMARKERS IN HEALTH, CHANGES THAT OCCUR WITH EXPERIMENTAL PERIODONTITIS, AND IMPACT OF A SUBSEQUENT SIV INFECTION. SPECIFIC AIM 2: TO DELINEATE THE EFFECT OF EXPERIMENTAL PERIODONTITIS AND AGE ON THE EFFICACY OF ART TREATMENT FOR AN SIV INFECTION. SPECIFIC AIM 3: TO DELINEATE THE EFFECT OF SEVERE PERIODONTITIS ON THE EFFICACY OF EXISTING ART TREATMENT TO CONTROL AN SIV INFECTION.

DOES AGE/STRESS-INDUCED MITOCHONDRIAL DYSFUNCTION INDUCE VARIATIONS IN RPE PHENOTYPE IN AMD? - PROJECT SUMMARY AGE-RELATED MACULAR DEGENERATION (AMD) COINCIDES WITH RETINAL PIGMENT EPITHELIUM (RPE) HETEROGENEITY. WHILE ORDERED CELLULAR HETEROGENEITY IS BENEFICIAL, PATHOGENIC SUBGROUPS RESULTED FROM AGE/STRESS-RELATED HETEROGENEITY COULD LEAD TO AGE-RELATED DISEASES. AGING AND CIGARETTE SMOKING (CS) ARE THE TWO STRONGEST NON-GENETIC FACTORS ASSOCIATED WITH AMD RISK. THE MECHANISMS WHEREBY AGING AND CS DRIVE RPE HETEROGENEITY AND THESE FOCAL AMD CHANGES ARE UNCLEAR. RPE MITOCHONDRIAL (MT) DYSFUNCTION IS A WELL-ESTABLISHED PATHOGENIC FACTOR IN AMD, AND BOTH AGING AND CS INDUCE MT DYSFUNCTION. WE RECENTLY REPORTED THAT MODEST MT DYSFUNCTION FROM IMPAIRED MITOPHAGY CAN TRIGGER REACTIVE OXYGEN SPECIES (ROS) MEDIATED RETROGRADE MT TO NUCLEAR SIGNALING AND RPE EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WHICH HAS BEEN IDENTIFIED IN HUMAN AMD TISSUE. SENESCENCE IS A SPECIFIC, TERMINAL CELLULAR PROGRAM THAT INDUCES CELL CYCLE ARREST WITH AGING, AND/OR METABOLIC AND OXIDATIVE STRESS. EVEN SMALL NUMBERS OF SENESCENT CELLS CAN DRIVE AGE-RELATED DISEASE. WE RECENTLY REPORTED THAT MICE DEFICIENT OF MT PHOSPHATASE PGAM5 HAD MT HYPERFUSION, WHICH INDUCED SIGNIFICANT MT DYSFUNCTION ASSOCIATED WITH CHANGES IN ROS AND ATP LEVEL. AS A RESULT, A SUBSET OF RPE BECAME SENESCENT DUE TO DYSREGULATED AMPK/MTOR SIGNALING. SIMILARLY, OUR PILOT DATA SHOW THAT RPE SENESCENCE AND EMT CAN BE INDUCED BY NON-LETHAL CIGARETTE SMOKE CONDENSATE (CSC). THESE OBSERVATIONS SUGGEST THAT MT DYSFUNCTION SEVERITY FROM AGING/CS CAN INITIATE RPE HETEROGENEITY. OUR OBJECTIVE IS TO DETERMINE HOW AGING AND SMOKING INDUCED MT DYSFUNCTION SEVERITY TRIGGERS RPE HETEROGENEITY INCLUDING EMT AND SENESCENCE, TO LINK THESE PHENOTYPES WITH RPE DYSFUNCTION AND AN AMD PHENOTYPE IN ANIMAL MODELS, AND IDENTIFY THE MOLECULAR IDENTITY OF RPE HETEROGENEITY INCLUDING EMT AND SENESCENCE IN A SMOKING MODEL OF AMD AND HUMAN AMD SAMPLES. OUR HYPOTHESIS IS THAT RPE MT DYSFUNCTION SEVERITY FROM SMOKING AND AGING INDUCES RPE HETEROGENEITY INCLUDING EMT, SENESCENCE, AND CELL DEATH, WHICH WILL BE TESTED IN TWO SPECIFIC AIMS (SA). SA I IS TO DETERMINE THE EXTENT THAT MT DYSFUNCTION SEVERITY FROM AGING DRIVES RPE HETEROGENEITY THROUGH REGULATING MT DYNAMICS. SA II IS TO DETERMINE THE EXTENT THAT MT DYSFUNCTION SEVERITY FROM SMOKING, ESPECIALLY WHEN COMBINED WITH AGING, PROMOTES RPE HETEROGENEITY AND AN AMD PHENOTYPE. BY THE END OF PROPOSED PROJECT, WE WILL HAVE EXPERIMENTALLY LINKED MT DYSFUNCTION SEVERITY WITH RPE EMT, SENESCENCE, AND CELL DEATH, AND IDENTIFIED THERAPEUTIC TARGETS TO TEST FOR DRY AMD, A LONG-TERM GOAL OF OUR LABS.

WHOLE-EXOME SEQUENCING STUDY OF DIABETIC NEPHROPATHY

COORDINATING CENTER FOR PRIMATE AGING RESEARCH - SUMMARY THE TULANE NATIONAL PRIMATE RESEARCH CENTER (TNPRC), CALIFORNIA NATIONAL PRIMATE RESEARCH CENTER (CNPRC), AND BAYLOR COLLEGE OF MEDICINE (BCM) PRESENT A UNIQUE COMBINATION OF RESOURCES AND EXPERTISE TO SUPPORT AND ENHANCE “STUDIES…OF PRIMATE SPECIES LIFE SPAN DIFFERENCES, AND MECHANISMS THAT MAY MEDIATE SUCH RELATIONSHIPS,” PER RFA-AG-24-019. THIS R61/R33 APPLICATION PROPOSES A NEWLY INSTANTIATED COORDINATING CENTER FOR PRIMATE AGING RESEARCH (CCPAR) JOINTLY LED BY THESE INSTITUTIONS. THE CCPAR WILL COORDINATE THE WORK OF A BROAD ARRAY OF SPECIALISTS ACROSS GEROSCIENCES AND FACILITATE INTEGRATION OF DATA FROM R01S ACROSS SITES, ENDPOINTS, APPROACHES TO MEASUREMENT, AND SPECIES. BOTH NPRCS HAVE WELL-ESTABLISHED NIA-SUPPORTED COLONIES OF AGED RHESUS MACAQUES AND CORE SCIENTISTS ENGAGED IN AGING-RELATED RESEARCH. THESE TWO NPRCS, ALONG WITH THE BROADER NIH-FUNDED NPRC CONSORTIUM AND BCM, ARE UNIQUELY QUALIFIED TO SUCCESSFULLY LEAD THE PROPOSED CCPAR. THE CCPAR WILL BUILD A COMMUNITY OF TRANSDISCIPLINARY NONHUMAN PRIMATE (NHP) AGING RESEARCHERS, DEVELOP NOVEL RESOURCES TO FACILITATE RIGOROUS STUDIES AND DATA HARMONIZATION, AND DISSEMINATE RESOURCES TO THE BROADER COMMUNITY THROUGH DATA SHARING AND PUBLIC-FACING COMMUNICATION. THERE WILL BE A FOCUS ON TRAINING, BEST PRACTICES, COMMUNICATION, AND OUTREACH WITHIN THE COORDINATING CENTER THAT FORMS THE BASIS OF BROADLY DISTRIBUTED “WHITE PAPERS.” THERE WILL BE A COMMITMENT TO ENHANCING THE QUALITY OF DATA ON LONGEVITY AND HEALTH SPAN, AS WELL AS THE AVAILABILITY OF SUCH DATA THROUGH DEDICATED IT EXPERTS, DATABASES, AND WEBSITES. THE OVERALL GOAL IS TO INCREASE THE HARMONIZATION AND INTEGRATION OF EXISTING DATA WHILE PUTTING SYSTEMS IN PLACE TO ENHANCE DATA SHARING FOR FUTURE STUDIES. THE CCPAR HAS THE EXPERTISE NECESSARY TO ASSIST IN THE DESIGN OF ROBUST METHODS, INTERPRET MULTIPLE TYPES OF DATA, AND LINK GENETIC DATA TO CELLULAR AND BEHAVIORAL DATA AS WELL AS KEY ENVIRONMENTAL EVENTS THAT INFLUENCE AGING. WE WILL PURSUE THE FOLLOWING THREE SPECIFIC AIMS, WITH THE FIRST TWO PURSUED IN THE R61 AND R33 PHASES, AND THE THIRD PRIMARILY PURSUED IN THE R33 PHASE: AIM 1. ENHANCE THE QUALITY AND SYNERGY OF PROJECTS SUPPORTED THROUGH RFA-AG-24-019 AND FACILITATE THE PUBLIC ACCESSIBILITY OF THEIR RESULTS; AIM 2. IDENTIFY PROMISING DIRECTIONS FOR FUTURE RESEARCH ON DETERMINANTS OF SPECIES DIFFERENCES IN HUMAN AND NONHUMAN PRIMATE LIFE SPANS AND AGE-RELATED OUTCOMES THROUGH ACTIVITIES THAT ENGAGE RESEARCHERS FROM PERTINENT FIELDS; AND AIM 3. ENHANCE THE QUALITY, PUBLIC AVAILABILITY, AND INTEROPERABILITY OF DATA SOURCES NEEDED TO DESIGN AND IMPLEMENT RESEARCH ON DETERMINANTS OF SPECIES DIFFERENCES IN HUMAN AND NONHUMAN PRIMATE LIFE SPANS AND AGE-RELATED OUTCOMES.

PROTECTING THE MATERNAL HEART FROM PREGNANCY-ASSOCIATED HEART DISEASE

ROLE OF LONG NONCODING RNAS IN HUMAN OCULAR ANGIOGENESIS

MOLECULAR DETERMINANTS FOR IN VIVO FUNCTIONAL REPROGRAMMING OF CORTICAL OUTPUT NEURONS AND CIRCUITS - PROJECT SUMMARY/ABSTRACT CURRENTLY THERE IS NO SUCCESSFUL TREATMENT THAT RESTORES DAMAGED BRAIN CIRCUITRY. NEURON LOSS BY EITHER NEURODEGENERATIVE DISEASES OR TRAUMA CAUSES NEUROLOGICAL AND COGNITIVE DYSFUNCTION, POSING A GREAT BURDEN FOR HUMAN HEALTH. THERE IS A CRITICAL NEED TO FIND STRATEGIES FOR NEURAL CIRCUIT REPAIR. DIRECT REPROGRAMMING APPROACHES HOLD GREAT PROMISE FOR BRAIN REPAIR. THEIR SUCCESS IN FUNCTIONAL CIRCUIT RESTORATION WILL DEPEND ON THEIR CAPACITY TO CONVERT OTHER CELLS INTO NEURONS WITH FUNCTIONS MATCHING THOSE OF THE NEURONS DAMAGED IN A CIRCUIT. THIS PRECISE CONVERSION HAS BEEN OBSERVED IN THE MOUSE CEREBRAL CORTEX BETWEEN CORTICAL OUTPUT (CORTICOFUGAL) NEURONS, WHICH CAN ACQUIRE THE CONNECTIVITY PROPERTIES, INCLUDING LONG-RANGE PROJECTIONS, TYPICAL OF OTHER CORTICOFUGAL SUBTYPES. THOUGH THIS IS A PROMISING STEP FORWARD TOWARD CIRCUIT REPAIR, THIS PRECISE CONVERSION HAS BEEN OBSERVED WHEN REPROGRAMMING IS INDUCED AT EMBRYONIC OR IMMATURE STATES. THE MECHANISMS THAT PRECLUDE REPROGRAMMING IN DIFFERENTIATED NEURONS OR THE MECHANISMS THAT KEEP NEURON IDENTITY UNCHANGED THROUGHOUT LIFE ARE NOT UNDERSTOOD. HENCE, OUR GOAL IS TO INVESTIGATE MECHANISMS CRITICAL FOR MAINTAINING NEURON SUBTYPE IDENTITY IN DIFFERENTIATED NEURONS AND DETERMINE HOW THEY LIMIT REPROGRAMMING OVER TIME. THIS WILL REVEAL BARRIERS THAT PRECLUDE FUNCTIONAL CONVERSION BETWEEN NEURON SUBTYPES IN VIVO. WE PROPOSE TO INVESTIGATE THESE MECHANISMS IN CORTICOFUGAL NEURONS, SPECIFICALLY IN THE CONTEXT OF IN VIVO REPROGRAMMING OF CORTICOTHALAMIC NEURONS (CTN) TO PRODUCE SUBCEREBRAL PROJECTION NEURONS (SCN), A CLINICALLY RELEVANT NEURON SUBTYPE THAT DEGENERATES IN AMYOTROPHIC LATERAL SCLEROSIS AND WHOSE AXONS ARE DAMAGED BY SPINAL CORD INJURY. IN THIS PROPOSAL WE WILL INVESTIGATE WHETHER IDENTITY MAINTENANCE MECHANISMS CAN BE MANIPULATED FOR IN VIVO REPROGRAMMING OF CTN INTO FUNCTIONAL SCN (AIM 1), WE WILL DETERMINE WHETHER THESE MECHANISMS CAN BE INACTIVATED IN MATURE CTN TO ELIMINATE BARRIERS THAT PRECLUDE CTN CONVERSION INTO SCN (AIM 2), AND WE WILL ELUCIDATE THE UNDERLYING DOWNSTREAM SIGNALS THAT PRECLUDE CONVERSION OF CTN INTO SCN IN VIVO (AIM 3).

MITOCHONDRIAL INTERACTIONS WITH THE PLASMAMEMBRANE: GENETIC UNDERPINNINGS AND FUNCTIONAL CONSEQUENCES AT DROSOPHILA NERVE TERMINALS. - ABSTRACT OUR OVERALL GOAL IS TO ELUCIDATE THE DIFFERENT MECHANISMS AVAILABLE TO A NEURON TO CONTROL MITOCHONDRIA AT A SUBCELLULAR LEVEL, AND THE GENETIC BASES OF THESE CAPABILITIES. MITOCHONDRIA ACCUMULATE WITHIN NERVE TERMINALS WHERE THEY GENERATE MOST OF THE ATP REQUIRED TO PACKAGE AND RECYCLE NEUROTRANSMITTERS AND TO MAINTAIN TRANSMEMBRANE ION-BALANCES. NEURAL FUNCTION IS RELIANT ON MITOCHONDRIAL FUNCTION TO SUSTAIN NEUROTRANSMITTER RELEASE, AND MITOCHONDRIAL DYSFUNCTION IS A HALLMARK OF MANY NEURODEGENERATIVE DISEASES. IT IS THEREFORE IMPERATIVE TO GAIN A BETTER UNDERSTANDING OF THE MECHANISMS THAT NEURONS USE TO CONTROL MITOCHONDRIA AT THE SUB-CELLULAR LEVEL OF NERVE TERMINALS, AND HOW THIS MIGHT DIFFER BETWEEN NEURON TYPES. HERE WE PRESENT THE HYPOTHESIS THAT SITES AT WHICH MITOCHONDRIA INTERACT WITH THE PLASMA MEMBRANE (PM) REPRESENT A FORM OF MITOCHONDRIAL UTILIZATION THAT CONFERS ADVANTAGES IN THOSE PARTS OF A NEURON WITH HIGH POWER DEMANDS, SUCH AS NERVE TERMINALS. WE PROPOSE TO ELUCIDATE THE FUNCTIONAL SIGNIFICANCE OF SUCH INTERACTIONS, AND THEIR GENETIC UNDERPINNINGS. TO DO THIS WE ARE ADOPTING A STRUCTURE-FUNCTION APPROACH, EXPLOITING THE SMALL SIZE AND GENETIC TOOLS OF DROSOPHILA. IN AIM 1 WE WILL USE SERIAL BLOCK FACE SCANNING ELECTRON MICROSCOPY TO DETERMINE THE NEURON TYPES, AND SUBCELLULAR REGIONS SERVED BY MITOCHONDRIAL-PM INTERACTIONS. IN AIM 2 WE WILL USE A NOVEL FORM OF SUPER-RESOLUTION TO INVESTIGATE THE FORMATION AND DISASSEMBLY OF THESE INTERACTIONS, AND THE FUNCTIONAL CONSEQUENCES FOR PRESYNAPTIC PHYSIOLOGY AND NEUROTRANSMISSION. IN AIM 3 WE WILL INVESTIGATE THE ROLE OF A SELECT GROUP OF GENES IDENTIFIED AS CANDIDATES FOR A ROLE IN MITOCHONDRIAL-PM INTERACTIONS. THE SIGNIFICANCE OF THIS PROPOSAL LIES IN ITS POTENTIAL TO UNCOVER NOVEL NEURONAL AND SUB-CELLULAR SPECIFIC MITOCHONDRIAL FUNCTIONS, AND THE GENETIC BASES OF THESE FUNCTIONS, WHICH MAY THROW LIGHT ON THE SELECTIVE NEURONAL VULNERABILITY OBSERVED IN DIFFERENT NEURODEGENERATIVE DISEASES AND NEUROLOGICAL CONDITIONS.

STRESS PLASTICITY OF CRH NEURONS - SUMMARY DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ALTERED CIRCULATING GLUCOCORTICOID LEVELS ARE CLOSELY LINKED TO THE DEVELOPMENT OF PSYCHIATRIC ILLNESS, AND MALES AND FEMALES SHOW DIFFERENTIAL SENSITIVITY TO ACUTE STRESS AND SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS. CORTICOTROPIN-RELEASING HORMONE (CRH) NEURONS OF THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN) CONTROL ACTIVATION OF THE HPA AXIS AND DIRECT STRESS AND ASSOCIATED BEHAVIORS. CHANGES IN CRH NEURON SYNAPTIC CIRCUITS RESULT IN ALTERED HPA ACTIVITY AND GLUCOCORTICOID SECRETION, WHICH CAUSE CHANGES IN PHYSIOLOGICAL HOMEOSTASIS AND BEHAVIORAL OUTPUTS. BRAINSTEM NORADRENERGIC CIRCUITS CONTROL CRH NEURON ACTIVITY AND HPA ACTIVATION IN RESPONSE TO INTEROCEPTIVE STRESS EXPOSURE, SUCH AS IMMUNE CHALLENGE, WHILE LIMBIC CIRCUITS ACTIVATE CRH NEURONS IN RESPONSE TO PSYCHOLOGICAL STRESS. YET, LITTLE IS KNOWN ABOUT THE SEX-DEPENDENT INPUT-OUTPUT ORGANIZATION OF CRH NEURONAL CIRCUITS IN THE HYPOTHALAMUS AND HOW THEY REGULATE SOMATIC VS. PSYCHOLOGICAL STRESS ACTIVATION OF THE HPA AXIS AND SEX- SPECIFIC STRESS BEHAVIORS. OUR PREVIOUS STUDIES IN MALE MICE REVEALED NOVEL MECHANISMS OF SOMATIC STRESS ACTIVATION OF THE HPA AXIS VIA NORADRENERGIC STIMULATION OF A CRH NEURONAL-GLIAL CIRCUIT AND DENDRITIC RETROGRADE VOLUME TRANSMISSION THAT STIMULATES LOCAL SYNAPTIC CIRCUITS IN THE PVN. WE ALSO FOUND A STRESS-INDUCED GLUCOCORTICOID FEEDBACK SUPPRESSION OF THE SOMATIC STRESS ACTIVATION OF THE HPA AXIS IN MALE MICE VIA DESENSITIZATION OF THE CRH NEURONS TO NOREPINEPHRINE (NE) DUE TO RAPID GLUCOCORTICOID-INDUCED TRAFFICKING OF 1 ADRENORECEPTORS OUT OF THE MEMBRANE. THIS RAPID GLUCOCORTICOID EFFECT IS SPECIFIC TO SOMATIC STRESS ACTIVATION OF THE HPA AXIS. RECENT PRELIMINARY FINDINGS INDICATE THAT MALES AND FEMALES RESPOND DIFFERENTLY TO NE, BUT STILL LITTLE IS KNOWN ABOUT THE SEX-DEPENDENT STRESS REGULATION OF THE CRH NEURONS AND THEIR AFFERENT AND EFFERENT CIRCUIT ORGANIZATION. HERE, WE WILL USE A COMBINATION OF EX VIVO PATCH CLAMP RECORDINGS AND FLUORESCENCE IMAGING OF CRH NEURONS, ACTIVITY-DEPENDENT TAGGING AND MONOSYNAPTIC RETROGRADE TRACING OF CRH NEURONAL CIRCUITS IN VIVO, AND STRESS-ASSOCIATED BEHAVIORAL ASSESSMENT TO TEST THE HYPOTHESIS THAT DISCRETE SOMATIC AND PSYCHOLOGICAL STRESS CIRCUITS ACTIVATE DISTINCT CRH NEURON POPULATIONS, WHICH IN TURN PROJECT TO DIFFERENT AREAS OF THE BRAIN AND DRIVE DIFFERENT ACUTE STRESS BEHAVIORS. SPECIFIC AIM 1 WILL EXPAND ON FINDINGS FROM THE PREVIOUS FUNDING PERIOD TO DETERMINE THE SEX-DEPENDENT MECHANISMS OF NE ACTIVATION OF PVN CRH NEURONS. SPECIFIC AIM 2 WILL DETERMINE WHETHER CRH NEURON SUBPOPULATIONS IN THE PVN ARE ACTIVATED BY DISCRETE AFFERENT CIRCUITS DRIVEN BY SOMATIC VS. PSYCHOLOGICAL STRESSORS. AND FINALLY, SPECIFIC AIM 3 WILL EXTEND THIS CRH NEURON CIRCUIT ANALYSIS TO DETERMINE THE DOWNSTREAM TARGETS OF THE SOMATIC AND PSYCHOLOGICAL STRESS- ACTIVATED SUBPOPULATIONS OF CRH NEURONS AND THEIR RESPECTIVE IMPACTS ON STRESS-RELATED BEHAVIORS. TOGETHER, THESE STUDIES WILL FILL A CRITICAL GAP IN OUR UNDERSTANDING OF THE CIRCUIT ORGANIZATION OF HYPOTHALAMIC CRH NEURONS IMPORTANT FOR STRESS MODALITY-SPECIFIC REGULATION OF THE HPA AXIS AND STRESS-ASSOCIATED BEHAVIORS.

KINASE SIGNALING DURING MAMMARY TUMOR INITIATION

METABOLIC REPROGRAMMING OF THE ALVEOLAR STEM CELL NICHE IN PULMONARY FIBROSIS - PROJECT SUMMARY CELL METABOLISM REGULATES EPIGENETIC REPROGRAMING TO DETERMINE CELLULAR IDENTITY AND FATE. INTERMEDIARY METABOLITES SERVE AS ESSENTIAL COFACTORS FOR EPIGENETIC MODIFYING ENZYMES. EPITHELIAL- MESENCHYMAL CROSSTALK IS CRITICAL FOR THE MAINTENANCE OF ADULT TISSUES/ORGANS AND IN REGENERATIVE RESPONSES TO TISSUE INJURY. IN THE LUNG, ALVEOLAR MAINTENANCE AND REGENERATION ARE ORCHESTRATED BY THE INTERACTION OF ALVEOLAR TYPE 2 (AT2) CELLS, A FACULTATIVE STEM/PROGENITOR CELL POPULATION, WITH THE ADJACENT MESENCHYME THAT CONTRIBUTES TO “NICHE” SUPPORT OF THE REGENERATING EPITHELIUM. THESE HOMEOSTATIC TYPE 2 NICHE-SUPPORTING STROMAL CELLS (T2NSCS) MAY TRANSITION TO PATHOLOGICAL MESENCHYMAL STATES/FATES DURING LUNG INJURY-REPAIR. WE HAVE IDENTIFIED A METABOLIC ENZYME, NICOTINAMIDE N-METHYLTRANSFERASE (NNMT), THAT REGULATES THE PLASTICITY OF TISSUE-RESIDENT FIBROBLASTS (FBS) AND THE TRANSITION OF LIPOFIBROBLASTS (LIPO-FBS) INTO MYOFIBROBLASTS (MYO-FBS). NNMT CATALYZES THE N-METHYLATION OF NICOTINAMIDE AND OTHER PYRIDINE COMPOUNDS; BY UTILIZING THE UNIVERSAL METHYL DONOR, SAM IN THIS REACTION, NNMT FUNCTIONS AS A “METHYL SINK” IN MANY TISSUES, WHILE ALSO DEPLETING CELLULAR NAD+ LEVELS. OUR DATA INDICATE THAT NNMT IS UPREGULATED IN LUNG MESENCHYMAL CELLS OF IDIOPATHIC PULMONARY FIBROSIS (IPF), AND IS INDUCED BY THE PRO-FIBROTIC CYTOKINE, TRANSFORMING GROWTH FACTOR-Β1, IN HUMAN LUNG FIBROBLASTS. NNMT FUNCTIONS AS A CRITICAL SWITCH FROM LIPO-FB TO MYO-FB DIFFERENTIATION THAT ACQUIRE APOPTOSIS RESISTANCE, THUS IMPAIRING FIBROSIS RESOLUTION. IN THIS PROJECT WE WILL TEST THE HYPOTHESIS THAT METABOLIC-EPIGENETIC REPROGRAMMING OF ACTIVATED STROMAL T2NSCS BY TARGETING NNMT POTENTIATES LUNG REGENERATIVE CAPACITY AND FACILITATES FIBROSIS RESOLUTION BY AUGMENTING CELLULAR LEVELS OF NAD+ AND/OR SAM. OUR SPECIFIC AIMS ARE TO: (1) IDENTIFY T2NSCS SUBPOPULATIONS AND CHARACTERIZE THEIR REGULATION BY NNMT; (2) DETERMINE MECHANISMS BY WHICH NNMT REGULATES LIPO-FB TO MYO-FB TRANSITION; AND (3) DETERMINE WHETHER TARGETING NNMT ACCELERATES FIBROSIS RESOLUTION IN AN ANIMAL MODEL OF LUNG INJURY-INDUCED FIBROSIS. A COMBINATION OF BULK AND SINGLE-CELL RNA-SEQ, ATAC-SEQ, METABOLOMICS, BIOENERGETICS, AND EPIGENETIC PROFILING IN 3D ALVEOLOSPHERES, IPF LUNG FBS, AND AN IN-VIVO LUNG INJURY MODEL WILL BE EMPLOYED. THE STUDIES PROPOSED IN THIS GRANT APPLICATION WILL ADVANCE THE FIELD BY IDENTIFYING A CRITICAL REGULATORY SWITCH IN LIPO-FB TO MYO-FB DIFFERENTIATION, LINKING METABOLISM TO EPIGENETICS BY AN ENZYME THAT CONTROLS BOTH CELLULAR BIOENERGETICS AND PROTEIN METHYLATION, DEFINING A THERAPEUTIC STRATEGY THAT ACHIEVES FIBROSIS RESOLUTION/REVERSAL IN ESTABLISHED LUNG FIBROSIS, AND ELUCIDATING A FUNCTIONAL ROLE OF ALVEOLAR STEM CELL NICHE-SUPPORTING FIBROBLASTS IN STEM CELL REJUVENATION AND TISSUE REGENERATION.

MATERNAL AND CHILD HEALTH NUTRITION TRAINING PROGRAM

ANP RECEPTOR: GENETIC AND EPIGENETIC MECHANISMS REGULATING BLOOD PRESSURE AND KIDNEY INJURY AND DYSFUNCTION - PROJECT SUMMARY THE MECHANISMS REGULATING HIGH BLOOD PRESSURE (BP) AND KIDNEY INJURY AND DYSFUNCTION ARE KNOWN TO HAVE A STRONG GENETIC COMPONENT; HOWEVER, THE SPECIFIC GENES INVOLVED IN THE PATHOGENESIS OF HYPERTENSION AND RENAL DISORDERS ARE NOT WELL DEFINED. THE KEY REGULATORS ARE ATRIAL AND BRAIN NATRIURETIC PEPTIDES (ANP, BNP), SIGNALING THROUGH NATRIURETIC PEPTIDE RECEPTOR-A (NPRA) AND THE SECOND MESSENGER CGMP. THERE IS A STRONG ASSOCIATION OF POLYMORPHISMS IN THE GENES THAT ENCODE ANP (NPPA), BNP (NPPB), AND NPRA (NPR1) WITH HIGH BP AND CARDIOVASCULAR DISORDERS IN HUMANS. IT IS NOT CLEAR HOW THE LACK OF NPR1 IN THE SPECIFIC CELL- TYPES OF THE KIDNEY MIGHT PROGRESSIVELY LEAD TO HIGH BP AND RENAL DISORDERS, NOR WHAT UNDERLIES THE SEX-SPECIFIC DIFFERENCES IN THE DISEASE ETIOLOGIES. THE GENETIC AND EPIGENETIC MECHANISMS INVOLVING TRANSCRIPTION FACTORS (TFS) AND MODIFIED HISTONE CODES, RESPECTIVELY, WHICH REGULATE THE PATHOGENESIS OF HIGH BP AND KIDNEY INJURY AND DYSFUNCTION ARE NOT WELL UNDERSTOOD. THE PRELIMINARY AND PUBLISHED RESULTS HAVE PROVIDED THE INTRIGUING EVIDENCE THAT RETINOIC ACID RECEPTOR-A (RAR-A) AGONISTS ENHANCE THE TRANSCRIPTION AND EXPRESSION OF NPR1 AND RECEPTOR SIGNALING; HOWEVER, ANGIOTENSIN II (ANG II) AND TRANSFORMING GROWTH FACTOR-BETA 1 (TGF-SS1) REPRESS NPR1 TRANSCRIPTION AND RECEPTOR FUNCTION IN PRIMARY CULTURED RENAL CELLS. THESE STIMULATING AND INHIBITING HORMONES ALSO GOVERN GENETIC AND EPIGENETIC MECHANISMS OF GENE EXPRESSION AND REGULATION BY INTERACTING ACTIONS OF TFS AND HISTONE CODES; HOWEVER, THEIR ROLES IN MODULATING GENE TRANSCRIPTION AND SIGNALING IN HYPERTENSION AND KIDNEY DISORDERS ARE NOT WELL UNDERSTOOD. THE OVERALL OBJECTIVE OF THE CURRENT PROPOSAL IS TO DETERMINE HOW THE HORMONAL CONTROL MECHANISMS INFLUENCE THE GENETIC AND EPIGENETIC FACTORS THAT GOVERN THE NPR1 AND RECEPTOR FUNCTION, REGULATING HIGH BP AND KIDNEY INJURY AND DYSFUNCTION IN A SEX-SPECIFIC MANNER. THE CENTRAL HYPOTHESIS IS THAT NPR1 EXPRESSION AND RECEPTOR SIGNALING IS RECIPROCALLY REGULATED BY GENETIC AND EPIGENETIC MECHANISMS, AND THAT THE LOSS OF CELL-SPECIFIC NPR1 IN NEPHRON TUBULES AND PODOCYTES WILL TRIGGER HIGH BP AND KIDNEY INJURY AND DISORDERS. THE PROPOSED SPECIFIC AIMS WILL TEST THE HYPOTHESES: 1) DETERMINE THE MECHANISMS THAT REPRESS NPR1 EXPRESSION AND RECEPTOR SIGNALING LEADING TO HIGH BP AND KIDNEY DAMAGE AND DISORDERS, 2) DELINEATE THE MECHANISMS THOSE ENHANCE NPR1 EXPRESSION AND RECEPTOR SIGNALING AND DECREASE HIGH BP AND KIDNEY INJURY AND DYSFUNCTION, AND 3) DELINEATE THE INTERACTIVE MECHANISMS THOSE IMPACT THE DIVERGENT STIMULATORY AND INHIBITORY FACTORS REGULATING THE PARADIGM SHIFT IN HIGH BP AND KIDNEY INJURY AND DYSFUNCTION. THE FINDINGS OF THE COMPLETED STUDIES SHOULD LEAD TO THE IDENTIFICATION OF MUCH-NEEDED NEW MOLECULAR BIOMARKERS AND THERAPIES FOR THE TREATMENT AND PREVENTION OF HIGH BP AND KIDNEY DISEASES IN A GENDER-SPECIFIC MANNER IN HUMANS.

THE ROLE OF P53-R249S?S GOF IN HCC DEVELOPMENT

MOLECULAR MECHANISMS UNDERLYING ARTERIOVENOUS MALFORMATIONS ASSOCIATED WITH HHT

RECOMBINANT FGF21 AS A NOVEL APPROACH FOR TREATING ISCHEMIC STROKE IN TYPE 2 DIABETES

RPMS1 CIRCULAR RNAS IN EBV MALIGNANCIES

KINASE MEDIATED SUPPRESSION OF METASTASIS IN BREAST CANCER

AIDS SPF RHESUS MONKEY BREEDING FACILITY EXPANSION

ELUCIDATING THE ROLE OF SMAD4 IN ARTERIOVENOUSE MALFORMATIONS ASSOCIATED WITH HHT

MOLECULAR MECHANISMS OF TISSUE INTERACTIONS DURING CORONAL SUTURE DEVELOPMENT

THE GENETIC BASIS AND ADAPTIVE SIGNIFICANCE OF DIVERGENCE IN QUANTITATIVE TRAITS IN SYMPATRIC MIMULUS SPECIES

G?13 SIGNALING ATTENUATES PERIODONTAL INFLAMMATION AND ALVEOLAR BONE LOSS IN THE MOUSE MODEL OF AGE-ASSOCIATED PERIODONTITIS

INTRATUBULAR ANGIOTENSIN II AND AT1A RECEPTORS IN THE PROXIMAL TUBULES: ROLES IN HYPERTENSION AND KIDNEY INJURY

MOLECULAR PATTERNING OF THE HARD PALATE DURING PALATOGENESIS

AN INTEGRATIVE APPROACH TO IDENTIFY VULNERABILITIES IN PEDIATRIC CANCER DSRCT

TISSUE MICROENVIRONMENT ANT TUMOR HOTSPOTS IN DROSOPHILA

THE LONG NONCODING RNA MALAT1 IN LIVER CANCER

MECHANISTIC INVESTIGATION OF MALIGNANT RHABDOID CHILDHOOD TUMOR USING THE DROSOPHILA MODEL

ROLE OF FIP200 IN RIG-I-MEDIATED INNATE IMMUNITY

GENOTOXIC STRESS RESPONSE AND MUTAGENESIS IN NORMAL TISSUES OF MICE DEFICIENT IN HOMOLOGY DIRECTED REPAIR - PROJECT SUMMARY/ABSTRACT THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO CHARACTERIZE THE PATHWAYS AND MECHANISMS THAT PRESERVE VIABILITY AND GENOME INTEGRITY IN ADULT MAMMALS EXPOSED TO ENVIRONMENTAL GENOTOXIC STRESSES. DNA DAMAGE CAN BE REPAIRED BY THE HIGH FIDELITY PATHWAY HOMOLOGY DIRECTED REPAIR (HDR) OR BY ERROR PRONE NON-HOMOLOGOUS END JOINING (NHEJ). THE CONSEQUENCES OF HDR LOSS IN ADULT VERTEBRATES IS NOT WELL UNDERSTOOD BECAUSE GERMLINE KNOCKOUTS ARE EMBRYONIC LETHAL, THUS, MOST OF OUR UNDERSTANDING HAS COME FROM CELL CULTURE MODELS OR INFERRED FROM TUMORS CAUSED BY HDR DEFICIENCY. TO ADDRESS THIS CRITICAL NEED, WE HAVE GENERATED GENETICALLY ENGINEERED MICE THAT CAN UNDERGO INDUCIBLE DELETION OF UP TO 99% OF THE ESSENTIAL HDR GENE BRCA1 IN EVERY TISSUE, POST DEVELOPMENT. WE WILL USE THIS MODEL TO ADDRESS CRITICAL QUESTIONS ON 1) THE ROLE OF HDR IN CELL/TISSUE/ORGANISMAL VIABILITY AFTER DIFFERENT TYPES OF DNA DAMAGE; 2) THE DEPENDENCE OF DIFFERENT TISSUES ON HDR TO MAINTAIN GENOME INTEGRITY AFTER DIFFERENT TYPES OF DNA DAMAGE; 3) MUTATION SIGNATURES IN TISSUES OF HDR DEFICIENT MICE CAUSED BY DIFFERENT STRESSES, ALLOWING INFERENCE OF REPAIR PATHWAY UTILIZED IN ABSENCE OF HDR; 4) HOW THE TRANSCRIPTION FACTOR P53 COOPERATES WITH HDR IN EACH OF THESE PHENOTYPES; 5) THE COOPERATIVE ROLE OF HDR AND NHEJ IN DNA REPAIR. WE HYPOTHESIZE THAT IN MICE WITH DELETION OF THE ESSENTIAL HDR GENE BRCA1, TISSUES KNOWN TO DEVELOP HDR DEFICIENT TUMORS WILL HAVE A HIGHER MUTATION RATE AND FAVOR P53 MEDIATED PROGRAMS OF ARREST OVER APOPTOSIS COMPARED TO NON-TUMOR PRONE TISSUES. SPECIFIC AIM 1. DETERMINE HOW HDR PRESERVES VIABILITY BY MEDIATING TISSUE SPECIFIC CELLULAR AND TRANSCRIPTIONAL RESPONSES. IN WILD TYPE OR BRCA1 DELETED MICE, WE WILL EXAMINE HOW BRCA1/HDR PRESERVES NEAR-TERM VIABILITY AFTER DIFFERENT TYPES OF DNA DAMAGE BY 3 MEASURES: 1) THE DNA DAMAGE RESPONSE AND CELL FATE (APOPTOSIS, CELL CYCLE ARREST); 2) TRANSCRIPTOMIC CHANGES; 3) PATHOLOGY OF DIFFERENT TISSUES. SPECIFIC AIM 2. DETERMINE TISSUE AND DNA DAMAGE-SPECIFIC ROLE OF BRCA1/HDR IN MAINTAINING GENOME INTEGRITY. IN THIS AIM, WE WILL EXAMINE LONG-TERM CONSEQUENCES OF HDR DEFICIENCY ON GENOME MAINTENANCE. SOMATIC MUTATIONS ARE KNOWN TO ACCUMULATE IN NORMAL HUMAN TISSUES WITH AGE AND ARE LINKED TO DISEASE. WE WILL EXAMINE FIDELITY OF REPAIR AND LONGEVITY OF MICE WITH OR WITHOUT FUNCTIONAL HDR THAT SURVIVE DIFFERENT TYPES OF DNA DAMAGE. DEEP SEQUENCING AND MUTATION SIGNATURE ANALYSIS WILL REVEAL WHAT TISSUES RELY ON HDR AND WHAT TYPE OF DNA PERTURBATION IS MOST MUTAGENIC IN DIFFERENT HDR DEFICIENT TISSUES. SPECIFIC AIM 3. DETERMINE VIABILITY AND STRESS RESPONSE IN MICE DEFICIENT IN NHEJ OR BOTH NHEJ AND HDR. BECAUSE EMBRYONIC DELETION OF EITHER BRCA1 OR THE NHEJ GENE LIG4 (CODING FOR LIGASE 4) IS LETHAL, THEIR INDIVIDUAL AND COOPERATIVE ROLES IN ADULT TISSUES ARE NOT KNOWN. IN THIS AIM, WE WILL EXAMINE SURVIVAL AND STRESS RESPONSE AFTER DELETION OF BOTH HDR AND NHEJ PATHWAYS IN ADULT MICE, LEAVING ONLY SSA AND ALT-NHEJ.

THE IMPACT OF AGING ON PROSTATE CANCER WITH AGE-RELATED DISRUPTION OF TH17/TREG AXIS - PROJECT SUMMARY/ABSTRACT: PROSTATE CANCER (PCA) IS PARTICULARLY IMPORTANT IN ELDERLY MEN BECAUSE OF THE HIGH INCIDENCE AND PREVALENCE OF DISEASE AND MORTALITY IN THIS GROUP OF PATIENTS. ALTHOUGH THE CASE-FATALITY RATE OF PCA IS QUITE LOW, DEATHS OCCUR DISPROPORTIONATELY IN THE ELDERLY. HOWEVER, THE REASONS FOR THE INCREASED INCIDENCE AND MORTALITY DUE TO PCA IN ELDERLY MEN ARE NOT ENTIRELY CLEAR. LOW-GRADE INFLAMMATION (I.E., INFLAMMAGING) PLAYS AN IMPORTANT ROLE IN THE AGING PROCESS, AND CHRONIC INFLAMMATION CONTRIBUTES TO THE ONSET AND PROGRESSION OF PCA. INFLAMMAGING IS OFTEN ATTRIBUTED TO THE PROGRESSIVE ACTIVATION OF IMMUNE CELLS. IN THAT REGARD, A DISRUPTION IN THE BALANCE OF PRO-INFLAMMATORY TH17 CELLS AND HOMEOSTATIC REGULATORY T (TREG) CELLS IN FAVOR OF TH17 CELLS WAS REPORTED PREVIOUSLY TO OCCUR IN NON-CANCER-RELATED AGING IN HUMANS AND MICE. PRELIMINARY DATA SUPPORT THAT ELDERLY HUMAN PROSTATE TISSUE HAD INCREASED TH17/TREG RATIO AND THE SIMILAR PHENOMENON WAS FOUND IN AGED MICE CIRCULATION AND PROSTATE TISSUE, AND CD4+ T CELL SECRETED FACTORS FROM AGED MICE COMPARED TO YOUNG MICE PROMOTE PCA CELL PROLIFERATION, MIGRATION, AND INVASION. THE LONG-TERM GOAL IS TO CONTRIBUTE TOWARD THE DEVELOPMENT OF NOVEL CLINICALLY USEFUL STRATEGIES TO TREAT OR PREVENT PCA ASSOCIATED WITH ADVANCED AGING. THE OVERALL OBJECTIVE IN THIS PROPOSAL IS TO DETERMINE HOW AGE-RELATED TH17/TREG IMBALANCE CONTRIBUTES TO PROSTATE CARCINOGENESIS. THE CENTRAL HYPOTHESIS IS THAT AGE-RELATED DISRUPTION OF TH17/TREG AXIS PROMOTES PCA INITIATION AND PROGRESSION. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A DETERMINATION OF HOW TH17/TREG IMBALANCE PROMOTES PROSTATE CARCINOGENESIS IS LIKELY TO PROVIDE NEW OPPORTUNITIES FOR THE SUBSEQUENT DEVELOPMENT OF TARGETED THERAPEUTICS TO THE PREVENTION/TREATMENT OF PROSTATE CANCERS ASSOCIATED WITH ADVANCED AGING. GUIDED BY STRONG PRELIMINARY DATA, THIS HYPOTHESIS WILL BE TESTED BY PURSUING THREE SPECIFIC AIMS: 1) IDENTIFY ASSOCIATIONS BETWEEN TH17/TREG RATIO ALTERATION AND PROGRESSION OF HUMAN PCA ASSOCIATED WITH ADVANCED AGING. 2) DEFINE HOW AGING-ASSOCIATED IMBALANCES IN TH17/TREG AXIS DRIVE PCA. 3) DETERMINE THE EFFICACY OF THERAPEUTIC TARGETING OF TH17/TREG AXIS IN PREVENTING AGING-ASSOCIATED PCA. IN AIM 1, THE EXPRESSION OF TH17/TREG AND NF-KB WILL BE EXAMINED IN HUMAN NORMAL AND PCA SPECIMENS AT DIFFERENT AGES. IN AIM 2, THE BATF AND PTEN (TUMOR SUPPRESSOR GENE) DOUBLE KNOCKOUT MOUSE MODEL GENERATED AT DIFFERENT AGES WILL BE USED TO ASSESS WHETHER BATF STATUS AND AGE PLAYS A CRITICAL ROLE IN PCA INITIATION AND PROGRESSION. IN AIM 3, THE ANTI- IL-23P19 ANTIBODY AND SMALL MOLECULE SR1555 (BOTH SUPPRESS TH17/STIMULATE TREG FUNCTION) WILL BE TESTED. THE APPROACH IS INNOVATIVE, IN THE APPLICANT’S OPINION, BECAUSE THE TUMOR GROWTH CAN BE COMPARED IN THE SAME TIME INTERVAL POST-PTEN EXCISION BETWEEN THE AGED AND NON-AGED MICE. THE PROPOSED RESEARCH IS SIGNIFICANT, AS THE CONCEPT IS NOVEL AND HAS CLINICAL SIGNIFICANCE BECAUSE RECTIFYING TH17/TREG IMBALANCE HAS THE POTENTIAL TO BE DEVELOPED INTO PROGNOSTIC INDICATOR OF PCA AND THERAPEUTICS IN THE PREVENTION AND TREATMENT OF PCA IN THE ELDERLY.