Augusta University

COORDINATING AND BIOINFORMATICS UNIT FOR THE AMDCC/MMPC

AGE-INDUCED IMPAIRMENT OF NUTRIENT SIGNALING RESULTS IN BONE LOSS

IMMUNE CELL INTERACTIONS IN ATHEROSCLEROSIS

STRESS RELATED MECHANISMS OF HYPERTENSION RISK IN YOUTH

HIGHER EDUCATION EMERGENCY RELIEF FUND (INSTITUTIONAL PORTION) UNDER THE CORONAVIRUS AID, RELIEF, AND ECONOMIC SECURITY (CARES) ACT

EMERGENCY FINANCIAL AID GRANTS TO STUDENTS UNDER THE CORONAVIRUS AID, RELIEF, AND ECONOMIC SECURITY (CARES) ACT

GEORGIA CARES

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

COORDINATING UNIT FOR DIACOMP

ENDOTHELIAL BARRIER PROTECTION AND REPAIR IN ACUTE LUNG INJURY

MANIPULATING NATURAL HOST IMMUNOREGULATION VIA IDO DURING VIRAL INFECTION

DAMAGE-ASSOCIATED MOLECULAR PATTERNS IN HYPERTENSION

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

THE ROLE OF ENDOTHELIN-1 IN SICKLE CELL DISEASE

MODEL STATE-SUPPORTED AREA HEALTH EDUCATION CENTERS

THE TEDDY STUDY: GEORGIA/FLORIDA CLINICAL CENTER

REGULATION OF HEAT SHOCK FACTOR 1 IN ANIMAL MODELS

NCMHD SOUTHEASTERN EXPLORATORY SICKLE CELL CENTER OF EXCELLENCE

ENDOTHELIAL METABOLISM AND REDOX IMBALANCE IN VASCULAR DISEASE - PROJECT SUMMARY REDOX IMBALANCE BETWEEN REACTIVE OXYGEN SPECIES (ROS) AND REACTIVE NITROGEN SPECIES (RNS) (HIGH ROS AND LOW NITRIC OXIDE NO) IS A FUNDAMENTAL MECHANISM OF ENDOTHELIAL CELL (EC) DYSFUNCTION AND A DRIVER OF CARDIOVASCULAR DISEASES (CVD) SUCH AS ATHEROSCLEROSIS, HYPERTENSION AND PERIPHERAL ARTERIAL DISEASE (PAD). STRATEGIES TO INDIVIDUALLY MITIGATE ROS OR AMPLIFY NO HAVE EXPERIENCED LIMITED SUCCESS. THEREFORE, A GREATER UNDERSTANDING OF THE KEY FACTORS AND EVENTS THAT LEAD TO REDOX IMBALANCE IS THEREFORE ESSENTIAL TO DEVELOP MORE EFFECTIVE TREATMENTS FOR CARDIOVASCULAR DISEASE (CLASSICAL CONCEPT) WHICH REMAINS THE LEADING CAUSE OF MORBIDITY AND MORTALITY. IN ECS, AEROBIC GLYCOLYSIS (“WARBURG EFFECT”) HAS BEEN REGARDED AS THE DOMINANT METABOLIC PATHWAY SUPPORTING HOMEOSTATIC FUNCTIONS. AN EMERGING CONCEPT IS THAT THE PATHWAYS OF CELLULAR METABOLISM ARE NOT FIXED, AND THAT ECS CAN ALTER THEIR METABOLIC PATHWAYS OR “REPROGRAM” TO MEET DIFFERENT NEEDS. A MAJOR GAP IN OUR KNOWLEDGE IS HOW EC METABOLISM AND ROS/RNS BALANCE ARE ALTERED IN VASCULAR DISEASE AND HOW METABOLISM INFORMS FUNCTION. RECENT STUDIES HAVE SHOWN THAT AEROBIC GLYCOLYSIS IS INCREASED IN ECS OF ATHEROSCLEROTIC, DIABETIC AND ANGIOGENIC BLOOD VESSELS, HOWEVER, THE FUNCTIONAL CONSEQUENCES OF THIS DYNAMIC HAS YET TO BE ELUCIDATED. ENZYMES THAT PRODUCE ROS ARE NOT ONLY INFLUENCED BY METABOLISM, BUT MAY ALSO PROMOTE CHANGES IN METABOLISM. OUR PRELIMINARY DATA ADVANCE THE NOVEL HYPOTHESIS THAT IMBALANCE BETWEEN CHANGES IN EC METABOLISM AND ROS/RNS (REDOX BALANCE), INDUCED BY VARIOUS RISK FACTORS, IS A KEY DRIVER OF EC DYSFUNCTION AND AN UNDERLYING MECHANISM OF VASCULAR DISEASE. TO TEST THIS HYPOTHESIS, A PROGRAMMATIC APPROACH IS ESSENTIAL AS IT IS THE ONLY MECHANISM CAPABLE OF SUPPORTING THE RIGOR NEEDED TO INVESTIGATE THE COMPLEX INTERPLAY BETWEEN METABOLISM AND REDOX SIGNALING IN DIFFERENT VASCULAR BEDS AND DISEASE STATES. OUR PROGRAM HAS 3 WELL ALIGNED PROJECTS THAT BENEFIT FROM THE SYNERGY OF MODEL AND REAGENT SHARING AND DEDICATED CORES. PROJECT 1 IS FOCUSED ON THE HYPOTHESIS THAT DISTURBED COPPER (CU) METABOLISM IN ECS ARISES FROM DYSFUNCTION OF THE CU EXPORTER, ATP7A, LEADING TO EXCESSIVE PFKFB3/GLYCOLYSIS, ROS/NO IMBALANCE AND MITOCHONDRIAL ROS-EPIGENETIC REMODELING THAT DRIVES ENDMT AND ACCELERATED ATHEROSCLEROSIS. PROJECT 2 WILL TEST THE HYPOTHESIS THAT EC METABOLISM SHAPES EC FUNCTION VIA SEX-SPECIFIC, NOX1 AND LEPTIN-DEPENDENT MECHANISMS. PROJECT 3 TESTS THE HYPOTHESIS THAT ABILITY OF THE MITOCHONDRIAL DYNAMICS PROTEIN, DRP1, TO PROMOTE REPARATIVE ANGIOGENESIS VIA CROSSTALK BETWEEN EC MITOCHONDRIAL REDOX SIGNALING AND GLYCOLYSIS IS IMPAIRED IN DIABETES DUE TO EXCESS PFKFB3/GLYCOLYSIS-ROS SIGNALING WHICH INCREASES THE SEVERITY OF PAD. TO TEST THESE CONCEPTS DIRECTLY, WE HAVE DEVELOPED A STATE-OF-THE-ART APPROACH USING CRISPR/CAS9 TO GENERATE KNOCK-IN MICE ENABLING INDUCIBLE REDUCTION OF GLYCOLYSIS ONLY IN ECS, THAT WILL BE SHARED ACROSS PROJECTS TO ENHANCE SYNERGY. OUR PROGRAM WILL IDENTIFY KEY MECHANISMS THROUGH WHICH CHANGES IN METABOLISM IMPACT ROS/NO BALANCE, EC FUNCTION AND VASCULAR DISEASE.

COORDINATING UNIT FOR THE INNOVATIVE SCIENCE ACCELERATOR PROGRAM - THE GOAL OF THE NIDDK INNOVATIVE SCIENCE ACCELERATOR (ISAC) PROGRAM IS TO NOT ONLY PROVIDE FUNDING FOR HIGHLY INNOVATIVE HYPOTHESIS DRIVEN RESEARCH BUT TO DELIVER A PLATFORM FOR THE KUH RESEARCH COMMUNITY TO COLLABORATE, EXCHANGE IDEAS AND FIND RESOURCES THAT WILL ACCELERATE INNOVATION IN AREAS OF INTEREST TO THAT COMMUNITY. OUR LABORATORY HAS EXTENSIVE EXPERIENCE IN DEVELOPING THESE TYPES OF RESOURCES AND MANAGING THE ACTIVITIES OF NATIONAL CONSORTIA. WE ARE CURRENTLY THE COORDINATING UNITS (CU) FOR TWO NIDDK CONSORTIA, THE MOUSE METABOLIC PHENOTYPING CENTERS (MMPC) AND THE DIABETIC COMPLICATIONS CONSORTIUM (DIACOMP). BOTH CONSORTIA ARE NIDDK FUNDED INITIATIVES THAT PROVIDE AN ENVIRONMENT TO FOSTER COMMUNICATION AND COLLABORATION BETWEEN INVESTIGATOR COMMUNITIES INVOLVED IN METABOLIC AND DIABETIC COMPLICATIONS RESEARCH. EACH SPONSORS ANNUAL MEETINGS IN RELEVANT SCIENTIFIC AREAS, SOLICITS AND FUNDS PILOT PROJECTS IN HIGH IMPACT AREAS OF NIDDK RESEARCH, AND SUPPORTS WEBSITES TO SERVE THEIR RESPECTIVE SCIENTIFIC COMMUNITIES. OVER THE LAST 14 YEARS, OUR GROUP HAS DEVELOPED AN EXTENSIVE INFRASTRUCTURE TO SUCCESSFULLY MANAGED THE COORDINATING UNITS (CU) FOR THESE NIDDK FUNDED CONSORTIA (MMPC, 2006-PRESENT, DIACOMP, 2011-PRESENT). THE ISAC-CU WILL BE RESPONSIBLE FOR SUPPORTING ISAC INVESTIGATORS THROUGH THE USE OF OPPORTUNITY POOLS (FUNDING PROGRAMS), MANAGE/MAINTAIN THE WEBSITE/RESOURCES AND ADMINISTRATIVELY ORGANIZE THE MEETINGS AND WORKSHOPS SPONSORED BY ISAC TO ENGAGE THE GREATER KUH SCIENTIFIC COMMUNITY. THE ISAC-CU IS RESPONSIBLE FOR CREATING AND MAINTAINING THE ADMINISTRATIVE, SCIENTIFIC AND INFORMATICS INFRASTRUCTURE NECESSARY TO ORGANIZE AND FACILITATE ISAC’S OPERATIONS. THE GOAL OF THIS PROPOSAL IS TO PROVIDE THAT INFRASTRUCTURE. WE WILL BUILD UPON THE SUCCESS OF THE CURRENT CU INFRASTRUCTURE TO PROVIDE ISAC WITH A ROBUST AND COMPREHENSIVE SERVICE ORIENTED SOLUTION THAT SUPPORTS THE UNIQUE ASPECTS OF THIS CONSORTIUM.

IMPACT OF HIV-1 TAT PROTEIN ON COCAINE-DOPAMINE TRANSPORTER INTERACTION

APOPTOTIC GENE REGULATION IN RENAL PATHOLOGY

CALCULATOR FOR LENGTH OF USE OF BISPHOSPHONATES (CLUB) - OSTEOPOROTIC FRACTURES ARE A MAJOR PUBLIC HEALTH PROBLEM, ESPECIALLY FOR OLDER PERSONS. BISPHOSPHONATES (BPS) ARE AN INEXPENSIVE THERAPEUTIC CLASS OF DRUGS EFFECTIVE AT PREVENTING THESE FRACTURES. HOWEVER, THERE HAS BEEN A SUBSTANTIAL DECLINE IN USE OF BPS FOR OSTEOPOROSIS AT LEAST IN PART BECAUSE OF CONCERNS FOR RARE, ALBEIT POTENTIALLY SERIOUS SIDE EFFECTS, NAMELY ATYPICAL FEMORAL FRACTURES (AFF) AND BISPHOSPHONATE MEDICATION RELATED OSTEONECROSIS OF THE JAW (MRONJ). DURATION OF TREATMENT IS A RISK FACTOR FOR LONG-TERM SIDE EFFECTS FROM BPS, INCLUDING AFF, AND TO A LESSER EXTENT, MRONJ. TO ASSIST WITH DECISION-MAKING REGARDING DURATION OF USE OF BPS, THE FDA AND PROFESSIONAL SOCIETIES DEVELOPED GUIDELINES SUGGESTING THAT AFTER THREE TO FIVE YEARS OF ORAL OR THREE YEARS OF INTRAVENOUS BP USE, THAT REASSESSMENT OF FRACTURE RISK WITH POSSIBLE PROVISION OF A DRUG HOLIDAY BE DONE. HOWEVER, THESE RECOMMENDATIONS WERE BASED ON VERY LIMITED EVIDENCE LARGELY DERIVED FROM WHITE, HEALTHY, COMMUNITY-DWELLING POSTMENOPAUSAL WOMEN. MOREOVER, THE RISK ASSOCIATED WITH DRUG HOLIDAYS IS UNCERTAIN, AS EMERGING REPORTS SUGGEST THAT A NUMBER OF WOMEN HAVE SUSTAINED OSTEOPOROTIC FRACTURES WHILE OFF THERAPY. IT IS PARAMOUNT TO BETTER UNDERSTAND THE RISK-BENEFIT PROFILE OF LONG-TERM BP THERAPY AND DRUG HOLIDAYS, IN BOTH MEN AND WOMEN, ALL RACES AND ETHNICITIES, AND THOSE WITH SERIOUS COMORBIDITIES. TO ACCOMPLISH THIS, WE HAVE AMASSED AN EXPERT MULTIDISCIPLINARY TEAM TO STUDY LARGE AND DIVERSE PATIENT POPULATIONS RANGING FROM COMMUNITY DWELLING TO LONG-TERM CARE RESIDENTS FROM KAISER PERMANENTE (KP; NORTHERN CALIFORNIA, GEORGIA, AND MID-ATLANTIC REGIONS), HEALTH PARTNERS (HP; MINNESOTA), AND THE NATIONAL VETERANS HEALTH ADMINISTRATION (VHA), SPANNING 30 YEARS (1996 TO 2025) AND INCLUDING OVER HALF A MILLION OLDER U.S. ADULTS WHO INITIATED OSTEOPOROSIS TREATMENT WITH A BP. UTILIZING THIS POPULATION, WE WILL DETERMINE RISKS AND BENEFITS, HEALTH CARE COSTS AND COST EFFECTIVENESS OF UNINTERRUPTED CONTINUATION OF BPS VERSUS BP DRUG HOLIDAYS. THESE INFORMATION WILL BE UTILIZED TO DEVELOP A RISK FACTOR CALCULATOR TO DETERMINE IF A DRUG HOLIDAY SHOULD BE DONE (CALCULATOR FOR LENGTH OF USE OF BISPHOSPHONATES (CLUB)). AN EXPERT PANEL INCLUDING BOTH CLINICIAN AND CONSUMER VOICES WILL INFORM THE FINAL DESIGN OF CLUB. WE ANTICIPATE THAT CLUB WILL BE A CLINICALLY USEFUL POINT-OF-CARE TOOL TO GUIDE SHARED DECISION-MAKING ON BP USE AND OPTIMIZE CARE FOR OLDER PATIENTS AT RISK FOR FRACTURE.

VASCULAR MACROPHAGES AND T CELLS IN ATHEROSCLEROSIS

IMPROVING AWARENESS OF WOMEN WITH HYPERTENSION: ROAR (RURAL, OBESE, AT RISK) - MORE THAN 1 IN 3 WOMEN ARE LIVING WITH HEART DISEASE AND MANY ARE UNAWARE OF THE RISKS. HYPERTENSION IS A MAJOR MODIFIABLE RISK FACTOR FOR CARDIOVASCULAR DISEASE (CVD), AND ~47% OF ADULTS IN THE US HAVE HYPERTENSION. IN ~85% OF CASES, THE CAUSE OF HYPERTENSION IS UNKNOWN AND ONLY ~50% OF PATIENTS TAKING MEDICATION ACHIEVE BLOOD PRESSURE (BP) CONTROL TO RECOMMENDED LEVELS. A CRITICAL BARRIER TO LIMITING PREMATURE DEATH FROM CVD IS LACK OF AWARENESS SURROUNDING THE RISKS OF CVD. OUR LOCATION IN THE SOUTHEAST OF THE US WILL CONTRIBUTE TO OUR IMPACT. THE PREVALENCE OF HYPERTENSION AND OBESITY ARE HIGH IN GA, MS, AND SC. THE PREVALENCE OF HYPERTENSION AND ASSOCIATED RISK IS NOT EQUAL AMONG ALL POPULATIONS. INDEED, THE PREVALENCE OF HYPERTENSION IN BLACK PEOPLE IN THE US IS AMONG THE HIGHEST IN THE WORLD. OUR OVERALL GOAL IS TO TRANSFORM ACADEMIC AND COMMUNITY UNDERSTANDING OF SEX AS A BIOLOGICAL VARIABLE (SABV) IN THE CONSIDERATION OF HYPERTENSION. WE WILL ACCOMPLISH THIS THROUGH THE CREATION AND DISSEMINATION OF INNOVATIVE EDUCATIONAL CONTENT, THE DEVELOPMENT OF STRATEGIC PARTNERSHIPS, AND ENHANCED COMMUNITY ENGAGEMENT IN THE SOUTHEAST OF THE US. THIS SCORE IS DESIGNED TO PROVIDE NOVEL INSIGHT INTO THE MECHANISMS CONTROLLING BP IN FEMALES VS. MALES, DEVELOP A COMPREHENSIVE EDUCATIONAL PLATFORM ON SABV IN CVD EXTENDING FROM GRADE SCHOOL TO MEDICAL SCHOOL, AND INCREASE AWARENESS AND EDUCATION OF CVD AND THE RISKS OF UNCONTROLLED HYPERTENSION IN WOMEN ACROSS THE HEALTH SPAN THROUGH COMMUNITY OUTREACH. THIS SCORE HAS 4 OBJECTIVES. OBJECTIVE 1 IS TO CONDUCT CUTTING EDGE RESEARCH TO ADVANCE OUR UNDERSTANDING OF SEX-SPECIFIC MECHANISMS THAT CONTROL BP TO LIMIT CARDIOVASCULAR RISK. OBJECTIVE 2 IS TO DEVELOP A CULTURALLY DIVERSE RESEARCH PIPELINE OF BIOMEDICAL SCIENTISTS TRAINED IN THE FIELD OF SABV IN CVD. OBJECTIVE 3 IS TO ESTABLISH A COMMUNITY OUTREACH PIPELINE OF TRAINED SCIENTISTS TO INCREASE AWARENESS OF SABV AND PROMOTE OPTIMAL CARDIOVASCULAR HEALTHCARE FOR MEN AND WOMEN. OBJECTIVE 4 IS TO EMPOWER THE COMMUNITY TO SELF-MONITOR AND WORK TO IDENTIFY BARRIERS TO IMPROVING ACCESS TO HEALTHCARE. THE OUTCOMES OF OUR PROPOSED SCORE INCLUDE NOT ONLY ADVANCES IN SCIENCE AND TRAINING OF THE NEXT GENERATION OF LEADERS IN THE STUDY OF THE IMPACT OF BIOLOGICAL SEX ON THE DEVELOPMENT AND PROGRESSION OF CVD, BUT ALSO THE DEVELOPMENT OF A RANGE OF EDUCATIONAL CONTENT THAT WILL BE FULLY AVAILABLE TO THE CONSORTIUM. THIS WILL INCLUDE 1) THE DEVELOPMENT EDUCATIONAL MATERIALS BY MEDICAL ILLUSTRATORS FOR STUDENTS/TRAINEES AT ALL STAGES, THE COMMUNITY, AND PHYSICIANS, 2) ESTABLISHING A SABV MENTORING ACADEMY, 3) CREATING A SABV CURRICULUM AND WORKSHOP FOR STUDENTS, FELLOWS, AND JUNIOR INVESTIGATORS. THE IMPACT OF OUR WORK WILL BE TO INCREASE RECOGNITION AND AWARENESS OF THE RISKS OF CVD AND HYPERTENSION TO WOMEN ACROSS THEIR HEALTH SPAN AND BEST PRACTICES FOR SAVB EXPERIMENTAL DESIGN. OUR COMPREHENSIVE COMMUNITY OUTREACH PLAN WILL ALSO BE CRITICAL TO REACH A HIGHLY AT-RISK POPULATION IN THE SOUTHEAST OF THE US TO INCREASE ROUTINE CARDIOVASCULAR HEALTH MONITORING AND DECREASE THE OVERALL CVD BURDEN ON BOTH THE POPULATION AND THE HEALTHCARE SYSTEM.

ACUTE KIDNEY INJURY BY CISPLATIN AND RENOPROTECTIVE STRATEGIES

THE TEDDY STUDY: GEORGIA/FLORIDA CLINICAL CENTER

EXERCISE & OVERWEIGHT CHILDREN'S COGNITION

PRIDE-FUNCTIONAL AND APPLIED GENOMICS OF BLOOD DISORDERS

IMPLEMENTATION OF MEDICAL HOMES FOR EVIDENCE BASED CARE OF ADOLESCENTS AND ADULTS WITH SICKLE CELL DISEASE

GALECTIN-3: A MEDIATOR OF VASCULAR REMODELING IN PULMONARY ARTERIAL HYPERTENSION

MODEL STATE-SUPPORTED AREA HEALTH EDUCATION CENTERS

CELLULAR MECHANISMS OF RETINAL ANGIOGENESIS

IDO-EXPRESSING IMMUNOREGULATORY DENDRITIC CELLS

GENETIC ANALYSIS OF MYELOPROLIFERATIVE DISEASE

SBIRT INITIATIVE FOR GEORGIA'S RURAL AND UNDERSERVED POPULATIONS

NEDDYLATION AND CARDIAC PROTEIN QUALITY CONTROL

NOVEL ROLE OF BSCL2 IN CARDIAC SUBSTRATE METABOLISM AND FUNCTION

NOVEL ROLE OF MAPK14 IN REGULATION OF VSMC CONTRACTILE PHENOTYPE

REGULATION OF LPS-RESPONSES BY ZBP1 - PROJECT SUMMARY THE GOAL OF THIS PROPOSAL IS INVESTIGATION OF THE MECHANISM OF ZBP1-MEDIATED RESPONSE TO LPS AND PROTECTION FROM BACTERIAL INFECTION THAT IS PROVIDED BY ZBP1. OUR PUBLISHED AND PRELIMINARY DATA CHARACTERIZE A NOVEL NONCANONICAL ACTIVATION FO CASPASE 8 IN RESPONSE TO LPS, WHICH RESULTS IN THE PYROPTOTIC CELL DEATH IN MACROPHAGES. IN FURTHER INQUIRY, WE IDENTIFIED THAT CONTAINING CASP8 PRO-DEATH COMPLEX II THAT ASSEMBLES IN RESPONSE TO LPS, IS NOT DEPENDENT ON TNFR1 AS WAS WIDELY ACCEPTED SO FAR, BUT RATHER ON TRIF THUS MAKING TRIF A CENTRAL COMPONENT OF THEIS ACTIVATION PATHWAY. TO REFLECT THE REQUIREMENT FOR TRIF IN COMPLEX II FORMATION AND ACTIVATION OF CASP8, WE TERMED THIS NEW PYROPTOSIS-INDUCING COMPLEX THE “TRIFOSOME”. IN FURTHER MECHANISTIC INQUIRY, WE FOUND THAT THE NUCLEIC ACID SENSOR, ZBP1, WHICH THUS FAR HAS BEEN IMPLICATED ONLY IN VIRAL INFECTIONS, PLAYS A SIGNIFICANT ROLE IN THE FORMATION OF THE TRIFOSOME COMPLEX BY SHUTTLING RIPK1 TO TRIF. THE RELIANCE OF COMPLEX II FORMATION ON ZBP1 RAISED A QUESTION WHETHER ZBP1 MEDIATES INFLAMMATORY RESPONSES TO LPS AS WELL. IN SUPPORT OF THIS HYPOTHESIS, OUR PRELIMINARY DATA SHOW THAT ZBP1 MEDIATES LPS- INDUCED INFLAMMATORY RESPONSES, THUS PROVIDING RATIONALE FOR FURTHER IN VIVO INVESTIGATIONS OF THE ROLE THAT ZBP1 MIGHT PLAY IN RESPONSES TO LPS AND YERSINIA INFECTION. TO ADDRESS WHETHER ZBP1-MEDIATED RESPONSE TO LPS PROVIDES PROTECTION FROM THE BACTERIAL INFECTION, WE PROPOSE 2 AIMS. IN AIM 1, WE WILL INVESTIGATE ZBP1- MEDIATED IN VITRO RESPONSE TO LPS USING DOUBLE KNOCKOUT AND GENE-SILENCING APPROACH. WE WILL USE ZBP1- SPECIFIC IMMUNOPRECIPITATION IN ORDER TO DETERMINE THE COMPONENTS OF ZBP1-INTERACTOME. DETERMINE THE CONTRIBUTION OF ZBP1 TO LPS-INDUCED IMMUNE RESPONSE, WHICH WILL INCLUDE ELUCIDATION SPECIFIC ROLE OF ZBP1 IN MEDIATING TRIF-DEPENDENT AND TRIF-INDEPENDENT RESPONSES. IT WILL ALSO INCLUDE DELINEATION OF THE ROLE OF ZBP1 IN THE RIPK1-SPECIFIC RESPONSE TO LPS. INCLUDING UNDERSTANDING THE ROLES OF THE FUNCTIONAL DOMAINS OF ZBP1 IN THIS PATHWAY, ANALYSIS OF THE RECRUITMENT OF ZBP1 INTO THE ENDOSOMAL TRIFOSOME COMPLEX, AND CHARACTERIZATION OF THE ZBP1-DEPENDENT CHANGES IN HOST RESPONSE TO BACTERIAL INFECTION IN VIVO. IN THE SECOND AIM, WE WILL CAPITALIZE ON OUR PRELIMINARY FINDINGS AND WILL FURTHER INVESTIGATE HOW THE KINETICS OF RESPONSE TO LSP THAT IS CONFERRED BY ZBP1 CONFERS SENSITIVITY TO LPS-INDUCED TOSICITY I VIVO, AND WHETHER THIS SENSITIVITY PROVIDES PROTECTION FROM GRAM-NEGATIVE INFECTION IN VIVO. THESE STUDIES WILL HELP ESTABLISHING THE ROLE OF ZBP1 IN HOST RESPONSE TO BACTERIAL INFECTION AND WILL POSITION ZBP1 AT THE CROSSTALK OF DIFFERENT IMMUNE RESPONSE PATHWAYS.

CENTER CORE GRANT FOR VISION RESEARCH

MCG MINORITY-BASED COMMUNITY CLINICAL ONCOLOGY PROGRAM

THE ADIPOCYTE PPARGAMA/ADIPONECTIN AXIS AND ALZHEIMER'S DISEASE

THE ROLE OF CHD7 IN ACC NEURONS - A LIMITED FUNDAMENTAL UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS UNDERLYING COMPLEX BEHAVIORS POSES A MAJOR BARRIER FOR DEVELOPMENT OF EFFECTIVE CLINICAL APPLICATIONS TO TREAT MENTAL DISORDERS. THE LONG-TERM GOAL OF OUR RESEARCH IS TO SHED LIGHT ON THE GAPS IN KNOWLEDGE REGARDING THE MOLECULAR SIGNATURES AND SYNAPTIC PROPERTIES OF BRAIN NEURONAL CIRCUITS THAT CONTROL RESPONSES TO STRESS. EPIGENETIC GENE REGULATION HAS EMERGED AS A KEY MOLECULAR DRIVER UNDERLYING NEURONAL CIRCUIT DYNAMICS AND BEHAVIORAL CHANGES. OUR PRELIMINARY DATA SUGGEST THAT CHD7, A CHROMATIN-REMODELING FACTOR PRIMARILY EXPRESSED IN THE EMBRYONIC BRAIN, REMAINS ENRICHED IN EXCITATORY NEURONS WITHIN LAYER 2/3 OF THE ANTERIOR CINGULATE CORTEX (ACC) IN ADULT MICE. THE ACC, A REGION WITHIN THE MEDIAL PREFRONTAL CORTEX IN RODENTS, PLAYS CRITICAL ROLES IN PROCESSING MOOD-RELATED INFORMATION AND MODULATING ANXIETY-RELATED BEHAVIORS. WHILE CRITICAL ROLES FOR CHD7 DURING NEURAL DEVELOPMENT HAVE BEEN WELL- DOCUMENTED, ITS FUNCTION IN POSTMITOTIC NEURONS REMAINS UNCLEAR. OUR DATA SUGGEST THAT POSTMITOTIC DELETION OF CHD7 FROM ACC EXCITATORY NEURONS (REFERRED TO AS CHD7CKO) SIGNIFICANTLY REDUCED INNATE ANXIETY LEVELS. IN ADDITION, NEURONAL ACTIVITY IN THE ACC OF CHD7CKO MICE EXPOSED TO AN ENVIRONMENTAL STRESSOR WAS SIGNIFICANTLY LOWER THAN THAT IN WILD TYPE (WT) MICE. INTRIGUINGLY, THESE PHENOMENA WERE OBSERVED ONLY IN MALE (AND NOT FEMALE) MICE, INDICATING SEXUAL DIMORPHISM OF CHD7 FUNCTION. OUR DATA PROVIDE THE FIRST EVIDENCE SUGGESTING AN ESSENTIAL ROLE FOR CHD7 IN POSTMITOTIC ACC NEURONS IN REGULATING NEURONAL ACTIVITY AND INNATE ANXIETY. OUR PRIMARY OBJECTIVES ARE TO INTERROGATE THE ROLE OF CHD7 IN CONTROLLING A COMPLEX GENE NETWORK TO REGULATE THE SYNAPTIC ACTIVITY OF ACC NEURONS AND THEIR DOWNSTREAM TARGETS. IN THIS PROPOSAL, WE WILL FIRST DETERMINE HOW CHD7 REGULATES THE ACTIVITY OF ACC NEURONS AND THEIR DOWNSTREAM TARGETS IN THE BED NUCLEUS OF THE STRIA TERMINALIS (BNST). OUR PRELIMINARY DATA SUGGEST THAT CHD7 PLAYS A CRITICAL ROLE IN MAINTAINING PROPER NEURONAL ACTIVITY IN THE ACC-BNST PATHWAY. NEXT, WE WILL USE UNBIASED HIGH-THROUGHPUT APPROACHES TO DETERMINE HOW CHD7 CONTROLS A COMPLEX GENE NETWORK IN POSTMITOTIC NEURONS TO REGULATE ACTIVITY-DEPENDENT GENE TRANSCRIPTION. FINALLY, WE WILL INVESTIGATE HOW CHD7 ACTIVITY IS REGULATED BY AN INTERACTING PARTNER THAT IS INVOLVED IN G PROTEIN SIGNALING. IF SUCCESSFUL, OUR RESEARCH WILL SHED NEW LIGHT ON THE MOLECULAR UNDERPINNINGS AND NEUROPHYSIOLOGY OF NEURONAL CIRCUITS THAT RESPOND TO STRESS. SUCH INFORMATION WILL ULTIMATELY HELP DEFINE MECHANISMS UNDERLYING COMPLEX EMOTIONAL BEHAVIORS IN HUMANS.

HYPOXIA AND CARDIAC STEM CELL HOMING

MECHANISMS FOR CARDIOVASCULAR CONTROL EARLY IN DIABETES

DEVELOPMENT OF A NOVEL SOLUBLE EPOXIDE HYDROLASE INHIBITOR AS A STRATEGY FOR TREATING NEUROPATHIC PAIN IN PATIENTS WITH SPINAL CORD INJURY

COOPERATIVE MULTICENTER REPRODUCTIVE MEDICINE NETWORK

THE ROLES OF SEMAPHORIN SIGNALING DURING MOUSE VALVULOSEPTAL DEVELOPMENT

GENE DISCOVERY IN FAMILIAL KERATOCONUS

ESTROGEN-MEDIATED IMPAIRMENTS OF VASCULAR HEALTH IN DIABETES

REDOX REGULATION OF CU IMPORTER CTR1 IN ANGIOGENESIS

EPIGENETIC BASIS OF OBESITY INDUCED CARDIOVASCULAR DISEASE AND TYPE 2 DIABETES

ROLE OF SKELETAL MUSCLE HEALTH ON POOR LIFESTYLE RELATED TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE RISK

CYBERCORPS SCHOLARSHIPS FOR SERVICE: AUGUSTA UNIVERSITY DEVELOPING IMMERSIVE EXPERIENCES FOR NOVEL CYBERSECURITY EDUCATION

LEPTIN AND PERIPHERAL GLUCOSE METABOLISM

GAMMA GLOBIN INDUCTION: MOLECULAR AND CELL-BASED STRATEGIES

SIGMA-1 RECEPTOR PROVIDES NEUROPROTECTION AGAINST OPTIC NEUROPATHY

VITAMIN D METABOLISM AND FUNCTION IN THE CORNEA AND ANTERIOR SEGMENT

MECHANISMS AND CONSEQUENCES OF IMPAIRED GLUTATHIONE HOMEOSTASIS IN THE AGING LENS

FIT BODY AND SOUL: A LIFESTYLE INTERVENTION FOR DIABETES PREVENTION CONDUCTED THR

CHARACTERIZATION OF LEPTIN'S ANTIDEPRESSANT ACTIVITY

ADIPOSE TISSUE DISTRIBUTION DETERMINES MICROGLIAL REGULATION OF HIPPOCAMPAL PLASTICITY

PSYCHOSOCIAL STRESS, EPIGENETICS AND HEALTH DISPARITY IN HYPERTENSION

CLINICAL PHENOTYPING AND DISEASE SPECIFIC SAMPLING TO IDENTIFY NON-CODING RNAS FOR HUMAN THERAPEUTICS IN PAD

REASONS FOR POOR DURABILITY OF RESIN-DENTIN BONDS

A GENOME-WIDE METHYLATION STUDY ON ESSENTIAL HYPERTENSION

SIGNALS AND TARGETS UNDERLYING MECHANISMS FOR NEUROVASCULAR COUPLING IN THE BRAIN

ROLE OF EPIGENETIC REPRESSION OF IRF8 IN TUMOR PROGRESSION/METASTASIS

EFFECT OF RANDOMIZED COCOA SUPPLEMENTATION ON INFLAMMAGING AND EPIGENETIC AGING - PROJECT SUMMARY/ABSTRACT COCOA PRODUCTS HAVE BECOME A WIDELY CONSUMED FOOD, WITH GROWING DEMAND ACROSS THE WORLD AND STEADILY INCREASING INTEREST IN ITS POTENTIAL HEALTH BENEFITS AND ANTI-AGING BIOLOGY. HOWEVER, THE ROLE OF COCOA CONSUMPTION ON EPIGENETIC AGING REMAINS ESSENTIALLY UNEXPLORED. THERE HAS BEEN COMPELLING EVIDENCE FOR THE ANTI- INFLAMMATORY ROLE OF COCOA AND COCOA-DERIVED FLAVANOLS BASED UPON IN VITRO AND ANIMAL MODELS. HOWEVER, A CRITICAL BARRIER OF RESEARCH PROGRESS REMAINS THE LACK OF DEFINITIVE LARGE-SCALE RANDOMIZED CONTROLLED TRIALS (RCTS). ACCELERATED EPIGENETIC AGING THAT COMPRISES DNA METHYLATION CHANGES HAS RECENTLY EMERGED AS A POWERFUL, NOVEL PREDICTOR FOR LIFESPAN AND HEALTH SPAN, DISEASE SUSCEPTIBILITY, MORBIDITY, AND MORTALITY RISK. FURTHER, INFLAMMAGING IS A HIGHLY SIGNIFICANT RISK FACTOR FOR BOTH MORBIDITY AND MORTALITY IN THE ELDERLY, AS MANY AGE-RELATED DISEASES INCLUDING CARDIOVASCULAR DISEASE (CVD) SHARE AN INFLAMMATORY PATHOGENESIS. AS SUCH, INTERVENTIONS TO SLOW OR MITIGATE EPIGENETIC AGING AND INFLAMMAGING ARE CRITICAL FOR PROMOTING HEALTHY AGING. THE COCOA SUPPLEMENT AND MULTIVITAMIN OUTCOMES STUDY (COSMOS) IS AN ONGOING RANDOMIZED, DOUBLE- BLIND, PLACEBO-CONTROLLED, 2X2 FACTORIAL RCT OF A HIGH-QUALITY COCOA EXTRACT SUPPLEMENT (CONTAINING 600 MG/D FLAVANOLS, INCLUDING 80 MG EPICATECHINS), AND A MULTIVITAMIN SUPPLEMENT TO REDUCE THE RISK OF CVD AND CANCER IN WOMEN AGED =65 YEARS AND MEN AGED =60 YEARS. COSMOS HAS RANDOMIZED 21,444 PARTICIPANTS INTO THE TRIAL, INCLUDING 2,006 PARTICIPANTS WITH BIO-SAMPLES ALREADY COLLECTED AT BASELINE, YEAR 1 AND YEAR 2 FOLLOW-UP. COSMOS IS THE ONLY LARGE RCT TESTING THE EFFECTS OF COCOA EXTRACT IN WOMEN AND MEN, AND FOR MULTIVITAMINS IN WOMEN. THUS, THIS PROPOSED ANCILLARY STUDY WILL BUILD UPON THE PARENT COSMOS TRIAL TO EXAMINE THE EFFECTS OF RANDOMIZED COCOA OR MULTIVITAMIN SUPPLEMENTATION ON ANTI-AGING (EPIGENETIC AGING AND INFLAMMAGING) IN 600 REPRESENTATIVE SUBJECTS WITH THREE BIO-SAMPLE COLLECTIONS AT BASELINE, YEAR 1, AND YEAR 2, AS WELL AS MEASURED CVD RISK FACTORS, AND EXAMINING THESE FINDINGS IN THE CONTEXT OF CVD OUTCOMES. WE WILL TEST OUR CENTRAL HYPOTHESES THAT COCOA SUPPLEMENTATION REDUCES EPIGENETIC AGING INDICES (E.G., AGEACCELHORVATH, AGEACCELHANNUM, AGEACCELGRIM, AGEACCELPHENO, AND DNAMTLADJAGE) AND INFLAMMAGING (SERUM HSCRP, IL- 1SS, IL-4, IL-6, AND TNF-A) OVER TIME. WE WILL ALSO DETERMINE TO WHAT EXTENT THE EFFECTS OF COCOA SUPPLEMENTATION ON INFLAMMAGING AND CVD RISK FACTORS ARE MEDIATED BY EPIGENETIC AGING. THE PURPORTED ANTI-AGING HEALTH BENEFITS OF COCOA-RICH PRODUCTS SUCH AS DARK CHOCOLATE HAVE POPULARIZED AND INCREASED CONSUMPTION OF COCOA-RICH PRODUCTS OVER THE PAST DECADE. MOREOVER, MULTIVITAMINS REMAIN THE MOST COMMON DIETARY SUPPLEMENT TAKEN BY AT LEAST ONE-THIRD OF OLDER US ADULTS. IT REMAINS OF CRITICAL PUBLIC HEALTH IMPORTANCE TO RIGOROUSLY TEST THE ANTI-AGING PROPERTIES OF THESE TWO SUPPLEMENTS VIA LARGE RCTS FOR MORE DEFINITIVE EVIDENCE OF THEIR POTENTIAL EFFICACY, AND TO APPROVE OR REFUTE THEIR POTENTIAL ANTI-AGING BENEFITS.

ANALYSIS OF NEURAL RETINA TRANSPORT FUNCTION

CHEMO-RADIO IMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS

REPARATIVE EFFECT OF JUVENILE FACTORS IN AGING AND INJURY - AGING AND INJURY ARE AMONG THE MAJOR GLOBAL HEALTH PROBLEMS AND DEATH DUE TO INJURY INCREASES SHARPLY WITH AGE. AS HEMORRHAGE ACCOUNTS FOR ALMOST HALF OF ALL TRAUMA-RELATED DEATHS, THERE IS A NEED TO DEVELOP METHODS TO REDUCE THE ADVERSE EFFECTS OF AGING ON INJURY TO FACILITATE HEALTHY LIVING. IN THIS PROPOSAL, OUR OBJECTIVE IS TO ESTABLISH THAT CIRCULATORY FACTORS OF JUVENILE ORIGIN CAN IMPROVE OUTCOME FOLLOWING INJURY IN THE MATURE AND AGED ANIMALS. THE EXPERIMENTS PROPOSED IN THIS PROJECT ARE BASED UPON OUR FINDING THAT FOLLOWING HEMORRHAGIC SHOCK IN A MOUSE MODEL (HEMORRHAGIC SHOCK INJURY; HI) JUVENILE MICE HAVE A SURVIVAL ADVANTAGE COMPARED TO ADULT MICE. WE ALSO FOUND THAT EVS FROM THE PLASMA OF JUVENILE MICE IMPROVED ORGAN FUNCTION AND SURVIVAL FOLLOWING HI. BASED UPON THESE DATA OUR HYPOTHESIS IS THAT PLASMA FACTORS FROM JUVENILE MICE CAN RESTORE MITOCHONDRIAL FUNCTION, ALLEVIATE OXIDATIVE STRESS AND REDUCE ORGAN DYSFUNCTION AND DEATH IN MATURE AND OLD MICE SUBJECTED TO HI. WE WILL TEST OUR HYPOTHESIS BY DETERMINING THE PROTECTIVE EFFECT OF JUVENILE MICE-DERIVED EVS IN MATURE AND OLD MICE AND IDENTIFY POTENTIAL MECHANISMS BY WHICH JUVENILE PLASMA FACTORS EXERT SALUTARY EFFECT IN MATURE AND AGED MICE FOLLOWING HI. USING 5XFAD MICE WE WILL DETERMINE WHETHER JUVENILE EVS CAN REDUCE PATHOLOGY IN ALZHEIMER’S DISEASE, AN AGE ASSOCIATED NEURODEGENERATIVE DISEASE. OUR GOAL IS TO DEVELOP METHODS TO REVITALIZE THE AGING SYSTEM BY IDENTIFYING MOLECULAR FACTORS INVOLVED IN MATURATIONAL DEVELOPMENT. WE WILL USE A COMBINATION OF CELL BIOLOGICAL, BIOCHEMICAL AND GENOMIC TOOLS AND TECHNIQUES TO TEST THE HYPOTHESIS. WE EXPECT THAT OUR STUDIES WILL RESULT IN THE IDENTIFICATION OF JUVENILE PROTECTIVE FACTORS THAT CAN IMPROVE OUTCOME FOLLOWING HEMORRHAGIC SHOCK. THE PROPOSED RESEARCH IS RELEVANT TO THE PART OF NIH’S MISSION PERTAINING TO DEVELOPING FUNDAMENTAL KNOWLEDGE TO POTENTIALLY HELP REDUCE THE BURDENS OF HUMAN DISEASE. THE OUTCOME OF THIS RESEARCH WILL BE SIGNIFICANT BECAUSE THE FUNDAMENTAL KNOWLEDGE GAINED FROM THIS STUDY IS EXPECTED TO ADVANCE METHODS TO PROMOTE HEALTHY LIVING.

MODULATION OF VASCULAR EXTRACELLULAR SUPEROXIDE DISMUTASE

CALPAIN/TALIN/MLCP AXIS IN PULMONARY ENDOTHELIAL BARRIER REGULATION - PROJECT SUMMARY ACUTE LUNG INJURY (ALI) IS CHARACTERIZED BY LUNG VASCULAR ENDOTHELIAL CELL (EC) BARRIER COMPROMISE RESULTING IN PULMONARY EDEMA. WHILE BACTERIAL INFECTIONS INDUCED BY E.COLI OR STREPTOCOCCUS PNEUMONIAE (SPN), AND THEIR RESPECTIVE BACTERIA TOXIN LIPOPOLYSACCHARIDES (LPS) AND PNEUMOLYSIN (PLY) ARE THE MAJOR CAUSES FOR ALI, THE MOLECULAR MECHANISMS INVOLVED IN LPS- OR PLY-INDUCED ALI ARE ILL-DEFINED. THE SCIENTIFIC PREMISE COMES FROM OUR NOVEL PRELIMINARY DATA, WHICH SHOW THAT BOTH LPS AND PLY ACTIVATE ENDOPEPTIDASE CALPAIN IN HUMAN LUNG MICROVASCULAR ECS (HLMVECS) IN ERK-DEPENDENT MANNER AND THAT SPECIFIC CALPAIN INHIBITION PREVENTS LPS- AND PLY-INDUCED DISRUPTION OF EC BARRIER IN HLMVECS AND LPS-INDUCED PULMONARY EDEMA IN ALI. FURTHER, WE FOUND THAT ERK-MEDIATED CALPAIN PHOSPHORYLATION AT SER-50 AND CALPAIN ACTIVITY WERE MUCH HIGHER IN MURINE LUNG MICROVASCULAR ECS ISOLATED FROM LUNGS EXPOSED TO LPS, INDICATING THAT ERK-CALPAIN PATHWAY IS HIGHLY RELATED TO ALI. WE SHOW THAT LPS/PLY INDUCES TALIN CLEAVAGE INTO HEAD AND ROD DOMAIN AND TALIN PHOSPHORYLATION IN HLMVECS AND THAT OVEREXPRESSION OF CALPAIN CAUSES TALIN CLEAVAGE, AND RHO-MEDIATED INHIBITION OF MYOSIN LIGHT CHAIN PHOSPHATASE (MLCP). TALIN IS ACTIVATED THROUGH EITHER TALIN CLEAVAGE OR PHOSPHORYLATION. TALIN CLEAVAGE SEPARATES HEAD FROM ROD DOMAIN THUS REMOVING AUTO-INHIBITION AND STIMULATING TALIN HEAD BINDING TO INTEGRIN AND THUS INDUCES ACTIVATION OF FOCAL ADHESIONS (FAS), LEADING TO RHOA-MEDIATED MLCP INHIBITION AND INCREASED LUNG EC PERMEABILITY. WE FOUND THAT MLCP, WHICH OPPOSES EC BARRIER COMPROMISE IN ALI, IS DOWN- REGULATED IN LUNGS OF ARDS PATIENTS, HIGHLIGHTING THE IMPORTANCE OF MLCP INHIBITION IN HUMAN ALI. MLCP BINDS TALIN AND INDUCED TALIN DEPHOSPHORYLATION, WHICH MAY LEAD TO TALIN DEGRADATION FOLLOWED BY FAS DISASSEMBLY. INTERESTINGLY, MLCP DEPHOSPHORYLATES ANOTHER CALPAIN SUBSTRATE, EZRIN, LEADING TO ITS DEACTIVATION AND WITHDRAWAL FROM MEMBRANE CYTOSKELETON. ACTIVATION OF TALIN/EZRIN AXIS IS INVOLVED IN FA FORMATION AND OUR DATA SUGGEST THAT TALIN IS UPSTREAM OF EZRIN IN LPS-INDUCED EC CYTOSKELETAL REMODELING. IT WAS SHOWN THAT EZRIN DEPLETION DECREASES CALPAIN ACTIVITY SUGGESTING POSITIVE FEEDBACK EFFECT OF MLCP INHIBITION ON LPS/PLY-INDUCED CALPAIN ACTIVATION AND EC BARRIER COMPROMISE VIA EZRIN PHOSPHORYLATION/MEMBRANE ATTACHMENT. THESE DATA LED TO OUR NOVEL HYPOTHESIS THAT CALPAIN/MLCP CROSSTALK COORDINATES TALIN ACTIVATION LEADING TO LUNG EC BARRIER DISRUPTION IN ALI. TO TEST THIS HYPOTHESIS WE WILL EMPLOY UNIQUE MOLECULAR TOOLS SUCH AS MURINE LUNG-TARGETING GENE DELIVERY IN VIVO, EC-SPECIFIC INDUCIBLE CALPAIN AND MLCP KO MICE AND ERK INSENSITIVE KNOCKIN MOUSE (CAPN2S50A). WE WILL: (1) EVALUATE WHETHER ERK-MEDIATED CALPAIN ACTIVATION IS INVOLVED IN LUNG MICROVASCULAR EC BARRIER DISRUPTION AND CYTOSKELETAL REORGANIZATION IN ALI INDUCED BY BACTERIAL TOXINS (LPS, PLY), LIVE BACTERIA (E.COLI, SPN) AND IN SEPSIC CONDITIONS; (2) DETERMINE WHETHER GRAM- AND GRAM+ BACTERIA, THEIR TOXINS AND SEPSIS INDUCE TALIN ACTIVATION (CLEAVAGE/PHOSPHORYLATION) AND FA STRENGTHENING LEADING TO LUNG MICROVASCULAR EC BARRIER DISRUPTION; (3) EXAMINE WHETHER MLCP ACTIVITY AFFECTS CALPAIN ACTIVATION INDUCED BY LPS/E.COLI, PLY/SPN AND SEPSIS.

ORAL PATHOGENS AND DENDRITIC CELL SUBSETS

COPPER TRANSPORT PROTEIN AND INFLAMMATORY ANGIOGENESIS

NURSING WORKFORCE DIVERSITY

PEDIATRIC AMBULATORY BLOOD PRESSURE TRAJECTORY AND BRAIN HEALTH IN MIDLIFE

NEURONAL HDAC9, SYNAPTIC PLASTICITY AND ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) IS AN AGE-RELATED NEURODEGENERATIVE DISORDER THAT CAUSES MEMORY LOSS AND COGNITIVE DECLINE. SYNAPTIC DYSFUNCTION AND LOSS CORRELATES STRONGLY WITH COGNITIVE IMPAIRMENT IN AD. AGING IS THE LEADING RISK FACTOR FOR AD, AND EPIGENETIC MECHANISMS INVOLVING HISTONE DEACETYLASES (HDACS) PLAY AN IMPORTANT ROLE IN AGING AND AGE-RELATED NEURODEGENERATIVE DISORDERS. AMONG THE 11 ZINC-DEPENDENT HDACS, HDAC9 IS THE MOST ABUNDANT ISOFORM IN THE BRAIN, FOUND EXCLUSIVELY IN NEURONS. WE PROVIDE KEY PRELIMINARY DATA SHOWING THAT HDAC9 EXPRESSION IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX (PFC) DIMINISHES WITH AGING IN WILD-TYPE MICE, AND THAT REDUCED HDAC9 EXPRESSION PRECEDES THE ONSET OF AMYLOID DEPOSITION IN THE APP/PS1 MOUSE MODEL OF AD. CONSISTENT WITH THESE PRECLINICAL FINDINGS, AD PATIENTS EXHIBITED DECREASED HDAC9 EXPRESSION IN THE DORSOLATERAL PFC. MOREOVER, GLOBAL OR HIPPOCAMPAL CA1-SPECIFIC DELETION OF HDAC9 INDUCES COGNITIVE IMPAIRMENT AND IMPAIRS SYNAPTIC PLASTICITY, WHILE HDAC9 OVEREXPRESSION PRODUCES COGNITIVE-ENHANCING EFFECTS. WE HYPOTHESIZE THAT REDUCED NEURONAL HDAC9 MEDIATES COGNITIVE DECLINE, SYNAPTIC DYSFUNCTION AND OTHER NEUROPATHOLOGIES ASSOCIATED WITH BRAIN AGING AND AD. TO TEST THIS HYPOTHESIS, WE PROPOSE THREE SPECIFIC AIMS. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT LOSS OF HDAC9 IN HIPPOCAMPAL AND PFC NEURONS MEDIATES AGE- AND AD-RELATED NEUROPATHOLOGY AND COGNITIVE IMPAIRMENT. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT THE HISTONE METHYLTRANSFERASE EZH2 [THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH CATALYZES REPRESSIVE H3K27ME3 MODIFICATIONS AT GENE PROMOTERS] EPIGENETICALLY SILENCES HDAC9 EXPRESSION IN THE HIPPOCAMPUS AND PFC DURING AGING AND IN AD. IN AIM 3, WE WILL TEST THE HYPOTHESIS THAT NEURONAL PENTRAXIN 2 (NP2), NERVE GROWTH FACTOR INDUCIBLE (VGF), AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MEDIATE THE DOWNSTREAM EFFECTS OF HDAC9 ON HIPPOCAMPAL SYNAPTIC PLASTICITY AND COGNITION. WE EXPECT THAT THE RESULTS WILL PROVIDE INSIGHT INTO MOLECULAR MECHANISMS UNDERLYING THE EPIGENETIC CONTROL OF GENES RELATED TO AGING AND AD AND OFFER POTENTIAL TARGETS FOR FUTURE THERAPEUTIC INTERVENTIONS.

RURAL COMMUNITIES OPIOID RESPONSE PROGRAM - MEDICATION ASSISTED TREATMENT ACCESS

THIS EDA INVESTMENT SUPPORTS THE GEORGIA AI MANUFACTURING (GA-AIM) COALITION, LED BY THE GEORGIA TECH RESEARCH CORPORATION, WITH INTEGRATING ARTIFICIAL INTELLIGENCE (AI) TECHNOLOGIES IN INDUSTRY BY ACCELERATING THE ADOPTION OF AI ACROSS THE STATE'S LEGACY INDUSTRIAL SECTORS. COALITION PROJECTS INCLUDE ESTABLISHING AN AI MANUFACTURING PILOT FACILITY AT GEORGIA TECH AND EXPAND JOB TRAINING OPPORTUNITIES IN AI FOR UNDERSERVED COMMUNITIES. THE GA-AIM COALITION AIMS TO SERVE AS A NATIONAL MODEL FOR HOW TO ACCELERATE THE TRANSITION TO AUTOMATION IN MANUFACTURING WHILE ENSURING THESE SYSTEMS COMPLEMENT RATHER THAN REPLACE EXISTING WORKERS. ONCE IMPLEMENTED, THE INVESTMENT WILL HELP DEVELOP AND STRENGTHEN REGIONAL INDUSTRY CLUSTERS - ALL WHILE EMBRACING ECONOMIC EQUITY, CREATING GOOD-PAYING JOBS, AND ENHANCING U.S. COMPETITIVENESS GLOBALLY.

MITOCHONDRIA-MEDIATED EFFECTS AND THERAPEUTIC POTENTIAL OF ATRIAL NATRIURETIC PEPTIDE IN SALT-SENSITIVE HYPERTENSION

MOLECULAR CONTROL OF VASCULAR SMOOTH MUSCLE REPROGRAMMING IN ARTERIOVENOUS FISTULA MATURATION - PROJECT SUMMARY A SURGICALLY CREATED ARTERIOVENOUS FISTULA (AVF) BETWEEN AN ARTERY AND VEIN IS NOW THE PREFERRED APPROACH TO PROVIDE A VASCULAR ACCESS FOR LIFE-SAVING HEMODIALYSIS IN CHRONIC KIDNEY DISEASE CKD) PATIENTS. HOWEVER, NEARLY 60% OF AVFS FAIL TO MATURE INTO A CLINICALLY USEFUL CONDUIT DUE TO INSUFFICIENT OUTWARD REMODELING AND FLOW CAPACITY, OCCLUSIVE NEOINTIMAL HYPERPLASIA, AND/OR FIBROTIC STENOSIS. CURRENTLY, THERE ARE NO THERAPIES THAT CAN IMPROVE AVF EARLY MATURATION FAILURE BY ENHANCING AVF OUTWARD REMODELING, LARGELY DUE TO OUR NASCENT UNDERSTANDING OF THE MECHANISMS UNDERLYING VEIN ADAPTATIONS TO AVF HEMODYNAMIC STRESSES. ACUTE INCREASES IN SHEAR STRESS AND PULSATILE PRESSURE IN THE VEIN ARE NORMALIZED BY RAPID DILATION FOLLOWED BY WALL THICKENING. VENOUS SMOOTH MUSCLE CELLS (VSMCS) ARE THE PREDOMINANT CELLS SENSING VESSEL WALL STRETCH IN RESPONSE TO INCREASED FLOW VOLUME AND BLOOD PRESSURE. A SIGNIFICANT BARRIER TO PROGRESS IS A DEFICIT IN OUR KNOWLEDGE OF THE MECHANISMS BY WHICH VSMCS RESPOND TO ARTERIAL HEMODYNAMICS IN EARLY AVF ADAPTATION. STRONG EVIDENCE FROM BOTH AVF MOUSE MODELS AND HUMAN SAMPLE STUDIES DEMONSTRATE, FOR THE FIRST TIME, A ROLE FOR DIFFERENTIATED VSMCS IN AVF OUTWARD REMODELING AND MATURATION. THIS IS FURTHER SUPPORTED BY NEW PRELIMINARY DATA FROM OUR CLINICALLY RELEVANT 5/6-NEPHRECTOMY CKD AVF MOUSE MODEL. WE FURTHER SHOW EARLY AVF MATURATION INVOLVES VSMCS REPROGRAMMING FROM A QUIESCENT TO A PREVIOUSLY UNCHARACTERIZED PROLIFERATIVE, SYNTHETIC STATE THAT SURPRISINGLY RETAINS DIFFERENTIATED CONTRACTILE PROPERTIES. MYOCARDIN RELATED TRANSCRIPTION FACTOR (TF) A AND B (MRTFA AND B, MRTFS) RESPOND TO CYCLIC STRETCH BY TRANSACTIVATING MULTIPLE GENE PROGRAMS. VSMC-DEFICIENCY OF MRTFS IMPAIRS AVF MATURATION WITH REDUCED AVF WALL THICKNESS. BEYOND THE CONTRACTILE GENE PROGRAM, MRTFA UPREGULATES NOVEL TARGET GENES (MMP2 AND ATF3) TO FACILITATE MATRIX REMODELING AND CELL PROLIFERATION. THIS SUGGESTS THAT MRTFS ACT AS NODAL TFS OF VSMC REPROGRAMMING. CAMK2 IS A MAJOR SIGNAL TRANSDUCER POISED TO INTEGRATE STRETCH-INDUCED VASCULAR REMODELING. PRELIMINARY DATA SHOW GROWTH FACTORS INDUCE NUCLEAR INTERACTION OF CAMK2 AND MRTFA IN CULTURED VSMCS. VSMC-DEFICIENCY OF A MAJOR VSMC CAMK2 ISOFORM, CAMK2D, PHENOCOPIES LOSS OF VSMC MRTFS, SUGGESTING THAT CAMK2D TRANSDUCES A SIGNAL(S) FROM AVF WALL STRESS TO TRIGGER MRTF TRANSACTIVITY. THESE PRELIMINARY DATA SUPPORT OUR CENTRAL HYPOTHESIS THAT SUCCESSFUL AVF ADAPTATION AND MATURATION INVOLVES CAMK2/MRTFS-DEPENDENT VSMC REPROGRAMMING TO A PROLIFERATIVE, MATRIX ORGANIZING, AND CONTRACTILE PHENOTYPE. AIM1 WILL ELUCIDATE MECHANISMS OF VSMC-DEPENDENT AVF ADAPTIVE REMODELING AND MATURATION USING ITGA8CREERT2CONFETTI REPORTER, SINGLE NUCLEUS (SN) ATAC/RNA-SEQ, AND SPATIAL OMICS TO DETERMINE VSMC CLONAL EXPANSION AND TRANSCRIPTOMICS UNDERLYING AVF MATURATION. AIM 2 WILL USE NOVEL VSMC-SPECIFIC MRTFS AND CAMK2D KNOCKOUT MICE TO ELUCIDATE THE MECHANISTIC ROLE OF CAMK2D/MRTFS IN AVF MATURATION. SUCCESSFUL COMPLETION OF THESE STUDIES WILL PROVIDE NOVEL INSIGHTS INTO, AND POTENTIAL THERAPEUTIC TARGETS FOR, AVF MATURATION FAILURE ATTRIBUTABLE TO INADEQUATE VEIN ADAPTION IN HUMANS.

A MOLECULAR EXAMINATION OF MRNA LOCALIZATION AND CELL POLARIZATION

CIRCADIAN ORIGINS OF VASCULAR DISEASE IN OBESITY

ROLE OF AGRP NEURONS IN CHRONIC STRESS-ACCELERATED BRAIN AGING AND PROGRESSION OF ALZHEIMER'S DISEASE - PROJECT SUMMARY CHRONIC STRESS IS INCREASINGLY BEING RECOGNIZED AS A RISK FACTOR FOR SPORADIC AD. DYSREGULATION OF THE HYPOTHALAMIC–PITUITARY–ADRENAL AXIS (HPA AXIS) IS COMMON IN AD PATIENTS. BY STIMULATING CORTICOTROPIN-RELEASING HORMONE (CRH) EXPRESSION AND GLUCOCORTICOID SECRETION, CHRONIC STRESS EXPOSURE EXACERBATES ASS AND TAU PATHOLOGIES AND COGNITIVE DECLINE. AGRP NEURONS, LOCATED IN THE ARCUATE NUCLEUS, CO-EXPRESS GABA AND SEND EXTENSIVE PROJECTIONS TO THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS. OUR RECENT STUDIES HAVE SHOWN THAT CHRONIC STRESS DECREASES FIRING RATES OF AGRP NEURONS, AND THAT STIMULATING AGRP NEURONS CAN REVERSE CHRONIC STRESS-INDUCED BEHAVIORAL DEFICITS, INCLUDING MEMORY IMPAIRMENT. HPA RESPONSES TO STRESS CAN ALSO BE DAMPENED BY STIMULATING AGRP NEURONS. IN ADDITION, WE PROVIDE NOVEL PRELIMINARY DATA SHOWING THAT AGING INDUCES SILENCING OF AGRP NEURONS. WE HYPOTHESIZE THAT CHRONIC STRESS AND AGING CONVERGE TO SILENCE AGRP NEURONS, WHICH LEADS TO REDUCED INHIBITORY INPUTS TO THE PVN. THIS WEAKENS NEGATIVE FEEDBACK AND DRIVES HPA HYPERACTIVITY, WHICH IN TURN ACCELERATES BRAIN AGING AND WORSENS AD PATHOLOGIES. TO TEST THIS HYPOTHESIS, WE PROPOSE THREE SPECIFIC AIMS. IN AIM 1, WE WILL IDENTIFY MOLECULAR MECHANISMS OF CHRONIC STRESS- AND AGING- INDUCED SILENCING OF AGRP NEURONS. IN AIM 2, WE WILL DETERMINE WHETHER CHRONIC STRESS-INDUCED INHIBITION OF AGRP NEURON ACTIVITY CONTRIBUTES TO OVERSTIMULATION OF THE HPA AXIS AND STRESS-EXACERBATED ASS AND TAU PATHOLOGIES. IN AIM 3, WE WILL DETERMINE WHETHER AGE-INDUCED SILENCING OF AGRP NEURONS ACCELERATES THE PROGRESSION OF ASS ACCUMULATION AND COGNITIVE DECLINE.

PBK: A NOVEL MEDIATOR OF VSMC PROLIFERATION AND VASCULAR REMODELING IN PAH - PROJECT SUMMARY PULMONARY ARTERIAL HYPERTENSION (PAH) IS A DEBILITATING AND EVENTUALLY LETHAL DISEASE THAT IS RESISTANT TO CURRENT THERAPEUTICS. A DEFINING CHARACTERISTIC OF PAH IS EXCESSIVE CELLULAR PROLIFERATION AND REMODELING OF PULMONARY ARTERIES (PA), THAT RESULTS IN PROGRESSIVE INCREASES IN PULMONARY VASCULAR RESISTANCE LEADING TO RIGHT VENTRICULAR FAILURE AND DEATH. PAH HAS A SURVIVAL TIME OF FIVE TO SEVEN YEARS POST DIAGNOSIS, AND MOST OF THE CURRENT THERAPIES FOR PAH ARE VASODILATORS, WHICH PROVIDE SYMPTOMATIC RELIEF, BUT DO NOT REVERSE PULMONARY VASCULAR REMODELING OR STOP DISEASE PROGRESSION. WE HAVE DISCOVERED A NOVEL GENE, PDZ-BINDING KINASE (PBK) THAT IS UPREGULATED IN HYPERTENSIVE PA. PBK IS A SERINE/THREONINE KINASE THAT IS OVEREXPRESSED IN A SUBSET OF AGGRESSIVE CANCERS. THE HYPERPROLIFERATIVE NATURE OF VASCULAR CELLS IN PAH SHARES MANY MECHANISMS WITH THAT OF CANCER CELLS, HOWEVER, THE THERAPEUTIC UTILITY OF TARGETING PBK IN PAH AND THE MECHANISMS BY WHICH PBK INFLUENCES PULMONARY VASCULAR REMODELING ARE NOT YET KNOWN AND ARE THE GOALS OF THIS PROPOSAL. IN PRELIMINARY EXPERIMENTS IN EXPERIMENTAL MODELS AND HUMAN PAH, WE SHOW THAT PBK IS ROBUSTLY UPREGULATED IN THE MEDIAL LAYER OF PA WHERE IT OVERLAPS WITH MARKERS OF SMOOTH MUSCLE CELLS. GAIN AND LOSS OF FUNCTION APPROACHES SHOW THAT PBK EXPRESSION REGULATES PULMONARY ARTERY SMOOTH MUSCLE CELL (PASMC) PROLIFERATION. IN EXPERIMENTAL RAT AND MOUSE MODELS OF PAH IN VIVO, WE FOUND THAT SELECTIVE INHIBITORS OF PBK IMPROVE PA REMODELING AND CARDIOPULMONARY FUNCTION. TO DETERMINE THE MECHANISMS UNDERLYING INCREASED EXPRESSION OF PBK, WE FOUND THAT THE TRANSCRIPTIONAL CO-ACTIVATOR, YES ASSOCIATED PROTEIN1 (YAP1) WAS UPREGULATED IN PAH AND INCREASED PBK PROMOTER ACTIVITY AND PBK PROTEIN EXPRESSION IN PASMC. WE EMPLOYED A PROXIMITY LIGATION APPROACH TO IDENTIFY NOVEL SUBSTRATES OF PBK WHICH REVEALED PROTEIN REGULATOR OF CYTOKINESIS 1 (PRC1) AS A BINDING PARTNER. PBK UPREGULATED PRC1 AND INDUCED PRC1 PHOSPHORYLATION AND CYTOKINESIS IN PASMC. THESE NOVEL PRELIMINARY DATA INFORM OUR CENTRAL HYPOTHESIS THAT YAP1 UPREGULATES PBK IN PASMC TO ENHANCE PROLIFERATION VIA PRC1 MEDIATED CYTOKINESIS. COLLECTIVELY THESE MECHANISMS CONTRIBUTE TO PATHOLOGIC PULMONARY VASCULAR REMODELING AND PAH. THIS HYPOTHESIS WILL BE TESTED USING INTEGRATED MOLECULAR, CELLULAR, GENETIC, IMAGING, AND TRANSLATIONAL PHARMACOLOGICAL APPROACHES IN MULTIPLE RODENT MODELS INCLUDING A PBK KO RAT. OUR LONG-TERM GOAL IS TO DEFINE THE KEY MECHANISMS BY WHICH PBK REGULATES PASMC PROLIFERATION TO ORCHESTRATE CHANGES IN ARTERIAL REMODELING, A HALLMARK OF PAH. AT THEIR CONCLUSION, THE PROPOSED STUDIES WILL MOVE THE FIELD FORWARD BY DEFINING NOVEL SIGNALING PATHWAYS IN PAH AND A NOVEL MECHANISM OF PASMC PROLIFERATION. THESE STUDIES WILL ALSO ADVANCE THE UTILITY OF NOVEL THERAPEUTIC APPROACHES TARGETING PBK AND CYTOKINESIS TO REDUCE PA REMODELING AND SUBSEQUENTLY IMPROVE THE MORBIDITY AND MORTALITY ASSOCIATED WITH PAH.

SYNAPTIC CIRCUITRY IN STROKE

TARGETING THE CD73-ADENOSINERGIC PATHWAY IN HEAD AND NECK CANCER - HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSC) RELATED TO TOBACCO AND ALCOHOL CONSUMPTION IS AGGRESSIVE AND RESPONDS POORLY TO AVAILABLE THERAPY. EVEN THE NEW PD-1/PD-L1 IMMUNE CHECKPOINT BLOCKADE IS INSUFFICIENT TO CONTROL PROGRESSION DUE TO OTHER HIGHLY IMMUNOSUPPRESSIVE CONDITIONS IN THE TUMOR MICROENVIRONMENT (TME). COMPELLING EVIDENCE IMPLICATES THE ECTO-5'-NUCLEOTIDASE (NT5E) CD73 AS ANOTHER IMPORTANT IMMUNE CHECKPOINT, AS HIGH CD73 EXPRESSION IN THE TME OF MANY TUMORS, INCLUDING HNSC, IS LINKED TO POOR PATIENT SURVIVAL. SEVERAL CONSISTENT TME CONDITIONS, SUCH AS HYPOXIA AND TREATMENT, CAUSE AN INCREASE IN EXTRACELLULAR (E)ATP, AND CD73 SERVES AT THE LAST, RATE-LIMITING STEP IN CONCERT WITH CD39 AND OTHER ECTOENZYMES, TO CONVERT EATP TO ADENOSINE (EADO). EADO ACTIVATES ADENOSINE RECEPTOR (AR) A2AR TO SUPPRESS T CELL ACTIVATION, WHILE A2BR PROMOTES IMMUNOSUPPRESSION VIA CANCER-ASSOCIATED FIBROBLASTS (CAF) AND MYELOID CELLS PRESENT IN THE TME. STUDIES, INCLUDING OUR OWN, SHOW THAT CD73 AND A2BR, AND TO A LESSER EXTENT A2AR, ARE EXPRESSED IN THE HIGHLY IMMUNOSUPPRESSIVE TME OF PROGRESSIVE HNSC OF BOTH CLINICAL AND PRECLINICAL SAMPLES, SUGGESTING THEIR ROLE IN THE IMMUNOSUPPRESSION. HOWEVER, THE CONTRIBUTIONS OF MOLECULES DOWNSTREAM OF CD73 ARE POORLY UNDERSTOOD. RECENT RAPID ADVANCES IN SPATIAL ANALYSIS OF THE TME HAVE REVEALED A CRITICAL ROLE OF IMMUNE EFFECTOR TO TARGET CELL DISTANCE IN GENERATING PRODUCTIVE ANTITUMOR IMMUNITY WITH IMPACT ON CLINICAL OUTCOMES. BECAUSE EADO IS SHORT-LIVED, THE SPATIAL RELATIONSHIP BETWEEN CD73 ON ONE HAND AND A2AR OR A2BR ON THE OTHER HAND, IS LIKELY TO AFFECT THE SPECIFIC AR ACTIVATED BY EADO. WE DISCOVERED IN HNSC CLINICAL SPECIMENS THAT A2AR IS RATHER LIMITED AND LOCATED REMOTELY FROM CD73, WHICH SUPPORTS THE HYPOTHESIS THAT THE MAJOR IMMUNOSUPPRESSIVE IMPACT OF CD73-AR IMMUNE CHECKPOINT IS MEDIATED PRIMARILY THROUGH THE CD73-A2BR AXIS. OUR PLAN IS TO: (1) DISSECT HOW THE CD73-A2BR PATHWAY REGULATES THE IMMUNE LANDSCAPE IN THE TME OF ECTOPIC PRECLINICAL HNSC MODELS DURING PROGRESSION AND TREATMENT; (2) DEVELOP EFFECTIVE CD73-ADO-A2BR ICB REGIMENS IN PRECLINICAL MODELS OF ORTHOTOPIC AND IN PRIMARY CARCINOGEN-INDUCED TONGUE HNSC; (3) ASSESS THE RELATIONSHIPS BETWEEN HNSC PATIENT PERIPHERAL BLOOD MYELOID PRECURSORS, LEVELS AND DISTRIBUTION OF CD73 AND A2BR ON MYELOID AND CAF SUBSETS IN THE TME, PATIENTS’ THREE-YEAR POST-OPERATIVE OUTCOMES. IMPACT: THE PROPOSED STUDY WILL IDENTIFY CD73-A2BR-DEPENDENT MECHANISMS OF IMMUNOSUPPRESSION IN HNSC PRECLINICAL MODELS AND DEVELOP TRANSLATABLE THERAPEUTIC INTERVENTION. THE RESULTS WILL PROVIDE HIGHLY VALUABLE INSIGHTS INTO THE EFFECTS OF CD73-A2BR AXIS ON DISEASE PROGRESSION AND THE THERAPEUTIC POTENTIAL OF BLOCKING IT.

GPCR ANTEROGRADE TRAFFICKING

THE ANTI-ANGIOGENIC VEGF165B AND VEGFR1 SIGNALING IN PERIPHERAL ARTERY DISEASE

WRESTLING STRESS: ROLE OF UFM1 MODIFICATION IN PATHOLOGICAL CARDIAC REMODELING

THE FY 2023 COPS OFFICE TECHNOLOGY AND EQUIPMENT PROGRAM (TEP) IS AN INVITATION-ONLY GRANT PROGRAM DESIGNED TO DEVELOP AND ACQUIRE EFFECTIVE EQUIPMENT, TECHNOLOGIES, AND INTEROPERABLE COMMUNICATIONS THAT ASSIST IN RESPONDING TO AND PREVENTING CRIME. THE OBJECTIVE IS TO PROVIDE FUNDING FOR PROJECTS WHICH IMPROVE POLICE EFFECTIVENESS AND THE FLOW OF INFORMATION AMONG LAW ENFORCEMENT AGENCIES, LOCAL GOVERNMENT SERVICE PROVIDERS, AND THE COMMUNITIES THEY SERVE. FUNDING SHALL BE USED FOR THE PROJECTS, AND IN THE AMOUNTS, SPECIFIED UNDER THE HEADING COMMUNITY ORIENTED POLICING SERVICES, TECHNOLOGY AND EQUIPMENT COMMUNITY PROJECTS/ COPS LAW ENFORCEMENT TECHNOLOGY AND EQUIPMENT IN THE JOINT EXPLANATORY STATEMENT DIVISION B, WHICH IS INCORPORATED BY REFERENCE INTO PUBLIC LAW 117-328.

VASCULAR SMOOTH MUSCLE PROTEIN QUALITY CONTROL AND AORTIC ANEURYSM FORMATION - PROJECT SUMMARY ABDOMINAL AORTIC ANEURYSM (AAA) IS A DEVASTATING DISEASE CARRYING HIGH MORBIDITY AND MORTALITY DUE TO THE HIGH LIKELIHOOD OF FATAL DISSECTION AND RUPTURE. THERE ARE CURRENTLY NO PROVEN PHARMACEUTICAL TREATMENTS TO PREVENT AAA PROGRESSION. VSMC DEGENERATION CONTRIBUTES LARGELY TO AAA PATHOGENESIS, BUT THE MECHANISM REMAINS ELUSIVE. THE UBIQUITIN PROTEASOME SYSTEM (UPS) SERVES AS AN ESSENTIAL PROTEIN QUALITY CONTROL MECHANISM BY DEGRADING MISFOLDED PROTEINS AND SURPLUS NORMAL PROTEINS. WHILE PROTEOTOXICITY RESULTING FROM INSUFFICIENT UPS FUNCTION HAS BEEN WIDELY ACCEPTED AS AN IMPORTANT MECHANISM FOR MULTIPLE DEGENERATIVE HUMAN CONDITIONS, THE IMPLICATION OF UPS DYSFUNCTION IN AAA IS COMPLETELY UNKNOWN. OUR PATHWAY ANALYSIS IN HUMAN AAA TISSUES REVEALED AN ASSOCIATION OF UPS FUNCTION WITH AAA. IN A MOUSE MODEL OF AAA, ACCUMULATION OF UBIQUITINATED PROTEINS, A HALLMARK OF IMPAIRED UPS PERFORMANCE, PRECEDES VSMC DEGENERATION AND AAA FORMATION AND IS EXACERBATED WITH DISEASE PROGRESSION. THIS SUGGESTS THAT INADEQUATE UPS PERFORMANCE MAY ACT AS A NOVEL MECHANISM UNDERLYING AAA ETIOLOGY. MYOCD IS A MASTER SWITCH OF VSMC CONTRACTILE GENE PROGRAM. HOW MYOCD IS REGULATED AND FUNCTIONS IN AAA IS UNKNOWN. BULK RNA-SEQ IN VSMCS SHOWED AN ENRICHMENT OF UPS- RELATED PATHWAYS IN THE TOP MYOCD-UPREGULATED GENE PROGRAMS BESIDES THOSE RELEVANT TO VSMC CONTRACTION. FORCED EXPRESSION OF MYOCD IMPROVED UPS PERFORMANCE WHILE SUPPRESSING VSMC DEGENERATION IN CULTURED VSMCS AND VSMC-SPECIFIC MYOCD TRANSGENIC (TG) MICE AT THE EARLY STAGE OF AAA FORMATION. MYOCD INCREASED THE EXPRESSION OF NFE2L1 AND KLHL3, TWO KEY PLAYERS OF UPS FUNCTION. THESE LINES OF EVIDENCE SUGGEST A NOVEL ROLE OF MYOCD IN UPS FUNCTION. PHOSPHODIESTERASES (PDES), BY CATALYZING THE HYDROLYSIS OF CAMP AND CGMP TO SPECIFICALLY MODULATE CYCLIC NUCLEOTIDE SIGNALING, PLAY CRITICAL ROLES IN VSMC PATHOPHYSIOLOGY AND ARE PROVEN DRUG TARGETS FOR MULTIPLE HUMAN DISEASES. WE FOUND THAT PDE10A WAS THE MOST INDUCED PDE FAMILY MEMBER DURING AAA FORMATION, WHILE MYOCD PROTEIN EXPRESSION WAS SUPPRESSED. INHIBITION OF PDE10A INCREASED MYOCD PROTEIN, IMPROVED UPS PERFORMANCE, AND SUPPRESSED AAA FORMATION. THESE EXCITING PRELIMINARY FINDINGS SUPPORT A NOVEL HYPOTHESIS THAT DOWNREGULATION OF MYOCD PROTEIN BY PDE10A IMPAIRS UPS PERFORMANCE, LEADING TO VSMC DEGENERATION AND AAA. WE PROPOSE THREE AIMS TO TEST THIS HYPOTHESIS. AIM 1 WILL USE NOVEL VSMC-SPECIFIC MYOCD KNOCKOUT AND TG MICE TO DETERMINE THE FUNCTION OF MYOCD IN ANGII-INDUCED AAA MODEL. AIM 2 WILL USE A NOVEL UPS REPORTER MOUSE LINE AND BIOCHEMICAL ASSAYS TO DETERMINE THE IMPORTANCE OF UPS FUNCTION IN MYOCD-REGULATED AAA AND HOW MYOCD MODULATES UPS FUNCTION. AIM 3 WILL DETERMINE HOW PDE10 PROMOTES MYOCD PROTEIN DEGRADATION AND PDE10A FUNCTIONS IN UPS PERFORMANCE AND AAA FORMATION. THIS PROPOSAL WILL ADDRESS FOR THE FIRST TIME THE IMPORTANCE OF UPS PERFORMANCE IN VSMC DEGENERATION AND AAA FORMATION, AND ELUCIDATE A NOVEL REGULATORY CASCADE COMPRISING A DRUGGABLE UPSTREAM MODULATOR (PDE10A) AND A DOWNSTREAM EFFECTOR (MYOCD) IN SAFEGUARDING UPS PERFORMANCE AND PROTEOSTASIS.

REGULATION AND FUNCTION OF MAMMALIAN HSF4 IN VIVO

FUNCTION AND REGULATION OF TSPAN2 IN VASCULAR DISEASE

TACE AND CLOCK MECHANISMS IN AGING AND VASCULAR STIFFENING

INNOVATIVE APPROACHES TO TREAT DUCHENNE MUSCULAR DYSTROPHY USING IPSC-DERIVED MUSCLE PROGENITORS

GRANTS TO STATES TO SUPPORT ORAL HEALTH WORKFORCE ACTIVITIES