Augusta University Research Institute Inc

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

GEORGIA CARES

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

THE ROLE OF ENDOTHELIN-1 IN SICKLE CELL DISEASE

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

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