University Of Mississippi

MISSISSIPPI CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

TELEHEALTH CENTER OF EXCELLENCE

MISSISSIPPI CENTER OF EXCELLENCE IN PERINATAL RESEARCH

CARDIOVASCULAR DYNAMICS AND THEIR CONTROL

CADIORENAL AND METABOLIC DISEASES RESEARCH CENTER

UNIVERSITY OF MISSISSIPPI MEDICAL CENTER BIOTECHNOLOGY RESEARCH PARK

VALUE-BASED MEDICAL STUDENT EDUCATION TRAINING PROGRAM

2009 THE INSTITUTE FOR THE IMPROVEMENT OF MINORITY HEALTH AND HEALTH DISPARITIES IN THE DELTA REGION

VALUE-BASED MEDICAL STUDENT EDUCATION TRAINING PROGRAM

HEALTH CARE AND OTHER FACILITIES

ARIC NEUROCOGNITIVE STUDY

EARLY CHILDHOOD HEALTH PROMOTION SYSTEM FOR HIGH NEED PROGRAM

MOLECULAR CENTER OF HEALTH AND DISEASE - OVERALL-ABSTRACT CHRONIC DISEASES, SUCH AS HEART DISEASE, DIABETES, AND CANCER ARE AMONG THE MOST PREVALENT HEALTH CONDITIONS IN THE UNITED STATES, RESPONSIBLE FOR 7 OUT OF EVERY 10 DEATHS. MISSISSIPPI RANKS FIRST OR SECOND IN 8 OF 10 LEADING CAUSES OF DEATH, WITH 90% OF THE POPULATION HAVING 1-2 CHRONIC DISEASES. WHILE CHRONIC DISEASES CAN BE TREATED THROUGH EARLY INTERVENTION, TARGETED MEDICAL THERAPIES, AND IMPROVED DIET AND EXERCISE, AN UNDERSTANDING OF GENETIC SUSCEPTIBILITY AND MOLECULAR MECHANISMS INVOLVED IN DISEASE ONSET HAS THE POTENTIAL TO HALT PROGRESSION AND RETURN AN INDIVIDUAL TO A HEALTHIER STATE. ADVANCES IN TECHNOLOGY NOW ALLOW FOR UNPRECEDENTED INSIGHT INTO GENOME COMPLEXITY AND ITS INTERACTION WITH THE ENVIRONMENT USING GENOMIC, TRANSCRIPTOMIC, PROTEOMIC, AND METABOLOMIC DATASETS. THE INTEGRATION OF THESE DATASETS WITH PHYSIOLOGICAL INFORMATION USING COMPUTATIONAL APPROACHES CAN PROVIDE SYSTEMATIC INSIGHT INTO THE MOLECULAR, CELLULAR, AND OVERALL PHYSIOLOGY ASSOCIATED WITH THE HEALTH-DISEASE CONTINUUM. WE PROPOSE TO ESTABLISH A NEW PHASE I COBRE, THE MOLECULAR CENTER OF HEALTH AND DISEASE (MCHD) TO FACILITATE RESEARCH UNDER A CENTRAL THEME OF MOLECULAR PHYSIOLOGY TO ENHANCE THE DEPTH OF EDUCATION, MENTORSHIP, AND TRAINING OF RESEARCHERS TO GENERATE UNIQUE OPPORTUNITIES IN THE APPLICATION OF OMICS TECHNOLOGY AND COMPUTATIONAL BIOLOGY. THE MCHD WILL BE COMPRISED OF MULTIPLE COMPONENTS INCLUDING AN ADMINISTRATIVE UNIT, EDUCATION AND MENTORING PROGRAMS, A PILOT PROJECT PROGRAM, TWO RESEARCH CORES, AND THREE MAJOR PROJECT INVESTIGATORS. THE OVERALL OBJECTIVES OF THE MCHD ARE: (1) TO DEVELOP INFRASTRUCTURE AND STATE-OF- THE-ART RESEARCH CORE FACILITIES ESSENTIAL FOR CUTTING EDGE BASIC, CLINICAL, AND TRANSLATIONAL APPROACHES TO STUDY THE HEALTH AND DISEASE CONTINUUM. THE MCHD, THROUGH CORE B WILL ENHANCE EXISTING -OMICS TECHNOLOGY (E.G., SINGLE CELL RNASEQ AND SPATIAL TRANSCRIPTOMICS), PROTEOMIC CAPABILITIES, AND ESTABLISH A NEW INNOVATIVE CORE, INVOLVING CRISPR/CAS9 GENE-EDITING TECHNOLOGY TO INTERROGATE GENE FUNCTION AND BIOLOGICAL PATHWAYS; AND CORE C WILL ESTABLISH CRITICAL COMPUTING INFRASTRUCTURE AND COMPUTATIONAL BIOLOGY ANALYSIS NOT CURRENTLY AVAILABLE AT THE UNIVERSITY; (2) TO ESTABLISH MEANINGFUL EDUCATION, MENTORING PROGRAMS, AND RESEARCH SUPPORT FOR PROMISING NEW INVESTIGATORS TO NURTURE THEM INTO PRODUCTIVE, INDEPENDENTLY FUNDED INVESTIGATORS, WHO WILL BE EFFECTIVE COLLABORATORS ON MULTIDISCIPLINARY RESEARCH TEAMS. THIS WILL BE ACCOMPLISHED THROUGH OFFERING A “GENETIC AND - OMICS ACADEMY” (DIDACTIC INSTRUCTION AND OBSERVERSHIP) TO STRENGTHEN RESEARCHER UNDERSTANDING OF MOLECULAR AND COMPUTATIONAL APPROACHES, A ROBUST MENTORING PROGRAM INVOLVING ONE-ON-ONE AND TEAM MENTORING, CAREER DEVELOPMENT OPPORTUNITIES, AND PROVIDING A HIGH LEVEL OF RESEARCH SUPPORT THROUGH EACH CORE; AND (3) TO ENHANCE COLLABORATIONS AND INTERACTIONS AMONG INVESTIGATORS ACROSS MULTIPLE DISCIPLINES AT UMMC, PROMOTE COOPERATION BETWEEN OTHER IDEA SUPPORTED PROGRAMS, INCLUDING EXISTING COBRE, IDEA-CTR, AND EXTERNAL PARTNERSHIP WITH THE MISSISSIPPI-INBRE.

CORBE: CENTER FOR PSYCHIATRIC NEUROSCIENCE

HYPERTENSION AND CARDIORENAL DISEASES RESEARCH TRAINING PROGRAM

AWARE IN MISSISSIPPI (AIM) - SUMMARY: AWARE IN MISSISSIPPI (AWARE MS) IS A PARTNERSHIP BETWEEN THE MS DEPARTMENT OF EDUCATION (MDE), THE MS ACHIEVEMENT SCHOOL DISTRICT (MASD), MS DEPARTMENT OF MENTAL HEALTH (MDH), OUR STATE’S FEDERATION OF FAMILIES ORGANIZATION, COMMUNITY PROVIDERS, AND MULTIPLE PROGRAMS ACROSS THREE MS UNIVERSITIES (MSU, USM, UMMC). AWARE MS AIMS TO INCREASE MENTAL HEALTH AWARENESS, FOSTER RESILIENCE, AND STRENGTHEN ACCESS TO TRAUMA-INFORMED, CULTURALLY RESPONSIVE, AND FAMILY DRIVEN MENTAL HEALTH SERVICES AND SUPPORTS IN HUMPHREYS COUNTY AND YAZOO CITY SCHOOL DISTRICTS (THE LEAS). BOTH DISTRICTS ARE HOUSED WITHIN THE MASD, A DISTINCT SEA THAT AIMS TO TRANSFORM PERSISTENTLY FAILING MS PUBLIC SCHOOLS. LED BY THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, AWARE MS WILL COLLABORATE TO DEVELOP AND IMPROVE A SCHOOL-BASED CONTINUUM OF AWARENESS, PREVENTION, TRAINING, AND SERVICE LINKAGE AND DELIVERY FOCUSED ON THE MASD AND PRIMED TO SCALE TO OTHER MISSISSIPPI LEAS ACROSS THE STATE. POPULATION: 3250 SCHOOL-AGED YOUTH (K-12) AND 535 SCHOOL STAFF IN HUMPHREYS AND YAZOO CITY SCHOOL DISTRICTS. BOTH MASD DISTRICTS ARE LOCATED IN THE MISSISSIPPI (MS) DELTA REGION, A RURAL AND UNDERSERVED REGION WITH SIGNIFICANT RATES OF CHILD ADVERSITY AND POVERTY. MASD DISTRICTS HAVE SIGNIFICANTLY HIGHER PROPORTIONS OF BLACK YOUTH (HUMPHREYS = 97%; YAZOO CITY = 98%) THAN STATE AVERAGES. PREVALENCE OF CHILDHOOD MENTAL HEALTH (MH) DISORDERS IN MS IS HIGHER (20%) THAN U.S. ESTIMATES, AND NEARLY 66% DO NOT RECEIVE TREATMENT—THE WORST RATE IN THE U.S. BOTH MASD DISTRICTS ARE IN HRSA-DESIGNATED MENTAL HEALTH PROFESSIONAL SHORTAGE AREAS. GOAL 1. INCREASE AWARENESS AND LITERACY AMONG TEACHERS, SCHOOL-BASED STAFF, CAREGIVERS, AND COMMUNITY ORGANIZATIONS TO IDENTIFY AND RESPOND EFFECTIVELY TO SCHOOL AGED YOUTH MH PROBLEMS AND CO-OCCURRING NEEDS. KEY OBJECTIVES: IMPLEMENT MH AWARENESS, SUICIDE PREVENTION AND POSTVENTION PROGRAMS; DISSEMINATE A TRAUMA-INFORMED TOOLKIT FOR SCHOOL STAFF AND PARENTS. EXPECTED TO REACH A 4-YEAR TOTAL OF 2200 UNIQUE INDIVIDUALS. GOAL 2. ENHANCE RESILIENCY AND MH WELL-BEING FOR ALL SCHOOL-AGED YOUTH THROUGH IMPLEMENTATION OF A SOCIAL-EMOTIONAL LEARNING (SEL) CURRICULUM INTEGRATED INTO GENERAL CURRICULUM AND LINKED TO SCHOOL-WIDE IMPLEMENTATION OF TRAUMA-INFORMED PRINCIPLES. KEY OBJECTIVES: IMPLEMENT SEL CURRICULUM AND TRAINING WITH TEACHERS TO PROMOTE SEL IN STUDENTS. OFFER TRAUMA-INFORMED TRAININGS TO YOUTH SERVING ADULTS AND PARENTS. EXPECTED TO REACH A 4-YEAR TOTAL OF 1830 UNIQUE INDIVIDUALS ACROSS STUDENTS, TEACHERS, SCHOOL STAFF, AND PARENTS. GOAL 3. IMPROVE A MULTI-TIERED SYSTEM OF SUPPORT VIA A ROBUST SUITE OF TRAINING AND WORKFORCE CAPACITY BUILDING ACTIVITIES TO SCHOOL STAFF AND PARENTS THAT PROVIDES MH PROMOTION, PREVENTION, AND INTERVENTION SERVICES ALONG A PUBLIC HEALTH CONTINUUM TO MEET STUDENTS’ NEEDS. KEY OBJECTIVES: SCHOOL-WIDE UNIVERSAL SCREENING FOR MH, ADVERSE CHILDHOOD EXPERIENCES AND SUICIDALITY; IMPLEMENT SUITE OF UNIVERSAL PREVENTION PROGRAMS; PROVIDE ON-DEMAND CONSULTATION AND DISTANCE LEARNING FOR MENTAL HEALTH THERAPISTS. EXPECTED TO REACH A 4-YEAR TOTAL OF 9100. GOAL 4. INCREASE AND IMPROVE STUDENT AND FAMILY ACCESS TO CULTURALLY RELEVANT, AND TRAUMA-INFORMED SCHOOL AND COMMUNITY-BASED ACTIVITIES AND SERVICES THROUGH A COORDINATED SYSTEM OF CARE ACROSS LEAS, COMMUNITY AGENCIES, AND LEA, SEA, AND SCHOOL-BASED POLICY DEVELOPMENT. KEY OBJECTIVES: COORDINATE COMMUNITY REFERRAL PATHWAYS, DEVELOP/IMPLEMENT (A)CRISIS RESPONSE AND (B) SCHOOL SAFETY AND THREAT/VIOLENCE PREVENTION PLAN WITH MULTIDISCIPLINARY TEAM. EXPECTED TO REACH A 4-YEAR TOTAL OF 200 INDIVIDUALS.

EARLY CHILDHOOD HEALTH PROMOTION SYSTEM FOR HIGH NEED PROGRAM

ANXIOLYTIC EFFECTS AND ABUSE OF BZ RECEPTOR LIGANDS

CENTER FOR PSYCHIATRIC NEUROSCIENCE

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

MS CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH - PROJECT SUMMARY/ABSTRACT, OVERALL MISSISSIPPI (MS) CURRENTLY STANDS AS THE LEAST HEALTHY STATE IN THE U.S., PLAGUED BY ALARMINGLY HIGH RATES OF INFANT AND MATERNAL MORTALITY AND CHRONIC DISEASE. WHILE POCKETS OF IMPROVEMENT OFFER HOPE, THE STATE STILL FACES MONUMENTAL STRUCTURAL AND ACCESS ISSUES. THUS, THE MAJOR FOCUS OF THE DURING PHASE III OF THE MISSISSIPPI CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH (MCCTR) IS TO LEVERAGE AN INTEGRATED CLINICAL AND TRANSLATIONAL (C/T) RESEARCH PROGRAM ACROSS UMMC AND ITS PARTNER INSTITUTIONS (MS STATE UNIVERSITY, UNIVERSITY OF SOUTHERN MS, OLE MISS, AND TOUGALOO COLLEGE) TO ADDRESS MAJOR CHRONIC DISEASES (E.G., OBESITY DIABETES, CKD, HYPERTENSION, HEART DISEASE, CANCER, MATERNAL/FETAL DISORDERS, AND DEMENTIA) IMPACTING MISSISSIPPIANS. THE MCCTR IMPACT ON C&T RESEARCH WILL ALSO BE GREATLY ENHANCED BY THE INVOLVEMENT OF OUR COLLABORATIVE PARTNERS: THE LOUISIANA C&T SCIENCE CENTER, THE MAYO CLINIC CENTER FOR C&T SCIENCE AND THE UNIVERSITY OF ALABAMA-BIRMINGHAM CENTER FOR C&T SCIENCE AND THE IDEA STATE CONSORTIUM FOR CLINICAL RESEARCH (ISCORE), OUR NEWLY FORMED PBRN CALLED THE “MISSISSIPPI PRIMARY CARE INNOVATION NETWORK”, AND FOUR NIGMS-SUPPORTED COBRES AT UMMC THAT ARE ALIGNED WITH THE MAJOR GOALS OF THE MCCTR. THE AIMS BELOW WILL BE ACCOMPLISHED USING OUR EFFECTIVE ADMINISTRATIVE CORE STRUCTURE AND GUIDED BY ADVISORY COMMITTEES AND PERFORMED BY OUR CORES: AIM 1: LEVERAGE A GOVERNANCE PLAN FOR THE MCCTR TO OVERSEE AN INTEGRATED C&T RESEARCH PROGRAM ACROSS UMMC AND ITS PARTNER INSTITUTIONS TO ADDRESS MAJOR CHRONIC DISEASES IMPACTING MISSISSIPPIANS. ALSO, ENHANCE OUR MARKETING TEAM AND TRACKING AND EVALUATION SPECIALISTS TO HELP MAXIMIZE ITS MCCTR EFFECTIVENESS AND EFFICIENCY TO REACH C&T FACULTY AT MISSISSIPPI INSTITUTIONS AND CTSA/CTR PARTNERS. AIM 2: UTILIZE HR CORE TO MANAGE ALL RESEARCH PROJECTS (1YR-PILOT PROJECT, 2-YR DEVELOPMENTAL PROJECTS, AND MULTI-INSTITUTIONAL COLLABORATIVE PROJECT) WITH THE GOAL OF DEVELOPING A C&T WORKFORCE, STRENGTHENING INVESTIGATOR-INITIATED C&T RESEARCH, AND INCREASING THE VOLUME/IMPACT OF CLINICAL TRIALS AND STUDIES WITHIN MCCTR’S NETWORK. AIM 3: EXPAND OUR COMMUNITY ENGAGEMENT AND OUTREACH (CEO) CORE TO ENHANCE ACTIVE ENGAGEMENT WITH OUR COMMUNITY ADVISORY BOARD, MS STATE EXTENSION SERVICE, PBRN CALLED THE “MISSISSIPPI PRIMARY CARE INNOVATION NETWORK”, AND MISSISSIPPI’S URBAN AND RURAL COMMUNITIES. AIM 4: ENHANCE OUR PROFESSIONAL DEVELOPMENT CORE (PDC) THAT PROVIDES MENTORSHIP AND SUPPORT IN CHRONIC DISEASE RESEARCH, INCLUDING RURAL AND CEO RESEARCH, TO JUNIOR FACULTY MEMBERS OF MCCTR PARTNER INSTITUTIONS, PROMOTING THEIR DEVELOPMENT INTO INDEPENDENT INVESTIGATORS. AIM 5: UTILIZE OUR RESEARCH DESIGN, COMPLIANCE, AND DATA MANAGEMENT (RDCD) CORE TO PROVIDE ACCESSIBLE, RIGOROUS RESEARCH DESIGN, ANALYTIC, AND DATA SUPPORT SERVICES, AND COMPLIANCE SUPPORT FOR MCCTR FACULTY. AIM 6: LEVERAGE OUR RESEARCH SERVICES CORE TO TRAIN, MENTOR AND SUPPORT INVESTIGATORS IN C&T RESEARCH AND TO ENHANCE THE DEVELOPMENT AND IMPLEMENTATION OF C&T RESEARCH PROJECTS UTILIZING MODERN TOOLS SUCH AS TELEMEDICINE AND OUR UNIQUE COHORT STUDIES AT UMMC.

CARDIORENAL AND METABOLIC DISEASES RESEARCH CENTER - PROJECT SUMMARY/ABSTRACT CARDIOVASCULAR (CV), RENAL AND METABOLIC DISEASES ARE HIGHLY PREVALENT IN THE U.S., ESPECIALLY IN MISSISSIPPI. WE ESTABLISHED THE CARDIORENAL AND METABOLIC DISEASES RESEARCH CENTER (CMDRC) AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER TO BRING TOGETHER A MULTIDISCIPLINARY GROUP OF BASIC, CLINICAL AND POPULATION SCIENTISTS WORKING ON CV, RENAL, AND METABOLIC DISEASES. UNDERSTANDING THE COMPLEX RELATIONSHIP BETWEEN THESE CHRONIC DISEASES REQUIRES THE COMBINED EFFORTS OF BASIC, CLINICAL AND POPULATION SCIENTISTS USING INNOVATIVE MULTIDISCIPLINARY INTEGRATIVE APPROACHES TO RESEARCH AND STATE-OF-THE-ART TECHNOLOGIES THAT FACILITATE DISCOVERY. THE MOLECULAR BASES FOR INTERDEPENDENCE OF CV, RENAL, AND METABOLIC DISEASES HAVE CLASSICALLY BEEN STUDIED VIA GENOMICS, TRANSCRIPTOMICS, AND PROTEOMICS PLATFORMS THAT ASSESS DNA SEQUENCES AND LEVELS OF RNA AND PROTEIN EXPRESSION. WHILE DATA GENERATED FROM THESE STUDIES ARE INFORMATIVE, REGULATION OF COMPLEX BIOLOGICAL SYSTEMS ALSO REQUIRES UNDERSTANDING PROTEIN ACTIVITY. PROTEIN KINASES ARE CENTRAL TO GOVERNING PROTEIN ACTIVITY NETWORKS AND LINK SEVERAL REGULATORY ELEMENTS, INCLUDING TRANSCRIPTION FACTORS, CHAPERONES, AND STRUCTURAL PROTEINS. THE KINOME REFERS TO THE BROAD-BASED ACTIVITY OF THE COMPLETE SET OF PROTEIN KINASES. SEVERAL METHODS HAVE RECENTLY BEEN DEVELOPED TO STUDY THE KINOME IN LIGHT OF THE VAST ACTIVITY OF PROTEIN KINASES. ONE OF THESE NEW TECHNOLOGIES IS THE PAMCHIP WHICH USES HUNDREDS OF ~13 RESIDUE-LONG REPORTER PEPTIDES WHICH ARE PHOSPHORYLATED WITH SAMPLES DERIVED FROM CELL CULTURES, TISSUES, OR CLINICAL BIOPSIES. THE DEGREE OF PHOSPHORYLATION IS MEASURED IN REAL-TIME USING FLUORESCENT ANTIBODIES. THIS TECHNOLOGY IS ENCOMPASSED IN THE PAMSTATION 12 FROM PAMGENE. THIS EQUIPMENT SUPPLEMENT APPLICATION IS FOR FUNDS TO PURCHASE A PAMSTATION 12 FOR THE CMDRC. THE ACQUISITION OF THIS STATE-OF-THE-ART SYSTEM WILL ALLOW INVESTIGATORS OF THE PARENT COBRE TO DETERMINE THE ROLE OF THE KINOME IN THE AREAS OF CV, RENAL, AND METABOLIC DISEASES. THIS NEW EQUIPMENT WILL ALSO INCREASE THE SOPHISTICATION OF EXPERIMENTAL APPROACHES AND STRENGTHEN FUTURE NIH GRANTS FROM CMDRC INVESTIGATORS AS WELL AS OTHER INVESTIGATORS AT UMMC, INCLUDING THOSE SUPPORTED BY OTHER NIGMS FUNDED IDEA CENTERS. THE CMDRC HAS BEEN A MAJOR DRIVER FOR MARKED EXPANSION OF CARDIORENAL AND METABOLIC DISEASES RESEARCH IN MISSISSIPPI. THIS LARGE EQUIPMENT GRANT WILL AMPLIFY AND ENSURE SUSTAINABILITY OF OUR EFFORTS TO DEVELOP A HIGHLY PRODUCTIVE CMDRC DEDICATED TO IMPROVING LIVES THROUGH RESEARCH, DISCOVERY, AND INNOVATION.

ENHANCING MENTAL HEALTH PROVIDERS OPPORTUNITIES WITH EDUCATIONAL RESOURCES IN SCHOOLS (EMPOWERS)

BALANCE AND AUDITORY RESEARCH CENTER (BARC) - PROJECT SUMMARY FOR THE BALANCE AND AUDITORY RESEARCH CENTER (BARC) VESTIBULAR AND AUDITORY FUNCTIONS ARE FUNDAMENTAL TO SURVIVAL AND QUALITY OF LIFE. CHILDHOOD HEARING LOSS IS THE MOST COMMON CONGENITAL DISORDER, ESTIMATED TO AFFECT 2-3 IN EVERY 1000 BIRTHS, AND OFTEN CO-MORBID WITH VESTIBULAR IMPAIRMENT. BALANCE IMPAIRMENT AND FALLS ARE AMONG THE MOST PREVALENT AND MORBID CONDITIONS AFFECTING OLDER ADULTS, THE MOST COMMON CAUSE OF TRAUMATIC BRAIN INJURY. HEARING LOSS IS THE THIRD MOST COMMON CHRONIC HEALTH CONDITION AND ONE OF THE STRONGEST MODIFIABLE RISK FACTORS FOR COGNITIVE DECLINE AND DEMENTIA. THE REPERCUSSIONS OF BALANCE AND HEARING DISORDERS FOR MORTALITY AND MORBIDITY ARE JUST NOW REACHING A NEW LEVEL OF RECOGNITION. YET, BALANCE AND HEARING ARE LARGELY UNINVESTED AREAS OF NEUROSCIENCE, WHICH HAS CONTRIBUTED TO THE LACK OF TRANSLATION OF MEDICAL INTERVENTIONS FOR BALANCE AND HEARING DISORDERS. UNDERSTANDING THE GENETIC, STRUCTURAL, AND NEUROPHYSIOLOGICAL MECHANISMS UNDERLYING BALANCE AND HEARING DISORDERS IS ESSENTIAL FOR DEVELOPING INNOVATIVE DIAGNOSTIC TOOLS, THERAPEUTIC STRATEGIES, AND REHABILITATION TECHNIQUES FOR PATIENTS. THE GOAL OF ESTABLISHING THE BALANCE AND AUDITORY RESEARCH CENTER (BARC) AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) IS TO BUILD A CRITICAL MASS OF INDEPENDENT INVESTIGATORS TO DEVELOP EFFECTIVE DIAGNOSTIC AND THERAPEUTICS FOR BALANCE AND AUDITORY DISORDERS. BARC WILL BE BUILT UPON A SOLID CORE OF WELL-SUPPORTED AND ESTABLISHED NEUROSCIENTISTS IN VESTIBULAR AND AUDITORY RESEARCH. BARC HAS THREE SPECIFIC AIMS: (1) FOSTER A RESEARCH ENVIRONMENT THAT SUPPORTS COLLABORATIVE AND INNOVATIVE VESTIBULAR AND AUDITORY NEUROSCIENCE RESEARCH; (2) DEVELOP RESEARCH CAPACITY TO CONDUCT STATE-OF-THE-ART VESTIBULAR AND AUDITORY NEUROSCIENCE RESEARCH THROUGH DEVELOPMENT OF TWO RESEARCH CORES AND ADDITIONAL FACULTY POSITIONS: AND (3) NURTURE A GROUP OF EARLY STAGE AND NEW INVESTIGATORS TO BECOME INDEPENDENT RESEARCHERS IN THE FIELD OF VESTIBULAR AND AUDITORY RESEARCH.

2006 MISSISSIPPI INSTITUTE FOR IMPROVEMENT OF GEOGRAPHIC MINORITY HEALTH AND HEALTH DISPARITIES

DETERRENTS FOR PRESCRIPTION OPIOID ABUSE

MISSISSIPPI PEDIATRIC CLINICAL TRIALS CENTER

CLINICAL AND GENETIC CORRELATES OF VASCULAR FUNCTION IN AFRICAN AMERICANS: JHS

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - AS THE STATE'S ONLY LEVEL I TRAUMA CENTER AS WELL AS THE STATE’S ONLY CHILDREN’S HOSPITAL, THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) IS ACCUSTOMED TO CARING FOR PATIENTS FROM ACROSS THE STATE WHO ARE AT THE HIGHEST LEVEL OF EMERGENCY MEDICAL NEED. FOLLOWING THE OCTOBER 2022 CLOSURE OF THE STATE OF MISSISSIPPI’S ONLY DEDICATED BURN UNIT AT MERIT HEALTH CENTRAL HOSPITAL, UMMC HAS STEADILY DEVELOPED ITS RESPONSE TO MISSISSIPPIANS NEEDING BURN CARE CLOSE TO HOME BY EXPANDING ITS CAPABILITIES AND COORDINATION OF CARE FOR PATIENTS WITH BURN INJURIES. THE MISSISSIPPI STATE DEPARTMENT OF HEALTH DESIGNATED UMMC AS A MISSISSIPPI BURN CENTER IN APRIL 2023. ALSO IN 2023, UMMC WAS AWARDED $2,000,000 IN ONE-TIME STATE APPROPRIATIONS PASSED THROUGH BY THE MISSISSIPPI STATE DEPARTMENT OF HEALTH TO HELP DEFRAY THE COST OF CONSTRUCTING AND EQUIPPING A BURN CENTER. TO COVER THE REMAINING EXPENSE OF CONSTRUCTING AND EQUIPPING A BURN UNIT WITHIN EXISTING HOSPITAL SPACE ON THE MEDICAL CENTER’S MAIN CAMPUS, UMMC ALSO SEEKS $4,300,000 IN FUNDING THROUGH HRSA’S COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING PROGRAM. FUNDS RECEIVED THROUGH THIS AWARD APPLICATION WILL GO TOWARDS THE DESIGN, DEMOLITION, RENOVATION, AND EQUIPPING OF A DEDICATED AND SPECIALIZED INPATIENT BURN UNIT. THE BURN UNIT WILL PROVIDE MUCH-NEEDED IN-STATE BURN CARE FOR MISSISSIPPIANS, WITH THE CAPABILITY OF TREATING PATIENTS REQUIRING VARYING LEVELS OF CARE AND WITH THE ABILITY TO PROVIDE THERAPEUTIC AND REHABILITATIVE CARE TO PATIENTS WHILE THEY ARE IN THE HOSPITAL. UMMC HAS A MULTIFACETED CARE TEAM FOR BURN PATIENTS THAT WILL INCLUDE SPECIALISTS IN EMERGENCY MEDICINE AND TRAUMA SURGERY, AS WELL AS SEVERAL SUB-SPECIALTIES IN PLASTIC SURGERY, CRITICAL CARE, LABORATORY MEDICINE, MENTAL HEALTH, NURSING, OCCUPATIONAL THERAPY, PHARMACISTS AND PHYSICAL THERAPY. THIS COLLABORATION BENEFITS MISSISSIPPIANS IN NEED OF A WIDE RANGE OF SPECIALISTS CENTRAL TO THEIR HEALING A ND RECOVERY FROM BURN INJURIES.

CIDA (CENTER FOR INNOVATION AND DISCOVERY IN ADDICTIONS) MISSISSIPPI HORIZONS PROJECT - THE CENTRAL AIM OF THE CIDA MISSISSIPPI HORIZON'S PROJECT IS, ON A STATEWIDE BASIS, TO LEVERAGE UMMC'S EXISTING MENTAL HEALTH AND TECHNOLOGY CLINICAL EXPERTISE AND RESOURCES TO EFFICIENTLY FILL GAPS IN ACCESS TO CARE, ACCESS TO TREATMENT, AND AVAILABILITY OF EVIDENCE BASED TREATMENT. UMMC, SPECIFICALLY THE CENTER FOR INNOVATION AND DISCOVERY IN ADDICTIONS (CIDA) AND THE DEPARTMENT OF PSYCHIATRY AND HUMAN BEHAVIOR, SEEKS TO FILL CARE GAPS BY PROVIDING EVALUATION AND LINKAGE TO SERVICES IN REAL TIME, WITH A FOCUS ON INCREASING AND IMPROVING ACCESS FOR PATIENTS IN RURAL AREAS. SPECIFICALLY, WE WILL: 1. OFFER 7 DAY/WEEK 7PM TO 7AM AVAILABILITY VIA OUR EXISTING TELEHEALTH INFRASTRUCTURE OF BOTH A LICENSED MENTAL HEALTH PROVIDE POSSESSING COMPETENCE IN SUBSTANCE USE DISORDERS AND A LICENSED PEER SUPPORT SPECIALIST. EVENING AVAILABILITY OF SERVICES WILL COMPLEMENT TELE-BEHAVIORAL HEALTH CONSULTATION PROVIDED DURING LIMITED DAYTIME HOURS. THIS CAPABILITY WOULD REDUCE UNNECESSARY TRANSFERS, ENSURE PATIENTS RECEIVE APPROPRIATE TREATMENT AND REDUCE THE OVERALL COST OF CARE FOR THESE PATIENT POPULATIONS. 2. FOR THOSE WITH OPIOID USE DISORDER, WE WILL PROVIDE IMMEDIATE AND SEAMLESS LINKAGE TO UMMC'S WELL-ESTABLISHED TELEMAT PROGRAM, AND FOR THOSE WITH ONGOING MENTAL HEALTH AND/OR SUBSTANCE ABUSE NEEDS, LINKAGE TO COMMUNITY RESOURCES. 3. STANDING UP A WEB BASED STATEWIDE PORTAL PROVIDING ACCESS TO ACCURATE, REAL TIME INFORMATION ON AVAILABILITY OF SUBSTANCE USE TREATMENT SLOTS. THIS PORTAL WILL PROVIDE TIMELY AND EFFICIENT ACCESS TO INFORMATION ESSENTIAL FOR REFERRAL AND APPLICATION FOR TREATMENT. SIMILAR FUNCTIONALITY HAS BEEN IMPLEMENTED IN KENTUCKY, DELAWARE, ALASKA, NEW MEXICO, AND SEVERAL OTHER STATES. 4. THROUGH CIDA'S ACADEMY OF ADDICTION TRAINING, WE WILL PROVIDE REGULAR EDUCATION AND TRAINING TO CLINICIANS, MEDICAL PROVIDERS, CONSUMERS AND THEIR FAMILIES ON TOPICS KEY TO IMPROVING ACCESS AND TREATMENT FOR THOSE WITH MENTAL HEALTH AND SUBSTANCE ABUSE DISORDERS. IN SUM, UTILIZING EXISTING TELEHEALTH INFRASTRUCTURE AND EMPIRICALLY VALIDATED APPROACHES TO CARE, WE WILL IMPROVE PATIENT MANAGEMENT AND QUALITY OF CARE. TAKEN IN ITS TOTALITY, THIS PROPOSAL WILL FILL MENTAL HEALTH AND SUBSTANCE ABUSE ACCESS AND TREATMENT AGAPS ACROSS ALL OF MISSISSIPPI'S 82 COUNTIES.

A PROPOSAL TO ESTABLISH THE MISSISSIPPI VIOLENCE INJURY PREVENTION (VIP) PROGRAM - PROJECT SUMMARY/ABSTRACT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC), IN PARTNERSHIP WITH FOUR WELL-ESTABLISHED COMMUNITY GROUPS—PEOPLE’S ADVOCACY INSTITUTE, STRONG ARMS OF JXN, OPERATION GOOD, AND THE MISSISSIPPI PUBLIC HEALTH INSTITUTE—PROPOSE TO PARTICIPATE IN THE COMMUNITY LEVEL INTERVENTIONS FOR FIREARM AND RELATED VIOLENCE, INJURY AND MORTALITY PREVENTION (CLIF-VP) RESEARCH NETWORK BY ESTABLISHING THE MISSISSIPPI VIOLENCE INJURY PREVENTION (VIP) PROGRAM. TOGETHER, INDIVIDUAL TEAM MEMBERS REPRESENT COMMUNITY ACTIVISTS AND SEVERAL ACADEMIC DISCIPLINES, INCLUDING EMERGENCY MEDICINE, PSYCHOLOGY, PUBLIC HEALTH, SURVEY RESEARCH, GIS AND REMOTE SENSING, LAW, AND NURSING. MISSISSIPPI HAD THE NATION’S HIGHEST FIREARM MORTALITY RATE IN 2020 AT 28.6 PER 100,000 RESIDENTS. JACKSON, THE STATE’S CAPITAL, HAD A 2021 HOMICIDE RATE OF 97.6 PER 100,000 RESIDENTS, MORE THAN THREE TIMES HIGHER THAN THE STATE AND 15 TIMES HIGHER THAN THE NATIONAL RATE OF 6.5 MURDERS PER 100,000 RESIDENTS. UMMC, WHICH IS THE ONLY LEVEL 1 TRAUMA CENTER IN THE STATE, ADMINISTERED CARE TO 1,129 PATIENTS PRESENTING WITH INJURIES FROM FIREARMS OR RELATED VIOLENCE. AS PART OF THE CLIF-VP RESEARCH NETWORK, THE MISSISSIPPI VIP PROGRAM WILL WORK CLOSELY WITH ITS COORDINATING CENTER, THE OTHER RESEARCH PROJECTS FUNDED THROUGH THIS AGREEMENT, THE CLIF-VP RESEARCH NETWORK’S STAKEHOLDER BOARD(S), STEERING COMMITTEE, AND WORKGROUPS TO SUCCESSFULLY CARRY OUT CROSS-PROJECT ACTIVITIES. THE MISSISSIPPI VIP PROGRAM’S RESEARCH DESIGN INCLUDES A TWO-YEAR PLANNING (UG3) PHASE AND A THREE- YEAR IMPLEMENTATION (UH3) PHASE. TWO SPECIFIC AIMS HAVE BEEN IDENTIFIED FOR THE UG3 PHASE: (1) DEFINE AND CREATE THE MACHINERY TO LONGITUDINALLY MONITOR THE COMMUNITY-LEVEL SOCIAL DETERMINANTS OF FIREARM INJURY IN THE GREATER JACKSON, MISSISSIPPI METROPOLITAN AREA WITH RESPECT TO (A) PERCEIVED NEEDS, (B) AVAILABLE RESOURCES AND THEIR UTILIZATION, AND (C) OPPORTUNITIES FOR CAPACITY BUILDING; AND (2) IDENTIFY PRINCIPAL COMMUNITY-SPECIFIC RISK ELEMENTS FOR (A) FIREARM INJURY, (B) SUBOPTIMAL FUNCTIONAL RECOVERY, AND (C) RETALIATION AND REINJURY, AND COLLABORATIVELY DEVELOP LINKED COMMUNITY- AND HOSPITAL-BASED PROTECTIVE RESOURCES TO ADDRESS THESE RISKS. TWO SPECIFIC AIMS HAVE BEEN IDENTIFIED FOR THE UH3 PHASE: (1) CONDUCT A CLINICAL TRIAL THAT IMPLEMENTS OPTIMIZED COMMUNITY-FOCUSED INTERVENTIONS DURING THE UG3 PHASE USING A STEP-WEDGE CLUSTER APPROACH, AND MEASURES LONGITUDINAL COMMUNITY AND INDIVIDUAL IMPACT OF VIOLENCE PREVENTION INTERVENTIONS ON (A) INCIDENCE OF FIREARM INJURY, (B) FUNCTIONAL VICTIM RECOVERY, (C) INCIDENCE OF RETALIATION AND REINJURY, AND (D) ECONOMIC IMPACT; AND (2) COORDINATE ONGOING COMMUNITY, REGIONAL, AND TELEHEALTH EXPANSION AND ADOPTION OF OPTIMIZED COMMUNITY-FOCUSED RESOURCES IN CONCERT WITH THE CLIF-VP RESEARCH NETWORK.

TOLERANCE AND PHYSICAL DEPENDENCE AFTER CHRONIC BENZODIAZEPINE TREATMENT

MISSISSIPPI DIABETES PROJECT: ADVANCING HEALTH EQUITY IN DIABETES CARE AND PREVENTION - MISSISSIPPI PERSISTENTLY HAS AMONG THE HIGHEST RATES OF DIABETES (14.4%) IN THE COUNTRY. THE SOCIO-CULTURAL AND ECONOMIC CONDITIONS IN MOSTLY RURAL AND MEDICALLY UNDERSERVED COMMUNITIES MAKE DIABETES MANAGEMENT AND PREVENTION A FORMIDABLE CHALLENGE FOR INDIVIDUALS AND FAMILIES. THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) PROPOSES TO LEAD THE IMPLEMENTATION AND EVALUATION OF 6 EVIDENCE-BASED STRATEGIES OUTLINED IN COMPONENT B AS A STRATEGIC APPROACH TO ADVANCING HEALTH EQUITY FOR PRIORITY POPULATIONS IN MISSISSIPPI. THE PRIMARY PURPOSE OF THE MISSISSIPPI DIABETES PROGRAM IS TO DEVELOP AND ACTIVATE SUSTAINABLE CLINICAL-COMMUNITY LINKAGES THAT WILL LEAD TO IMPROVED DIABETES OUTCOMES AND DIABETES PREVENTION. THE PROJECT IS ANCHORED IN HEALTH EQUITY AND COMMUNITY ENGAGEMENT AND WILL SEEK TO ADDRESS SOCIAL NEEDS AT THE COMMUNITY (I.E., ESTABLISH FOOD PANTRIES) AND INDIVIDUAL/FAMILIAL (I.E., TRANSPORTATION, HEALTH LITERACY) LEVELS. THE PROJECT TEAM AND PARTNERS PROPOSE TO WORK IN 41 OF MISSISSIPPI’S HIGH-NEEDS COUNTIES TO REACH 1,066,150 MISSISSIPPIANS WITH THE HIGHEST RATES OF DIABETES (GREATER THAN OR EQUAL TO 14%). AS THE ONLY ACADEMIC MEDICAL CENTER IN THE STATE, UMMC WILL SERVE AS THE LEAD ORGANIZATION OF THIS PROPOSAL INCLUDING THE TELEHEALTH CENTER OF EXCELLENCE, MYRLIE EVERS-WILLIAMS INSTITUTE FOR THE ELIMINATION OF HEALTH DISPARITIES, LIFESTYLE MEDICINE, POPULATION HEALTH SCIENCE, AND DATA SCIENCE. THE PROJECT PARTNERS INCLUDE THE COMMUNITY HEALTH CENTER ASSOCIATION OF MISSISSIPPI (CHCAMS), LOCAL COMMUNITY HEALTH CENTERS, THE MISSISSIPPI STATE DEPARTMENT OF HEALTH, COMMUNITY-BASED ORGANIZATIONS, THE MISSISSIPPI STATE UNIVERSITY EXTENSION AGENCY, COUNTY-LEVEL EXTENSION AGENCIES, AND THE MISSISSIPPI FOOD NETWORK. THE CENTER FOR RESEARCH EVALUATION AT THE UNIVERSITY OF MISSISSIPPI WILL LEAD THE PROJECT EVALUATION. THE TARGETED PRIORITY POPULATIONS WHO HAVE SYSTEMATICALLY EXPERIENCED GREATER OBSTACLES TO OPTIMAL HEALTH IN MISSISSIPPI INCLU DE RESIDENTS IN RURAL AND MEDICALLY UNDERSERVED COMMUNITIES, BLACKS OR AFRICAN AMERICANS, AND SOCIOECONOMICALLY DISADVANTAGED FAMILIES. THE TARGETED HIGH-NEEDS COUNTIES INCLUDE ADAMS, AMITE, ATTALA, BOLIVAR, CHICKASAW, CLAIBORNE, CLARKE, CLAY, COAHOMA, COPIAH, COVINGTON, HINDS, HOLMES, HUMPHREYS, ISSAQUENA, JASPER, JEFFERSON, JEFFERSON DAVIS, KEMPER, LAUDERDALE, LEAKE, LEFLORE, MARION, MARSHALL, MONTGOMERY, NESHOBA, NOXUBEE, PANOLA, PIKE, QUITMAN, SCOTT, SHARKEY, SUNFLOWER, TALLAHATCHIE, TUNICA, UNION, WALTHALL, WARREN, WASHINGTON, WINSTON, YAZOO COUNTIES IN MISSISSIPPI. THE PROPOSED PROJECT HAS A HIGH LIKELIHOOD TO IMPROVE DIABETES OUTCOMES AND PREVENTION AND ADVANCE HEALTH EQUITY AMONG MISSISSIPPI’S MOST VULNERABLE RESIDENTS.

A NOVEL PROTEIN DELIVERY SYSTEM FOR THERAPY OF PREECLAMPSIA

MIDBRAIN CIRCUITRY FOR NEURONAL CONTROL OF GAZE

IMPLEMENTING, ENHANCING, AND SUSTAINING THE MISSISSIPPI CANCER REGISTRY - THE MISSION OF THE MISSISSIPPI CANCER REGISTRY (MCR) IS TO COLLECT COMPLETE AND HIGH QUALITY CANCER INCIDENCE DATA TO GUIDE PROGRAM PLANNING AND EVALUATION STATEWIDE, MONITOR CANCER TRENDS IN GEOGRAPHIC AREAS AND IN SPECIFIC POPULATIONS, PROVIDE DATA FOR RESEARCH AND PUBLIC HEALTH, AND EDUCATE THE GENERAL PUBLIC AND POLICY MAKERS ON THE BURDEN OF CANCER IN MISSISSIPPI. EACH YEAR, THE MCR SUBMITS DATA TO THE NATIONAL PROGRAM OF CANCER REGISTRIES (NPCR) FOR EVALUATION AND INCLUSION IN NATIONAL CANCER INCIDENCE. THE MCR CONSISTENTLY MEETS THE NATIONAL DATA QUALITY STANDARDS FROM THE CDC. AGGREGATE DATA IS AVAILABLE BY SITE, RACE, SEX, STAGE FOR SCREENABLE CANCERS, AND GEOGRAPHIC AREA THROUGH AN INTERACTIVE WEB SITE FOR PUBLIC USE. INFORMATION ON LIFESTYLE-RELATED CANCERS IS ALSO ON THE MCR WEB SITE. THE GOAL OF THE MCR IS TO CONTINUE TO IMPROVE THE COMPLETENESS, TIMELINESS, QUALITY, AVAILABILITY AND UTILITY OF THE INCIDENCE DATA COLLECTED. TO ACCOMPLISH THIS GOAL, THE MCR WILL INCREASE THE PROPORTION OF PHYSICIAN OFFICES, PATHOLOGY LABORATORIES, HOSPITALS AND CLINICS THAT DIAGNOSE AND TREAT CANCER WHO REPORT TIMELY DATA TO THE MCR IN AN ELECTRONIC FORMAT. THIS WILL BE ACCOMPLISHED THROUGH UTILIZING WEB-BASED ABSTRACTING SOFTWARE AND ELECTRONIC MEDICAL AND LABORATORY RECORDS. THE MCR WILL ALSO PROVIDE COMPREHENSIVE EDUCATION TO BOTH MCR STAFF AND TO CANCER REPORTERS TO ENSURE QUALITY DATA. EDUCATION WILL BE GEARED TOWARD ADDRESSING CHANGES IN CODING RULES, COMMON CODING ERRORS, INCREASING THE NUMBER OF CERTIFIED TUMOR REGISTRARS IN MISSISSIPPI, AND MEETING THE NEEDS OF THE NEW ABSTRACTORS IN THE STATE. LASTLY, THE MCR WILL MAKE THE DATA AVAILABLE TO THE PUBLIC STAKEHOLDERS ACROSS THE STATE. THE MCR WILL FOSTER COLLABORATIVE RELATIONSHIPS WITH PARTNERS IN CANCER CONTROL EFFORTS. PARTNERSHIPS WITH OTHER STATE CANCER REGISTRIES WILL PROMOTE THE SHARING OF IDEAS AND BEST PRACTICES, AS WELL AS, EXCHANGE OF DATA TO ENSURE COMPLETE COLLECTION OF CANCER IN MISSISSIPPI RESIDENTS. THE MCR WILL WORK WITH THE MISSISSIPPI STATE DEPARTMENT OF HEALTH (MSDH) VITAL RECORDS AND STATISTICS TO INCREASE COMPLETENESS OF INCIDENCE DATA THROUGH MATCHING THE MORTALITY DATA AND TO INCREASE THE AVAILABILITY OF AGGREGATE CANCER MORTALITY DATA. THE MCR WILL ALSO PARTNER WITH MSDH TO IMPROVE THE QUALITY OF INCIDENCE DATA THROUGH MATCHING WITH THE HOSPITAL DISCHARGE DATA AND WILL EXPLORE LINKAGES WITH IMMUNIZATION. PARTNERING WITH THE MISSISSIPPI BREAST AND CERVICAL CANCER EARLY DETECTION PROGRAM WILL PROVIDE AN OPPORTUNITY TO IMPROVE THE QUALITY OF THEIR DATA AND THE COMPLETENESS OF INCIDENCE DATA. THE MCR WILL ALSO PARTNER WITH THE MISSISSIPPI PARTNERSHIP FOR COMPREHENSIVE CANCER CONTROL AND OTHER CHRONIC DISEASE PROGRAMS TO INCREASE THE UTILIZATION OF CANCER INCIDENCE DATA IN STATEWIDE EFFORTS AROUND PREVENTION OF CHRONIC DISEASES, CANCER CONTROL AND RESEARCH. THE MISSISSIPPI CANCER REGISTRY WILL ACTIVELY PARTICIPATE IN THE LEADERSHIP TEAM FOR ADDRESSING THE CANCER BURDEN IN MISSISSIPPI. THE ADVISORY COMMITTEE, COMPRISED OF PHYSICIANS AND OTHER STATEWIDE PARTNERS WILL SERVE AS A TECHNICAL ADVISOR TO THE MCR AND A CHAMPION FOR THE USE OF THE MCR DATA THROUGHOUT THE STATE.

IMPLEMENTING, ENHANCING, AND SUSTAINING THE MISSISSIPPI CANCER REGISTRY

OPIOID REGULATION OF GNRH PULSES

EFFECTS OF YOGA ON CVD RISK FACTORS AMONG AFRICAN AMERICANS: JACKSON HEART STUDY

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC), WHICH SERVES AS THE STATE’S ONLY LEVEL I TRAUMA CENTER AS WELL AS THE STATE’S ONLY CHILDREN’S HOSPITAL, IS THE EPICENTER OF EMERGENCY CARE FOR THE STATE OF MISSISSIPPI, INCLUDING EMERGENCY CARE PROVIDED TO AN INCREASING NUMBER OF PATIENTS IN ACUTE PSYCHIATRIC DISTRESS. SEVERAL HOSPITALS IN THE JACKSON METRO AREA AND ACROSS THE STATE ARE LIMITING PSYCHIATRIC SERVICES AND/OR CLOSING INPATIENT PSYCHIATRIC BEDS, FORCING PATIENTS TO SEEK CARE ELSEWHERE AND FUNNELING MANY OF THEM TO UMMC. IN PARTICULAR, IN 2023, A LARGE HOSPITAL IN THE LOCAL JACKSON AREA DISCONTINUED ITS BEHAVIORAL HEALTH SERVICES, RESULTING IN THE LOSS OF 83 INPATIENT AND GERIATRIC PSYCHIATRY BEDS FOR THE REGION. CONSEQUENTLY, PATIENTS SEEKING CARE AT UMMC’S ADULT EMERGENCY DEPARTMENT (AED) EXPERIENCE LONG WAIT TIMES DUE TO LACK OF AVAILABILITY OF PATIENT ROOMS. THIS IS A PARTICULARLY CHALLENGING SCENARIO, GIVEN THE INCREASING NUMBERS OF PATIENTS EXPERIENCING MENTAL HEALTH CRISES AND IN NEED OF IMMEDIATE MEDICAL ATTENTION AND INTERVENTION. THROUGH THIS PROJECT, UMMC PLANS TO REDESIGN, DEMOLISH, AND RENOVATE PORTIONS OF ITS EXISTING ACUTE SERVICES WING AND SOUTH WING ON THE MEDICAL CENTER’S MAIN CAMPUS IN JACKSON, MISSISSIPPI, TO ALLOW FOR THE CONSTRUCTION OF A DEDICATED PSYCHIATRIC EMERGENCY SERVICES (PES) UNIT CAPABLE OF TREATING BOTH ADULT AND ADOLESCENT PATIENTS. UMMC SEEKS $3,200,000 IN FUNDING THROUGH HRSA’S COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING PROGRAM TO HELP COVER THE DEMOLITION AND RENOVATION COSTS OF THE PROJECT. FUNDS REQUESTED THROUGH THIS PROGRAM WILL ALSO GO TOWARDS EQUIPPING THE NEWLY REDESIGNED EMERGENCY CARE AREAS. IN ADDITION TO $3,200,000 IN FUNDS BEING SOUGHT THROUGH THIS APPLICATION, THIS PROJECT IS ALSO BEING FUNDED IN PART BY $3,000,000 IN INTERNALLY DESIGNATED UMMC FUNDS OVER THE COURSE OF THE PROJECT TIMELINE. THIS PROJECT WILL HELP UMMC EMERGENCY CARE TEAMS PROVIDE IMMEDIA TE CARE TO INDIVIDUALS EXPERIENCING ACUTE MENTAL HEALTH CRISES, INCLUDING SEVERE DEPRESSION, SUICIDAL IDEATION, ACUTE ANXIETY, PSYCHOSIS, SUBSTANCE USE ISSUES, AND OTHER CONDITIONS REQUIRING URGENT PSYCHIATRIC INTERVENTION. THIS PROJECT WILL ALSO PROVIDE A SAFER CARE ENVIRONMENT FOR NON-PSYCHIATRIC PATIENTS BEING TREATED IN THE AED.

THE ROLE OF POU4F3 IN AGE-RELATED VESTIBULAR DYSFUNCTION - PROJECT SUMMARY: IT HAS BEEN ESTIMATED THAT MORE THAN 40% OF OLDER ADULTS SUFFER VESTIBULAR (I.E. BALANCE) DEFICITS. THESE LOSSES CAUSE NUMEROUS OTHER PROBLEMS ASSOCIATED WITH AGING INCLUDING COGNITIVE DECLINE AND INJURIOUS OR FATAL FALLS. THERE IS ALSO A STRONG LINK BETWEEN AGE-RELATED VESTIBULAR DYSFUNCTION (ARVD) AND ALZHEIMER'S DISEASE AND RELATED DEMENTIAS. DESPITE THE PREVALENCE OF THESE ISSUES AND THE MASSIVE TOLL THEY EXERT ON PUBLIC HEALTH AND ASSOCIATED FINANCIAL COSTS, THE UNDERLYING CAUSES FOR ARVD ARE POORLY UNDERSTOOD. AS A RESULT, THERE ARE CURRENTLY NO FDA APPROVED THERAPIES FOR ARVD. WHILE A DEEP UNDERSTANDING OF MECHANISTIC CAUSES IS LACKING, IT HAS BEEN KNOWN FOR SOME TIME THAT A VERY COMMON PATHOLOGY THAT CAUSES AGE RELATED INNER EAR DYSFUNCTION IS THE DEATH OF SENSORY CELLS CALLED HAIR CELLS. EXACTLY WHY THESE CELLS DIE WITH AGE REMAINS A MYSTERY. HERE, WE HAVE IDENTIFIED A PREVIOUSLY UNCHARACTERIZED PATTERN IN THE EXPRESSION OF THE PRO-SURVIVAL GENE, POU4F3, WHERE IT IS NORMALLY HIGHLY EXPRESSED IN INNER EAR HAIR CELLS, BUT IS DOWNREGULATED WITH AGE IN A FASHION THAT IS CORRELATED WITH HAIR CELL DEATH IN THE BALANCE ORGANS OF THE INNER EAR. FURTHERMORE, PRELIMINARY DATA SUGGEST THAT DELETING POU4F3 CAUSES DETRIMENTAL PHENOTYPES IN VESTIBULAR HAIR CELLS, EXACERBATES HAIR CELL DEATH, AND LEADS TO SIGNIFICANT DECLINES IN VESTIBULAR FUNCTION. WE PROPOSE TO BUILD ON THESE PRELIMINARY DATA BY FURTHER EXAMINING POU4F3 CHANGES IN EXPRESSION IN VESTIBULAR ORGANS WITH AGE AND IN MODELS OF ALZHEIMER'S DISEASE. WE WILL ALSO MORE THOROUGHLY CHARACTERIZE THE EFFECTS OF POU4F3 DELETION TO BETTER UNDERSTAND THE EFFECTS THAT DELETION OR HYPOMORHPISM HAVE ON BALANCE AND NEUROLOGICAL FUNCTIONS. WE ALSO PROPOSE TO EXAMINE GENOMIC REGULATORY ELEMENTS IN INNER EAR TISSUES FROM YOUNG AND AGED MICE TO IDENTIFY CAUSAL MECHANISMS FOR POU4F3 DOWNREGULATION WITH AGE AS WELL AS POSSIBLY DISCOVER OTHER KEY GENES INVOLVED IN AGING PROCESSES IN THE INNER EAR. FINALLY, WE WILL TEST WHETHER OVEREXPRESSION OF POU4F3 CAN PREVENT SENSORY CELL DEATH AND AGE RELATED VESTIBULAR DECLINES. OUR PRELIMINARY DATA SUGGEST THAT POU4F3 IS A PROMISING THERAPEUTIC TARGET FOR PRESERVING BALANCE FUNCTION IN THE AGING HUMAN POPULATION. THE EXPERIMENTS PROPOSED WILL DETERMINE THE VALIDITY OF THAT OVERARCHING HYPOTHESIS AND WILL PROVIDE A FOUNDATION FROM WHICH TO LAUNCH SEVERAL NEW INVESTIGATIONS INTO POU4F3-TARGETED PHARMACOLOGICAL AND GENE THERAPY APPROACHES FOR THE PREVENTION OF AGE RELATED VESTIBULAR DECLINE.

MISSISSIPPI CANCER REGISTRY - NPCR

THE KIDNEY, HYPERTENSION, PREGNANCY AND INFLAMMATION

PROMOTING RESILIENCE AND MENTAL HEALTH AMONG HEALTH PROFESSIONAL WORKFORCE

WATER CONTAMINANTS AND CARDIOVASCULAR RISK: THE JACKSON HEART STUDY - PROJECT SUMMARY/ABSTRACT IN JACKSON, MS, DECADES OF UNDER-INVESTMENT IN PUBLIC WATER SYSTEM INFRASTRUCTURE HAVE RESULTED IN SEVERE DISRUPTIONS TO WATER ACCESS AND DIMINISHED WATER QUALITY. JACKSON HAS BEEN UNDER A CONSENT DECREE SINCE 2012 FOR FAILING TO MEET OPERATIONAL AND MAINTENANCE STANDARDS AND CONTINUES TO HAVE BOIL WATER NOTICES ISSUED REGULARLY, ELICITING CONCERN ABOUT THE HEALTH EFFECTS OF CHRONIC WATER CONTAMINANT EXPOSURES. DESPITE EMERGING RECOGNITION OF THE IMPORTANCE OF ENVIRONMENTAL EXPOSURES IN CARDIOMETABOLIC-CARDIOVASCULAR DISEASE (CM-CVD) RISK, FEW EPIDEMIOLOGIC STUDIES HAVE INVESTIGATED THE CM-CVD EFFECTS OF PUBLIC WATER CONTAMINANTS, EVEN THOUGH THESE DATA CAN PRIORITIZE POLICY-BASED SOLUTIONS TO LIMIT THEIR IMPACT. IN THIS CONTEXT, THE FLAGSHIP NHLBI/NIMHD- FUNDED JACKSON HEART STUDY (JHS), A PROSPECTIVE COHORT STUDY OF 5,306 AFRICAN-AMERICAN ADULTS, OFFERS A RARE OPPORTUNITY TO EVALUATE THE EFFECTS OF CHRONIC WATER CONTAMINANT EXPOSURES ON CM-CVD. IN PREPARATION FOR THIS APPLICATION, WE EXTRACTED ALL 165,580 COMPLIANCE MONITORING RECORDS (2000-2023) COLLECTED BY THE MISSISSIPPI DEPARTMENT OF HEALTH FOR 74 WATER SYSTEMS SERVING MADISON, HINDS, AND RANKIN COUNTIES COMPRISING JHS (ENCOMPASSING 38 UNIQUE ZIP CODES), DEMONSTRATING (1) SUBSTANTIAL TEMPORAL VARIABILITY (SEASONAL/YEARLY) IN PRIORITIZED WATER CONTAMINANTS (E.G., TOTAL TRIHALOMETHANES, HALOACETIC ACIDS, LEAD) ACROSS THESE WATER SYSTEMS; (2) SELECT WATER CONTAMINANTS LINKED TO CM-CVD (E.G., LEAD, DISINFECTION BYPRODUCTS) ARE HIGHER IN WATER SYSTEMS SERVING JHS COMMUNITIES COMPARED TO THOSE NATIONWIDE. STRIKINGLY, DISINFECTION BYPRODUCTS AND LEAD ARE LARGELY UNRELATED TO SOURCE WATER AND ARE DIRECTLY RELATED TO THE DETERIORATION AND MANAGEMENT OF WATER SYSTEM INFRASTRUCTURE, RELEVANT TO THE ONGOING JACKSON WATER CRISIS. OUR CENTRAL HYPOTHESIS IS THAT WATER TOXICANTS (CAPTURED BY WATER SYSTEM MONITORING RECORDS AND QUANTIFICATION OF ≈1000 CIRCULATING CHEMICALS IN THE BLOOD [“MOLECULAR EXPOSOME”] PIONEERED BY OUR GROUP) WILL BE ASSOCIATED WITH CM-CVD PHENOTYPES OVER ≈2 DECADES IN JHS. IN AIM 1, WE QUANTIFY 26 PUBLIC WATER CONTAMINANT EXPOSURES (INCLUDING DISINFECTION BYPRODUCTS, INORGANIC METALS, RADIONUCLIDES, ORGANIC COMPOUNDS) FOR ALL JHS PARTICIPANTS OVER ≈2 DECADES AND MEASURE THEIR ASSOCIATION WITH KEY CM-CVD RISK FACTORS (E.G., BLOOD PRESSURE, INSULIN RESISTANCE, OBESITY). AIM 2 PROVIDES A COMPLEMENTARY BIOCHEMICAL APPROACH, QUANTIFYING RELATION OF THE MOLECULAR EXPOSOME–AND ITS CHANGES OVER TIME–WITH THESE ENVIRONMENTAL EXPOSURES OVER ≈2 DECADES AND MEASURING THEIR RELATION TO CM-CVD PHENOTYPES. IN AIM 3, WE EXAMINE ASSOCIATION OF BOTH WATER MONITORING RECORDS AND BIOCHEMICAL EXPOSURES (MOLECULAR EXPOSOME) WITH 20-YEAR INCIDENT CVD RISK, INCLUDING HOW THESE RELATIONS MAY BE MEDIATED BY THE EFFECT OF WATER CONTAMINANT EXPOSURES ON TRADITIONAL CM-CVD RISK FACTORS. IF SUCCESSFUL, THIS APPLICATION WILL DEFINE THE IMPORTANCE OF WATER TOXICANT EXPOSURES TO CM-CVD OVER 2 DECADES IN A HIGHLY VULNERABLE, MINORITIZED COMMUNITY WITH A CONTAMINATED WATER SUPPLY, WITH DIRECT IMPLICATIONS FOR POLICY. RESOURCES GENERATED HERE WILL BE ACCESSIBLE TO THE SCIENTIFIC COMMUNITY FOR FUTURE DISCOVERY AND COMPARISON TO OTHER POPULATIONS.

IMPACT OF SOCIAL FACTORS ON BREAST CANCER BIOLOGY IN AFRICAN-AMERICAN WOMEN

MECHANISMS OF BLAST-INDUCED VESTIBULAR INJURY

SCREENING AND TREATMENT FOR MATERNAL DEPRESSION AND RELATED BEHAVIORAL DISORDERS PROGRAM

L-CARNITINE TREATMENT FOR VASOPRESSOR DEPENDENT SEPTIC SHOCK

CAUSES OF SEX DIFFERENCES IN MALE AND FEMALE OFFSPRING BORN FROM INFLAMMATION MEDIATED HYPERTENSIVE PREGNANCY - OVERALL SUMMARY PREECLAMPSIA (PE) IS CHARACTERIZED BY HYPERTENSION, PROTEINURIA, RENAL AND ENDOTHELIAL DAMAGE, INTRAUTERINE GROWTH RESTRICTION AND CEREBROVASCULAR DYSFUNCTION DURING PREGNANCY. THE OVERALL THEME OF THIS SCORE APPLICATION IS TO ELUCIDATE NOVEL MECHANISMS LINKING PLACENTAL ISCHEMIA AND MATERNAL SYSTEMIC HEMODYNAMIC, CEREBRAL AND RENAL DYSFUNCTION AND TO IDENTIFY THERAPEUTIC TARGETS FOR THE TREATMENT OF PE AND ASSOCIATED IUGR/LOW BIRTH WEIGHT-INDUCED PROGRAMMING OF HYPERTENSION IN OFFSPRING. THE PREMISE OF THE SCORE DERIVES FROM THE FACT THAT DESPITE ITS POSITION AS A LEADING CAUSE OF MATERNAL DEATH AND MAJOR CONTRIBUTOR TO MATERNAL AND PERINATAL MORBIDITY, THERE IS NO EFFECTIVE DRUG TREATMENT TO PREVENT OR DELAY THE PROGRESSION OF PE. AT PRESENT, THE ONLY EFFECTIVE TREATMENT FOR PE IS EARLY DELIVERY. THE LACK OF PROGRESS IN ELUCIDATING NOVEL PATHOPHYSIOLOGICAL MECHANISMS LINKING PLACENTAL ISCHEMIA AND MATERNAL CARDIOVASCULAR DYSFUNCTION AND IN IDENTIFYING NEW THERAPEUTIC TARGETS FOR THE TREATMENT OF PE IS DUE IN PART TO PAUCITY OF ANIMAL MODELS THAT REPLICATE HUMAN PE. WE HAVE DEMONSTRATED THAT PLACENTAL ISCHEMIA IS CRITICAL IN CAUSING MATERNAL ENDOTHELIAL AND CARDIOVASCULAR DYSFUNCTION IN PE. OUR LABORATORIES HAVE DEVELOPED AND CHARACTERIZED 3 DISTINCT MODELS OF MODELS OF PE (RUPP MODEL AND SPONTANEOUS MODEL OF SUPERIMPOSED PE AND PE DERIVED CD4+ T CELL INDUCED PE) THAT IS ASSOCIATED WITH PLACENTAL ISCHEMIA, MATERNAL ENDOTHELIAL AND CARDIOVASCULAR DYSFUNCTION, IUGR AND LOW BIRTHWEIGHT (LBW) OFFSPRING THAT DEVELOP HYPERTENSION AT AN EARLY AGE. THESE MODELS HAVE MANY OF THE FEATURES OF PE IN WOMEN AND PROVIDE A SUPERB INVESTIGATIVE TOOL TO ELUCIDATE NOVEL PATHOPHYSIOLOGICAL MECHANISMS IN PE, IDENTIFY NOVEL THERAPEUTIC TARGETS AND THE CARDIOVASCULAR AND CEREBROVASCULAR CONSEQUENCES IN THE MOTHER AND IN LBW OFFSPRING. THE GOALS OF THIS SCORE WILL BE TO EXAMINE RELEVANT FACTORS IN ASSOCIATION WITH HYPERTENSION AND CEREBROVASCULAR DYSFUNCTION IN A CLINICAL POPULATION OF PE AND NORMOTENSIVE WOMEN AND THEIR CHILDREN(PROJECT 1) AND UTILIZE MULTIFACETED TRANSLATIONAL APPROACHES INCLUDING CELLULAR, MOLECULAR, PHYSIOLOGICAL AND PHARMACOLOGICAL TOOLS TO EXAMINE THE IMPORTANCE OF THESE FACTORS TO CAUSE PE AND POTENTIAL SEX DIFFERENCE THAT CAUSE LONGTERM CONSEQUENCES IN IUGR OFFSPRING FROM ANIMAL MODELS OF PE POSTPARTUM (PROJECTS 2, 3, 4). THE PROPOSED PROGRAM BRINGS TOGETHER INVESTIGATORS WITH EXPERTISE IN THE FIELD OF NEUROVASCULAR, PHARMACOLOGICAL AND PE RESEARCH. THE SYNERGY BETWEEN THIS HIGHLY COLLABORATIVE AND PRODUCTIVE TEAM OF INVESTIGATORS SHOULD ENSURE EFFICIENCY AND EFFECTIVENESS OF THE PROGRAM AND CONTINUED DEVELOPMENT OF INNOVATIVE IDEAS, APPROACHES, AND STATE OF THE ART TECHNIQUES.

SLEEP-DISORDERED BREATHING AND RISK FOR CVD AND STROKE IN THE JACKSON HEART STUDY

PURPOSE: THE PROJECT FUNDS WILL SUPPORT THE PROCUREMENT OF FURNISHINGS AND EQUIPMENT RELATED TO CANCER RESEARCH FOR THE TRANSLATIONAL RESEARCH CENTER (TRC) BUILDING ON THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) CAMPUS IN JACKSON, MS. ACTIVITIES TO BE PERFORMED: THE PROJECT CONSISTS OF FURNISHING AND EQUIPPING APPROXIMATELY 7,625 SQUARE FEET OF EXISTING SPACE FOR CANCER RESEARCH LABORATORIES, SUPPORT SPACE AND INFRASTRUCTURE IN THE TRC. THE BUDGET FOR THIS PROJECT IS $2.8M WHICH INCLUDES $2.75M IN EQUIPMENT AND $50,000 IN FURNISHINGS. UMMC IS CURRENTLY IN THE PLANNING PROCESS FOR EQUIPMENT SELECTION AND HAS BASED THE CURRENT BUDGET ON MARKET RESEARCH. A FINAL LIST OF EQUIPMENT WITH VENDOR QUOTES WILL BE SUBMITTED LATER. ONCE EQUIPMENT DECISIONS HAVE BEEN MADE UMMC WILL SEEK APPROVAL FROM UMMC'S SHARED GOVERNING BOARD, THE INSTITUTIONS OF HIGHER LEARNING AS WELL AS ADHERING TO OTHER INTERNAL AND STATE PROCUREMENT REQUIREMENTS. EXPECTED OUTCOMES: THE EQUIPMENT WILL SUPPORT GROWTH OF THE CCRI WITH THE ULTIMATE GOAL FOR UMMC TO APPLY FOR NATIONAL CENTER INSTITUTE DESIGNATION IN 10 YEARS. WITH UMMC'S GOAL TO RECRUIT 30 NEW CANCERRESEARCH FACULTY, THIS PROJECT WILL PROVIDE MODERN LAB AND SUPPORT SPACE FOR UP TO EIGHT RESEARCH FACULTY, PLUS THEIR SUPPORT STAFF. INTENDED BENEFICIARIES: EXPANDING AND MODERNIZING THE CURRENT RESEARCH SPACE TO SUPPORT UMMC'S CANCER RESEARCH FACULTY IS A CRITICAL COMMITMENT TO BRING CUTTING EDGE CANCER CARE TO MISSISSIPPIANS, AS THERE IS CURRENTLY NOT A NCI-DESIGNATED CANCER CENTER IN MISSISSIPPI, LUISIANA, OR ARKANSAS. THIS PROJECT WILL HELP FACILITATE THAT DESIGNATION AND WILL IMPROVE CANCER RESEARCH, PATIENT CARE, AND MEDICAL OUTCOMES FOR THE REGION'S CANCER PATIENTS. SUBRECIPIENT ACTIVITIES: THE RECIPIENT DOES NOT INTEND TO SUBAWARD FUNDS.

DISCRETIONARY

20-HETE-TGF-BETA IN HYPERTENSION-INDUCED RENAL INJURY

COMMUNITY BASED DENTAL PARTNERSHIP

REGULATION OF VASCULAR MATURATION/REGRESSION IN DIABETES

TELEHEALTH CENTER OF EXCELLENCE

BENZODIAZEPINE CHOICE AND POLYDRUG USE - PROJECT SUMMARY BENZODIAZEPINES (BZS) ARE EFFECTIVE AND SAFE WHEN USED APPROPRIATELY, BUT THEIR UTILITY IS LIMITED BY UNWANTED SIDE EFFECTS LIKE MISUSE AND REDUCED SAFETY WHEN COMBINED WITH OTHER DRUGS. INDIVIDUALS WITH SUBSTANCE-USE DISORDERS (SUDS) MISUSE BZS AS MUCH AS 20X GREATER THAN THE GENERAL POPULATION, AND THE RISING NUMBER OF OVERDOSE DEATHS ATTRIBUTED TO BZS ARE LARGELY DRIVEN BY OPIOID CO-ADMINISTRATION. GIVEN THE HIGH RATES OF POLYDRUG USE AMONG INDIVIDUALS WHO ALSO MISUSE BZS, PRECLINICAL EVALUATIONS OF BZS SHOULD CONSIDER THE POLYDRUG SCENARIOS IN WHICH THEY ARE BEING MISUSED. THE GOAL OF THIS RESEARCH IS TO IDENTIFY PHARMACOLOGICAL DETERMINANTS OF BZ MISUSE, WITH THE GOAL OF IDENTIFYING BZ-TYPE LIGANDS WITH REDUCED ABUSE POTENTIAL IN POLYDRUG SITUATIONS. WE REPORTED PREVIOUSLY THAT NONSELECTIVE, PARTIAL-EFFICACY BZ LIGANDS OR THOSE THAT LACK INTRINSIC EFFICACY AT A1- SUBUNIT CONTAINING GABAA (A1GABAA) RECEPTORS HAVE REDUCED ABUSE POTENTIAL RELATIVE TO TRADITIONAL BZS. HOWEVER, OUR DATA SUGGEST THAT THE DEGREE TO WHICH THESE BZ-TYPE LIGANDS EXHIBIT ABUSE POTENTIAL DEPENDS ON THE SUBJECT’S DRUG HISTORY. THIS NEW APPLICATION WILL USE CHOICE MODELS TO EVALUATE THE OVERALL HYPOTHESIS THAT DRUG EXPERIENCE IS A KEY DETERMINANT OF THE ROLE OF GABAA RECEPTOR SUBTYPES IN THE ABUSE POTENTIAL OF BZ-TYPE LIGANDS. A KEY FINDING FROM OUR CHOICE RESEARCH IS THAT EFFICACY AT A1GABAA RECEPTORS MAY BE NECESSARY FOR SELF- ADMINISTRATION OF BZS IN COCAINE-EXPERIENCED SUBJECTS, BUT NOT REQUIRED FOR ENHANCEMENT OF COCAINE CHOICE. IT IS UNKNOWN WHETHER THIS PATTERN OF EFFECTS IS OBSERVED WITH OTHER DRUGS OF ABUSE, IN PARTICULAR OPIOIDS. MOREOVER, THE PHARMACOLOGICAL MECHANISM UNDERLYING THESE EFFECTS IS UNKNOWN, WITH POSSIBILITIES INCLUDING (1) A DIFFERENTIAL ROLE FOR A1GABAA RECEPTORS IN REINFORCEMENT-ENHANCING VS. REINFORCING EFFECTS OF BZS ALONE, OR (2) DIFFERENCES IN OVERALL INTRINSIC EFFICACY, IRRESPECTIVE OF SUBTYPE SELECTIVITY. WE WILL ADDRESS THESE POTENTIAL MECHANISMS IN TWO AIMS ORGANIZED BY UNIQUE APPROACHES. IN AIM 1, WE WILL USE DRUG VS. DRUG CHOICE TO EVALUATE THE EXTENT TO WHICH BZ-TYPE LIGANDS VARYING IN EFFICACY AND SELECTIVITY WILL ENHANCE OR ATTENUATE DRUG CHOICE WHEN DELIVERED AS A COMBINATION WITH COCAINE, HEROIN, OR ALPRAZOLAM IN SEPARATE GROUPS OF SUBJECTS. IN AIM 2, WE WILL USE DRUG VS. NONDRUG CHOICE TO EVALUATE THE HYPOTHESIS THAT NONSELECTIVE, PARTIAL MODULATORS OR A1-SPARING BZS WILL HAVE REDUCED REINFORCING EFFECTS WHEN DELIVERED ALONE IN SUBJECTS WITH A HISTORY OF COCAINE, HEROIN, ALPRAZOLAM, OR FOOD CHOICE. A SIGNIFICANT ADDITION TO OUR GROUPS OF MONKEYS WITH DIFFERENT REINFORCEMENT HISTORIES WILL BE THE FOOD-EXPERIENCED ANIMALS, PROVIDING A QUANTITATIVE MODEL OF DRUG-NAÏVE INDIVIDUALS’ INITIAL EXPOSURE TO DRUG TAKING. BZ USE AMONG INDIVIDUALS WITH A SUD, IN OR OUT OF TREATMENT, IS INCREASINGLY COMMON AND IS ASSOCIATED WITH INCREASED RISK OF BZ MISUSE AND OVERDOSE. TESTING THE HYPOTHESES PROPOSED WILL PROVIDE CRITICAL INFORMATION FOR UNDERSTANDING HOW PAST AND CURRENT DRUG USE AFFECTS THE ABUSE LIABILITY OF BZ-TYPE DRUGS.

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

NOVEL GABA-A MODULATORS AS COGNITIVE ENHANCERS

MISSISSIPPI -- BEHAVIORAL HEALTH IN INFANTS AND PRESCHOOLERS (MS-BE HIP)

GABAA RECEPTOR SUBTYPE MECHANISMS IN NONHUMAN PRIMATE MODELS OF ALCOHOL ABUSE

PURPOSE:THIS PROJECT SUPPORTS THE ACQUISITION OF LAB EQUIPMENT TO OUTFIT A VIVARIUM SPACE FOR ANIMAL RESEARCH ORIGINALLY CONSTRUCTED IN 1962 AND LAST REMODELED IN 1997. IT IS ONE OF FOUR LARGE VIVARIUM SPACES AVAILABLE AT UMMC AND, AT 14,500 SQUARE FEET, REPRESENTS 21% OF THE TOTAL VIVARIUM SPACE AVAILABLE ON THE MEDICAL CENTER'S CAMPUS.ACTIVITIES TO BE PERFORMED:THIS PROJECT WILL INCLUDE EQUIPPING OF APPROXIMATELY 14,000 SQUARE FEET OF VIVARIUM SPACE IN THE MEDICAL CENTER'S ORIGINAL VIVARIUM LOCATED IN THE RESEARCH WING. THE OVERALL PROJECT WILL ENCOMPASS RENOVATION, HVAC REPLACEMENT, AND ROOF REPLACEMENT OF THE 8TH FLOOR VIVARIUM IN THE RESEARCH WING. THIS GRANT WILL BE UTILIZED TO PURCHASE FIXED EQUIPMENT, INCLUDING THE HVAC EQUIPMENT, COLD STORAGE ROOM, AND AUTOCLAVE, AS WELL AS UNFIXED EQUIPMENT FOR RESEARCH IMAGING. THE CONSTRUCTION AND RENOVATION PORTION OF THE PROJECT WILL BE FUNDED FROM SEPARATE, NON-NIST FUNDS.EXPECTED OUTCOMES:THE REQUESTED EQUIPMENT WILL ALLOW UMMC'S RESEARCHERS TO CONTINUE ITS WORLD-CLASS CARDIOMETABOLIC DISEASE RESEARCH, BUILD A NEW CANCER RESEARCH PORTFOLIO FOCUSED ON CANCER HEALTH DISPARITIES AND EXPAND ITS NEUROSCIENCE RESEARCH IN ADDICTION, NEUROTRAUMA, AND CEREBROVASCULAR DISEASE.THIS PROJECT WILL MODERNIZE SPACE ENABLING GROWTH OF THE UMMC'S CANCER CENTER RESEARCH INSTITUTE WITH THE ULTIMATE GOAL FOR UMMC TO APPLY FOR NCI DESIGNATION IN 7-10 YEARS. WITH UMMC'S GOAL TO RECRUIT 30 NEW CANCER RESEARCH FACULTY, THIS PROJECT WILL PROVIDE MODERN VIVARIUM SPACE TO SUPPORT THE RESEARCH PROGRAMS OF OUR NEW RECRUITS AND STATE-OF-THE-ART IMAGING EQUIPMENT FOR EXECUTION OF THESE RESEARCH PROGRAMS.INTENDED BENEFICIARIES:FUNDING FROM THIS PROJECT WILL SUPPORT UMMC'S STRATEGIC EFFORT TO EXPAND AND MODERNIZE ITS CANCER RESEARCH PROGRAM TO ACHIEVE NCI-DESIGNATION. CURRENTLY THERE IS NO NCI-DESIGNATED CANCER CENTER IN MISSISSIPPI, LOUISIANA, OR ARKANSAS DESPITE SOME OF THE HIGHEST HEALTH DISPARITIES IN THE NATION.SUBRECIPIENT ACTIVITIES:THE RECIPIENT DOES NOT INTEND TO SUBAWARD FUNDS.

ANTI-INFLAMMATORY ROLES AND MACROPHAGE METABOLISM OF LACTATE AND KETONES DURING MYOCARDIAL INFARCTION - PROJECT SUMMARY/ABSTRACT APPROXIMATELY 1 MILLION PEOPLE IN THE UNITED STATES SUFFER A MYOCARDIAL INFARCTION (MI) EACH YEAR, LEADING TO PROGRESSIVE CARDIAC DYSFUNCTION AND DEVELOPMENT OF HEART FAILURE (HF) IN ~25% OF SURVIVING PATIENTS. DIABETES MELLITUS IS A MAJOR RISK FACTOR FOR MI, AND PATIENTS WITH DIABETES SUFFER FROM HIGHER MORTALITY RATES AND INCREASED RISK OF DEVELOPING HF. DUE TO THE LIMITED SUCCESS OF CURRENT THERAPIES IN PREVENTING ADVERSE CARDIAC REMODELING AFTER MI, NOVEL THERAPEUTIC TARGETS ARE NEEDED TO EFFECTIVELY PROMOTE ADEQUATE HEALING AND LIMIT TISSUE DAMAGE, ESPECIALLY IN DIABETIC PATIENTS. EXCESSIVE MACROPHAGE-MEDIATED INFLAMMATION IS A KEY MECHANISM LEADING TO ADVERSE CARDIAC REMODELING AFTER MI, AND PATIENTS WITH DIABETES DISPLAY EXACERBATED AND PERSISTENT POST-MI INFLAMMATORY RESPONSES. A KEY MECHANISM BY WHICH MACROPHAGES POLARIZE BETWEEN THE PRO-INFLAMMATORY “M1” AND ANTI-INFLAMMATORY/PRO-REPARATIVE “M2” SUBSETS IS VIA METABOLIC REPROGRAMMING CHARACTERIZED BY PHENOTYPIC SWITCHES BETWEEN GLYCOLYTIC METABOLISM, WHICH PROMOTES M1 POLARIZATION, AND MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION (OXPHOS), WHICH PROMOTES M2 POLARIZATION. USING SEAHORSE METABOLIC FLUX ANALYSIS, I HAVE FOUND THAT DURING THE EARLY INFLAMMATORY PHASE (DAY 1 AND 3 AFTER MI IN MICE), INFARCT MACROPHAGES BECOME GLYCOLYTIC, WHEREAS DURING THE HEALING PHASE (DAY 7), MACROPHAGES REVERT TO GLUCOSE OXIDATION AND OXPHOS. IN ADDITION TO GLUCOSE, MACROPHAGES CAN METABOLIZE “ALTERNATIVE” FUELS, INCLUDING LACTATE AND KETONE BODIES, WHICH PROMOTE AN M2 PHENOTYPE. HOWEVER, THE ROLE OF LACTATE AND KETONE BODY METABOLISM BY MACROPHAGES DURING MI IS UNKNOWN, AND WHETHER ADMINISTRATION OR ENDOGENOUS PRODUCTION OF THESE COMPOUNDS CAN PROMOTE M2 MACROPHAGE POLARIZATION DURING MI IS ALSO NOT KNOWN. MY PRELIMINARY DATA INDICATE THAT EXPRESSION OF GENES RELATED TO LACTATE (MCT1, LDHB) AND KETONE (OXCT1) METABOLISM ARE UPREGULATED IN MACROPHAGE DURING THE WOUND HEALING PHASE OF MI. FURTHER PRELIMINARY DATA INDICATES THAT IN VIVO ADMINISTRATION OF LACTATE OR KETONES, OR FEEDING A KETOGENIC DIET ATTENUATES THE MACROPHAGE IMMUNOMETABOLIC PHENOTYPE AFTER MI. THIS INDICATES THAT METABOLISM OF THESE SUBSTRATES MAY UNDERLIE M2 POLARIZATION AND CARDIAC HEALING AFTER MI. THUS, THE HYPOTHESIS FOR THIS PROPOSAL IS THAT ELEVATED ENDOGENOUS PRODUCTION OR EXOGENOUS ADMINISTRATION OF LACTATE AND KETONES WILL IMPROVE CARDIAC REMODELING AND REDUCES CARDIAC INJURY AFTER MI VIA IMPROVED MACROPHAGE METABOLISM AND POLARIZATION. I ALSO PROPOSE THAT DIABETES EXACERBATES MI INJURY VIA IMPAIRED MACROPHAGE LACTATE AND KETONE METABOLISM. TO ADDRESS THESE HYPOTHESES, I WILL USE CLINICALLY RELEVANT MOUSE MODELS OF MI AND DIABETES MELLITUS, AND MACROPHAGE-SPECIFIC GENETICALLY MODIFIED MICE, COUPLED WITH STATE-OF- THE-ART TECHNIQUES FOR MEASURING CARDIAC FUNCTION (HIGH RESOLUTION ULTRASOUND ECHOCARDIOGRAPHY AND 4D IMAGING), LIVE CELLULAR METABOLISM, MACROPHAGE ISOLATION BY IMMUNOMAGNETIC SORTING, AND FLOW CYTOMETRY. THESE STUDIES WILL PROVIDE NEW MECHANISMS OF LACTATE AND KETONE-MEDIATED CARDIOPROTECTION, AND NOVEL STRATEGIES FOR TARGETING MACROPHAGE METABOLISM FOLLOWING CARDIAC INJURY.

NEUROSTEROID-BZ COMBINATIONS: STRATEGY FOR REDUCING ABUSE AND SEDATION

GABA-A RECEPTOR SUBTYPE MECHANISMS AND THE ABUSE-RELATED EFFECTS OF ALCOHOL

IDENTIFYING NOVEL BIOLOGICAL PATHWAYS FOR GOUT USING DNA METHYLATION AND GENETICS

CARDIAC PROTECTIVE MECHANISMS OF MELANOCORTIN SYSTEM ACTIVATION - PROJECT SUMMARY/ABSTRACT OVER 1.5 MILLION AMERICANS SUFFER FROM MYOCARDIAL INFARCTION (MI) EACH YEAR, AND ABOUT 25% OF THESE PATIENTS DEVELOP SEVERE CARDIAC DYSFUNCTION INCLUDING CONGESTIVE HEART FAILURE (HF), WHICH HAS A HIGH 5-YEAR MORTALITY RATE OF ~50%. CURRENT THERAPIES FOLLOWING MI HAVE LIMITED SUCCESS IN ATTENUATING CARDIAC DYSFUNCTION AND SLOWING HF PROGRESSION. THUS, THERE IS A CRITICAL NEED FOR NOVEL, MORE EFFECTIVE THERAPIES THAT PROTECT THE HEART, IMPROVE ITS FUNCTION, AND SLOW/HALT PROGRESSION OF CARDIAC DYSFUNCTION. WE RECENTLY DEMONSTRATED THAT ACTIVATION OF THE BRAIN LEPTIN-MELANOCORTIN SYSTEM PATHWAY GREATLY IMPROVES CARDIOMYOCYTE ENERGY METABOLISM AND CONTRACTILITY, PRESERVES CARDIAC FUNCTION, AND PREVENTS PROGRESSION OF HF FOLLOWING MI INDUCED BY LIGATION OF THE LEFT ANTERIOR DESCENDING CORONARY ARTERY. WE OBSERVED THAT INTRACEREBROVENTRICULAR (ICV) INFUSION OF LEPTIN FOR 4 WEEKS, AT A LOW DOSE THAT DID NOT ALTER BLOOD LEPTIN CONCENTRATION, RESTORED EJECTION FRACTION, CARDIAC OUTPUT, LEFT VENTRICLE (LV) MUSCLE STRAIN AND LEFT ATRIUM/AORTA DIAMETER RATIO ALMOST ALL THE WAY BACK TO NORMAL BASELINE VALUES, AND PRELIMINARY DATA SUGGEST THAT OTHER MEASURES OF CARDIAC FUNCTION SUCH AS +DP/DTMAX AND EXERCISE CAPACITY WERE ALSO MARKEDLY IMPROVED. WE ALSO OBSERVED THAT THESE CARDIAC PROTECTIVE EFFECTS ARE ABSENT IN MELANOCORTIN 4 RECEPTOR (MC4R) DEFICIENT RATS AND THAT ACTIVATION OF BRAIN MC4R USING SYNTHETIC AGONISTS INFUSED INTO THE CEREBRAL VENTRICLES PROTECTED THE HEART AGAINST PROGRESSIVE CARDIAC DYSFUNCTION AFTER MI IN A SIMILAR FASHION COMPARED TO LEPTIN TREATMENT. OUR PRELIMINARY DATA ALSO INDICATE THAT ACTIVATION OF THE CNS LEPTIN-MC4R PATHWAY INCREASES SIRTUIN-3 (SIRT3) EXPRESSION, MITOCHONDRIAL BIOGENESIS AND SUBSTRATE OXIDATION (I.E., GLUCOSE AND FATTY ACID OXIDATION), AND IMPROVES CARDIOMYOCYTE CONTRACTILITY IN NON-INFARCTED REGIONS OF THE LV, INCLUDING AREAS AT RISK BUT STILL VIABLE. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT ACTIVATION OF THE BRAIN MELANOCORTIN SYSTEM IMPROVES CARDIAC FUNCTION AND PREVENTS PROGRESSION OF HF AFTER MI, INCREASES MYOCARDIUM MITOCHONDRIAL BIOGENESIS AND SIRT3 LEVELS, ENHANCES SUBSTRATE OXIDATION, AND IMPROVES ENERGY PRODUCTION AND CARDIOMYOCYTE CONTRACTILITY IN HEALTHY PORTIONS OF THE HEART. WE ALSO PROPOSE THAT THESE BENEFICIAL EFFECTS OF THE MELANOCORTIN SYSTEM ON THE HEART REQUIRE MC4R ACTIVATION IN PVN AND/OR DMV/NTS/IML, AND THAT MC4R AGONISTS THAT CROSS THE BLOOD-BRAIN BARRIER (E.G. SETMELANOTIDE) AND CAN BE ADMINISTERED SYSTEMICALLY WILL BE EFFECTIVE TO PROVIDE CARDIOPROTECTIVE EVEN IN THE SETTING OF OBESITY. WE WILL USE STATE-OF-THE-ART CHRONIC IN VIVO PROTOCOLS WITH HIGH-RESOLUTION ULTRASOUND TECHNIQUES FOR IMAGING CARDIAC FUNCTION (INCLUDING 4D-STRAIN ECHOCARDIOGRAPHIC IMAGING TECHNOLOGY) IN GENETICALLY ENGINEERED ANIMAL MODELS COMBINED WITH EX VIVO AND IN VITRO PREPARATIONS FOR DETAILED MEASUREMENTS OF CARDIAC MUSCLE FUNCTION, MORPHOLOGY, ENERGY METABOLISM AND CONTRACTILITY TO TEST OUR HYPOTHESES. THE OUTCOMES FROM THIS STUDY COULD LEAD TO NOVEL AND MORE EFFECTIVE THERAPEUTIC APPROACHES FOR MI AND HF, AND WILL PROVIDE A NEW TARGET FOR MC4R AGONISTS WHICH ARE CURRENTLY BEING USED TO TREAT RARE FORMS OF GENETIC OBESITY IN HUMANS.

MECHANISM OF? PD1 ON CARDIAC INFLAMMATION RESOLUTION DURING HEART FAILURE DEVELOPMENT - CARDIOVASCULAR INFLAMMATION PROMOTES HEART FAILURE (HF) DEVELOPMENT. HOWEVER, MECHANISM OF CARDIAC INFLAMMATION RESOLUTION DURING HF DEVELOPMENT IS STILL POORLY UNDERSTOOD. PROGRAMMED CELL DEATH PROTEIN 1 (PD1) IS A PROTEIN THAT KEEPS THE BODY’S IMMUNE RESPONSES IN CHECK, BOTH BY INHIBITING INITIAL T CELL INDUCTION AND BY MAINTAINING T CELL TOLERANCE. PD1 BLOCKING ANTIBODIES ARE USED IN CANCER TREATMENT, BUT THE TREATMENT ALSO LEADS TO CARDIAC TOXICITY IN SOME PATIENTS. WE FOUND THAT PD1 KO OR PD1 BLOCKING ANTIBODIES DRAMATICALLY EXACERBATED TRANSVERSE AORTIC CONSTRICTION (TAC)-INDUCED CARDIAC INFLAMMATION, HF, AND DEATH, INDICATING PD1 EXERTS A MORE IMPORTANT ROLE UNDER STRESS CONDITIONS. TO UNDERSTAND MECHANISMS OF PD1 INHIBITION IN CARDIAC INFLAMMATION, WE STUDIED CARDIAC IMMUNE CELLS AND VASCULAR ENDOTHELIAL CELLS FROM WILD TYPE AND PD1 KO MICE AFTER SHAM OR TAC BY USING SINGLE-CELL CITE-SEQ TOGETHER WITH BARCODED ANTIBODIES FOR MEMBRANE PROTEIN LABELING. USING SINGLE-CELL CITE-SEQ, WE ALSO STUDIED LUNG IMMUNE CELLS FROM HF MICE AND SHAM MICE. BIOINFORMATICS ANALYSES HAVE PROVIDED ENORMOUSLY INFORMATION OF THESE CELLS – SHOWING DRAMATIC ALTERATIONS OF CELL CLUSTERS, ENRICHED PATHWAYS OF INNATE & ADAPTIVE IMMUNE RESPONSES, AND CHANGES OF METABOLIC PATHWAYS IN VARIOUS IMMUNE CELL SUBSETS IN HF MICE, OR IN PD1 KO AFTER TAC. GDT CELLS (A SUBSET OF T CELLS) CAN BE DIVIDED INTO EITHER IL-17 (GDT17) OR IFNG PRODUCERS. CITE-SEQ OF LUNG IMMUNE CELLS SHOWED THAT HF CAUSED DRAMATIC CHANGES OF VARIOUS T CELL AND MACROPHAGE CLUSTERS, A DRAMATIC INCREASE OF PD1 IN TH17 AND GDT17 CELLS, SUGGESTING PD1 EXERTS AN IMPORTANT ROLE IN SUPPRESSING TH17, AND GDT17 CELLS AS WELL AS HF PROGRESSION. CITE-SEQ IN CARDIAC IMMUNE CELLS SHOWED THAT INFILTRATION OF CD8+ T CELLS AND GDT CELLS INCREASED IN PD1 KO MICE AFTER TAC, AND THESE INFILTRATED CELLS ARE IFNG+ CELLS, INDICATING THAT CD8+ T CELLS, GDT CELLS, AND IFNG MAY CONTRIBUTE TO THE EXACERBATED CARDIAC INFLAMMATION IN PD1 KO MICE. BASED ON THESE EXCITING FINDINGS, WE HYPOTHESIZE THAT TAC-INDUCED CARDIAC AND PULMONARY INFLAMMATION RESOLUTION IS REGULATED BY PD1 THROUGH BOTH CONSERVED AND UNIQUE PATHWAYS AT LEAST PARTIALLY CONTROLLED BY IFNG AND IL17 PRODUCED BY CD8+ T CELLS, GDT CELLS, AND TH17, RESPECTIVELY. TO ENHANCE THE INNOVATIVE RIGOR OF OUR INVESTIGATION OF THE ROLE OF PD1 IN CARDIAC INFLAMMATION AND HF, WE WILL ALSO STUDY CD8 CELL SPECIFIC PD1 KO MICE. AIM-1. TEST THE HYPOTHESIS THAT IFNG AND CD8+ T CELLS CONTRIBUTE TO THE EXACERBATED CARDIAC INFLAMMATION, CYTOKINE STORM, AND HF IN PD1 KO AFTER TAC. IN ADDITON, WE WILL DETERMINE WHETHER PD1 KO IN CD8+ T CELLS IS SUFFICIENT TO EXACERBATE TAC-INDUCED CARDIAC INFLAMMATION AND HF. AIM-2. DETERMINE THE ROLES AND UNDERLYING MECHANISMS OF IL17 AND GDT CELLS IN PROMOTING TAC-INDUCED CARDIAC INFLAMMATION AND HF AFTER PD1 INHIBITION. THIS APPLICATION IS HIGHLY RESPONSIVE TO THE NOTICE OF SPECIAL INTEREST NOT-ES-20-018 AS THE PROPOSED STUDIES WILL ADVANCE OUR UNDERSTANDING OF THE MECHANISMS OF PD1 AND T CELLS IN CARDIAC AND LUNG INFLAMMATION RESOLUTION, AND THE CONSERVED & UNIQUE CHANGES IN CARDIAC AND LUNG IMMUNE CELL CLUSTERS DURING HF DEVELOPMENT AND PROGRESSION.

MOBILITY DECLINE: RELATIONS TO CEREBRAL PERFUSION, SMALL VESSEL DISEASE PROGRESSION, AND LONGITUDINAL BLOOD PRESSURE EXPOSURES

ROLE OF MINERALOCORTICOIDS IN HYPERTENSION

SHORT SLEEP DURATION AS A PREDICTOR OF METHAMPHETAMINE INTAKE: ROLE OF OREXIN MECHANISMS - PROJECT SUMMARY_________________________________________________________________________ INSUFFICIENT SLEEP PREDICTS SUBSTANCE USE AND ASSOCIATED PSYCHOSOCIAL PROBLEMS, AND PUTS INDIVIDUALS AT A HIGHER RISK FOR SUBSTANCE USE DISORDERS. IN FACT, OUR PRELIMINARY DATA SUGGEST THAT THE QUALITY OF OVERALL BASELINE SLEEP MAY INFLUENCE METHAMPHETAMINE INTAKE IN RHESUS MONKEYS. THESE FINDINGS RAISE THE IMPORTANT POSSIBILITY THAT SHORT SLEEP INCREASES THE PROBABILITY OF ENHANCED METHAMPHETAMINE USE AND/OR USE DISORDER. WE RECENTLY DIS- COVERED THAT SHORT SLEEP IS A STRIKINGLY PREVALENT PHENOTYPE AMONG ADULT FEMALE RHESUS MONKEYS, WITH A PREVA- LENCE OF NEARLY 40%. WHILE THE BIOLOGICAL FACTORS CONTRIBUTING TO THIS PARTICULAR PHENOTYPE REMAIN UNKNOWN, AL- TERED CIRCADIAN RHYTHM OF OREXIN (HYPOCRETIN) REGULATION HAS BEEN PROPOSED AS A KEY MEDIATOR OF SHORT SLEEP (INSOMNIA) IN HUMANS, AND OUR STUDIES SUGGEST THAT THE OREXIN SYSTEM IS INVOLVED IN THE SHORT SLEEP PHENOTYPE IN FEMALE MONKEYS. MOREOVER, OUR RECENT RESEARCH ALSO HAS IMPLICATED THE OREXIN SYSTEM AS A POTENTIAL MODU- LATOR OF BOTH THE SLEEP IMPAIRING AND REINFORCING EFFECTS OF METHAMPHETAMINE, SUGGESTING AN IMPORTANT MECHA- NISTIC LINK BETWEEN SLEEP REGULATION AND METHAMPHETAMINE PHARMACOLOGY. BASED ON THESE OBSERVATIONS, THE WORKING HYPOTHESIS OF THIS APPLICATION IS THAT DYSREGULATION OF OREXIN PROCESSES AND SPECIFIC OREXIN RECEPTOR SUBTYPES PLAY A KEY ROLE IN PHENOTYPIC SHORT SLEEP IN FEMALE MONKEYS THAT, IN TURN, INCREASES VULNERABILITY TO THE ADDICTIVE PROPERTIES OF METHAMPHETAMINE. OUR RESEARCH STRATEGY IS ORGANIZED AROUND THREE SPECIFIC AIMS, AND ALL EXPERIMENTS WILL BE CONDUCTED IN FEMALE SHORT SLEEPERS AND FEMALE NORMAL SLEEPERS. AIM 1 WILL EVALUATE THE HYPOTHESIS THAT DYSREGULATION OF OREXIN PROCESSES UNDERLIES THE SHORT SLEEP PHENOTYPE IN FEMALE MONKEYS VIA OX2 RECEPTORS. WE WILL INVESTIGATE THE EFFECTS OF NOVEL OREXIN RECEPTOR LIGANDS ON ELECTRO- ENCEPHALOGRAPHY-BASED TELEMETRIC RECORDINGS OF SLEEP-WAKE CYCLES, AND WILL EVALUATE DIURNAL RHYTHMS OF CIRCU- LATING OREXIN LEVELS IN BLOOD. AIM 2 WILL EVALUATE THE HYPOTHESIS THAT PHENOTYPIC SHORT SLEEP INCREASES VULNERABILITY TO THE ADDICTIVE PROPERTIES OF METHAMPHETAMINE IN FEMALE RHESUS MONKEYS. ACQUISITION OF METHAMPHETAMINE SELF-ADMINISTRATION WILL BE EVALUATED ACROSS PHENOTYPES, AND WE WILL USE BEHAVIORAL ECONOMICS TO INVESTIGATE THE REINFORCING EFFECTIVENESS OF METHAMPHETAMINE. AIM 3 WILL EVALUATE THE HYPOTHESIS THAT THE REINFORCING EFFECTS OF METHAMPHETAMINE IN SHORT SLEEPERS ARE MODULATED UNIQUELY BY THE OX2 RECEPTOR SYSTEM. WE WILL INVESTIGATE THE EFFECTS OF DAYTIME AND NIGHTTIME TREATMENTS WITH OREXIN RECEPTOR AGONISTS AND ANTAGONISTS ON METHAMPHETA- MINE INTAKE IN SHORT VS NORMAL SLEEPERS. THE RESEARCH IN THIS APPLICATION ADDRESSES A KEY TOPIC FOR PUBLIC HEALTH BY PROPOSING TO INVESTIGATE THE EFFECTS OF SHORT SLEEP ON METHAMPHETAMINE INTAKE AND THE OREXIN MECHANISMS INVOLVED IN THIS PHENOMENON.

MISSISSIPPI CANCER REGISTRY - NPCR

MECHANISMS OF TREG AND IL-35 IN REGULATING LV FAILURE-INDUCED LUNG REMODELING AND RIGHT HEART HYPERTROPHY

DEVELOPMENT OF MODULAR CRISPR GENOME EDITING TECHNOLOGIES AND TOOLS

ENDOTHELIN-1 IN OBESITY AND INSULIN RESISTANCE - PROJECT SUMMARY INSULIN RESISTANCE (IR) IS A MAJOR HEALTH PROBLEM IN THE U.S. IT PRECLUDES TYPE II DIABETES AND IS OFTEN PRESENT IN PATIENTS SUFFERING FROM OBESITY, BOTH BEING MAJOR RISK FACTORS FOR CARDIOVASCULAR DISEASE. CURRENTLY, MECHANISMS LEADING TO IR ARE NOT FULLY UNDERSTOOD. ET-1 IS A VASOACTIVE PEPTIDE PRIMARILY RELEASED BY ENDOTHELIAL CELLS. IT IS INCREASED IN PATIENTS WITH OBESITY AND ASSOCIATED WITH IR. ET-1 IS ELEVATED IN RESPONSE TO HYPOXIA, WHICH OCCURS IN INDIVIDUALS WITH OBESITY. IT ACTIVATES TWO RECEPTORS, ETA AND ETB, WHICH TYPICALLY OPPOSE EACH OTHER PHYSIOLOGICALLY. OUR PRELIMINARY DATA INDICATE THAT INHIBITING ETB RECEPTORS IN RODENTS, EITHER GENETICALLY OR PHARMACOLOGICALLY, IMPROVES INSULIN TOLERANCE AND REDUCES FASTING BLOOD GLUCOSE. THIS IMPROVEMENT IN GLUCOSE CONTROL IS ASSOCIATED WITH AN INCREASE IN PLASMA ADIPONECTIN AND ADIPOSE ADIPONECTIN AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-) MRNA. IN ADDITION, ADIPOCYTE SPECIFIC ETB GAIN OF FUNCTION MICE HAVE EXACERBATED GLUCOSE INTOLERANCE IN RESPONSE TO HIGH FAT FEEDING, WHILE ADIPOCYTE ETB KNOCKOUT MICE HAVE IMPROVED GLUCOSE AND INSULIN TOLERANCE COMPARED TO FLOXED CONTROL LITTERMATES. THESE DATA SUGGEST THE ADIPOSE TISSUE AS A POSSIBLE TARGET FOR ET-1 INDUCED REDUCTION IN INSULIN SIGNALING. IT HAS BEEN PREVIOUSLY SHOWN THAT ACTIVATION OF ETB RECEPTORS ON CULTURED ADIPOCYTES INHIBITS THE ANTI-LIPOLYTIC EFFECTS OF INSULIN. FURTHERMORE, BLOCKADE OF ETB RECEPTORS IMPROVES INSULIN SENSITIVITY IN A RODENT MODEL OF SLEEP APNEA. THESE DATA SUGGEST THAT INCREASED ET-1 OBSERVED IN PATIENTS WITH OBESITY MAY PROMOTE IR VIA THE ETB RECEPTOR. THUS, WE HYPOTHESIZE THAT THAT OBESITY INDUCED TISSUE HYPOXIA PROMOTES ET-1/ETB RECEPTOR ACTIVATION IN ADIPOSE LEADING TO IR ON ADIPOCYTES, PPAR- INHIBITION AND REDUCED ADIPONECTIN RELEASE BY ADIPOCYTES THEREBY CAUSING IR IN MUSCLE AND LIVER TISSUE. TO TEST THIS HYPOTHESIS, WE WILL UTILIZE BOTH IN VIVO AND IN VITRO TECHNIQUES. FIRST, USING CULTURED ADIPOCYTES, WE WILL DETERMINE WHETHER ACTIVATION OF ETB RECEPTORS INHIBITS PPAR-, REDUCES ADIPONECTIN SECRETION, AND CAUSES INSULIN RESISTANCE ON ADIPOCYTES. NEXT, WE WILL USED CLINICALLY APPROVED INHIBITORS OF ET-1 RECEPTORS IN A MODEL OF DIET INDUCED OBESITY AND IR, AND WE WILL UTILIZE TWO NOVEL MOUSE MODELS THAT WERE PRODUCED BY OUR LAB THAT ALLOW US TO OVER-EXPRESS OR KNOCKOUT THE ETB. TO TEST THIS HYPOTHESIS, THE FOLLOWING SPECIFIC AIMS WILL BE TESTED: SPECIFIC AIM 1: TO TEST THE HYPOTHESIS THAT ETB RECEPTOR ACTIVATION DIRECTLY INHIBITS INSULIN SIGNALING ON ADIPOCYTES AND REDUCES ADIPONECTIN PRODUCTION BY INHIBITING PPAR-. SPECIFIC AIM 2: TO TEST THE HYPOTHESIS THAT ETB RECEPTOR ACTIVATION ON ADIPOCYTES PROMOTES INSULIN RESISTANCE BY INHIBITING PPAR- AND REDUCING ADIPONECTIN RELEASE IN MICE. SPECIFIC AIM 3: TO TEST THE HYPOTHESIS THAT ETB RECEPTOR BLOCKADE INCREASES PLASMA ADIPONECTIN AND IMPROVES INSULIN RESISTANCE IN OBESE MICE.

MISSISSIPPI PREVENTION TRAINING CENTER

HUMORAL FACTORS IN GENDER DIFFERENCES IN BP CONTROL

SUD AND IPV AMONG MISSISSIPPI'S MOMS: INITIATIVE TO PREVENT AND TREAT (SIMM INITIATIVE) - THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) AND ITS PARTNERS, (1) MISSISSIPPI COALITION AGAINST DOMESTIC VIOLENCE, OFFERING SERVICES IN 78 OF MISSISSIPPI’S 82 COUNTIES; (2) CONVERGE: PARTNERS IN ACCESS; (3) MISSISSIPPI COALITION AGAINST SEXUAL ASSAULT; (4) MISSISSIPPI STATE DEPARTMENT OF HEALTH; (5) COMMUNITY HEALTH CENTER ASSOCIATION OF MISSISSIPPI, REPRESENTING 21 COMMUNITY HEALTH CENTERS THROUGHOUT MISSISSIPPI; AND (6) UNIVERSITY OF MISSISSIPPI’S CENTER FOR RESEARCH EVALUATION, PROPOSE TO ESTABLISH THE SUD AND IPV AMONG MISSISSIPPI’S MOMS: INITIATIVE TO PREVENT AND TREAT (SIMM INITIATIVE). THE SIMM INITIATIVE RECOGNIZES THE INTERCONNECTIONS BETWEEN SUBSTANCE USE DISORDER (SUD) AND INTERPERSONAL VIOLENCE (IPV) AMONG PREGNANT AND POSTNATAL WOMEN, AND IS AWARE OF THE NEED TO SCREEN AND TREAT FOR BOTH. MISSISSIPPI’S MENTAL HEALTH AND SUD PROVIDERS NEED TO BE TRAINED TO SCREEN AND REFER FOR TREATMENT THOSE WOMEN SUFFERING FROM IPV. CONCOMITANTLY, MISSISSIPPI’S COMMUNITY-BASED SERVICE PROVIDERS FOR PREGNANT AND POSTPARTUM WOMEN SUFFERING FROM IPV NEED TO BE TRAINED TO SCREEN AND REFER PATIENTS FOR SUD. THE SIMM INITIATIVE TEAM INCLUDES ACADEMIC MEMBERS AND PRACTITIONERS WITH EXPERTISE IN IDENTIFYING AND TREATING THOSE WITH SUD AND IPV, NURSING, PUBLIC HEALTH/DATA SCIENCE, BIOSTATISTICS, AND EVALUATION METHODOLOGY, AS WELL AS STATE- AND COMMUNITY-BASED ORGANIZATIONS AND PRACTITIONERS PROVIDING SERVICES TO MISSISSIPPIANS WITH A HISTORY OF EITHER SUD AND/OR IPV. TO COMPLETE ITS WORK, THE SIMM INITIATIVE HAS IDENTIFIED SEVEN GOALS AND 21 SMART OBJECTIVES (SMART IS AN ACRONYM FOR “SPECIFIC, MEASURABLE, ACHIEVABLE, RELEVANT, AND TIME-ORIENTED). THE GOALS ARE TO (1) ESTABLISH AND IMPLEMENT A PILOT PROJECT THAT INCENTIVIZES SUD PROVIDERS TREATING PREGNANT AND POSTPARTUM WOMEN IN MISSISSIPPI TO BE TRAINED ON IDENTIFYING AND ADDRESSING IPV; (2) DEVELOP AND IMPLEMENT AN SUD TRAINING PROGRAM FOR MISSISSIPPI’S COMMUNITY-BASED IPV STAFF MEMBERS THAT FOCUSES ON PREGNANT AND POSTPARTUM WOMEN; (3) BASED ON FEEDBACK FROM RECIPIENTS OF INITIAL SUD AND IPV TRAINING PROGRAMS, REVISE AS NECESSARY, AND DISSEMINATE WIDELY BEST PRACTICES FOR MANAGING CO-OCCURRING IPV AND SUD AMONG PREGNANT AND POSTPARTUM WOMEN; (4) DEVELOP AND IMPLEMENT STATEWIDE PLAN FOR INTEGRATING IPV AND SUD PROTOCOLS ACROSS HEALTHCARE SETTINGS; (5) PROVIDE TECHNICAL ASSISTANCE TO COMMUNITY-BASED IPV PROGRAMS TO BETTER ACCOMMODATE THE NEEDS OF PREGNANT AND POSTPARTUM WOMEN WITH SUD; (6) DEVELOP AND DISSEMINATE A DISPARITY IMPACT STATEMENT ON MISSISSIPPI’S PREGNANT AND POSTPARTUM WOMEN AT RISK FOR CO-OCCURRING SUD AND IPV; AND (7) MONITOR, EVALUATE, AND CONTINUOUSLY IMPROVE THE PROGRAMS AND SERVICES OFFERED BY THE SIMM INITIATIVE. TIMELY DISSEMINATION OF ITS WORK IS KEY TO THE SUCCESS OF THE SIMM INITIATIVE. TRAINING COURSES WILL BE PROVIDED BOTH IN PERSON AND THROUGH CONTINUING EDUCATION ON WEB-BASED PLATFORMS. ITS TRAINING AND INFORMATIONAL MATERIALS WILL BE WIDELY AVAILABLE AND DESIGNED TO BE EMBRACED BY MISSISSIPPI’S GENERAL PUBLIC, HEALTHCARE PROVIDERS, SERVICE PROVIDERS, COMMUNITY LEADERS, PUBLIC HEALTH OFFICIALS, AND STATE LEGISLATORS. NATIONALLY, THE SIMM INITIATIVE WILL SHARE ITS EXPERIENCES WITH COLLEAGUES, OTHER ORGANIZATIONS ATTEMPTING SIMILAR PROGRAMS, AND NATIONAL POLICY LEADERS. PLANS INCLUDE A ROBUST WEBSITE, PAMPHLETS AND OTHER MATERIALS WITH CULTURALLY-SENSITIVE MESSAGING DESIGNED FOR DIFFERENT AUDIENCES (PARTICULARLY THOSE IN RURAL SETTINGS), TRAINING GUIDES THAT ARE STRAIGHTFORWARD AND EASY TO UNDERSTAND, AND PRESENTATIONS DESIGNED FOR DIFFERENT AUDIENCES (E.G., COMMUNITY MEMBERS, HEALTH CARE PROFESSIONALS, POLICY ANALYSTS, ACADEMIC COLLEAGUES). FINALLY, MEMBERS OF THE SIMM INITIATIVE TEAM WILL PRESENT POSTERS AT PROFESSIONAL MEETINGS (E.G., REGIONAL AND NATIONAL MEETINGS OF ACADEMIC SOCIETIES AND ASSOCIATIONS), AND SUBMIT MANUSCRIPTS FOR PUBLICATION IN PEER-REVIEW

PROVISION OF TREATMENT FOR SUBSTANCE USE DISORDERS AND MENTAL HEALTH DISORDERS IN MISSISSIPPI TO REDUCE TRANSMISSION AND IMPROVE CLINICAL OUTCOMES IN PEOPLE LIVING WITH HIV

ADVANCED NURSING EDUCATION GRANTS

FENTANYL USE DURING PREGNANCY: IMPACT ON DAM, PLACENTA, AND OFFSPRING DEVELOPMENT. - ABSTRACT OPIOID ABUSE OF PREGNANT WOMEN OR WOMEN OF CHILDBEARING AGE IN GENERAL IS AN URGENT PUBLIC HEALTH CONCERN. THE NUMBER OF WOMEN USING OPIOIDS PRESENTING AT LABOR AND DELIVERY HAS MORE THAN QUADRUPLED IN THE LAST DECADE. WHILE THE IMMINENT EFFECTS OF OPIOID USE DURING PREGNANCY, NAMELY NEONATAL OPIATE WITHDRAWAL SYNDROME, ARE WELL DESCRIBED, THERE IS ONLY LIMITED KNOWLEDGE ABOUT HARMFUL EFFECT OF OPIOID ABUSE DURING PREGNANCY ON MATERNAL HEALTH, PLACENTAL FUNCTION, AND THE DEVELOPING CHILD. THIS PROPOSAL AIMS TO INVESTIGATE THE EFFECTS OF FENTANYL USE DURING PREGNANCY AND ITS CONSEQUENCES ON MATERNAL PHYSIOLOGY, STRESS REACTIVITY, PLACENTAL FUNCTION, AND OFFSPRING DEVELOPMENT USING A TRANSLATIONALLY RELEVANT APPROACH IN WHICH RAT DAMS SELF - ADMINISTER FENTANYL INTRAVENOUSLY UNDER EXTENDED-ACCESS CONDITIONS PRIOR AND THROUGHOUT PREGNANCY. IN THREE AIMS WE WILL TEST THE HYPOTHESES THAT FENTANYL SELF-ADMINISTRATION BEFORE AND THROUGHOUT PREGNANCY WILL 1) AFFECT THE MATERNAL CARDIOVASCULAR SYSTEM, RESPIRATION AND STRESS REACTIVITY, 2) INDUCE PROFOUND IMPAIRMENTS IN PLACENTAL FUNCTION, AND 3) INDUCES NEONATAL OPIOID WITHDRAWAL, IMPAIRS OFFSPRING DEVELOPMENT AND INCREASES STRESS REACTIVITY IN THE OFFSPRING. WE WILL ASSESS COMPREHENSIVELY HEALTH, BLOOD PRESSURE, RESPIRATION RATE, STRESS HORMONE LEVELS AND OXIDATIVE STRESS, AND PLACENTAL FUNCTION IN PREGNANT, FENTANYL SELF-ADMINISTERING FEMALES. IN THE OFFSPRING, WE WILL ASSESS THE OVERALL HEALTH, OCCURRENCE AND SEVERITY OF NEONATAL OPIATE WITHDRAWAL AND ACHIEVEMENT OF AG E-APPROPRIATE SOMATIC AND BEHAVIORAL DEVELOPMENTAL MILESTONES BY THE OFFSPRING. IN COMPARISON TO YOKED SALINE AND SHAM CONTROL DAMS, WE HYPOTHESIZE THAT FENTANYL SELF-ADMINISTRATION OF DAMS WILL LEAD TO DECREASED BLOOD PRESSURE, RESPIRATORY DEPRESSION AND AN INCREASE IN STRESS REACTIVITY. WE ALSO EXPECT A REDUCED SUFFICIENCY OF THE PLACENTA, AS WELL AS NEONATAL OPIOID WITHDRAWAL SYMPTOMS, IMPAIRMENTS IN OFFSPRING DEVELOPMENT, AND OFFSPRING STRE SS REACTIVITY. THE RESULTS FROMTHE PROPOSED STUDIES WILL PROVIDE NEEDED INFORMATION REGARDING THE EFFECTS OF FENTANYL ON THE PREGNANT FEMALE PHYSIOLOGY AND BEHAVIOR AND ON OFFSPRING DEVELOPMENT. ULTIMATELY, OUR STUDIES SHOULD LEAD TO KNOWLEDGE THAT IS VITAL FOR THE IDENTIFICATION OF TREATMENT OPPORTUNITIES, BOTH PRE- AND POSTPARTUM.

COMMUNITY BASED DENTAL PARTNERSHIP

ROLE OF OBESITY IN BLOOD PRESSURE REGULATION AND INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME - POLYCYSTIC OVARY SYNDROME (PCOS) IS THE MOST COMMON ENDOCRINE DISORDER IN REPRODUCTIVE-AGE WOMEN. PCOS IS DIAGNOSED BY ELEVATED ANDROGENS, OVULATORY DYSFUNCTION, AND POLYCYSTIC OVARIES. WOMEN WITH PCOS HAVE A HIGH PREVALENCE OF CARDIOVASCULAR RISK FACTORS (CRFS), SUCH AS OBESITY, INSULIN RESISTANCE (IR), AND ELEVATED BLOOD PRESSURE (BP). EFFECTIVE THERAPEUTIC AGENTS TO TREAT CRFS FOUND IN PCOS WOMEN ARE LIMITED. THE LONG- TERM GOAL IS TO FIND EFFECTIVE AND SAFE THERAPEUTIC AGENTS TO TREAT CRFS IN PCOS WOMEN. THE RENIN-ANGIOTENSIN SYSTEM (RAS), WITH ITS CLASSICAL AND NONCLASSICAL PATHWAYS, IS A REGULATORY SYSTEM FOR BP CONTROL AND METABOLIC FUNCTION. THE ADIPOSE TISSUE HAS A FULLY FUNCTIONAL RAS WITH SYSTEMIC, PARACRINE, AND AUTOCRINE ACTIONS. THIS RESEARCH PROPOSAL WILL ELUCIDATE THE ROLE THAT THE ADIPOSE CLASSICAL AND NONCLASSICAL RAS PLAYS IN IR AND BP REGULATION IN PCOS. IR IS PRESENT IN LEAN AND OBESE PCOS WOMEN. PLASMA ADIPONECTIN LEVELS, AN INSULIN- SENSITIZING HORMONE, ARE LOW IN PCOS WOMEN, MAKING IT AN ATTRACTIVE MOLECULAR TARGET TO DECREASE IR. THE GOAL OF THIS PROPOSAL IS TO STUDY THE INTERPLAY BETWEEN ANDROGENS, ADIPOSITY, ADIPOSE CLASSICAL AND NONCLASSICAL RAS, AND ADIPONECTIN TO MEDIATE CRFS IN PCOS WOMEN. OUR CENTRAL HYPOTHESIS IS THAT “HYPERANDROGENEMIA HAS OBESITY-DEPENDENT AND -INDEPENDENT EFFECTS, LEADING TO INCREASED BP AND IR IN PCOS. ACTIVATION OF THE CLASSICAL AND INACTIVATION OF THE NONCLASSICAL ADIPOSE RAS LEAD TO INCREASED BP. FURTHERMORE, INDEPENDENT OF OBESITY, ANDROGENS CAUSE IR VIA DECREASED ADIPONECTIN LEVELS IN PCOS”. THIS NOVEL AND CLINICALLY RELEVANT HYPOTHESIS WILL BE TESTED WITH THESE AIMS: AIM 1: TO TEST THE HYPOTHESIS THAT OBESITY AS A RESULT OF HYPERANDROGENEMIA CAUSES AN ACTIVATION OF THE RAS AND INCREASES BP IN THE PCOS MODEL; AIM 2: TO TEST THE HYPOTHESIS THAT AN IMBALANCE OF THE ADIPOSE CLASSICAL AND NONCLASSICAL RAS IN RESPONSE TO HYPERANDROGENEMIA LEADS TO INCREASED BP IN THE PCOS MODEL; AIM 3: TO TEST THE HYPOTHESIS THAT DECREASES IN ADIPONECTIN IN RESPONSE TO HYPERANDROGENEMIA LEAD TO OBESITY-INDEPENDENT IR IN THE PCOS MODEL. WE WILL TEST THIS HYPOTHESIS USING AN INNOVATIVE COMBINATION OF GOLD-STANDARD METHODS TO MEASURE BP, IR, FAT DISTRIBUTION AND FUNCTION, AND SYSTEMIC AND ADIPOSE RAS PEPTIDES IN TWO WELL-CHARACTERIZED, CLINICALLY RELEVANT MODELS OF PCOS AND A 3D ADIPOCYTES CELL CULTURE. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT WILL SHED LIGHT ON THE ANDROGENS- MEDIATED MECHANISMS AND THE INTERPLAY BETWEEN OBESITY, THE CLASSICAL AND NONCLASSICAL RAS, AND ADIPOKINES IN THE PATHOPHYSIOLOGY OF THE CRFS IN PCOS WOMEN. MOREOVER, THIS STUDY WILL IDENTIFY POTENTIAL NEW THERAPEUTIC OPTIONS TO AMELIORATE CRFS IN PCOS WOMEN.

INTEGRATIVE ROLE OF BILIRUBIN ON OBESITY

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) IS HOME TO CHILDREN’S OF MISSISSIPPI, THE STATE’S ONLY CHILDREN’S HOSPITAL SERVING PEDIATRIC AND ADOLESCENTS ACROSS MISSISSIPPI. CHILDREN’S OF MISSISSIPPI IS CURRENTLY ABLE TO PROVIDE PSYCHIATRIC AND BEHAVIORAL HEALTH SERVICES FOR CHILDREN UP TO 13 YEARS OF AGE ON CAMPUS, AND FOR THOSE UP TO 17 YEARS OLD THERE ARE OUTPATIENT SERVICES AT THE CENTER FOR THE ADVANCEMENT OF YOUTH CENTER WHERE CHILDREN HAVE ACCESS TO A MULTIDISCIPLINARY TEAM PROVIDING SUPPORT FOR CONTINUING THERAPY. PSYCHIATRIC AND BEHAVIORAL HEALTH SERVICES FOR PATIENTS 18 YEARS AND OLDER ARE PROVIDED IN THE ADULT FACILITIES AT UMMC. HOWEVER, THESE SAME SERVICES FOR ADOLESCENTS BETWEEN 13 AND 17 YEARS OF AGE ARE SEVERELY LIMITED. THIS GAP RESULTS IN ADOLESCENTS NEEDING SPECIALIZED PSYCHIATRIC AND/OR BEHAVIORAL HEALTH SERVICES BEING HOUSED IN A REGULAR HOSPITAL PATIENT ROOM WITH 24-HOUR OBSERVATION. THESE VULNERABLE PATIENTS ARE UNABLE TO GET THE THERAPEUTIC INTERVENTIONS THEY NEED UNTIL AN ALTERNATIVE PLACEMENT CAN BE FOUND, WHICH CAN TAKE DAYS, WEEKS AND EVEN MONTHS. UMMC IS COMMITTED TO ACTIVELY ADDRESS THIS DISPARITY WITH THE CREATION OF A LEADING-EDGE ADOLESCENT BEHAVIORAL HEALTH INPATIENT FACILITY THAT PROMOTES HIGH QUALITY PATIENT AND FAMILY CENTERED CARE AND ADDRESSES THE NEEDS OF THE COMMUNITY, MEDICAL CENTER AND STAFF. GRANT FUNDING FROM CPF/CDS WILL ALLOW UMMC TO BEGIN CREATING THE SPACE NEEDED TO MEET THE MENTAL, EMOTIONAL AND PHYSICAL NEEDS OF THIS UNIQUE ADOLESCENT PATIENT POPULATION THROUGH AN ADOLESCENT BEHAVIORAL HEALTH INPATIENT UNIT (ABHIU). THIS NEW 10-BED INPATIENT UNIT WILL BE CONSTRUCTED ON THE SECOND FLOOR OF EXISTING UMMC HOSPITAL SPACE ONCE THE PEDIATRIC MEDICAL SUPPORT AND PATIENT SERVICES AND THAT CURRENTLY OCCUPY THE AREA ARE SUCCESSFULLY RELOCATED. THE IDENTIFIED SPACE, ONCE EMPTY, WILL NEED TO UNDERGO A COMPLETE RENOVATION IN ORDER TO MAKE IT CODE COMPLIANT, SAFE AND FUNCTIONAL FOR THESE ADOLESCENT PATIENTS. THE NUMBER OF MISSISSIPPI CHILDREN AND ADOLESCENTS IN DESPERATE NEED OF BEHAVIORAL HEALTH SERVICES IS INCREASING. INFORMATION IN THE STATE OF MENTAL HEALTH IN AMERICA 2022 , REPORTS THAT MISSISSIPPI IS RANKED LAST IN THE NATION FOR YOUTH WITH MAJOR DEPRESSION WHO DID NOT RECEIVE ANY MENTAL HEALTH TREATMENT. THIS PROJECT WILL PROVIDE MISSISSIPPI WITH A LEADING-EDGE ADOLESCENT BEHAVIORAL HEALTH UNIT THAT PROMOTES HIGH QUALITY PATIENT AND FAMILY CENTERED CARE, AND ADDRESSES THE NEEDS OF THE COMMUNITY, MEDICAL CENTER AND STAFF.

RURAL EMERGENCY MEDICAL COMMUNICATIONS DEMONSTRATION PROJECT (REMCDP)

RURAL EMERGENCY MEDICAL COMMUNICATIONS DEMONSTRATION PROJECT

REGULATION OF IL-6-TYPE CYTOKINE CARDIOPROTECTIVE SIGNALING IN THE ISCHEMIC HEART

RURAL EMERGENCY MEDICAL COMMUNICATIONS DEMONSTRATION PROJECT

LOW BIRTH WEIGHT, THE KIDNEY, AND HYPERTENSION

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING (BHWET) PROGRAM

OPIOID RECEPTOR POLYMORPHISMS AND NONHUMAN PRIMATE MODELS OF ALCOHOL ABUSE

FRACTAL ANALYSIS OF CERAMIC FPDS

A NOVEL THERAPY FOR PREECLAMPSIA

GENETIC DETERMINANTS OF HYPERTENSION-INDUCED CEREBRAL VASCULAR DYSFUNCTION

HYPERTENSION, INFLAMMATION, AND VASCULAR FUNCTION

THE RENAL MEDULLA AND HYPERTENSION

MECHANISMS OF CARDIORENAL DISEASE FOLLOWING PREECLAMPSIA

NEURAL MECHANISMS OF SOUND ACTIVATION OF VESTIBULAR SYSTEM

FUNCTIONAL GENETIC EVOLUTION OF HUMAN BRAIN AND BEHAVIOR

GENETICS OF RENAL END ORGAN DAMAGE IN HYPERTENSION

UNPREDICTABLE AVAILABILITY AS A DETERMINANT OF DRUG-RELATED OUTCOMES

DESIGN OPTIMIZATION OF REDUCED-DIAMETER IMPLANTS IN SIMULATED AND CADAVER BONE

RURAL COMMUNITIES OPIOID RESPONSE PROGRAM ? MENTAL AND BEHAVIORAL HEALTH - - PROJECT TITLE: EVIDENCE-BASED TREATMENT FOR RURAL INTERVENTION COURTS (ERIC) - REQUESTED AWARD AMOUNT: $1,941,559.00 - APPLICANT ORGANIZATION NAME: UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) - APPLICANT ORGANIZATION ADDRESS: 2500 N. STATE ST., JACKSON, MS, 39216 - APPLICANT ORGANIZATION FACILITY TYPE: ACADEMIC MEDICAL CENTER - PROJECT DIRECTOR NAME AND TITLE: ANDREW VOLUSE, PH.D., ASSOCIATE PROFESSOR - PROJECT DIRECTOR CONTACT INFORMATION: PHONE: (601) 984-5818; EMAIL: AVOLUSE@UMC.EDU - DATA COORDINATOR NAME AND TITLE: TO BE HIRED - EIN/DUNS NUMBER EXCEPTION REQUEST IN ATTACHMENT 8?: NO - HOW THE APPLICANT FIRST LEARNED ABOUT THE FUNDING OPPORTUNITY: HRSA PROJECT OFFICER - NUMBER OF CONSORTIUM MEMBERS & LIST OF CONSORTIUM MEMBERS: 8 TOTAL: UMMC AND THE MISSISSIPPI ADULT FELONY DRUG INTERVENTION COURTS FOR THE 4TH, 10TH, 12TH, 14TH, 17TH, 18TH, AND 19TH JUDICIAL CIRCUITS - IS THE APPLICANT ORGANIZATION A PREVIOUS OR CURRENT RCORP AWARD RECIPIENT OR CONSORTIUM MEMBER?: NO - INDICATE IF APPLICANT ORGANIZATION INTENDS TO APPLY FOR FY22 RCORP-IMPLEMENTATION: YES - DOES THE TARGET SERVICE AREA OVERLAP WITH THE SERVICE AREAS OF THE NORTHERN BORDER REGIONAL COMMISSION, THE DELTA REGIONAL AUTHORITY, OR THE APPALACHIAN REGIONAL COMMISSION?: YES. DELTA REGIONAL AUTHORITY - RCORP-BHS TARGET SERVICE AREA O FULLY RURAL COUNTIES IN MISSISSIPPI: CLARKE; GEORGE; GREENE, JONES, KEMPER, LAUDERDALE, LEFLORE, LINCOLN, PANOLA, PERRY, PIKE, SUNFLOWER, TALLAHATCHIE, TATE, WALTHALL, WASHINGTON, WAYNE, & YALOBUSHA O PARTIALLY RURAL COUNTIES: NONE - BRIEF DESCRIPTION OF THE TARGET POPULATION: THIS PROJECT WILL PROVIDE MENTAL HEALTH SERVICES TO MISSISSIPPI ADULT FELONY DRUG INTERVENTION COURT PARTICIPANTS LIVING IN RURAL COUNTIES. ANTICIPATED DEMOGRAPHIC CHARACTERISTICS FOR THIS POPULATION ARE 23% AFRICAN AMERICAN OR BLACK, 0.5% HISPANIC, 0.2% NATIVE AMERICAN, AND 29.8% FEMALE. BRIEF SUMMARY: THIS PROPOSAL, ENTITLED EVIDENCE-BASED TREATMENT FOR RU RAL INTERVENTION COURTS (ERIC), SEEKS TO REDUCE MORBIDITY AND MORTALITY OF SUBSTANCE USE DISORDERS (SUDS) AND CO-OCCURRING MENTAL HEALTH DISORDERS (WITH PARTICULAR EMPHASIS ON POST-TRAUMATIC STRESS DISORDER) IN TARGETED HIGH NEED (I.E., SUBSTANTIAL BURDEN OF SUD AND MENTAL ILLNESS), LOW RESOURCE (I.E., SCARCITY OF MENTAL HEALTH PROVIDERS) RURAL MISSISSIPPI COUNTIES BY IMPROVING ACCESS TO EVIDENCE-BASED MENTAL HEALTH SERVICES FOR INDIVIDUALS PARTICIPATING IN THE STATE’S ADULT FELONY DRUG INTERVENTION COURT PROGRAM.

RURAL EMERGENCY MEDICAL COMMUNICATIONS DEMONSTRATION PROJECT (REMCDP)

HYPERTENSION, KIDNEY AND PREGNANCY

DEGENERIN AND TRPC6 CHANNELS IN RENAL VASCULAR MECHANOSESNSOR SIGNALING AND PROTECTION AGAINST INJURY. - ABSTRACT MECHANOSENSING IS A PROCESS INHERENT TO NEARLY ALL CELL TYPES, INCLUDING VASCULAR SMOOTH MUSCLE (VSM) CELLS WHERE PRESSURE-INDUCED VASCULAR STRETCH INITIATES A MECHANO-DEPENDENT VASOCONSTRICTION. THIS RESPONSE, TERMED PRESSURE-INDUCED CONSTRICTION, OCCURS IN NUMEROUS ORGANS INCLUDING THE KIDNEY AND SERVES AT LEAST TWO FUNCTIONS: CONTROL OF LOCAL BLOOD FLOW AND PREVENTION OF TRANSMISSION OF DAMAGING HIGH SYSTEMIC PRESSURES TO DELICATE MICROVESSELS. A LOSS OF THE PRESSURE-INDUCED CONSTRICTION RESPONSE INCREASES SUSCEPTIBILITY TO VASCULAR INJURY IN ORGANS, INCLUDING THE KIDNEY WHERE A LOSS OF THIS RESPONSE ACCELERATES PROGRESSION OF CHRONIC KIDNEY DISEASE. DESPITE THE IMPORTANCE OF THE PRESSURE-INDUCED CONSTRICTION RESPONSE, MOLECULAR MECHANISM(S) UNDERLYING ITS INITIATION REMAIN UNCLEAR. WE HAVE SHOWN THAT MEMBERS OF EPITHELIAL NA+ CHANNEL (ENAC)/DEGENERIN FAMILY OF ION CHANNELS (BENAC AND ASIC2) ARE REQUIRED FOR RENAL AFFERENT ARTERIOLAR PRESSURE- INDUCED CONSTRICTION. THE ROLE OF OTHER FAMILY MEMBERS, INCLUDING GENAC, IS UNKNOWN. TRPC6 HAS BEEN SUGGESTED TO CONTRIBUTE TO VASCULAR MECHANOSIGNALING IN CEREBRAL ARTERIES. HOWEVER, ITS ROLE IN PRESSURE-INDUCED CONSTRICTION IN RENAL AFFERENT ARTERIOLES IS UNKNOWN. WE RECENTLY FOUND THAT B AND GENAC AND ASIC2 FORM FUNCTIONAL, MECHANOACTIVATED CHANNELS WHEN EXPRESSED IN XENOPUS OOCYTES. OUR PROPOSED STUDIES ADDRESS THE HYPOTHESIS THAT B/GENAC-ASIC2 CHANNELS AND TRPC6 HAVE DIFFERENT ROLES IN VSM CELL MECHANO-SIGNALING IN RENAL AFFERENT ATHERIOLES. SPECIFICALLY, B/GENAC-ASIC2 CHANNELS MEDIATE MECHANO-RECEPTOR CURRENTS, WHEREAS TRPC6 CHANNELS CONTRIBUTE TO SIGNAL AMPLIFICATION. IN SPECIFIC AIM 1, WE WILL USE THE XENOPUS OOCYTE EXPRESSION SYSTEM TO DEFINE THE FUNCTIONAL CHARACTERISTICS OF B/GENAC-ASIC2 CHANNELS, AND DETERMINE THE MECHANISTIC ROLES OF B AND GENAC, ASIC2 AND TRPC6 IN MECHANO-RECEPTOR CURRENTS AND POST-MECHANO-RECEPTOR CA2+ SIGNALING IN RENAL AFFERENT VSM CELLS. IN SPECIFIC AIM 2, WE WILL DETERMINE THE CONTRIBUTIONS OF B AND GENAC, ASIC2 AND TRPC6 TO PRESSURE- INDUCED CONSTRICTION IN RENAL AFFERENT ARTERIOLES. IN SPECIFIC AIM 3, WE WILL DETERMINE IF VSM-SPECIFIC LOSS OF EXPRESSION OF ENAC SUBUNITS, ASIC2 OR TRPC6 CONTRIBUTES TO RENAL INJURY IN THE SETTING OF HYPERTENSION. IN SUMMARY, OUR PROPOSED STUDIES WILL DETERMINE THE MECHANISTIC ROLES OF B/GENAC-ASIC2 AND TRPC6 CHANNELS IN MECHANICAL SIGNALING AND IN PROTECTING AGAINST KIDNEY INJURY.

MECHANISMS RESPONSIBLE FOR TOOTH MORPHOGENESIS IN VERTEBRATES - ABSTRACT MISSHAPEN TEETH ARE HIGHLY COMMON IN HUMANS. IN MOST INSTANCES, THEY ARE DUE TO GENETIC MUTATIONS IN GENES CONTROLLING THE MORPHOGENESIS OF TEETH. THIS IS THE CASE FOR THE RUNX2 GENE, WHICH ONCE MUTATED LEADS TO CLEIDOCRANIAL DYSPLASIA (CCD) AN AUTOSOMAL DOMINANT GENETIC SYNDROME PRESENTING WITH PEG-LIKE TEETH IN HUMANS. WHILE MANY FACTORS HAVE BEEN IDENTIFIED IN THE PROCESS OF TOOTH MORPHOGENESIS, CURRENTLY, LITTLE IS KNOWN ABOUT HOW CELL SIGNALING PARTICIPATES IN ESTABLISHING ORGAN SHAPE DURING ODONTOGENESIS. OUR PREVIOUS WORK HAS IDENTIFIED THE SIGNALING MOLECULE RETINOIC ACID (RA) TO BE ONE OF THE MAIN ACTORS OF TOOTH INDUCTION IN FISH AND RECENT DATA SUGGEST THAT RA ALSO PLAYS A ROLE DURING TOOTH MORPHOGENESIS. FISH AND ZEBRAFISH, IN PARTICULAR, ARE GOOD MODELS TO STUDY GENETICS, CELL AND MOLECULAR BIOLOGY, AND ORGANOGENESIS OF THE TOOTH IN VERTEBRATES. THE OBJECTIVE OF THE PROPOSED STUDIES IS TO UNDERSTAND THE ROLES PLAYED BY RETINOIC ACID DURING TOOTH MORPHOGENESIS IN DIFFERENT FISH SPECIES, TO DEVELOP A FISH MODEL OF CCD, TO CLARIFY THE ROLE PLAYED BY RUNX2 DURING TOOTH MORPHOGENESIS, AND TO UNDERSTAND ITS LINK WITH RA SIGNALING. FINALLY, THIS PROJECT PROPOSES TO IDENTIFY NOVEL GENES IMPLICATED IN TOOTH MORPHOGENESIS AND TO STUDY THEIR FUNCTION BY GENE KNOCK-OUTS IN ZEBRAFISH. BY EXPOSING FISH EMBRYOS AND LARVAE TO EXOGENOUS RA AND RA INHIBITOR DURING TOOTH MORPHOGENESIS WE WILL BE ABLE TO UNDERSTAND THE MECHANISM OF ACTION OF RA SIGNALING DURING TOOTH MORPHOGENESIS IN FISH. OUR PRELIMINARY DATA IDENTIFIED THAT THE LEVELS OF RA IN DIFFERENT CELLS OF THE TOOTH GERM ARE CONTROLLED BY THE TIMING AND LEVEL OF EXPRESSION OF THE RA DEGRADING ENZYME CYP26B1 IN A SUBSET OF CELLS OF THE DEVELOPING TOOTH GERM. MODIFYING THE ONSET OF CYP26B1 EXPRESSION IN THE TOOTH GERM WILL, THEREFORE, CHANGE THE LEVEL OF RA AVAILABLE IN THE TOOTH GERM ULTIMATELY MODIFYING THE SHAPE OF THE TOOTH. WE WILL STUDY THE CIS-REGULATORY CHANGES RESPONSIBLE FOR EVOLUTIONARY CHANGES IN THE TIMING OF CYP26B1 EXPRESSION DURING TOOTH MORPHOGENESIS BETWEEN TWO CLOSELY RELATED FISH SPECIES, THE ZEBRAFISH AND THE MOUNTAIN MINNOW, THAT BEAR DRAMATICALLY DIFFERENT SHAPE OF TEETH IN ADULTS AND DURING EMBRYONIC DEVELOPMENT. WE HAVE IN HANDS THE ZEBRAFISH RUNX2B (THE ZEBRAFISH ORTHOLOG OF THE HUMAN RUNX2 GENE THAT IS EXPRESSED IN THE TOOTH GERM) LOSS-OF-FUNCTION MUTANT. THIS MUTANT WILL BE USED TO PERFORM A PHENOTYPIC ANALYSIS OF TOOTH MORPHOGENESIS AND TO UNDERSTAND THE RELATIONSHIP BETWEEN RA SIGNALING AND RUNX2 EXPRESSION DURING TOOTH MORPHOGENESIS. TO IDENTIFY NOVELS GENES PLAYING A ROLE DURING TOOTH MORPHOGENESIS, WE WILL SELECT BY CELL SORTING, TOOTH GERM CELLS EXPOSED TO EXOGENOUS RA SIGNALING AND COMPARE THEIR TRANSCRIPTOME TO CONTROL DEVELOPING TOOTH CELLS AT THE SAME DEVELOPMENTAL STAGE. THE RESULTING GENES DIFFERENTIALLY EXPRESSED WILL BE SUBJECTED TO PHENOTYPIC ANALYSIS BY GENE KNOCK-OUT USING THE CRISPR/CAS9 TECHNOLOGY. THIS WORK WILL REVEAL MORE ABOUT HOW RA AND GENES IT REGULATES, INCLUDING RUNX2, CONTROLS TOOTH MORPHOGENESIS IN DEVELOPMENT, DISEASES (CLEIDOCRANIAL DYSPLASIA) AND EVOLUTION.

POISON CONTROL STABILIZATION AND ENHANCEMENT PROGRAM

MECHANISMS OF HAEMOPHILUS INFLUENZAE PATHOGENESIS IN THE LUNG

RENAL MICROCIRCULATION AND HYPERTENSION INDUCED RENAL INJURY

DEVELOPMENT OF A NOVEL TREATMENT FOR BENZODIAZEPINE ADDICTION - BENZODIAZEPINES (BZS) ARE PRESCRIBED WIDELY AS ANXIOLYTICS AND SLEEP AIDS BUT THEIR UTILITY IS LIMITED BY UNWANTED SIDE EFFECTS SUCH AS ADDICTION LIABILITY. THIS UG3/UH3 PROPOSAL IS FOR NON-CLINICAL EFFICACY AND INVESTIGATIONAL NEW DRUG (IND) ENABLING STUDIES FOR DEVELOPING THE FIRST MEDICATION TO TREAT BZ MISUSE/USE DISORDER. BASED ON OUR PRIOR RESEARCH AND THE SUCCESS OF PARTIAL AGONIST THERAPIES FOR OTHER USE DISORDERS, WE HAVE IDENTIFIED A DRUG CANDIDATE THAT ACTS AS A MIXED EFFICACY PARTIAL POSITIVE ALLOSTERIC MODULATOR (“MIXED EFFICACY PAM”) THERAPY FOR BZ ADDICTION. THIS COMPOUND (“IMP-001”) IS A NOVEL HEMIFUMARATE SALT OF AN OFF-PATENT, ANXIOLYTIC DEVELOPMENT COMPOUND FROM MERCK THAT HAS US PATENT SUPPORT VIA THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC). THE AIMS FOR THE UG3 PHASE OF THE PROPOSAL INCLUDE (AIM 1) DETERMINATION OF BINDING TO GABAA RECEPTORS IN NATIVE RAT CNS AND FUNCTIONAL SELECTIVITY AT Α1-Α6 SUBUNIT-CONTAINING GABAA RECEPTORS FOR IMP-001, COMPARED WITH THE ACTIVE PHARMACEUTICAL INGREDIENT (API), MRK-898. WE PREDICT THAT THE PROFILE OF IMP-001 WILL REPLICATE WITH THE API, I.E., THE SALT FORMULATION WILL NOT ALTER SELECTIVE EFFICACY OR BINDING. TO COMPLETE THE UG3 PHASE, WE WILL CONDUCT NON-CLINICAL EFFICACY STUDIES (AIM 2) TO ASSESS THE ABILITY OF ORAL DOSES OF IMP-001 TO INDUCE ANXIOLYTIC AND SEDATIVE-MOTOR EFFECTS IN RATS, AND TO ALTER BZ SELF-ADMINISTRATION (WHILE NOT ALTERING FOOD SELF-ADMINISTRATION) IN MONKEYS. IF ALL EXPECTED OUTCOMES, DRIVEN BY OUR TARGET PRODUCT PROFILE (TPP), ARE MET, THEN IMP-001 WILL UNDERGO FURTHER EVALUATION AS A BZ ADDICTION THERAPY AND SAFETY/TOXICOLOGY STUDIES FOR THE UH3 PHASE. FOLLOWING SCALE-UP SYNTHESIS OF IMP-001, OUR FIRST AIM FOR THE UH3 PHASE WILL FOCUS ON ADDITIONAL TPP-BASED STUDIES IN MONKEYS AND RATS, INCLUDING ASSESSMENT OF CHRONIC TREATMENT DURING BZ SELF-ADMINISTRATION, EVALUATION OF ANXIOLYTIC POTENTIAL; AND EVALUATION OF PHYSICAL DEPENDENCE POTENTIAL. AIM 2 OF THE UH3 PHASE WILL CONSIST OF A SERIES OF NON-GLP SAFETY/TOXICOLOGY STUDIES. THESE STUDIES INCLUDE THE FOLLOWING: (1) SAFETY PHARMACOLOGY, INCLUDING OFF-TARGET ASSESSMENTS, CIPA, MITOCHONDRIAL TOXICITY, LYSOSOMAL PERTURBATION ASSAYS, (2) DRUG METABOLISM AND PK, INCLUDING PLASMA PROTEIN BINDING, HEPATOCYTE STABILITY, METABOLIC STABILITY, METABOLITE IDENTIFICATION, METABOLISM-MEDIATED DRUG INTERACTIONS (CYP INDUCTION AND INHIBITION), TRANSPORTER-MEDIATED DRUG INTERACTION (HUMAN BCRP AND MDR-1 MEDIATED TRANSPORT); AND (3) TOXICOLOGY, INCLUDING DOSE RANGE-FINDING NON- GLP ORAL STUDIES IN DOGS AND RATS. IF ALL MILESTONES FOR EFFICACY AND SAFETY ARE MET, IN AIM 3, WE WILL PURSUE A PRE-IND MEETING WITH FDA IN ORDER TO DETERMINE NEXT STEPS IN DEVELOPMENT. AIM 4 WILL CONSIST OF RECOMMENDED STUDIES BY FDA, AS WELL AS THE REQUIRED GLP STUDIES: HERG ASSAYS; RESPIRATORY TESTING IN RATS; CARDIOVASCULAR TESTING IN DOGS; ORAL, 28-DAY TOXICITY STUDY (WITH CNS SAFETY PHARMACOLOGY) IN RATS; GLP 28-DAY TOXICITY STUDIES IN BEAGLE DOGS; GLP AMES TESTING AND GLP IN VITRO GENETIC TOXICITY TESTS. BY THE PROJECT'S END, AND IF ALL ENDPOINTS ARE MET, IMP-001WILL BE SUBMITTED TO FDA FOR ASSESSMENT OF SUITABILITY FOR INITIATING FIRST-IN-HUMAN (FIH) STUDIES.

PLACENTAL ISCHEMIA, HYPERTENSION AND HEMODYANMICS

MECHANISMS INVOLVED IN THE EARLY DEVELOPMENT OF RENAL DISEASE ASSOCIATED WITH PREPUBERTAL OBESITY

RYAN WHITE TITLE IV PROGRAM

VASCULAR MECHANISMS OF INHIBITION OF SEH AS A NOVEL THERAPY FOR AD/ADRD - ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD) IS AN EMERGING GLOBAL HEALTH CARE CRISIS. HOWEVER, UNDERLYING MECHANISMS HAVE NOT BEEN UNDERSTOOD WELL ENOUGH FOR TRANSLATION TO PRECISION MEDICINE. UNDERSTANDING VASCULAR CONTRIBUTION TO AD/ADRD IS IMPERATIVE SINCE INCREASING EVIDENCE SUGGESTS AD AND DIABETIC (DM)-RELATED ADRD ARE ASSOCIATED WITH BRAIN HYPOPERFUSION, AND 67% OF AD GWAS GENES ARE EXPRESSED IN THE CEREBRAL VASCULATURE. RECENT STUDIES DEMONSTRATED THAT REDUCTION OF SOLUBLE EPOXIDE HYDROLASE (SEH) IS BENEFICIAL TO COGNITION IN AD, DM-ADRD, AND CEREBRAL HYPOPERFUSION ANIMAL MODELS DUE TO ITS ANTI- INFLAMMATORY AND NEURONAL PROTECTIVE EFFECTS, BUT VASCULAR CONTRIBUTION HAS BEEN NEGLECTED. SEH IS AN ENZYME THAT TRANSFORMS ARACHIDONIC ACID (AA)-DERIVED EETS AND LINOLEIC ACID (LA)-DERIVED EPOMES TO THEIR CORRESPONDING DIOLS DHETS AND DIHOMES, RESPECTIVELY. CHANGES IN OXYLIPINS, SUCH AS THE ELEVATED RATIO OF DHETS/EETS AND DIHOMES/EPOMES, WERE FOUND IN AD MICE AND ADRD PATIENTS. WE PRELIMINARY FOUND THAT SNPS IN GENES (CYP2J2, 2C8, 2C9) ENCODING ENZYMES THAT CATALYZE AA AND LA TO EETS AND EPOMES, AND EPHX2 ENCODING SEH ARE LINKED WITH AD IN THE ARIC-NCS. WE ALSO FOUND THAT A HIGHLY SELECTIVE SEH INHIBITOR (SEHI) TPPU REVERSED COGNITIVE DISABILITY, IMPAIRED MYOGENIC RESPONSE (MR) AND AUTOREGULATION OF CEREBRAL BLOOD FLOW (CBF), AND NEUROVASCULAR UNIT (NVU) DYSFUNCTION IN DM-ADRD AND AD RATS. MOREOVER, AD/ADRD RATS DISPLAYED BRAIN HYPOPERFUSION, ENHANCED BLOOD-BRAIN BARRIER (BBB) LEAKAGE, NEURODEGENERATION, AND REDUCED BRAIN KIR2.1 ACTIVITY THAT HAS BEEN REPORTED TO ASSOCIATE WITH REDUCED PIP2 LEVELS IN CEREBRAL CAPILLARY ENDOTHELIAL CELLS DUE TO ENHANCED PLA2 ACTIVITY. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT INHIBITION OF SEH SYNERGISTICALLY MODULATES THE PLA2-AA-EETS-DHETS AND PLA2-LA-EPOMES-DIHOMES PATHWAYS TO REVERSE COGNITIVE IMPAIRMENTS AND ENHANCE BRAIN PERFUSION BY AMELIORATING CBF AUTOREGULATION, MAINTAINING BBB AND NVU FUNCTION. WE WILL COMPARE VASCULAR FUNCTION (MR, CBF AUTOREGULATION, AND FUNCTIONAL HYPEREMIA), AD PHENOTYPES, REGIONAL BRAIN LEVELS OF PLA2, SEH, PLP2, KIR2.1, AND OXYLIPINS IN TPPU-TREATED BOTH SEXES OF DM- ADRD AND AD RATS. WE WILL ALSO COMPARE VASCULAR RESPONSES TO ISOMER MIXTURES OF EETS/DHETS, AND EPOMES/DIHOMES IN CEREBRAL ARTERIES AND ARTERIOLES, AND VASODILATION RESPONSES TO ELEVATED POTASSIUM AND ISOMER MIXTURES OF OXYLIPINS IN ARTERIOLES-CAPILLARIES ISOLATED FROM BOTH SEXES OF CONTROL, AD, AND ADRD RATS TO FURTHER EXPLORE THE SPECIFIC PATHWAYS THAT ARE AFFECTED BY INHIBITION OF SEH. THIS PROJECT WILL ADDRESS CRITICAL KNOWLEDGE GAPS OF THE VASCULAR CONTRIBUTION OF SEHI ON COGNITIVE PROTECTION AND THE “NEXT STEPS” IN EXPLAINING THE BIOLOGY OF THE CATALYTIC ACTIVITY OF THE SEH. RESULTS GENERATED FROM THIS PROPOSAL SHOULD LAY THE FOUNDATION FOR THE DISCOVERY OF NEW DRUGS TARGETING THESE PATHWAYS TO REVERSE CEREBRAL VASCULAR DYSFUNCTION TO PREVENT THE ONSET AND SLOW THE PROGRESSION OF AD/ADRD. .

EVIDENCE-BASED TELE-BEHAVIORAL HEALTH NETWORK PROGRAM

SCN5A GENE AND PROLONGED QT IN SICKLE CELL DISEASE

DENTAL FACULTY LOAN REPAYMENT

MOLECULAR DETERMINANTS OF CELL FATE IN THE INNER EAR

ADDUCIN, ACTIN CYTOSKELETON AND COGNITIVE IMPAIRMENTS

ROLE OF TGIF IN WNT-INDUCED BONE FORMATION

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

POISON CONTROL STABILIZATION AND ENHANCEMENT PROGRAM

NEURAL MECHANISMS OF ACTIVE GAZE STABILIZATION (AGS) IN MONKEYS

MISSISSIPPI PERINATAL COVID-19 REGISTRY - PERINATAL COVID-19 DATABANK PROJECT SUMMARY THE COVID-19 PANDEMIC AFFECTED MOSTLY ADULT POPULATION OVER 60 YEARS OF AGE DURING THE FIRST MONTHS OF ITS INCEPTION AROUND THE WORLD. HOWEVER, DUE TO THE RAPID SPREAD OF THE VIRUS IN THE COMMUNITY CHILDREN AND PREGNANT WOMEN WERE AFFECTED WITHIN THE FIRST YEAR OF THE PANDEMIC. THE EFFECT OF COVID-19 IN CHILDREN WAS REPORTED IN OVER TWO THOUSAND ARTICLES SINCE THE BEGINNING OF THE PANDEMIC. THE MAJORITY OF THESE ARTICLES FOCUSED ON THE CLINICAL FEATURE OF ACUTE COVID-19 ONSET IN THE PEDIATRIC POPULATION. MOREOVER, REPORTS OF COVID-19 CASES IN CHILDREN ARE GROWING STEADILY SINCE MARCH 2020 ACCORDING TO THE CDC’S MORBIDITY AND MORTALITY WEEKLY REPORT ON 6/ 2021. THE PERINATAL EXPOSURE TO SARS COV-2 IN INFANTS FROM MOTHERS DIAGNOSED WITH COVID-19 IS A TOPIC CHARACTERIZED BY CONTROVERSY AND LACK OF CLEAR UNDERSTANDING ON THE ETIOLOGY OF THE CONDITION, AND THE SHORT AND LONG TERM CONSEQUENCES. THEREFORE, THE BEST APPROACH TO UNDERSTAND THE ETIOLOGY, MANAGEMENT AND CONSEQUENCES OF COVID-19 IS TO STUDY ITS NATURAL PROGRESSION. BIRTH COHORT STUDIES PROVIDE CRITICAL INFORMATION FOR THE INVESTIGATION OF THE ORIGINS, AND NATURAL PROGRESSION OF DISEASES. THIS PROJECT PROPOSES THE DEVELOPMENT OF A SHAREABLE COMPENDIUM OF PERINATAL COVID-19 CASES FROM THE STATE OF MISSISSIPPI. THE PATIENT COHORT EXPLORER AND COVID-19 RESEARCH REGISTRY DATABASES DEVELOPED AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER WILL SERVE AS THE FOUNDATION TO BUILD A COMPENDIUM OF PERINATAL COVID-19 CASES INCLUDING MOTHER/INFANT DYADS. THIS DATABASE WILL CAPTURE CLINICAL AND DEMOGRAPHIC INFORMATION FROM MOTHER AND NEWBORNS INFANT AFFECTED BY COVID-19, AND RECEIVING MEDICAL CARE IN THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, WHICH IS THE ONLY REFERRAL CENTER FOR MATERNAL FETAL HEALTHCARE IN THE STATE. IN ADDITION, THE DATABASE WILL INCLUDE INFORMATION FROM SATELLITE CLINICS ASSOCIATED WITH THE MEDICAL CENTER, AND COVID-19 DATA FROM PUBLIC HEALTH DATASETS FROM THE MISSISSIPPI STATE DEPARTMENT OF HEALTH. THIS DATABASE WILL PROVIDE SHAREABLE DE-IDENTIFIED PATIENT INFORMATION WITH QUERY, PAIRING AND FOLLOW-UPS CAPABILITIES ON MEDICAL CONDITIONS, DIAGNOSIS, MANAGEMENT, TREATMENT AND OUTCOMES. IN ADDITION, THIS PROJECT WILL INCORPORATE AND LINK DATA FROM THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER BIOBANK MANAGEMENT SYSTEM AND THE GEOGRAPHIC INFORMATION SYSTEM PROVIDING ACCESS TO BIOLOGICAL SAMPLES AND GEOLOCATION OF COVID-19 CASES.

GENETIC TARGETS OF HYPERTENSION END ORGAN DAMAGE

PREVENTIVE MEDICINE RESIDENCY

EARLY LIFE BRAIN INFLAMMATION AND VULNERABILITY TO NEURODEGENERATION IN LATE LIFE

DIURNAL MOLECULAR RHYTHMS OF THE HUMAN HYPOTHALAMUS AND INVOLVEMENT IN BIPOLAR DISORDER - PROJECT SUMMARY ACCUMULATING EVIDENCE SUPPORTS THE INVOLVEMENT OF CIRCADIAN RHYTHM DYSFUNCTION IN BIPOLAR DISORDER (BD). THERE IS CURRENTLY A CRITICAL NEED FOR IDENTIFYING THE NEUROPATHOLOGICAL CORRELATES OF CIRCADIAN DYSFUNCTION IN HUMAN SUBJECTS WITH BD, AND LINKING THESE CORRELATES TO FUNCTIONAL CONSEQUENCES. WE FOCUS ON THE SUPRACHIASMATIC NUCLEUS (SCN), THE MASTER CLOCK OF MAMMALIAN ORGANISMS, AND ITS MAJOR OUTPUT AREA THE PARAVENTRICULAR NUCLEUS (PVN), A REGION CRITICALLY INVOLVED IN THE REGULATION OF STRESS AND ANXIETY. OUR PRELIMINARY DATA SHOWING DECREASED EXPRESSION OF SOMATOSTATIN AND THE CLOCK PROTEIN PERIOD 2 IN THE SCN INDICATE IMPAIRED SCN MOLECULAR CLOCK RHYTHMS IN BD. FURTHERMORE, DECREASED PERIOD 2 ALONG WITH INCREASED EXPRESSION OF THE STRESS SIGNALING MOLECULE CORTICOTROPIN RELEASING FACTOR IN THE PVN DURING THE MORNING IN SUBJECTS WITH BIPOLAR DISORDER SUGGESTS THAT WEAKER SCN RHYTHMS IMPACT DOWNSTREAM STRESS SIGNALING, COINCIDING WITH THE ESTABLISHED INCREASE IN SEVERITY OF ANXIETY AND DEPRESSION AND INCREASED CORTISOL AT THIS TIME OF DAY. STUDIES IN NOCTURNAL RODENTS HAVE PROVIDED INSIGHT INTO HOW THE SCN AND PVN ARE INVOLVED IN REGULATING STRESS AND MOOD, SUGGESTING THAT DISRUPTED SCN MOLECULAR CLOCK RHYTHMS CAN ALTER EXPRESSION RHYTHMS OF CLOCK MOLECULES AND STRESS RESPONSE MOLECULES IN REGIONS INVOLVED IN MOOD REGULATION. OUR PRELIMINARY EVIDENCE SUGGESTING WEAKENED MOLECULAR CLOCK RHYTHMS IN THE SCN OF SUBJECTS WITH BD SUPPORTS THIS HYPOTHESIS. THERE IS CURRENTLY A LACK OF INFORMATION REGARDING THE CELL SPECIFIC EXPRESSION RHYTHMS OF NEUROPEPTIDES AND CLOCK MOLECULES, AND THEIR ASSOCIATION WITH STRESS RESPONSE MOLECULES IN THESE REGIONS IN HUMANS. THE PROPOSED STUDIES WILL ESTABLISH THE FOUNDATION NECESSARY TO TEST OUR OVERARCHING HYPOTHESIS THAT ALTERED MOLECULAR CLOCK RHYTHMS IN THE SCN IN BD ARE ASSOCIATED WITH ALTERED CLOCK RHYTHMS AND INCREASED EXPRESSION OF STRESS RESPONSE MOLECULES IN DOWNSTREAM REGIONS INVOLVED IN STRESS RESPONSE AND MOOD REGULATION. WE WILL TEST THE HYPOTHESES THAT I) EXPRESSION OF CLOCK MOLECULES, NEUROPEPTIDES, AND CORTICOTROPIN RELEASING FACTOR FOLLOW DIURNAL RHYTHMS OF EXPRESSION IN THE HUMAN SCN AND PVN II) SCN AND PVN MOLECULAR RHYTHMS ARE DISRUPTED IN SUBJECTS WITH BD, ASSOCIATED WITH ALTERED EXPRESSION OF MOLECULES IMPLICATED IN GENOME WIDE ASSOCIATION STUDIES.

MISSISSIPPI CANCER REGISTRY - NPCR

HORIZONTAL GENETIC TRANSFER IN STRAPHYLOCOCI

NURSE EDUCATION, PRACTICE, QUALITY, AND RETENTION - INTERPROFESSIONAL COLLBORATIVE PRACTICE

ENDOTHELIAL PHD2 IN HYPERTENSIVE VASCULAR REMODELING - SUMMARY: ARTERIAL STIFFNESS IS THE CENTER FEATURE OF HYPERTENSION AND HAS SIGNIFICANT IMPACT UPON DISEASE ETIOLOGY AND OUTCOMES. SO FAR, THERE IS NO CURE FOR HYPERTENSIVE ARTERIAL STIFFNESS. THEREFORE, IT IS URGENT TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS THAT CAN REDUCE HYPERTENSIVE ARTERIAL STIFFNESS. EMERGING EVIDENCE INDICATES THAT PERICYTE IS A NOVEL TARGET OF ANGIOGENESIS AND VASCULAR REMODELING. PERICYTES ARE A SUBPOPULATION OF MESENCHYMAL STEM CELLS WHICH CAN DIFFERENTIATE INTO OSTEOBLASTS, VASCULAR SMOOTH MUSCLE CELLS (VSMCS) AND FIBROBLASTS. PERICYTES PROMOTES FIBROSIS FORMATION VIA PERICYTE-(MYO)-FIBROBLAST TRANSITION (PFT). PERICYTE ALSO HAS BEEN SHOWN TO DIFFERENTIATE INTO VSMCS AT ARTERIAL REMODELING ZONES IN THE HEART. OUR RECENT STUDY FOUND THAT DELETION OF OXYGEN SENSOR PROLYL HYDROXYLASE-2 (PHD2) IN THE ENDOTHELIUM RESULTED IN EXCESSIVE PERICYTE RECRUITMENT AND ARTERIAL STIFFNESS, AND EXACERBATION OF ANGIOTENSIN II (ANG-II)-INDUCED HYPERTENSION. KNOCKOUT OF ENDOTHELIAL PHD2 CAUSED AN IMBALANCED ARGINASE-2/ENOS FAVORING IN ARGINASE-2. FURTHERMORE, KNOCKOUT OF ENDOTHELIAL PHD2 SIGNIFICANTLY INCREASED OSTEOGENIC DIFFERENTIATION MARKERS (SOX9, BMP2 AND OSTEOPONTIN) IN THE AORTA AND PROMOTED VSMC CALCIFICATION. USING NG2 PERICYTE TRACING REPORTER NG2DSREDBAC MICE, OUR PRELIMINARY STUDY FURTHER SUGGESTED AN IMPORTANT ROLE OF NG2+ PERICYTE IN ANG-II MEDIATING VASCULAR REMODELING. BASED ON OUR FINDINGS, WE HYPOTHESIZE THAT DEACTIVATION OF PHD2 IN EC ENHANCES ARTERIAL STIFFNESS AND HYPERTENSION BY THE MECHANISMS INVOLVING AN IMBALANCED ARGINASE-2/ENOS AND PERICYTE DIFFERENTIATION INTO VSMCS, OSTEOGENIC CELLS AND FIBROBLASTS VIA HIF-2A-PFKFB3 SIGNALING PATHWAY. TWO SPECIFIC AIMS WILL BE PROPOSED TO TEST: AIM 1: TO DEFINE THE MOLECULAR MECHANISMS BY WHICH ENDOTHELIAL PHD2 REGULATES ARTERIAL STIFFNESS WITH A FOCUS ON AN IMBALANCED ARGINASE-2/ENOS. WE WILL DETERMINE: (I) WHETHER DEFICIENCY OF ENDOTHELIAL PHD2 INDUCES AN IMBALANCED ARGINASE-2/ENOS VIA HIF-2A-PFKFB3 SIGNALING PATHWAY, (II) WHETHER PHARMACOLOGIC BLOCKADE OF HIF-2A USING A CLINIC RELEVANT AND HIGHLY SPECIFIC INHIBITOR PT2385 ATTENUATES PFKFB3 EXPRESSION, RESTORES ARGINASE-2/ENOS BALANCES AND REDUCES ANG-II-INDUCED ARTERIAL STIFFNESS IN PHD2ECKO MICE; AND (3) WHETHER KNOCKOUT OF ARGINASE-2 REDUCES VASCULAR REMODELING AND ARTERIAL STIFFNESS IN PHD2ECKO MICE. AIM 2: TO DEFINE THE ROLE OF PHD2- PFKFB3 IN MEDIATING PERICYTE DIFFERENTIATION AND HYPERTENSIVE ARTERIAL STIFFNESS. USING PERICYTE TRACING REPORTER NG2DSREDBAC (TG) MICE CROSSING WITH PHD2ECKO MICE, WE WILL TEST WHETHER INHIBITION OF PFKFB3 ATTENUATES OSTEOGENIC DIFFERENTIATION OF PERICYTES, AND REDUCES VASCULAR CALCIFICATION. WE WILL FURTHER DETERMINE WHETHER PHARMACOLOGICAL ACTIVATION OF PHD2 OR INHIBITION OF PFKFB3 ATTENUATES ANG- II-INDUCED PERICYTE-FIBROBLAST/VSMC TRANSITION, ARTERIAL STIFFNESS AND HYPERTENSIVE VASCULAR REMODELING. OUR STUDY HAS CLINICAL TRANSLATIONAL SIGNIFICANCE FOR THE UNDERSTANDING OF PERICYTES IN VASCULAR STIFFNESS.

PREVENTIVE MEDICINE RESIDENCIES

POSTDOCTORAL TRAINING IN GENERAL, PEDIATRIC AND PUBLIC HEALTH DENTISTRY AND DENTAL HYGIENE

NUCLEAR BODIES AND RIBONUCLEOPROTEIN BIOGENESIS

MIRNA-MEDIATED STROMAL CELL SURVIVAL UNDER STRESS SUPPORTS BREAST CANCER GROWTH

SEX DIFFERENCES IN HYPERTENSION, COGNITIVE FUNCTION AND RENAL HEMODYNAMICS; A ROLE FOR B CELLS AND AUTOANTIBODIES - PREECLAMPSIA (PE) A DISEASE ESTIMATED TO AFFECT 12% OF DELIVERIES AT UNIVERSITY OF MISSISSIPPI MEDICAL CENTER. THE INCIDENCE OF PE DELIVERIES INCREASED SIGNIFICANTLY AT OUR HOSPITAL DUE TO THE COVID-19 PANDEMIC. THE RATE OF PE AT UMMC ROSE FROM 12% TO 28% IN DECEMBER OF 2020 AND WAS UP TO 42 % IN APRIL OF 2021. PE IS CHARACTERIZED BY PLACENTAL ISCHEMIA, INFLAMMATION, ENDOTHELIAL DYSFUNCTION, VASOCONSTRICTION, HYPERTENSION (HTN), IUGR AND DEVELOPMENTAL ORIGINS OF HTN IN THE OFFSPRING. WE HAVE SHOWN THAT AGONISTIC AUTOANTIBODIES TO THE ANGIOTENSIN II TYPE I RECEPTOR (AT1-AA) STIMULATE TO CAUSE PLACENTAL AND CEREBRAL DYSFUNCTION CONTRIBUTING TO HTN IN PREGNANT RATS WHICH IS ATTENUATED BY BLOCKADE OF THE AT1-AA WITH THE PEPTIDE ‘N7AAC’. ONE IMPORTANT UNANSWERED QUESTION IN PE RESEARCH IS THE RELATIVE IMPORTANCE OF B CELLS SECRETING AT1-AA TO CAUSE HTN AND CEREBRAL DYSFUNCTION IN THE PREGNANT MOM OR TO CAUSE ADULT HTN IN HER OFFSPRING. A SECOND IMPORTANT UNANSWERED QUESTION IS DOES THE SEX OF THE BABY CORRELATE WITH IMMUNE CELL (B CELL) ACTIVATION, LEVEL OF AT1-AA AND HTN DURING PREGNANCY OR IN ADULT OFFSPRING. MOREOVER, WE DON’T KNOW THE ROLE OF B CELLS TO SECRETE THE AT1-AA AS MECHANISMS OF A PE PHENOTYPE IN PREGNANT PATIENTS WITH A HISTORY (HX) OF COVID 19 INFECTION. OUR PRELIMINARY DATA SUPPORTING AIM 1 ARE THAT AT1-AA ARE ELEVATED IN RESPONSE TO PE AND IN NORMAL PREGNANT ADOPTIVE TRANSFER RECIPIENTS OF PE B CELLS. IN ADDITION, WE SHOW THAT POSTPARTUM (PP) AT1-AA INDUCED HYPERTENSIVE PREGNANT RATS EXHIBIT CEREBROVASCULAR DYSFUNCTION 4 MONTHS PP. PRELIMINARY DATA SUPPORTING AIM 2 IS THAT ADOPTIVE TRANSFER OF PE B CELLS CAUSE HTN AND AT1-AA IN PREGNANT ATHYMIC NUDE RECIPIENT RATS. PRELIMINARY DATA SUPPORTING AIM 3 IS THAT AT1-AA IS PRODUCED IN PREGNANT WOMEN WITH HTN AND A HISTORY (HX) OF COVID DURING PREGNANCY AND THAT ADOPTIVE TRANSFER OF B CELLS FROM PE WOMEN WITH A COVID 19 HX DURING PREGNANCY INCREASES BLOOD PRESSURE AND AT1-AA IN PREGNANT NUDE ATHYMIC RECIPIENT RATS COMPARED TO B CELLS FROM NORMOTENSIVE WOMEN WITH A HX OF COVID DURING PREGNANCY. BASED ON OUR FINDINGS, WE HYPOTHESIZE THAT PE STIMULATED B CELLS SECRETING AT1- AA CAUSE CEREBRAL DYSFUNCTION AND HTN DURING PREGNANCY AND PROGRAMMING OF HTN IN ADULT MALE AND FEMALE OFFSPRING WHICH COULD BE ATTENUATED BY AT1-AA BLOCKADE. MOREOVER, WE HYPOTHESIZE THAT A COVID 19 HX DURING PREGNANCY RESULTS IN AT1-AA THAT CAUSES A PE PHENOTYPE DURING PREGNANCY WHICH COULD BE ATTENUATED WITH AT1- AA BLOCKADE. SPECIFIC AIM 1. TO TEST THE HYPOTHESIS THAT PERINATAL AT1-AA RESULTS HTN, CEREBROVASCULAR DYSFUNCTION AND COGNITIVE DECLINE IN THE DAM AND IN ADULT MALE OR FEMALE OFFSPRING. SPECIFIC AIM 2. TO TEST THE HYPOTHESIS THAT B2 CELLS SECRETING AT1-AA FROM PE WOMEN CAUSE CEREBRAL DYSFUNCTION AND HTN DURING PREGNANCY AND IN ADULT MALE AND FEMALE OFFSPRING. DOES SEX OF THE BABY INFLUENCE THE ACTIVATION OF THE PLACENTAL B2 CELLS AND LEVELS OF AT1-AA FROM PE WOMEN? SPECIFIC AIM 3. TO TEST THE HYPOTHESIS THAT B2 CELLS FROM PE+COVID-19 HX PATIENTS CAUSE AT1AA, CEREBRAL DYSFUNCTION, IUGR, AND HTN RECIPIENT PREGNANT RATS. DOES SEX OF THE BABY INFLUENCE THE ACTIVATION OF THE PLACENTAL B2 CELLS AND LEVELS OF AT1-AA FROM PE WOMEN?

THE AKT-ASSOCIATED MICRORNAS IN CANCER CELLS

MICROCIRCULATION IN HEALTH AND DISEASE

MECHANISMS OF VASCULAR DYSFUNCTION IN DIET-INDUCED OBESITY

AFFORDABLE CARE ACT: NURSE MANAGED HEALTH CLINICS

DELAY DISCOUNTING AND THE CHOICE TO TAKE A DRUG

STAPH KERATITIS: MECHANISM AND ARREST OF OCULAR DAMAGE

HEALTH DISPARITIES AND CVD: ADMIXTURE MAPPING IN THE JACKSON HEART STUDY

BLOOD PRESSURE, RENAL HEMODYNAMICS, AND INFLAMMATION

ETHANOL INDUCED BRAIN INJURY IS DECREASED BY INHIBITING TIEG2 MEDIATED CELL DEATH

ENHANCING STI AND SEXUAL HEALTH CLINIC INFRASTRUCTURE (ESSHCI)

IMPLEMENTATION OF A PERINATAL TO PRESCHOOL (P2P) BEHAVIORAL HEALTH CONTINUUM - MISSISSIPPI PERINATAL TO PRESCHOOL (P2P) BEHAVIORAL HEALTH PROJECT THIS PROPOSED PROJECT IMPACTS (1) PREGNANT MOTHERS AND FATHERS AT-RISK FOR OR WHO EXPERIENCE HIGH-RISK TERM AND PRE-TERM PREGNANCIES AND RESULTING IN (2) INFANTS BEING CARED FOR IN THE NEONATAL INTENSIVE CARE UNIT (NICU) AT THE CHILDREN’S HOSPITAL OF MISSISSIPPI AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) AND ONE ADDITIONAL LEVEL III NICU MANAGED BY UMMC: MEMORIAL HOSPITAL GULFPORT (MHG). OUR PROPOSAL ESTABLISHES THE UMMC PERINATAL MENTAL HEALTH PROGRAM TO MEET THE MENTAL HEALTH NEEDS OF CAREGIVERS AND THEIR CHILDREN. BROADLY, MISSISSIPPI MOTHERS REPORT POORER MENTAL HEALTH FUNCTIONING COMPARED TO THE REST OF THE NATION AND THIS RISK IS HIGHER IN WOMEN WHO DELIVER PREMATURELY OR EXPERIENCE BIRTHING TRAUMAS. MISSISSIPPI MOTHERS LACK ACCESS TO EVIDENCE-BASED PERINATAL MENTAL HEALTHCARE AS ONLY 10 THERAPISTS EXIST WITH PERINATAL MENTAL HEALTH EXPERTISE. MOREOVER, HIGH-RISK INFANTS SERVED AT UMMC REPRESENT A BROAD SPECTRUM OF HEALTH CONDITIONS EACH CONVEYING RISK FOR MYRIAD SUBSEQUENT MENTAL/BEHAVIORAL HEALTH AND/OR DEVELOPMENTAL OUTCOMES. SINCE 2018, OUR TEAM HAS SUCCESSFULLY IMPLEMENTED A BEHAVIORAL HEALTH CONTINUUM FOR HIGH-RISK INFANTS AND THEIR CAREGIVERS THROUGH OUR BEHAVIORAL HEALTH IN INFANTS AND PRESCHOOLERS (BEHIP) PROGRAM, BUT WE HAVE A NEED TO EXPAND SERVICES BECAUSE THE BEHIP PROGRAM IS ONLY AVAILABLE AT UMMC’S MAIN CAMPUS. PROVIDING MENTAL HEALTH SUPPORT ALONG A CONTINUUM OF CARE FOR CAREGIVERS OF THESE HIGH-RISK CHILDREN BEFORE AND AFTER DELIVERY, AND INTO THEIR COMMUNITIES AS THEY DEVELOP IS CRITICAL TO OPTIMIZING HEALTH, MENTAL HEALTH AND DEVELOPMENTAL OUTCOMES. THE PROPOSED PROGRAM OF CARE FOR MISSISSIPPI’S HIGH-RISK TERM AND PRE-TERM INFANTS WILL ENSURE THAT THIS POPULATION HAS ACCESS TO A CONTINUUM OF MENTAL HEALTH SERVICES (PROMOTION, PREVENTION, ASSESSMENT, AND INTERVENTION) BEGINNING PRENATALLY, AT UMMC’S NICU, EXTENDING TO THE NICU FOLLOW UP CLINIC, AND TO THE COMMUNITIES WHERE FAMILIES RESIDE, INCLUDING EXPANDED SERVICES TO THE MS GULF COAST TO MEET THE NEEDS OF YOUNG CHILDREN AND THEIR FAMILIES ACROSS THE STATE. THE PERINATAL TO PRESCHOOL (P2P) PROGRAM WILL ESTABLISH THE FIRST PERINATAL MENTAL HEALTH PROGRAM IN THE STATE AND WILL INCREASE STATEWIDE CAPACITY TO DELIVER EVIDENCED-BASED SERVICES TO CAREGIVERS AND THEIR CHILDREN PRENATALLY AND AS THEY DEVELOP IN THEIR COMMUNITIES. WE WILL CONDUCT MATERNAL PRE/POST-NATAL AND INFANT SCREENINGS (ANNUALLY 560) AND INFANT DEVELOPMENTAL EVALUATIONS (260), PROVIDE INTERVENTION TO CAREGIVERS (45) AND CHILDREN USING EVIDENCE-BASED INTERVENTIONS (160), PROVIDE PROMOTION AND PREVENTION TRAININGS USING CARE (75), AND TRAIN COMMUNITY PROVIDERS IN PCIT (25) WHO WILL FURTHER REACH ADDITIONAL CHILDREN IN THEIR COMMUNITIES ACROSS THE STATE. OVERALL, THIS PROPOSAL FILLS CRITICAL GAPS IN OUR MENTAL HEALTH WORKFORCE AND SYSTEM OF CARE. THE PROPOSED PROGRAM IS SYNERGISTIC WITH AND WILL SUPPORT KEY GROWTH AND DEVELOPMENT IN GRANTS AT UMMC, BUT DOES NOT DUPLICATE EFFORTS. IT ENSURES THE VALUABLE DATA OBTAINED WILL RESULT IN SUSTAINABLE STATEWIDE INFANT/CHILD MENTAL HEALTH CARE CAPACITY.

SIGNALING INTERPLAY UNDERLYING PROSTATE CANCER RACIAL DISPARITY

3D SPHEROID MODEL OF ADIPOSE PATHOPHYSIOLOGY

A PROPOSAL TO ESTABLISH THE MISSISSIPPI VIOLENCE INJURY PREVENTION (VIP) PROGRAM - PROJECT SUMMARY/ABSTRACT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC), IN PARTNERSHIP WITH FOUR WELL-ESTABLISHED COMMUNITY GROUPS—PEOPLE’S ADVOCACY INSTITUTE, STRONG ARMS OF JXN, OPERATION GOOD, AND THE MISSISSIPPI PUBLIC HEALTH INSTITUTE—PROPOSE TO PARTICIPATE IN THE COMMUNITY LEVEL INTERVENTIONS FOR FIREARM AND RELATED VIOLENCE, INJURY AND MORTALITY PREVENTION (CLIF-VP) RESEARCH NETWORK BY ESTABLISHING THE MISSISSIPPI VIOLENCE INJURY PREVENTION (VIP) PROGRAM. TOGETHER, INDIVIDUAL TEAM MEMBERS REPRESENT COMMUNITY ACTIVISTS AND SEVERAL ACADEMIC DISCIPLINES, INCLUDING EMERGENCY MEDICINE, PSYCHOLOGY, PUBLIC HEALTH, SURVEY RESEARCH, GIS AND REMOTE SENSING, LAW, AND NURSING. MISSISSIPPI HAD THE NATION’S HIGHEST FIREARM MORTALITY RATE IN 2020 AT 28.6 PER 100,000 RESIDENTS. JACKSON, THE STATE’S CAPITAL, HAD A 2021 HOMICIDE RATE OF 97.6 PER 100,000 RESIDENTS, MORE THAN THREE TIMES HIGHER THAN THE STATE AND 15 TIMES HIGHER THAN THE NATIONAL RATE OF 6.5 MURDERS PER 100,000 RESIDENTS. UMMC, WHICH IS THE ONLY LEVEL 1 TRAUMA CENTER IN THE STATE, ADMINISTERED CARE TO 1,129 PATIENTS PRESENTING WITH INJURIES FROM FIREARMS OR RELATED VIOLENCE. AS PART OF THE CLIF-VP RESEARCH NETWORK, THE MISSISSIPPI VIP PROGRAM WILL WORK CLOSELY WITH ITS COORDINATING CENTER, THE OTHER RESEARCH PROJECTS FUNDED THROUGH THIS AGREEMENT, THE CLIF-VP RESEARCH NETWORK’S STAKEHOLDER BOARD(S), STEERING COMMITTEE, AND WORKGROUPS TO SUCCESSFULLY CARRY OUT CROSS-PROJECT ACTIVITIES. THE MISSISSIPPI VIP PROGRAM’S RESEARCH DESIGN INCLUDES A TWO-YEAR PLANNING (UG3) PHASE AND A THREE- YEAR IMPLEMENTATION (UH3) PHASE. TWO SPECIFIC AIMS HAVE BEEN IDENTIFIED FOR THE UG3 PHASE: (1) DEFINE AND CREATE THE MACHINERY TO LONGITUDINALLY MONITOR THE COMMUNITY-LEVEL SOCIAL DETERMINANTS OF FIREARM INJURY IN THE GREATER JACKSON, MISSISSIPPI METROPOLITAN AREA WITH RESPECT TO (A) PERCEIVED NEEDS, (B) AVAILABLE RESOURCES AND THEIR UTILIZATION, AND (C) OPPORTUNITIES FOR CAPACITY BUILDING; AND (2) IDENTIFY PRINCIPAL COMMUNITY-SPECIFIC RISK ELEMENTS FOR (A) FIREARM INJURY, (B) SUBOPTIMAL FUNCTIONAL RECOVERY, AND (C) RETALIATION AND REINJURY, AND COLLABORATIVELY DEVELOP LINKED COMMUNITY- AND HOSPITAL-BASED PROTECTIVE RESOURCES TO ADDRESS THESE RISKS. TWO SPECIFIC AIMS HAVE BEEN IDENTIFIED FOR THE UH3 PHASE: (1) CONDUCT A CLINICAL TRIAL THAT IMPLEMENTS OPTIMIZED COMMUNITY-FOCUSED INTERVENTIONS DURING THE UG3 PHASE USING A STEP-WEDGE CLUSTER APPROACH, AND MEASURES LONGITUDINAL COMMUNITY AND INDIVIDUAL IMPACT OF VIOLENCE PREVENTION INTERVENTIONS ON (A) INCIDENCE OF FIREARM INJURY, (B) FUNCTIONAL VICTIM RECOVERY, (C) INCIDENCE OF RETALIATION AND REINJURY, AND (D) ECONOMIC IMPACT; AND (2) COORDINATE ONGOING COMMUNITY, REGIONAL, AND TELEHEALTH EXPANSION AND ADOPTION OF OPTIMIZED COMMUNITY-FOCUSED RESOURCES IN CONCERT WITH THE CLIF-VP RESEARCH NETWORK.

HYPERTENSION IN ADULT IUGR OFFSPRING: BENEFICIAL EFFECTS OF PERINATAL INTERVENTION

MODEL STATE-SUPPORTED AREA HEALTH EDUCATION CENTERS

NURSE EDUCATION PRACTICE AND RETENTION

MECHANISMS OF CHANGE, MOTIVATION, AND TREATMENT OUTCOME IN AD-PTSD

REGULATION OF SUPEROXIDE PRODUCTION BY THE MACULA DENSA DURING TGF

SURVEILLANCE, PREVENTION, AND EDUCATION EFFORTS FOR SOIL TRANSMITTED HELMINTH HOOKWORM NECATOR AMERICANUS INFECTION IN CHILDREN FROM HIGH RISK COUNTIES IN MISSISSIPPI

SEROTONIN, CORPUS CALLOSUM, AND AUTISM

ADIPOSITY, INFLAMMATION AND NEUROCOGNITIVE DECLINE IN AFRICAN AMERICANS

STREPTOCOCCUS PNEUMONIAE OCULAR PATHOGENESIS AND THERAPY

CHILDRENS' OF MISSISSIPPI NEONATAL RESEARCH GROUP - THIS APPLICATION STRONGLY SUPPORTS THE MISSISSIPPI STATE'S ONLY ACADEMIC LEVEL IV NEWBORN FACILITY, THE CHILDREN'S OF MISSISSIPPI NEWBORN INTENSIVE CARE UNIT (NICU) AT THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC)'S CANDIDACY AS A CLINICAL CENTER BY THE NICHD NEONATAL RESEARCH NETWORK (NRN). WE WORK TO IMPROVE THE LIFE OF MISSISSIPPI CHILDREN BY PROVIDING EXCEPTIONAL PATIENT CARE, TRAINING THE NEXT GENERATION OF HEALTHCARE PROVIDERS, AND ENGAGING IN INNOVATIVE RESEARCH TO ACHIEVE THE VISION OF UMMC TO IMPROVE MISSISSIPPIAN'S HEALTH OUTCOMES AND ELIMINATE HEALTH CARE DISPARITIES. RESEARCHERS IN THE NEWBORN DIVISION ARE CONTRIBUTING BY PERFORMING INNOVATIVE, DEFINITIVE, RIGOROUS, AND REPRODUCIBLE TRANSLATION, SINGLE AND MULTI-SITE CLINICAL, AND COMMUNITY INTERVENTIONS RESEARCH FOCUSED ON IMPROVING NEWBORN HEALTH TO REDUCE THE GAP BETWEEN “BENCH TO BEDSIDE TO COUNTRYSIDE” RESEARCH. THE NEWBORN CENTER AT THE UMMC IS EXCEPTIONALLY WELL POSITIONED TO BE SELECTED FOR THE FOLLOWING REASONS. 1) WE SERVE A VERY HIGH-RISK AND UNDERSERVED POPULATION, THE MAJORITY WITH LOW SOCIOECONOMIC STATUS AND PUBLIC INSURANCE FROM URBAN AND RURAL AREAS WITH HIGH REPRESENTATION OF RACIAL/ETHNIC MINORITIES FACING HEALTH DISPARITIES. 2) MISSISSIPPI HAS SOME OF THE HIGHEST RATES OF MATERNAL HYPERTENSION, PREECLAMPSIA, OBESITY, METABOLIC DISORDERS, PRETERM BIRTH, LOW BIRTH WEIGHT, AND CONGENITALLY LINKED BEHAVIORAL DISORDERS, SUCH AS AUTISM IN THE USA. 3) THE CENTER FOR MATERNAL AND FETAL CARE AT UMMC, THE ONLY QUATERNARY CENTER FOR ADVANCED FETAL CARE IN THE STATE, MANAGES AROUND 3,000 DELIVERIES EACH YEAR, OF WHICH 75% ARE CONSIDERED HIGH RISK. 4) ABOUT 1000 NICU ADMISSIONS PER YEAR, OF WHICH ALMOST 160 ARE BORN LESS THAN 29 WEEKS OF GESTATION, AND ABOUT 70% ARE INBORN. 5) THE DIVISION OF NEWBORN MEDICINE HAS A WELL-ORGANIZED CLINICAL RESEARCH INFRASTRUCTURE WITH A SUCCESSFUL TRACK RECORD OF PARTICIPATION IN MULTI-CENTER NIH, INDUSTRY-SPONSORED, AND INVESTIGATOR-INITIATED CLINICAL TRIALS IN NEWBORNS. 6) THE DIVISION HAS CONSISTENTLY BEEN THE HIGHEST STUDY SUBJECT RECRUITING SITE IN MANY MULTI-CENTER CLINICAL TRIALS. THIS SUCCESS IS ATTRIBUTABLE TO THE STRONG RESEARCH CULTURE AND A UNIQUE SYSTEM OF ROUND-THE-CLOCK AVAILABILITY OF DEDICATED RESEARCH COORDINATORS, INCLUDING AFTER- HOURS AND WEEKENDS. THIS IS AN EXCEPTIONAL STRENGTH OF OUR PROGRAM. 7) THE INSTITUTION MAINTAINS A LONG- STANDING MULTIDISCIPLINARY NEWBORN FOLLOW-UP PROGRAM THAT SERVES THE ENTIRE STATE. 8) THE DIVISION OF NEWBORN MEDICINE HAS CONSISTENTLY RECEIVED INSTITUTIONAL SUPPORT. IT HAS A LONG-STANDING HISTORY OF COLLABORATION WITH OTHER INSTITUTIONAL CENTERS/DEPARTMENTS WITH NIH-FUNDED PROGRAMS. IF SELECTED, WE WILL BE FULLY COMMITTED TO PARTICIPATING IN ALL NETWORK STUDIES UNLESS THEY DO NOT HAVE THE RELEVANT ELIGIBLE POPULATION. WE AGREE TO PRIORITIZE NETWORK STUDIES OVER OTHER STUDIES, INCLUDING OTHER NIH- FUNDED STUDIES, FOR SUBJECT RECRUITMENT AT OUR CENTER.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION

SUD TREATMENT EXPANSION IN MISSISSIPPI (STEM) - THIS PROPOSAL, ENTITLED SUD TREATMENT EXPANSION IN MISSISSIPPI (STEM), SEEKS TO REDUCE RECIDIVISM AS WELL AS MORBIDITY AND MORTALITY OF SUBSTANCE USE DISORDERS (SUDS) AND CO-OCCURRING MENTAL HEALTH DISORDERS (WITH PARTICULAR EMPHASIS ON POST-TRAUMATIC STRESS DISORDER [PTSD]) IN A TARGETED HIGH-NEED (I.E., SUBSTANTIAL BURDEN OF SUDS AND MENTAL ILLNESS), LOW-RESOURCE (I.E., SCARCITY OF MENTAL HEALTH PROVIDERS) ADULT FELONY DRUG COURT IN MISSISSIPPI. THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER'S DEPARTMENT OF PSYCHIATRY AND HUMAN BEHAVIOR WILL PARTNER WITH THE 2ND CIRCUIT DRUG INTERVENTION COURT OF MISSISSIPPI WHOSE 133 PARTICIPANTS ARE MOSTLY MALE (58%) AND WHITE (69%), WITH THE AVERAGE AGE BEING 37 YEARS OLD. THE DRUG COURT’S CATCHMENT AREA HAS AN AVERAGE OF 17.3% OF ITS CITIZENS LIVING AT OR BELOW THE POVERTY LEVEL AND THE AVERAGE RATIO OF CITIZENS TO MENTAL HEALTH PROVIDER IS 1,787:1. IMPORTANTLY, THE DRUG COURT’S JURISDICTION INCLUDES THE COUNTY RANKED HIGHEST IN THE STATE FOR NUMBER OF SUSPECTED OVERDOSE DEATHS AND NUMBER OF NALOXONE ADMINISTRATIONS PERFORMED BY EMERGENCY MEDICAL SERVICES. FINALLY, 54% OF THE CURRENT PARTICIPANTS IN THE 2ND CIRCUIT DRUG COURT ARE UNINSURED. INTERVENTIONS AND STRATEGIES TO ADDRESS NEEDS INCLUDE PROVIDING NO COST, EVIDENCED-BASED PSYCHOTHERAPY EXCLUSIVELY VIA TELEHEALTH AS WELL AS INCREASING ACCESS TO MEDICATIONS FOR OPIOID USE DISORDERS (MOUD) AND SCREENINGS FOR INFECTIOUS DISEASES. THE SPECIFIC GOALS (AND OBJECTIVES) OF THE STEM PROJECT INCLUDE THE FOLLOWING: (A) INCREASE SCREENING FOR SUDS AND PTSD AS WELL AS OTHER COMORBID MENTAL HEALTH DISORDERS USING EMPIRICALLY VALIDATED MEASURES (≥75% OF NEWLY ELIGIBLE PARTICIPANTS WILL BE SCREENED FOR ENROLLMENT INTO THE STEM PROGRAM), (B) PROVIDE EVIDENCED-BASED, NO-COST, TIMELY INDIVIDUAL SUDS AND PTSD TREATMENT VIA TELEHEALTH (≥90% OF ALL FIRST TREATMENT SESSIONS WILL OCCUR WITHIN 2 WEEKS OF THE INITIAL SCREENING; ≥80% OF ENROLLED PARTICIPANTS WILL RECEIVE AN ADEQUATE DOSE OF EVIDENCED-BASED TREATMENT), (C) DELIVER EVIDENCE-BASED TELEHEALTH GROUPS (≥ 1 TELEHEALTH GROUP WILL BE CONDUCTED PER WEEK), (D) TRACK THE PROGRESS FOR PARTICIPANTS THROUGHOUT THE PROJECT PERIOD AT ROUTINE TIMEPOINTS (≥70% OF ELIGIBLE PARTICIPANTS WILL COMPLETE POST-TREATMENT FOLLOW-UP MEASURES EVERY 6 MONTHS), (E) INCREASE ACCESS TO MOUD (THE STEM PROGRAM WILL FULLY SUBSIDIZE THE PRESCRIPTION COSTS FOR AN AVERAGE OF 8 ELIGIBLE PARTICIPANTS PER YEAR), AND (F) INCREASE ACCESS TO FREE AND CONFIDENTIAL HIV, VIRAL HEPATITIS, AND SEXUALLY TRANSMITTED INFECTION SCREENINGS (≥3 ON-SITE TESTING EVENTS WILL BE OFFERED PER YEAR). IT IS PROJECTED THAT THIS PROPOSAL WILL SERVE AT LEAST 45 UNIQUE DRUG COURT PARTICIPANTS YEARLY, TOTALING AT LEAST 225 INDIVIDUALS FOR THE LIFE OF THE GRANT.

NOVEL LIVER-MEDIATED MECHANISMS IN HYPERTENSION AND CARDIAC DYSFUNCTION - OBESITY AND METABOLIC DISEASES SUCH AS TYPE II DIABETES ARE AT AN ALL-TIME HIGH. THE RATES OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) OR RECENTLY RENAMED METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) HAVE DRAMATICALLY INCREASED TO 25% OF THE POPULATION IN THE U.S. REFLECTING THE INCREASE IN OBESITY IN THE GENERAL POPULATION. CARDIOVASCULAR DISEASE (CVD) IS A SIGNIFICANT COMPLICATION OF NAFLD. IN FACT, MORE NAFLD PATIENTS DIE FROM CVD THAN FROM LIVER DISEASE. THERE ARE MANY FACTORS THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF CVD IN PATIENTS WITH NAFLD AS THIS CONDITION IS OFTEN ASSOCIATED WITH OBESITY, TYPE II DIABETES, AND DYSLIPIDEMIA. ALL OF WHICH CAN SIGNIFICANTLY CONTRIBUTE TO THE DEVELOPMENT OF CVD. HOWEVER, THE CONTRIBUTION OF HEPATIC STEATOSIS ITSELF TO THE DEVELOPMENT OF CVD IN NAFLD IS NOT KNOWN. THERE IS A SUBGROUP OF NAFLD PATIENTS WHO DEVELOP HEPATIC STEATOSIS INDEPENDENTLY OF OBESITY AND METABOLIC DISEASE SO CALLED “LEAN” NAFLD PATIENTS. INTERSTINGLY, THESE PATIENTS ARE ALSO AT GREATER RISK FOR THE DEVELOPMENT OF CVD. WE HAVE DEVELOPED A UNIQUE MODEL TO DETERMINE THE ROLE OF HEPATIC STEATOSIS IN THE DEVELOPMENT OF CVD INDEPENDENT OF OBESITY AND METABOLIC DYSFUNCTION SUCH AS INSULIN RESISTANCE AND DYSLIPIDEMIA. WE HAVE EXCITING DATA SHOWING THAT HEPATOCYTE-SPECIFIC DELETION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR Α (PPARAHEPKO) RESULTS IN SIGNIFICANT HEPATIC STEATOSIS EVEN ON MICE MAINTAINED ON A STANDARD LABORATORY DIET. PPARAHEPKO MICE DEVELOP HYPERTENSION, CARDIAC SYSTOLIC AND DIASTOLIC DYSFUNCTION, AND INCREASED VASCULAR STIFFNESS. WE ALSO FOUND THAT PPARAHEPKO MICE EXHIBIT REDUCED HEPATIC KETONE Β-HYDROXYBUTYRATE (ΒOHB) PRODUCTION AND PPARΑ-REGULATED HEPATIC-DERIVED HORMONES IN THEIR PLASMA COMPARED TO LITTERMATES. THIS PROPOSAL WILL TEST THE CENTRAL HYPOTHESIS THAT NAFLD REDUCES ΒOHB PRODUCTION AND SUPPRESSES PPARΑ-REGULATED HEPATOKINES THAT PROMOTE HEALTHY CARDIOVASCULAR FUNCTION. AIM 1 OF THE PROPOSAL WILL DETERMINE IF INCREASING PLASMA ΒOHB LEVELS REVERSES HYPERTENSION AND CARDIOVASCULAR REMODELING TO IMPROVE CARDIAC FUNCTION IN PPARAHEPKO MICE. IN ADDITION, WE WILL USE STATE-OF-THE-ART PAMGENE KINOME CHIP TECHNOLOGY TO DETERMINE WHICH SIGNALING MECHANISMS ARE IMPACTED BY INCREASING ΒOHB LEVELS IN PPARAHEPKO MICE. AIM 2 WILL DETERMINE WHETHER INCREASING PPARΑ-REGULATED HEPATIC-DERIVED HORMONES IN THE PLASMA OF THE PPARAHEPKO MICE REDUCES CARDIOVASCULAR COMPLICATIONS. WE WILL INCREASE THE LEVELS OF NERVE GROWTH FACTOR (NGF) AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN PPARAHEPKO MICE TO DETERMINE IF INCREASING THE PLASMA LEVELS OF THESE HEPATOKINES REVERESES HYPERTENSION AND CARDIOVASCULAR REMODELING TO IMPROVE CARDIAC FUNCTION IN PPARAHEPKO MICE. WE WILL ALSO USE STATE-OF-THE-ART PAMGENE KINOME CHIP TECHNOLOGY TO DETERMINE WHICH SIGNALING MECHANISMS ARE IMPACTED BY INCREASES IN THE PLASMA LEVELS OF THESE HEPATOKINES. OUR INVESTIGATIONS WILL IDENTIFY NOVEL TARGETS FOR TREATMENT OF NAFLD-DERIVED CVD. COLLECTIVELY, THIS PROJECT IS THE FIRST SYSTEMATIC INVESTIGATION OF THE ROLE OF HEPATIC STEATOSIS IN THE DEVELOPMENT OF CVD IN NAFLD.

THE OXIDATION OF HEME-CARRYING PROTEINS IN THE PATHOPHYSIOLOGY OF PNEUMOCOCCAL DISEASE - STREPTOCOCCUS PNEUMONIAE (SPN) COLONIZES THE UPPER AIRWAYS OF CHILDREN, AND THE ELDERLY, RESULTING IN MILLIONS OF DEATHS DUE TO PNEUMONIA ANNUALLY.PNEUMONIA IS AN ACUTE INFECTION OF THE PULMONARY PARENCHYMA THAT CAUSES CYTOTOXICITY LEADING TO INVASION OF PNEUMOCOCCI INTO THE LUNG EPITHELIUM. INVASIVE BACTERIA PRODUCE CAPSULE TO TRANSLOCATE TO THE BLOODSTREAM CAUSING DEATH. ALL SPN STRAINS PRODUCE ABUNDANT HYDROGEN PEROXIDE (SPN-H2O2) AS A BYPRODUCT OF THE AEROBIC FERMENTATION OF CARBOHYDRATES AND IT HAS A DEMONSTRATED CYTOTOXIC ACTIVITY AGAINST IN VITRO CULTURED LUNG EPITHELIAL CELLS. DESPITE THAT PRODUCTION OF SPN-H2O2 FINDS OPTIMAL CONDITIONS IN THE LUNG, WE LACK FUNDAMENTAL INFORMATION ABOUT THE MOLECULAR MECHANISM DRIVING SPN-H2O2 TOXICITY DURING REPLICATION OF PNEUMOCOCCI IN THE LUNG PARENCHYMA. THE LONG-TERM OBJECTIVE OF THIS RESEARCH PROGRAM IS TO IDENTIFY THE MOLECULAR MECHANISM(S) LEADING TO SPN-H2O2 TOXICITY IN THE LUNG TO FIND NEW TARGETS FOR INTERVENTIONS. THE RATIONALE UNDERLYING THIS PROPOSAL IS THAT COMPLETION WILL IDENTIFY KEY MOLECULAR TARGETS FOR CURING PNEUMOCOCCAL PNEUMONIA AND PREVENTING BACTEREMIA. WE HYPOTHESIZE THAT OXIDATION OF HOST HEMOPROTEINS BY SPN-H2O2 IS KEY IN THE PATHOPHYSIOLOGY OF PNEUMOCOCCAL DISEASE. WE HAVE MADE FUNDAMENTAL DISCOVERIES SUPPORTING THIS HYPOTHESIS. WE DEMONSTRATED THAT HEMOGLOBIN INDUCES FORMATION OF ROBUST PNEUMOCOCCAL BIOFILMS AND THAT, CONCURRENTLY, SPN-H2O2 OXIDIZES HEMOGLOBIN RELEASING HEME AND IRON. REMARKABLY, THE OXIDATION OF HEMOGLOBIN BY SPN-H2O2 SELECTED FOR ENCAPSULATED PNEUMOCOCCI. THE GOAL OF THIS R01 PROPOSAL IS THEREFORE TO CHARACTERIZE THE ROLE OF THE OXIDATION OF HEMOGLOBIN IN THE PATHOPHYSIOLOGY OF PNEUMOCOCCAL DISEASE. THREE INTERCONNECTED AIMS ARE PROPOSED TO ACHIEVE OUR GOAL. IN AIM 1, WE WILL INVESTIGATE THE FITNESS COST OF SPN-H2O2 OXIDATION OF HEMOGLOBIN DURING BIOFILM FORMATION, AND THE RESULTING SELECTION OF ENCAPSULATED PNEUMOCOCCI. WE WILL STUDY THIS MECHANISM(S) BY USING A SERIES OF SCAVENGERS AND A SYSTEMATIC APPROACH USING MUTANTS AND COMPLEMENTED STRAINS WITH DIFFERENT CAPACITY TO PRODUCE H2O2. INHIBITION OF BIOFILMS, TOXICITY AND THE SELECTION OF ENCAPSULATED SPN WILL GUIDE US TOWARDS THE MECHANISM. IN AIM 2, WE WILL USE AN IN VIVO MODEL OF PNEUMOCOCCAL PNEUMONIA, ALONG WITH A QUANTITATIVE CONFOCAL IMAGING APPROACH, WESTERN BLOT ANALYSIS, GENES EXPRESSION STUDIES, AND ESTABLISHED TECHNIQUES, TO INVESTIGATE NICHE-SPECIFIC TOXICITY OF SPN-H2O2, THE CELL'S ANTI-OXIDANT RESPONSE AGAINST SPN-H2O2, THE OXIDATION OF HEMOGLOBIN AND THE MECHANISM LEADING TO SELECTION OF ENCAPSULATED PNEUMOCOCCI. IN THE FINAL AIM 3, WE WILL STUDY THE IMPORTANCE OF SPN-H2O2 FOR THE ACQUISITION OF HEME/IRON FROM HEMOGLOBIN TO OVERCOME NUTRIENTS SEQUESTRATION BY THE HOST. WE WILL ADDRESS THIS GOAL BY USING A BIOCHEMICAL APPROACH, A SYSTEMATIC APPROACH WITH MUTANTS AND A TRANSPOSON INSERTION SEQUENCING SCREEN. THIS INNOVATIVE STUDY WILL SIGNIFICANTLY ADVANCE OURKNOWLEDGE ABOUT THE CELLULAR, ANDMOLECULAR PATHOPHYSIOLOGY OF SPN DISEASE. THIS IS SIGNIFICANT BECAUSE IT WILL PROVIDE A FRAMEWORK FOR INTERVENTIONS AIMING AT OXIDATIVE REACTIONS.

ADRENAL CELL ATP1A1 MUTATIONS AND MECHANISMS OF ALDOSTERONE BIOSYNTHESIS

: IMPACT OF NICOTINE EXPOSURE ON PROSTATE CANCER PROGRESSION AND THERAPEUTIC OUTCOME

MULTIPLICATIVE COMPUTATION IN THE VESTIBULO-OCULAR REFLEX (VOR)

ESTROGEN AND INFLAMMATION IN DIABETIC NEPHROPATHY

VASCULAR MECHANISMS OF INHIBITION OF SEH AS A NOVEL THERAPY FOR AD/ADRD - ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (AD/ADRD) IS AN EMERGING GLOBAL HEALTH CARE CRISIS. HOWEVER, UNDERLYING MECHANISMS HAVE NOT BEEN UNDERSTOOD WELL ENOUGH FOR TRANSLATION TO PRECISION MEDICINE. UNDERSTANDING VASCULAR CONTRIBUTION TO AD/ADRD IS IMPERATIVE SINCE INCREASING EVIDENCE SUGGESTS AD AND DIABETIC (DM)-RELATED ADRD ARE ASSOCIATED WITH BRAIN HYPOPERFUSION, AND 67% OF AD GWAS GENES ARE EXPRESSED IN THE CEREBRAL VASCULATURE. RECENT STUDIES DEMONSTRATED THAT REDUCTION OF SOLUBLE EPOXIDE HYDROLASE (SEH) IS BENEFICIAL TO COGNITION IN AD, DM-ADRD, AND CEREBRAL HYPOPERFUSION ANIMAL MODELS DUE TO ITS ANTI- INFLAMMATORY AND NEURONAL PROTECTIVE EFFECTS, BUT VASCULAR CONTRIBUTION HAS BEEN NEGLECTED. SEH IS AN ENZYME THAT TRANSFORMS ARACHIDONIC ACID (AA)-DERIVED EETS AND LINOLEIC ACID (LA)-DERIVED EPOMES TO THEIR CORRESPONDING DIOLS DHETS AND DIHOMES, RESPECTIVELY. CHANGES IN OXYLIPINS, SUCH AS THE ELEVATED RATIO OF DHETS/EETS AND DIHOMES/EPOMES, WERE FOUND IN AD MICE AND ADRD PATIENTS. WE PRELIMINARY FOUND THAT SNPS IN GENES (CYP2J2, 2C8, 2C9) ENCODING ENZYMES THAT CATALYZE AA AND LA TO EETS AND EPOMES, AND EPHX2 ENCODING SEH ARE LINKED WITH AD IN THE ARIC-NCS. WE ALSO FOUND THAT A HIGHLY SELECTIVE SEH INHIBITOR (SEHI) TPPU REVERSED COGNITIVE DISABILITY, IMPAIRED MYOGENIC RESPONSE (MR) AND AUTOREGULATION OF CEREBRAL BLOOD FLOW (CBF), AND NEUROVASCULAR UNIT (NVU) DYSFUNCTION IN DM-ADRD AND AD RATS. MOREOVER, AD/ADRD RATS DISPLAYED BRAIN HYPOPERFUSION, ENHANCED BLOOD-BRAIN BARRIER (BBB) LEAKAGE, NEURODEGENERATION, AND REDUCED BRAIN KIR2.1 ACTIVITY THAT HAS BEEN REPORTED TO ASSOCIATE WITH REDUCED PIP2 LEVELS IN CEREBRAL CAPILLARY ENDOTHELIAL CELLS DUE TO ENHANCED PLA2 ACTIVITY. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT INHIBITION OF SEH SYNERGISTICALLY MODULATES THE PLA2-AA-EETS-DHETS AND PLA2-LA-EPOMES-DIHOMES PATHWAYS TO REVERSE COGNITIVE IMPAIRMENTS AND ENHANCE BRAIN PERFUSION BY AMELIORATING CBF AUTOREGULATION, MAINTAINING BBB AND NVU FUNCTION. WE WILL COMPARE VASCULAR FUNCTION (MR, CBF AUTOREGULATION, AND FUNCTIONAL HYPEREMIA), AD PHENOTYPES, REGIONAL BRAIN LEVELS OF PLA2, SEH, PLP2, KIR2.1, AND OXYLIPINS IN TPPU-TREATED BOTH SEXES OF DM- ADRD AND AD RATS. WE WILL ALSO COMPARE VASCULAR RESPONSES TO ISOMER MIXTURES OF EETS/DHETS, AND EPOMES/DIHOMES IN CEREBRAL ARTERIES AND ARTERIOLES, AND VASODILATION RESPONSES TO ELEVATED POTASSIUM AND ISOMER MIXTURES OF OXYLIPINS IN ARTERIOLES-CAPILLARIES ISOLATED FROM BOTH SEXES OF CONTROL, AD, AND ADRD RATS TO FURTHER EXPLORE THE SPECIFIC PATHWAYS THAT ARE AFFECTED BY INHIBITION OF SEH. THIS PROJECT WILL ADDRESS CRITICAL KNOWLEDGE GAPS OF THE VASCULAR CONTRIBUTION OF SEHI ON COGNITIVE PROTECTION AND THE “NEXT STEPS” IN EXPLAINING THE BIOLOGY OF THE CATALYTIC ACTIVITY OF THE SEH. RESULTS GENERATED FROM THIS PROPOSAL SHOULD LAY THE FOUNDATION FOR THE DISCOVERY OF NEW DRUGS TARGETING THESE PATHWAYS TO REVERSE CEREBRAL VASCULAR DYSFUNCTION TO PREVENT THE ONSET AND SLOW THE PROGRESSION OF AD/ADRD. .

DIGITAL ASTRONAUT PROJECT: INTEGRATIVE COMPUTER MODEL FOR THE ANALYSIS OF HUMAN PHYSIOLOGY IN MICROGRAVITYAN INTEGRATIVE COMPUTER MODEL OF THE HUMA

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION - PROJECT ABSTRACT – ELIMINATION OF CONGENITAL SYPHILIS IN MISSISSIPPI OVER THE PAST DECADE, SYPHILIS RATES HAVE INCREASED DRAMATICALLY IN THE U.S. MISSISSIPPI HAS HAD ONE OF THE HIGHEST RATES OF SYPHILIS IN THE COUNTRY, ALONG WITH A HIGH RATE OF CONGENITAL SYPHILIS. IN 2021, MISSISSIPPI RANKED SIXTH ON SYPHILIS INCIDENCE (28.1 PER 100,000 POPULATION), AND FOURTH (182.0 PER 100,000 LIVE BIRTHS) ON CONGENITAL SYPHILIS INCIDENCE. OF SPECIAL PUBLIC HEALTH INTEREST IS MISSISSIPPI’S RAPID INCREASE IN CONGENITAL SYPHILIS. BETWEEN 2017 AND 2021, THE CONGENITAL SYPHILIS RATE ROSE BY 220% NATIONWIDE, WHILE THIS RATE SKYROCKETED BY A STAGGERING 6,641% IN MISSISSIPPI. ALARMINGLY, THESE NUMBERS MAY BE EVEN HIGHER SINCE THE DETECTION AND REPORTING OF STIS (SEXUALLY TRANSMITTED INFECTIONS) DURING THE PANDEMIC YEARS WERE IMPACTED NEGATIVELY BY DISRUPTIONS TO SCREENING PRACTICES AND THE DIVERSION OF PUBLIC HEALTH RESOURCES TO FIGHT COVID. NUMEROUS FACTORS HAVE CONTRIBUTED TO THIS STUNNING RISE IN MISSISSIPPI INCLUDING: THE MARKED INCREASE IN SYPHILIS AMONG REPRODUCTIVE AGE ADULTS, BARRIERS TO PRENATAL CARE, UNDERTESTING FOR SYPHILIS IN PREGNANCY, UNDER INVESTMENT IN THE PUBLIC HEALTH INFRASTRUCTURE, PROCUREMENT BARRIERS FOR TREATMENT, AND A LACK GENERAL AWARENESS OF THE CRISIS. WE PROPOSE TO ADDRESS THE CONGENITAL SYPHILIS CRISIS IN MISSISSIPPI THROUGH FIVE LANES OF WORK THAT TARGET SPECIFIC IMPEDIMENTS TO PREVENTING, DIAGNOSING, AND TREATING SYPHILIS IN PREGNANCY. TARGETED SOCIAL MEDIA AND TRADITIONAL MEDIA MARKETING TO RAISE THE AWARENESS OF CONGENITAL SYPHILIS AND THE NEED FOR EARLY PRENATAL CARE. AREAS WITH THE HIGHEST RATES OF DELAYED PRENATAL CARE AND SYPHILIS IN PREGNANCY WILL BE TARGETED MOST AGGRESSIVELY. PHYSICIAN AND PROVIDER OUTREACH WILL BE CONDUCTED THROUGH MULTIPLE MECHANISMS (MEDICAL STAFF PRESENTATION, DIRECT ENGAGEMENT, ORGANIZATIONAL PARTNERSHIP) TO ENHANCE AWARENESS OF SYPHILIS IN PREGNANCY AND THE EXISTING STATE REQUIREMENTS FOR UNIVE RSAL TESTING AND REPORTING. A SYPHILIS HOTLINE WILL BE MAINTAINED TO PROVIDE EXPERT CONSULTATION ON DIAGNOSIS, TREATMENT, AND ACCESS TO CARE. THE UNIVERSITY OF MISSISSIPPI MEDICAL CENTER (UMMC) WILL ENGAGE IN A UNIVERSAL TESTING INITIATIVE TO ALL EMERGENCY ROOM PATIENTS THAT SEEK CARE IN THE EMERGENCY ROOMS AT UMMC AND AFFILIATE HOSPITALS IN GRENADA AND HOLMES COUNTIES. EFFORTS WILL BE MADE TO EXTEND THIS INITIATIVE TO OTHER HOSPITALS THROUGHOUT THE STATE. THIS EVIDENCE-BASED INTERVENTION IS HIGHLY EFFECTIVE IN IDENTIFYING UNDIAGNOSED SYPHILIS. UMMC, THROUGH THE MYRLIE EVERS-WILLIAMS INSTITUTE FOR THE ELIMINATION OF HEALTH DISPARITIES (MEWI), WILL ENGAGE A TEAM OF COMMUNITY HEALTH WORKERS AND SOCIAL WORKERS TO SUPPORT ACCESS TO CARE THROUGH INSURANCE NAVIGATION (MEDICAID), LINKAGE TO CARE AND TRANSPORTATION RESOURCES. BUILDING FROM ITS CURRENT PORTFOLIO OF WORK, MEWI WILL ASSIST PATIENTS WITH HEALTH-RELATED SOCIAL NEEDS SUCH AS FOOD INSECURITY, INTERPERSONAL VIOLENCE, HOUSING INSECURITY, FINANCIAL INSECURITY, AND OTHERS. THIS CASE MANAGEMENT TEAM WILL WORK TO ENSURE PROPER ACCESS TO CLINICAL CARE AND SOCIAL SUPPORT. UMMC WILL WORK TO ENHANCE THE DIAGNOSIS AND TREATMENT OF SYPHILIS IN THE GENERAL POPULATION THROUGH TARGETED PARTNERSHIPS WITH CLINICS AND COMMUNITY-BASED ORGANIZATIONS ACROSS THE STATE, WITH A SPECIFIC FOCUS ON AREAS WITH THE HIGHEST INCIDENCE OF SYPHILIS, THROUGH THE FUNDING OF TESTING, TREATMENT, AND REFERRAL. UMMC WILL PARTNER WITH THE MISSISSIPPI STATE DEPARTMENT OF HEALTH TO ENSURE COMPLETION OF TREATMENT AND PARTNER TRACING.

DISCRETIONARY

ADVANCED NURSING EDUCATION GRANTS

VASCULAR MECHANOSENSOR

BRAIN MC4R-BAT-HEART CROSSTALK: A POTENTIAL NEW THERAPEUTIC TARGET FOR MYOCARDIAL ISCHEMIA/REPERFUSION INJURY - PROJECT SUMMARY: ISCHEMIC HEART DISEASE IS THE LEADING CAUSE OF DEATH IN U.S. AND TIMELY REPERFUSION OF THE OCCLUDED CORONARY ARTERY AFTER MYOCARDIAL INFARCTION (MI) IS THE MOST EFFECTIVE THERAPY CURRENTLY AVAILABLE. HOWEVER, ADDITIONAL ISCHEMIA/REPERFUSION (I/R) INJURY OCCURS IN ~25% OF PATIENTS WHO SUFFER MI AND THESE PATIENTS OFTEN DEVELOP HEART FAILURE (HF). WE RECENTLY DEMONSTRATED THAT ACTIVATION OF THE BRAIN LEPTIN-MELANOCORTIN SYSTEM PATHWAY GREATLY IMPROVES CARDIOMYOCYTE ENERGY METABOLISM AND CONTRACTILITY, PRESERVES CARDIAC FUNCTION, AND PREVENTS PROGRESSION OF HF FOLLOWING I/R INJURY. INTRACEREBROVENTRICULAR (ICV) INFUSION OF LEPTIN FOR 4 WEEKS, AT A LOW DOSE THAT DID NOT ALTER BLOOD LEPTIN CONCENTRATION, IMPROVED CARDIAC FUNCTION AND METABOLISM AFTER I/R INJURY. WE ALSO OBSERVED THAT THESE CARDIAC PROTECTIVE EFFECTS WERE ABSENT IN MELANOCORTIN 4 RECEPTOR (MC4R) DEFICIENT RATS AND THAT DIRECT ACTIVATION OF BRAIN MC4R USING SYNTHETIC AGONISTS (E.G. MTII), CIRCUMVENTING LEPTIN SIGNALING, ALSO PROTECTED THE HEART FROM PROGRESSIVE CARDIAC DYSFUNCTION AFTER MI. HOW THE BRAIN COMMUNICATES WITH THE HEART DURING LEPTIN-MELANOCORTIN SYSTEM ACTIVATION IS STILL UNKNOWN. OUR PRELIMINARY DATA SUGGEST THAT THE CARDIOPROTECTIVE EFFECT OF ICV LEPTIN OR MTII INFUSION AFTER I/R MAY BE MEDIATED BY BROWN ADIPOSE TISSUE (BAT) SINCE BAT SURGICAL REMOVAL AND BAT SYMPATHECTOMY MARKEDLY ATTENUATED THE EFFECTS OF CENTRAL LEPTIN OR MTII ADMINISTRATION TO IMPROVE HEART FUNCTION POST-I/R. SINCE OBESITY, A MAJOR CAUSE OF CARDIOVASCULAR DISEASES, MAY INDUCE LEPTIN RESISTANCE, WE WILL FOCUS ON ACTIVATION OF CENTRAL MC4R PATHWAY, BYPASSING LEPTIN RESISTANCE. THEREFORE, WE PROPOSE THAT ACTIVATION OF BRAIN MC4R, VIA INFUSION OF MTII DIRECTLY INTO THE BRAIN, INCREASES BAT ACTIVITY THROUGH THE SYMPATHETIC NERVOUS SYSTEM; ONCE ACTIVATED, BAT RELEASES EXTRACELLULAR VESICLES (EVS) CONTAINING CARDIOPROTECTIVE MICRORNAS THAT REACH THE HEART VIA THE CIRCULATION AND IMPROVE CARDIAC FUNCTION AND METABOLISM POST-I/R. OUR RESEARCH STRATEGY IS ORGANIZED IN TWO AIMS. AIM 1 WILL TEST THE HYPOTHESIS THAT BAT-DERIVED EVS ARE ESSENTIAL FOR THE CARDIOPROTECTIVE ACTIONS OF ACTIVATING BRAIN MC4R AFTER CARDIAC I/R INJURY. AIM 2 WILL TEST THE HYPOTHESIS THAT CHRONIC ACTIVATION OF BRAIN MC4R INCREASES BAT-DERIVED EVS THAT PROTECT THE HEART FROM I/R INJURY BY DELIVERING CARDIOPROTECTIVE MICRORNAS, INCLUDING MIR- 125B-5P. WE WILL USE STATE-OF-THE-ART CHRONIC IN VIVO PROTOCOLS WITH HIGH-RESOLUTION ULTRASOUND TECHNIQUES FOR IMAGING CARDIAC FUNCTION IN RATS AND MICE COMBINED WITH SOPHISTICATED MOLECULAR TECHNIQUES FOR IDENTIFICATION OF THE BAT-DERIVED EVS CARGO. OUTCOMES FROM THIS STUDY COULD LEAD TO NOVEL AND MORE EFFECTIVE THERAPEUTIC APPROACHES FOR I/R AND HF, AND WILL PROVIDE A NEW TARGET FOR MC4R AGONISTS WHICH ARE CURRENTLY BEING USED TO TREAT RARE FORMS OF GENETIC OBESITY IN HUMANS.

DISSECTING ROLES OF LUNATIC FRINGE-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER - DESPITE IMPROVEMENTS IN OVERALL SURVIVAL FOR MOST CANCERS, SURVIVAL FOR PATIENTS WITH PANCREATIC CANCER REMAINS DISMALLY LOW DUE TO THE LATE DIAGNOSIS AND RAPID SPREADING. UNDERSTANDING PANCREATIC CANCER INITIATION AND PROGRESSION IS OF GREAT IMPORTANCE FOR THE DEVELOPMENT OF EFFECTIVE INTERVENTION STRATEGY. MOUSE MODELS RECAPITULATING HUMAN PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) HAVE BEEN GENERATED THROUGH ACTIVATION OF ONCOGENIC KRAS COMBINED WITH VARIOUS GENETIC MUTATIONS IN DIFFERENT PANCREATIC CELL TYPES, AND STUDIES USING MOUSE GENETICS SUGGEST THAT BOTH ACINAR AND DUCTAL CELLS CAN GIVE RISE TO PDAC, AND CELLULAR ORIGINS AND SPECIFIC GENE MUTATIONS MAY DETERMINE THE PRECURSOR LESION INITIATION, PROGRESSION, AS WELL AS MOLECULAR SUBTYPE OF PDAC. NOTCH SIGNALING PATHWAY IS A MASTER REGULATOR OF CELL FATE DECISION AND DIFFERENTIATION CRITICAL FOR PANCREATIC DEVELOPMENT AND IS DYSREGULATED IN PANCREATIC CANCER. WE RECENTLY DISCOVERED THAT EXPRESSION OF A NOTCH MODULATOR, LUNATIC FRINGE (LFNG), IS CONFINED TO A SUBSET OF CENTROACINAR CELLS IN THE NORMAL PANCREAS. LFNG-EXPRESSING CENTROACINAR CELLS ARE UNIQUELY SUSCEPTIBLE TO ONCOGENIC TRANSFORMATION AND DELETION OF LFNG BLOCKS TUMOR INITIATION FROM THESE CELLS. LFNG IS UPREGULATED IN ACINAR AND DUCTAL CELL-DERIVED PRECURSOR LESIONS, AND DELETION OF LFNG DECELERATES TUMOR DEVELOPMENT FROM THESE TWO CELL TYPES. THUS, LFNG EXERTS ONCOGENIC ROLES IN THE DEVELOPMENT OF PDAC FROM THREE DISTINCT CELLULAR ORIGINS: CENTROACINAR, ACINAR AND DUCTAL CELLS. AMPLIFICATION AND UPREGULATION OF LFNG ARE NOTED IN HUMAN PDAC AND ARE ASSOCIATED WITH POOR SURVIVAL. THEREFORE, WE PROPOSE TO DISSECT ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER USING MULTIPLE APPROACHES INCLUDING ORGANOID CULTURE, LINEAGE TRACING, TEMPORAL AND LINEAGE-SPECIFIC GENETIC MANIPULATIONS, DIFFERENTIAL GENE EXPRESSION ANALYSIS, AS WELL AS FUNCTIONAL ANALYSIS OF CANDIDATE GENES IN HUMAN PDAC CELL LINES TO ADDRESS THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN PANCREATIC CANCER DEVELOPMENT FROM LFNG- EXPRESSING CENTROACINAR CELLS; 2) DETERMINE ROLES OF LFNG-DEPENDENT NOTCH SIGNALING IN ACINAR- AND DUCTAL-DERIVED PDAC PATHOGENESIS; AND 3) CHARACTERIZE LFNG-EXPRESSING PANCREATIC CANCER CELLS AND IDENTIFY GENES DIFFERENTIALLY EXPRESSED IN THESE CELLS AS POTENTIAL THERAPEUTIC TARGETS. WE HOPE TO DEMONSTRATE THAT LFNG IS CRITICAL FOR THE INITIATION AND PROGRESSION OF PANCREATIC CANCERS ARISING FROM DIFFERENT CELL TYPES OF THE PANCREAS, AND THAT LFNG MARKS PANCREATIC CANCER STEM CELLS THOUGHT TO BE RESPONSIBLE FOR DRUG RESISTANCE AND CANCER RELAPSE. IDENTIFICATION OF GENES DOWNSTREAM OF LFNG-DEPENDENT NOTCH SIGNALING MAY LEAD TO THE DEVELOPMENT OF BIOMARKERS FOR TARGETED THERAPY FOR THIS PARTICULARLY DEADLY DISEASE.

MENTHOL: AN ACCOMPLICE OF NICOTINE IN TOBACCO SMOKING

MIF AND CARDIOVASCULAR INFLAMMATION - PROJECT SUMMARY CLINICAL STUDIES HAVE REPORTED A HIGHER INCIDENCE OF SURGICAL STRESS-INDUCED ACUTE INJURY IN THE ELDERLY. THE MORTALITY AFTER CARDIAC SURGERY, ATHEROSCLEROSIS, SEPSIS, OR CORONARY ANGIOPLASTY IN PATIENTS OLDER THAN 60 YEARS OF AGE APPEARS TO BE RELATED TO A DECLINE IN INTRINSIC RESISTANCE TO SURGICAL STRESS-RELATED ACUTE INJURY. THE MECHANISMS RESPONSIBLE FOR THE ATHEROSCLEROSIS-RELATED VASCULAR INTOLERANCE IN AGING ARE INCOMPLETELY UNDERSTOOD AND THE SIGNALING PATHWAYS INVOLVED IN REGULATING CELLULAR RESPONSES TO ACUTE INJURY RELATED INFLAMMATION ARISING FROM SURGICAL STRESS REMAIN LARGELY UNKNOWN. THE BLOCKED VESSELS BY ATHEROTHROMBOSIS CAUSE ATP DEPLETION AND SUBSEQUENT AMP ACCUMULATION, WHICH ACTIVATES AMP-ACTIVATED PROTEIN KINASE (AMPK), A CENTRAL COMPONENT OF THE CELLULAR STRESS RESPONSE THAT REGULATES OXIDATIVE METABOLISM TOWARDS ATP RESTORATION UNDER STRESS CONDITIONS. AMPK REGULATES PATHWAYS THAT CONTROL THE OXIDATIVE STRESS-RELATED VASCULAR INFLAMMATION. WE HAVE REPORTED THAT AN AGING-RELATED REDUCTION IN THE MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)-AMPK SIGNALING CASCADE IS AN IMPORTANT CONTRIBUTING FACTOR LEADING TO INCREASED SENSITIVITY TO REACTIVE OXYGEN SPECIES (ROS) BY SURGICAL LIGATION OF THE LEFT ANTERIOR DESCENDING CORONARY ARTERY. ACCORDINGLY, WE HYPOTHESIZE THAT AGING IS ASSOCIATED WITH A DECLINE IN THE ABILITY OF VASCULAR CELLS TO RENDER THE MIF-AMPK SIGNALING CASCADE ACTIVE IN RESPONSE TO INFLAMMATION CAUSED BY ATHEROSCLEROSIS, THUS RESULTING IN EXACERBATED VASCULAR INJURY. WE WILL TEST THIS HYPOTHESIS IN THE FOLLOWING SPECIFIC AIMS: AIM 1, DEFINE THE ROLE OF THE MIF RECEPTOR IN AGE-RELATED IMPAIRED AMPK SIGNALING IN RESPONSE TO VASCULAR INFLAMMATION BY OXIDATIVE STRESS; AND AIM 2, EVALUATE THE CAPABILITY OF SMALL-MOLECULE MIF AGONIST TO IMPROVE STRESS-INDUCED MIF-AMPK ACTIVATION IN THE CARDIOVASCULAR SYSTEM. IN THIS MANNER, WE SEEK TO ADVANCE OUR UNDERSTANDING OF THE MECHANISMS BEHIND AGING-RELATED ALTERATIONS IN CARDIAC AMPK SIGNALING PATHWAYS IN RESPONSE TO INFLAMMATION BY SURGICAL LIGATION OF THE CORONARY ARTERY. FURTHERMORE, WE PROPOSE BOTH EXERCISE AND A NOVEL PHARMACOLOGICAL STRATEGY AIMED AT AMELIORATING OXIDATIVE STRESS-INDUCED VASCULAR INFLAMMATION THAT OCCURS IN THE OLDER POPULATION.

INTEGRATING BEHAVIORAL HEALTH INTO PRIMARY CARE THROUGH TELEHEALTH EVIDENCE-BASED TELEHEALTH NETWORK

CHARACTERIZATION OF HEARING STATUS IN THE JACKSON HEART STUDY COHORT

ADVANCED EDUCATION NURSING GRANTS

GENDER AND SUSCEPTIBILITY TO KIDNEY DAMAGE IN HIGH BP

FATIGUE OF DENTAL IMPLANTS

ADVANCED NURSING EDUCATION GRANTS

SUPRESSOR ANGII DETERMINES ACUTE & CHRONIC RENAL INJURY

ENABLING IMPUTATION AND CNV ANALYSIS IN GENETIC STUDIES OF AFRICAN AMERICANS

SELF-ADMINISTRATION OF DRUG COMBINATIONS: POLYDRUG ABUSE

BASIC AHEC

POLYDRUG ABUSE: OPIOID-ALCOHOL COMBINATIONS - POLYDRUG USE REFERS TO THE USE OF TWO OR MORE SUBSTANCES ON THE SAME OCCASION OR ON SEPARATE BUT RECENT OCCASIONS. ONE OF THE MOST COMMON POLYDRUG COMBINATIONS REPORTED IN OPIOID USERS IS THE COMBINATION OF AN OPIOID WITH ALCOHOL. UNFORTUNATELY, COMBINATIONS OF OPIOIDS AND ALCOHOL ARE ASSOCIATED WITH A NUMBER OF SIGNIFICANT NEGATIVE OUTCOMES INCLUDING HIGHER FATALITY RATES, HIGHER RELAPSE RATES TO BOTH ALCOHOL AND OPIOIDS, AND POORER TREATMENT OUTCOMES. THERE IS A CLEAR NEED TO BETTER UNDERSTAND THE COMBINED EFFECTS OF OPIOIDS WITH ALCOHOL AT THE BEHAVIORAL LEVEL, AND TO BEGIN TO PROBE INFLUENCING FACTORS. BOTH ILLICIT AND CLINICALLY USEFUL OPIOIDS EXERT THEIR BEHAVIORAL EFFECTS PRIMARILY THROUGH BINDING AT AND STIMULATION OF MU OPIOID RECEPTORS (MORS). NOTABLY, SOME OF THE BEHAVIORAL EFFECTS OF ALCOHOL ALSO CAN BE ATTRIBUTED TO THE STIMULATION OF MORS. CONSIDERABLE EVIDENCE SUGGESTS THAT A FUNCTIONAL VARIANT OF THE HUMAN MOR (OPRM1 A118G) MAY BE ASSOCIATED WITH INCREASED SENSITIVITY TO THE BEHAVIORAL EFFECTS OF BOTH OPIOIDS AND ALCOHOL. IT IS LOGICAL, THEN, TO ASSUME THAT THIS SAME SINGLE NUCLEOTIDE POLYMORPHISM MAY INFLUENCE THE BEHAVIORAL RESPONSE TO OPIOID-ALCOHOL COMBINATIONS. THIS PROPOSAL CAPITALIZES ON OUR ACCESS TO RHESUS MONKEYS THAT HAVE BEEN GENOTYPED FOR AN ORTHOLOGOUS MOR SINGLE NUCLEOTIDE POLYMORPHISM (C77G) THAT RESULTS IN A VARIANT OF THE RHESUS MONKEY MOR THAT APPEARS TO HAVE MANY OF THE SAME FUNCTIONAL, PHYSIOLOGICAL AND BEHAVIORAL CONSEQUENCES AS THE HUMAN POLYMORPHISM. WE WILL USE THESE ANIMALS TO EVALUATE THE HYPOTHESIS THAT MOR NEUROGENETIC VARIATION CONTRIBUTES TO INDIVIDUAL DIFFERENCES IN THE REINFORCING EFFECTS OF ALCOHOL, OPIOIDS AND THEIR COMBINATION AND IS A KEY CONTRIBUTOR TO VULNERABILITY TO COMBINED OPIOID-ALCOHOL TAKING. USING AN ESTABLISHED ORAL ALCOHOL SELF- ADMINISTRATION PROCEDURE, SPECIFIC AIM 1 WILL TEST THE HYPOTHESIS THAT THE C77G POLYMORPHISM INFLUENCES THE REINFORCING EFFECTS OF ALCOHOL ALONE. USING A NEW ORAL OXYCODONE SELF-ADMINISTRATION PROCEDURE, SPECIFIC AIM 2 WILL EVALUATE THE HYPOTHESIS THAT THIS POLYMORPHISM INFLUENCES THE REINFORCING EFFECTS OF OXYCODONE ALONE. FINALLY, SPECIFIC AIM 3 WILL ASSESS THE HYPOTHESIS THAT THE C77G POLYMORPHISM WILL INFLUENCE THE REINFORCING EFFECTS OF ORAL OXYCODONE-ALCOHOL COMBINATIONS. IN ALL AIMS, A NOVEL BEHAVIORAL ECONOMIC ANALYSIS WILL BE USED TO RIGOROUSLY EVALUATE THE REINFORCING EFFECTIVENESS OF THE INDIVIDUAL DRUGS AND DRUG COMBINATIONS IN THE TWO GENOTYPES. SPECIFICALLY, WE PREDICT THAT INDIVIDUALS HOMOZYGOUS FOR THE FUNCTIONAL VARIANT (I.E., GG SUBJECTS) WILL SELF- ADMINISTER THE COMPONENT DRUGS AND DRUG COMBINATIONS TO A GREATER DEGREE AND WILL BE MORE RESISTANT TO BEHAVIORAL MANIPULATIONS DESIGNED TO REDUCE DRUG TAKING (I.E., INCREASES IN PRICE). OUR RESULTS WILL PROVIDE NOVEL DATA REGARDING THE CONTRIBUTION OF GENETIC VARIANCE IN OPRM1 TO INDIVIDUAL DIFFERENCES IN THE REINFORCING EFFECTS OF OPIOIDS, ALCOHOL AND OPIOID-ALCOHOL COMBINATIONS. ULTIMATELY, OUR FINDINGS CAN BE LEVERAGED TO TARGET PREVENTION AND TREATMENT STRATEGIES TO SPECIFIC INDIVIDUALS AT GREATEST RISK FOR DEVELOPING OPIOID, ALCOHOL, AND/OR POLYDRUG USE DISORDERS.

THE OVARIAN CANCER ACADEMY 2015-2020: A TEAM-BASED SCIENCE APPROACH

TELEHEALTH NETWORK GRANT PROGRAM

OXYTOCIN AS A POTENTIAL THERAPEUTIC FOR ENDOCRINE DYSFUNCTION IN COCAINE USE DISORDER - PROJECT SUMMARY COMPARED WITH MEN, WOMEN PROGRESS MORE RAPIDLY FROM CASUAL COCAINE USE TO MISUSE, HAVE GREATER DIFFICULTY QUITTING, AND HAVE SHORTER PERIODS OF COCAINE ABSTINENCE. HORMONAL MILIEU BOTH IMPACTS, AND IS IMPACTED BY, THE PROGRESS OF COCAINE USE DISORDER (CUD) IN WOMEN, LEADING TO LASTING ENDOCRINE DYSFUNCTION THAT MAY CONTRIBUTE TO A WORSENED PHENOTYPE. PROGESTERONE (P4) IS A KEY HORMONE IN REGULATION OF COCAINE USE IN WOMEN AND IN COCAINE SELF-ADMINISTRATION IN NONHUMAN ANIMALS. FURTHERMORE, CHRONIC COCAINE SUBSTANTIALLY DISRUPTS CYCLICITY OF ENDOGENOUS P4 IN ANIMALS. UNFORTUNATELY, P4 ADMINISTRATION IS NOT A VIABLE TREATMENT FOR ENDOCRINE DYSFUNCTION AS IT DOES NOT RESTORE THE ESTROUS OR MENSTRUAL CYCLE. CONVERSELY, THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN) NEUROPEPTIDE OXYTOCIN (OXT) SHOWS PROMISE AS A PHARMACOTHERAPY FOR BOTH ENDOCRINE DYSFUNCTION AND CUD. CIRCULATING AND CENTRAL OXT LEVELS FLUCTUATE WITH HORMONE CYCLES AND CO-VARY WITH P4. NOTABLY, ROSTRAL PVN- OXT NEURONS, WHICH EXPRESS P4 RECEPTORS, HAVE STRONG PROJECTIONS TO THE NUCLEUS ACCUMBENS (NAC), A CRUCIAL TARGET FOR COCAINE REINFORCEMENT. SYSTEMIC OXT ADMINISTRATION REDUCES COCAINE TAKING AND RESTORES NORMAL ESTROUS CYCLES DURING COCAINE EXPOSURE. HOWEVER, THE NEURAL MECHANISMS BY WHICH OXT EXERTS ITS EFFECTS IN RATS, ITS INTERACTIONS WITH P4, AND ITS THERAPEUTIC EFFICACY IN MONKEYS REMAINS UNKNOWN. OUR WORKING HYPOTHESIS IS THAT OXT'S THERAPEUTIC EFFECTS ON ENDOCRINE DYSFUNCTION AND COCAINE MISUSE ARE MEDIATED THROUGH RECIPROCAL INTERACTIONS WITH P4, AN EFFECT CONSISTENT ACROSS ESTROUS (RAT) AND MENSTRUAL (MONKEY) CYCLES. IN AIM 1 WE WILL EVALUATE THE NEURAL MECHANISMS DRIVING OXT’S THERAPEUTIC EFFECTS IN FEMALE RATS. WE HYPOTHESIZE THAT AS COCAINE USE INCREASES, THE SUPPRESSION OF P4 REDUCES PVN-OXT SIGNALING TO THE NAC, LEADING TO GREATER MOTIVATION TO EARN COCAINE (I.E., DEMAND) IN FEMALE RATS. TO INVESTIGATE P4 AND OXT INTERACTIONS, WE WILL USE RETROGRADELY TRANSPORTED OXT-PROMOTER-DRIVEN DREADDS COMBINED WITH A DAILY BEHAVIORAL-ECONOMIC DEMAND PROCEDURE, WHICH WILL ALLOW US TO MANIPULATE PVN-OXT SIGNALING TO THE NAC AND MEASURE ITS EFFECTS ON ESTROUS CYCLICITY AND COCAINE DEMAND. IN AIM 2 WE WILL EVALUATE THE THERAPEUTIC POTENTIAL OF OXT TO TREAT ENDOCRINE DYSFUNCTION AND DECREASE COCAINE DEMAND IN THE HIGHLY TRANSLATIONAL, FEMALE RHESUS MONKEY WITH A MENSTRUAL CYCLE THAT IS LIKE HUMANS. WE WILL CHARACTERIZE MENSTRUAL CYCLES WITH AWAKE DAILY BLOOD SAMPLING PRIOR TO, DURING, AND AFTER ACTIVE COCAINE TAKING USING A DAILY BEHAVIORAL-ECONOMIC DEMAND PROCEDURE AS IN AIM 1. WE WILL ADMINISTER OXT DURING COCAINE DEMAND AND IN ABSTINENCE TO EVALUATE ITS THERAPEUTIC POTENTIAL TO RESTORE THE MENSTRUAL CYCLE AND REDUCE DEMAND. OUR COMPLEMENTARY APPROACH WILL LEVERAGE THE STRENGTHS OF EACH MODEL, AS RATS PROVIDE THE OPPORTUNITY TO EVALUATE NEURAL MECHANISMS RESPONSIBLE FOR OXT’S THERAPEUTIC EFFECTS AND MONKEYS PROVIDE THE OPPORTUNITY TO EVALUATE THE TRANSLATABILITY OF OXT’S THERAPEUTIC EFFECTS ON THE ESTROUS CYCLE TO THE MENSTRUAL CYCLE. ENDOCRINE DYSFUNCTION IS A NEGLECTED CONTRIBUTOR TO ADDICTION, AND THE CURRENT APPLICATION WILL ADDRESS KEY KNOWLEDGE GAPS IN THIS AREA THAT WILL CONTRIBUTE TO OUR UNDERSTANDING AND TREATMENT OF WOMEN’S HEALTH AND ADDICTION.

CEREBROVASCULAR ABNORMALITIES IN PREECLAMPSIA

RESIDENCY TRAINING IN PRIMARY CARE

RYAN WHITE PART C OUTPATIENT EIS PROGRAM