UNIVERSITY OF LOUISVILLE

FUNCTIONAL MICROBIOMICS, INFLAMMATION AND PATHOGENICITY

ENVIRONMENTAL EXPOSURE AND CARDIOMETABOLIC DISEASE

VALUE-BASED MEDICAL STUDENT EDUCATION TRAINING PROGRAM

CENTER FOR CANCER IMMUNOLOGY AND IMMUNOTHERAPY (CCII)

ANESTHESIOLOGY PHYSICIAN SERVICES

COVID WASTEWATER

UOFL RBL OPERATIONS, WORKFORCE DEVELOPMENT AND PANDEMIC PREPAREDNESS RESEARCH - SUMMARY (OVERALL): THE UNIVERSITY OF LOUISVILLE REGIONAL BIOCONTAINMENT LABORATORY (RBL) IS OPERATED BY THE UNIVERSITY CENTER FOR PREDICTIVE MEDICINE FOR BIODEFENSE AND EMERGING INFECTIOUS DISEASES (CPM). THE RBL IS A REGIONAL RESOURCE THAT FACILITATES TRANSLATIONAL RESEARCH TO DEVELOP DIAGNOSTICS, PROGNOSTICS, THERAPEUTICS AND VACCINES TO MITIGATE BIODEFENSE AND EMERGING INFECTIOUS DISEASE THREATS. OUR CENTER OPERATES THE ONLY BSL-3 AND ABSL-3 FACILITIES CURRENTLY OPERATING IN THE COMMONWEALTH OF KENTUCKY. THE CPM MANDATE IS TO PREPARE FOR AND RESPOND TO PUBLIC HEALTH EMERGENCIES, SUCH AS THE COVID-19 PANDEMIC. THE BROAD, LONG-RANGE OBJECTIVES AND GOALS OF THE UNIVERSITY OF LOUISVILLE (UOFL) CPM RBL ARE: 1. TO OFFER STATE-OF-THE-ART RESEARCH SERVICES TO THE REGIONAL AND NATIONAL BIOMEDICAL RESEARCH COMMUNITY TO LEARN FROM PAST PANDEMICS AND BIOLOGICAL WARFARE EXPERIENCES AND EFFECTIVELY PREDICT AND MITIGATE FUTURE EMERGING INFECTIOUS DISEASE THREATS. 2. TO MANAGE, MAINTAIN AND OPERATE THE UOFL RBL TO SERVE THE NATIONAL AND REGIONAL NEED FOR BIOCONTAINMENT FACILITIES SUITABLE FOR RESEARCH ON RISK GROUP 3 PATHOGENS AND OTHER BIOTHREATS. 3. TO FOLLOW A PHILOSOPHY OF CONTINUOUS IMPROVEMENT IN BSL-3 AND ABSL-3 WORK PRACTICES AND TO ENSURE THAT ALL PERSONNEL WHO NEED TO ACCESS BSL-3 AND ABSL-3 CONTAINMENT LABORATORIES ARE APPROPRIATELY TRAINED AND PREPARED TO SERVE THE NATIONAL AND REGIONAL NEED FOR BIOCONTAINMENT RESEARCH PROFESSIONALS. TO ACHIEVE THESE AIMS WE PROPOSE TO ESTABLISH THREE COLLABORATIVE CORES. THE FACILITIES MANAGEMENT MAINTENANCE AND OPERATIONS CORE (FMMO CORE) IS RESPONSIBLE FOR ENSURING THAT THE FACILITY IS ALWAYS AVAILABLE TO MEET THE RESEARCH AND EMERGENCY PREPAREDNESS MISSION OF THE RBL. THE BSL-3 PRACTICES AND WORKFORCE DEVELOPMENT CORE (BSL-3PWD CORE) FORMALIZES OUR MENTOR-MENTEE TRAINING PLAN TO ENSURE OUR LABORATORY IS STAFFED WITH BSL-3 RESEARCH PROFESSIONALS WHO ARE PROFICIENT AT BIOCONTAINMENT RESEARCH PROFESSIONALS. THIS CORE RESPONDS TO THE REALITY THAT RESPONSE TO RAPIDLY EMERGING PUBLIC HEALTH EMERGENCIES LIKE COVID-19 IS LIMITED BY THE NUMBER OF AVAILABLE BSL-3 TRAINED AND EXPERIENCED RESEARCH PROFESSIONALS. OUR PANDEMIC PREPAREDNESS AND RESPONSE INTEGRATED RESEARCH CORE (PAPR CORE) RESPONDS TO THE SUBSTANTIALLY INCREASED REQUESTS FOR OUR BSL-3 RESEARCH SERVICES BY ORGANIZING AN INTEGRATED FULL-SERVICE BSL-3 RESEARCH SUPPORT FUNCTION TO SUPPORT INVESTIGATOR NEEDS. THESE CORES WILL WORK IN UNISON TO ACHIEVE THE CPM MISSION: TO PREPARE FOR AND RESPOND TO PUBLIC HEALTH EMERGENCIES LIKE THE COVID-19 PANDEMIC.

MODEL STATE-SUPPORTED AHEC PROGRAM

UNIVERSITY OF LOUISVILLE CENTER FOR INTEGRATIVE ENVIRONMENTAL HEALTH SCIENCES

URBAN GREENNESS AND CARDIOVASCULAR HEALTH

CHROMOSOME INSTABILITY DRIVES METAL-INDUCED LUNG CANCER - PROJECT SUMMARY OF THE FUNDED PARENT GRANT LUNG CANCER IS THE LEADING CAUSE OF CANCER DEATH WITH LITTLE IMPROVEMENT IN SURVIVABILITY OVER MANY DECADES. UNDERSTANDING AND SUPPORT FOR LUNG CANCER HAVE SUFFERED FROM THE STIGMA THAT THE DISEASE IS MERELY A CONSEQUENCE OF TOBACCO USE, WHEN IN FACT OTHER AGENTS ARE A MAJOR FACTOR IN THE DISEASE. MANY PEOPLE WITH LUNG CANCER HAVE NEVER USED TOBACCO AND ONLY A MINORITY OF TOBACCO USERS ACTUALLY GET LUNG CANCER. HOWEVER, WHILE LUNG CANCER KILLS MORE PEOPLE THAN COLON, BREAST AND PROSTATE CANCER COMBINED, IT RECEIVES LESS FEDERAL FUNDING THAN EACH OF THESE CANCERS ALONE. CHROMOSOME INSTABILITY (CIN) IS A HALLMARK OF LUNG CANCER. ALL ESTABLISHED LUNG CARCINOGENS CAUSE CIN, YET THE MECHANISMS FOR HOW THEY DO HAVE RECEIVED LITTLE ATTENTION. METAL EXPOSURE IS A WORLDWIDE HEALTH CONCERN. METALS CAUSE LUNG CANCER, AND CARCINOGENIC METALS ARE A COMPONENT IN TOBACCO. METALS ARE POOR MUTAGENS BUT POTENTLY INDUCE CIN, YET, HOW METALS CAUSE LUNG CANCER AND CIN IS POORLY UNDERSTOOD. WE FOCUS OUR R35 PROGRAM ON UNDERSTANDING THE MECHANISMS FOR HOW METAL CARCINOGENS INDUCE CIN IN LUNG CANCER. WE USE HEXAVALENT CHROMIUM [CR(VI)], A HUMAN LUNG CARCINOGEN OF MAJOR PUBLIC HEALTH CONCERN, AS OUR PRIMARY METAL OF INTEREST, ALTHOUGH WE WILL COMPARE CR(VI) OUTCOMES WITH OTHER METAL LUNG CARCINOGENS. WE WILL STUDY HOW CR(VI) INDUCES STRUCTURAL AND NUMERICAL CIN, CONSIDERING HUMAN LUNG FIBROBLAST, EPITHELIAL AND INDUCED PLURIPOTENT STEM CELL MODELS. WE WILL PROGRESS OUR STUDIES FROM INDIVIDUAL CELL TYPES TO MORE COMPLEX, THREE-DIMENSIONAL, MIXED CELL CULTURE STUDIES. WE ENHANCE AND DEEPEN OUR UNDERSTANDING OF THESE MECHANISMS WITH A ONE ENVIRONMENTAL HEALTH APPROACH, WHICH LEVERAGES THE ABILITY OF WILDLIFE TO RESIST CR(VI)-INDUCED CIN AND PROVIDE NOVEL INSIGHTS INTO ITS CARCINOGENIC MECHANISM. MOREOVER, WE MAXIMIZE THE IMPACT OF THESE FINDINGS BY TRANSLATING OUR OUTCOMES INTO ANIMALS AND INTO A POWERFUL AND UNIQUE COLLECTION OF HUMAN SUBJECTS AND POPULATIONS RANGING FROM WORKERS WITH PRIMARILY CR(VI) EXPOSURE, TO WORKERS WITH A MIXED METAL EXPOSURE INCLUDING CR. THIS COMBINED APPROACH OF HUMANS, ANIMALS AND CELL LINES WITH ONE ENVIRONMENTAL HEALTH TOOLS WILL GIVE US UNPRECEDENTED INSIGHT INTO HOW METALS INDUCE STRUCTURAL AND NUMERICAL CIN. IN PARTICULAR, WE WILL DEFINE: 1) KEY MECHANISMS FOR METAL-INDUCED CIN; 2) HOW THESE MECHANISMS PERSIST AND ARE HERITABLE AT THE CELLULAR LEVEL TO CAUSE NEOPLASTIC DISEASE; AND 3) HOW THEY TRANSLATE TO ANIMALS AND HUMANS. THUS, OUR PROPOSED R35 PROGRAM WILL REVOLUTIONIZE OUR UNDERSTANDING OF CR(VI), CIN, METAL CARCINOGENESIS, AND LUNG CANCER WHILE ALSO PROVIDING IMPORTANT INSIGHTS FOR OTHER CANCERS THAT INVOLVE CIN. OUTCOMES WILL INCLUDE MAJOR SCIENTIFIC BREAKTHROUGHS IN UNDERSTANDING: 1) HOW METALS CAUSE NORMAL HUMAN LUNG CELLS TO BECOME NEOPLASTIC; 2) HOW TO DETECT THIS NEOPLASTIC TRANSFORMATION WHEN IT OCCURS; 3) HOW TO MORE EFFECTIVELY TARGET LUNG CELLS THAT HAVE TRANSFORMED AND 4) HOW TO PREVENT NEOPLASTIC CHANGE FROM OCCURRING, LEADING TO IMPROVED RISK ASSESSMENT, TREATMENTS, AND HEALTH OUTCOMES FOR PEOPLE EXPOSED TO METALS.

ANESTHESIOLOGY SERVICES IGF::OT::IGF

AN ETHNICALLY DIVERSE GENOMIC REFERENCE RESOURCE FOR THE HUMAN HEAVY AND LIGHT CHAIN IMMUNOGLOBULIN LOCI

LOUISVILLE CLINICAL AND TRANSLATIONAL RESEARCH CENTER (LCTRC) - THE VISION OF THE LOUISVILLE CLINICAL AND TRANSLATIONAL RESEARCH CENTER (LCTRC) IS TO BUILD AN IMPACTFUL CLINICAL AND TRANSLATIONAL (C&T) RESEARCH PROGRAM AT THE UNIVERSITY OF LOUISVILLE (UOFL) TO IMPROVE THE HEALTH OF KENTUCKY (KY) COMMUNITIES. KENTUCKY IS, BY ANY MEASURE, A POOR AND LARGELY RURAL STATE WITH A SINGLE LARGE METROPOLITAN CENTER THAT SUFFERS DISPROPORTIONATELY FROM MANY CHRONIC DISEASES. FOR EXAMPLE, KY IS RANKED FIRST IN THE U.S. IN CANCER AND COPD INCIDENCE. TO ADDRESS THESE PROBLEMS THE UOFL IN ITS RESEARCH STRATEGIC PLANNING PROCESS CREATED PROGRAMS OF DISTINCTION IN CARDIOVASCULAR DISEASE, NEUROSCIENCE, CANCER AND METABOLIC DISEASE. THUS, UOFL HAS BEEN VERY DELIBERATE ABOUT DEVELOPING RESEARCH PROGRAMS TO MEET THE STATE’S MOST PRESSING HEALTH PROBLEMS. HOWEVER, UOFL HAS APPROACHED C&T RESEARCH OF THESE HEALTH PROBLEMS THROUGH UNDERFUNDED AND ADMITTEDLY UNCOORDINATED EFFORTS IN CLINICAL TRIALS INFRASTRUCTURE, RESEARCH DESIGN, RESEARCH FUNDING, AND MENTORSHIP. ALSO, UNTIL 2019, UOFL C&T RESEARCH WAS PERFORMED ALMOST EXCLUSIVELY AT TWO FACILITIES. IN 2019, UOFL CREATED UOFL HEALTHCARE (ULH) THAT HAS 11 HOSPITALS, A CANCER CENTER, AND MULTIPLE OUTPATIENT CENTERS. ULH WITH ITS LARGER FOOTPRINT AND PATIENT VOLUME HAS CHALLENGED THE CAPACITY OF OUR C&T INFRASTRUCTURE, BUT ALSO CREATED A MAJOR OPPORTUNITY TO INCREASE THE AMOUNT AND QUALITY OF OUR C&T RESEARCH. THE LONG-TERM GOAL OF THE LCTRC IS TO BUILD THE NEEDED WORKFORCE AND EXPERTISE AT UOFL AND OUR AFFILIATED HEALTHCARE SYSTEMS TO CONDUCT IMPACTFUL AND COMMUNITY ENGAGED C&T RESEARCH. WE WILL ACHIEVE THIS GOAL THROUGH THESE FIVE SPECIFIC AIMS: SPECIFIC AIM 1: EXPAND AND FULLY INTEGRATE CLINICAL AND TRANSLATIONAL RESEARCH AT UOFL, ULH AND OTHER HEALTHCARE PARTNERS. (ADMINISTRATIVE AND COMMUNITY ENGAGEMENT AND OUTREACH CORES). SPECIFIC AIM 2: CREATE AND IMPLEMENT PROFESSIONAL DEVELOPMENT FOR EARLY-CAREER CLINICIAN INVESTIGATORS, STUDENTS AND C&T RESEARCH STAFF (PROFESSIONAL DEVELOPMENT CORE). SPECIFIC AIM 3: DEVELOP PILOT AND DEVELOPMENTAL PROJECTS TO SUPPORT COMMUNITY SCIENTISTS, TRAINEES, EARLY-CAREER AND ESTABLISHED C&T INVESTIGATORS (HEALTH RESEARCH CORE). SPECIFIC AIM 4: ESTABLISH A CENTRALIZED RESOURCE THAT PROVIDES LCTRC INVESTIGATORS WITH ESSENTIAL SUPPORT IN RESEARCH DESIGN, DATA ANALYSIS, COMPLIANCE, AND DATA MANAGEMENT (RESEARCH DESIGN, COMPLIANCE AND DATA MANAGEMENT CORE). SPECIFIC AIM 5: INVEST IN BOTH COMMUNITY-LED AND COMMUNITY-PARTICIPATORY C&T RESEARCH TO IMPROVE PUBLIC HEALTH USING MULTI-DIRECTIONAL INPUTS SENSITIVE TO THE CULTURE AND NEEDS OF UNDERSERVED POPULATIONS. (SYNERGISTIC AMONG ALL CORES). SUCCESSFUL IMPLEMENTATION OF THE LCTRC WILL CREATE A SINGLE POINT OF ACCESS PROGRAM FOR C&T RESEARCH THAT ALLOWS US TO PERFORM STUDIES IN URBAN AND RURAL POPULATIONS THAT ULTIMATELY IMPROVE PUBLIC HEALTH.

RADIOLOGY WRVU SERVICES

MECHANISM FOR ARSENIC INDUCED CARCINOGENESIS

THE KENTUCKY PEDIATRIC CLINICAL TRIALS RURAL/URBAN PARTNERSHIP

BLOOD OUTER RETINA BARRIER REGULATION

IGF::OT::IGF OTHER FUNCTIONS - RADIOLOGY SERVICES (RVU)- TASK ORDER ISSUED FOR SERVICES THROUGH 9/30/17.

IGF::OT::IGF INTERPRETATION OF RADIOLOGIC EXAMS. FY16 PURCHASE ORDER FOR PROVISION OF SERVICES.

EARLY INTERVENTION SERVICES

ENVIRONMENTAL LIVER DISEASE

RADIOLOGY RVU SERVICES (6 MONTH BRIDGE)

RADIOLOGY SERVICES FOR THE ROBLEY REX VAMC - OPTION YEAR 4

RADIOLOGY SERVICES FOR THE ROBLEY REX VAMC - TASK ORDER FOR THE PERIOD 10/1/2020 - 9/30/2021

EPIDURAL SPINAL CORD STIMULATION AND RESPIRATORY MOTOR FUNCTION AFTER INJURY - PROJECT SUMMARY/ABSTRACT RESPIRATORY MOTOR CONTROL DEFICIT IS THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN PATIENTS WITH SPINAL CORD INJURY. THE LONG-TERM GOAL OF THIS RESEARCH IS TO DEVELOP A REHABILITATION STRATEGY FOR RESPIRATION IN PATIENTS WITH SPINAL CORD INJURY AS A STANDARD OF CARE. OUR PREVIOUS FINDINGS DEMONSTRATE THAT RESPIRATORY FUNCTION IN PATIENTS WITH CHRONIC SPINAL CORD INJURY CAN BE IMPROVED BY USING OUR ORIGINAL INSPIRATORY-EXPIRATORY PRESSURE THRESHOLD RESPIRATORY TRAINING PROTOCOL. HOWEVER, THE EFFECTIVENESS OF THIS INTERVENTION IS LIMITED BY THE LEVELS OF FUNCTIONAL CAPACITY PRESERVED BELOW THE NEUROLOGICAL LEVEL OF INJURY. OUR PRELIMINARY DATA OBTAINED FOR THIS PROPOSAL DEMONSTRATE THAT ELECTRICAL SPINAL CORD STIMULATION APPLIED EPIDURALLY AT THE LUMBAR LEVEL IN COMBINATION WITH RESPIRATORY CAN ACTIVATE AND RE-ORGANIZE SPINAL MOTOR NETWORKS FOR RESPIRATION. WE PROPOSE TO INVESTIGATE RESPIRATORY MOTOR CONTROL-RELATED RESPONSES TO EPIDURAL SPINAL CORD STIMULATION ALONE AND IN COMBINATION WITH RESPIRATORY TRAINING. BY CHARACTERIZATION OF RESPIRATORY MUSCLE ACTIVATION PATTERNS USING SURFACE ELECTROMYOGRAPHY IN ASSOCIATION WITH PULMONARY FUNCTIONAL AND RELATED CARDIOVASCULAR MEASURES, WE EXPECT TO DETERMINE SPECIFIC STIMULATION PARAMETERS NEEDED TO INCREASE SPINAL EXCITABILITY BELOW LEVEL OF INJURY TO ENHANCE RESPONSES TO THE INPUT FROM SUPRASPINAL CENTERS THAT REMAIN AFTER INJURY AND TO PROMOTE THE NEURAL PLASTICITY DRIVEN BY THE RESPIRATORY TRAINING. THIS HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: 1) EVALUATE THE ACUTE EFFECTS OF EPIDURAL SPINAL CORD STIMULATION ON RESPIRATORY FUNCTIONAL AND MOTOR CONTROL PROPERTIES; AND 2) EVALUATE THE EFFECTIVENESS OF EPIDURAL SPINAL CORD STIMULATION COMBINED WITH RESPIRATORY TRAINING.

RADIOLOGY SERVICES FOR THE ROBLEY REX VAMC - TASK ORDER FOR 10/1/21 - 9/30/22

TAS::75 0844::TAS NATIONAL CHILDREN'S STUDY

NNCI: KY MULTISCALE

RADIOLOGY SERVICES FOR ROBLEY REX DURING THE PERIOD 10/1/18-9/30/2019

RADIOLOGY SERVICES FOR THE ROBLEY REX VAMC - WITH POP OF 10/1/2019-9/30/2020

IRON INDEPENDENT ROLE FOR YERSINIABACTIN IN YERSINIA PESTIS - SUMMARY TRANSITIONAL METALS (E.G., FE, ZN, MN) ARE REQUIRED BY BACTERIA IN ORDER TO GROW. AS SUCH, MAMMALS HAVE A VARIETY OF MECHANISMS TO SEQUESTER THESE METALS DURING INFECTION, EFFECTIVELY LIMITING THEIR AVAILABILITY FOR USE BY BACTERIA (REFERRED TO AS NUTRITIONAL IMMUNITY). YERSINIA PESTIS, WHICH CAUSES THE HUMAN DISEASE PLAGUE, NEEDED TO EVOLVE HIGH-AFFINITY METAL ACQUISITION MECHANISMS TO OVERCOME NUTRITIONAL IMMUNITY AND COLONIZE ITS HOSTS. BECAUSE THESE MECHANISMS ARE KEY TO Y. PESTIS VIRULENCE, THEY REPRESENT POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OR PREVENTION OF PLAGUE. THEREFORE, OUR LONG TERM GOALS ARE TO IDENTIFY THE MECHANISMS USED BY Y. PESTIS TO EVADE HOST NUTRITIONAL IMMUNITY AND DEFINE THEIR ROLES IN VIRULENCE. RECENTLY, WE HAVE MADE THE EXCITING DISCOVERY THAT YERSINIABACTIN (YBT), A SIDEROPHORE ESSENTIAL FOR Y. PESTIS IRON (FE) ACQUISITION, IS ALSO ABLE TO BIND TO ZINC (ZN), AND CONTRIBUTES TO ZN ACQUISITION IN VITRO. FURTHERMORE, USING A HEMOCHROMATOSIS MOUSE MODEL THAT IS DEFECTIVE IN FE-MEDIATED NUTRITIONAL IMMUNITY, WE DEMONSTRATED FOR THE FIRST TIME THAT YBT CONTRIBUTES TO VIRULENCE IN AN FE-INDEPENDENT MANNER. USING A Y. PESTIS MUTANT DEFECTIVE IN ZN ACQUISITION, WAS ALSO SHOWED THAT THE HOST PROTEIN CALPROTECTIN, WHICH IS A KEY COMPONENT TO ZN-MEDIATED NUTRITIONAL IMMUNITY, IS A BARRIER TO Y. PESTIS INFECTION, AND YBT CONTRIBUTES TO OVERCOMING THIS BARRIER IN BOTH PNEUMONIC AND BUBONIC PLAGUE. TOGETHER, THESE DATA ARE OUR PREMISE FOR THE CONCEPTUALLY INNOVATIVE HYPOTHESIS THAT YBT NOT ONLY CONTRIBUTES TO VIRULENCE THROUGH FE ACQUISITION, BUT ALSO CONTRIBUTES TO ZN ACQUISITION, WHICH AIDS IN OVERCOMING CALPROTECTIN MEDIATED NUTRITIONAL IMMUNITY. IN THIS PROPOSAL, WE WILL BUILD ON THESE EXCITING DISCOVERIES. IN AIM 1, WE WILL DEFINE THE MECHANISMS THAT GOVERN METAL SELECTIVITY OF YBT AND THE RE-ACQUISITION OF YBT-ZN BY THE BACTERIUM. IN AIM 2, WE WILL DEFINE THE YBT SECRETION MECHANISMS USED BY Y. PESTIS AND DETERMINE THE THERAPEUTIC POTENTIAL OF INHIBITING THESE SECRETION SYSTEMS DURING PLAGUE. FINALLY, IN AIM 3, WE WILL DEFINE THE ROLE OF HOST CALPROTECTIN DURING PLAGUE AND THE CONTRIBUTION OF YBT TO THE ABILITY OF Y. PESTIS IN OVERCOMING CALPROTECTIN MEDIATED ZN SEQUESTRATION. IMPORTANTLY, YBT IS A CONSERVED VIRULENCE FACTOR IN MANY GRAM-NEGATIVE BACTERIA. THEREFORE, THE DATA GENERATED FROM THESE STUDIES HAS THE POTENTIAL TO PROVIDE US WITH A BROADER UNDERSTANDING OF THE ROLE OF YBT IN THE VIRULENCE OF MULTIPLE PATHOGENS. ULTIMATELY, THESE DATA WILL PROVIDE A FOUNDATION FOR THE RATIONAL DESIGN OF NEW THERAPEUTIC APPROACHES TARGETING THESE MECHANISMS TO COMBAT Y. PESTIS INFECTION.

RNA MODIFICATIONS IN APOLIPOPROTEIN REGULATION BY ENVIRONMENTAL EXPOSURES - EXPOSURE TO PERSISTENT ENVIRONMENTAL CONTAMINANTS INCLUDING POLYCHLORINATED BIPHENYLS (PCBS) CONTRIBUTES TO METABOLIC DISEASES INCLUDING METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD). ALTHOUGH PCB EXPOSURES ARE POSITIVELY ASSOCIATED WITH ALTERED LIVER ENZYMES, MIRNAS, MASLD, AND MORTALITY IN HUMAN COHORTS, HOW PCBS ACT IN COLLABORATION WITH A HIGH FAT DIET (HFD) TO PROMOTE INCREASED HEPATIC TRIGLYCERIDE ACCUMULATION, FIBROSIS, AND INFLAMMATION IN PROGRESSION TO METABOLIC-DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH) REMAINS UNKNOWN. FURTHER, ALTHOUGH LIVER SEXUAL DIMORPHISM AND SEX-SPECIFIC DIFFERENCES IN HUMAN HEALTH OUTCOMES AFTER PCB EXPOSURE HAVE BEEN REPORTED, FEW MECHANISTIC STUDIES HAVE ADDRESSED THESE DIFFERENCES. WE REPORTED THAT LIVERS FROM HFD-FED MALE MICE WITH MASH AFTER A SINGLE ORAL EXPOSURE TO AN ENVIRONMENTALLY-RELEVANT MIXTURE OF NON-DIOXIN-LIKE PCBS, AROCLOR1260 (AR1260), AND THE DIOXIN-LIKE PCB126 SHOWED INCREASED N(6)-METHYLADENOSINE (M6A), THE MOST COMMON RNA MODIFICATION, THAT REGULATES TRANSCRIPT STABILITY AND ALTERNATIVE SPLICING (AS). WE IDENTIFIED M6A IN APOB (APOLIPOPROTEIN B) AND OTHER MASLD-RELATED TRANSCRIPTS USING M6A MRNA IMMUNOPRECIPITATION (RIP)-SEQUENCING AND CONFIRMED SELECT M6A-DIFFERENTIALLY EXPRESSED GENES USING NANOPORE DIRECT RNA-SEQ. IN AML12 MOUSE HEPATOCYTES. REDUCED APOB PROTEIN IS CRITICAL FOR HEPATIC LIPID ACCUMULATION IN HUMAN MASLD. APOB IS CONSTITUTIVELY TRANSCRIBED, SUGGESTING THAT POST- TRANSCRIPTIONAL REGULATION AND PROTEIN STABILITY DETERMINE APOB LEVELS. THESE DATA SUPPORT OUR OVERARCHING HYPOTHESIS THAT PCB EXPOSURES AND DIET ALTER M6A TO REGULATE LIPID METABOLISM PATHWAYS IN MASLD. WE ADDRESS A CRITICAL KNOWLEDGE GAP IN HOW DIET, ENVIRONMENTAL POLLUTANT EXPOSURES, AND SEX MODIFY THE M6A EPITRANSCRIPTOME TO REGULATE APOLIPOPROTEIN HOMEOSTASIS. WE WILL 1) DETERMINE IF THE ALTERED M6A MARKS IN THE APOB TRANSCRIPT WITH PCB EXPOSURES REGULATE TRANSCRIPT STABILITY AND TRANSLATION. 2) DETERMINE HOW SEX AND DIET IMPACT M6A MARKS IN LIPOPROTEIN TRANSCRIPTS IN A HIGH FAT, HIGH FRUCTOSE DIET (HFHFD) + PCB EXPOSURE MODEL OF MASH. 3) IDENTIFY THE EXTENT OF M6A-INDUCED ALTERNATIVE SPLICING (AS) IN LIVERS IN HFHFD-FED MICE WITH PCB EXPOSURES. THE RESULTING DATA WILL BE THE FIRST TO DIRECTLY EXAMINE HOW MA6-CONTAINING APOB REGULATES PROTEIN ABUNDANCE AFFECTING HEPATIC LIPID PATHOLOGY. DETERMINING THE MECHANISTIC INTERPLAY OF M6A, DIET, AND PCB EXPOSURES IN PROMOTING NAFLD PROGRESSION WILL REVEAL POSSIBLE TARGETS FOR THERAPEUTIC INTERVENTION.

3D-BIOPRINTING OF SUSTAINED- AND PHASED-RELEASE ANTIBIOTIC AND PROBIOTIC SCAFFOLDS TO TREAT BACTERIAL VAGINOSIS - PROJECT SUMMARY BACTERIAL VAGINOSIS (BV) IS A DYSBIOSIS OF THE VAGINAL MICROBIOME THAT AFFECTS ~29% OF REPRODUCTIVE AGE WOMEN AND IS LINKED WITH HIGHER RISKS OF ADVERSE PREGNANCY OUTCOMES, POSTSURGICAL INFECTIONS, AND SEXUALLY TRANSMITTED INFECTIONS. WHILE LACTOBACILLI TYPICALLY DOMINATE THE HEALTHY VAGINA, BV IS CHARACTERIZED BY LOW LACTOBACILLI LEVELS AND AN OVERGROWTH OF DIVERSE ANAEROBIC BACTERIA, MOST OFTEN INCLUDING GARDNERELLA AND PREVOTELLA. CURRENT ORAL OR TOPICAL ANTIBIOTIC TREATMENTS ALLEVIATE SYMPTOMS IN 80% OF WOMEN, AT LEAST TEMPORARILY. HOWEVER, MOST WOMEN WILL EXPERIENCE A RECURRENCE OF BV WITHIN ONE-YEAR POST-TREATMENT. A RECENT CLINICAL STUDY SHOWED THAT A VAGINAL PROBIOTIC TREATMENT REGIMEN (WITH LACTOBACILLUS CRISPATUS), USED FOLLOWING A VAGINAL COURSE OF ANTIBIOTICS (METRONIDAZOLE), SIGNIFICANTLY IMPROVED LONG-TERM TREATMENT EFFICACY. UNFORTUNATELY, CURRENT TOPICALLY-APPLIED FORMULATIONS REQUIRE REPEATED ADMINISTRATIONS (ONCE TO TWICE DAILY), WHICH CAN HINDER FEMALE CONVENIENCE AND ADHERENCE TO TREATMENT, PARTICULARLY WHEN UNDERGOING MULTIPLE WEEKS OF TREATMENT (REQUIRED TO ADMINISTER BOTH ANTIBIOTIC AND PROBIOTICS). IN THIS PROJECT WE WILL USE 3D PRINTING AND COMPUTATIONAL MODELING, ITERATIVELY ENABLED BY FUNCTIONAL INVESTIGATION OF PROTOTYPE SCAFFOLDS IN VITRO AND IN VIVO, TO DESIGN LONG-ACTING PRODUCTS THAT SUSTAIN THERAPEUTIC DELIVERY, WHILE ENABLING PHASED-DELIVERY OF ANTIBIOTICS AND PROBIOTICS TO THE FEMALE REPRODUCTIVE TRACT. OUR TEAM BRINGS TOGETHER FEMALE REPRODUCTIVE TRACT-SPECIFIC EXPERTISE IN DELIVERY VEHICLE DESIGN, COMPUTATIONAL MODELING, AND PRECLINICAL BV MODELS. THE ULTIMATE GOAL IS TO USE 3D-BIOPRINTING TO INCORPORATE DIFFERENT DEVICE COMPARTMENTS, WHICH SEQUENTIALLY RELEASE ANTIBIOTICS THAT TARGET ANAEROBIC OVERGROWTH, FOLLOWED BY LIVE PROBIOTICS THAT RESTORE BALANCE BACK IN FAVOR OF VAGINAL LACTOBACILLI. IN AIM 1, WE WILL DESIGN AND CHARACTERIZE 3D-PRINTED SILICONE SCAFFOLDS THAT SUSTAIN ANTIBIOTIC-ONLY DELIVERY. AIM 2 WILL DESIGN AND EVALUATE 3D-PRINTED SILICONE AND GELATIN ALGINATE COMPOSITES THAT SEQUENTIALLY RELEASE ANTIBIOTICS FOLLOWED BY PROBIOTICS, PROVIDING A “1-2 PUNCH” STRATEGY TO KILL BV BACTERIA AND PROVIDE A ‘HEALTHY’ LACTOBACILLUS ALTERNATIVE. EACH AIM WILL FOCUS FIRST ON A MATERIALS-BASED CHARACTERIZATION OF MET-CONTAINING SILICONE (1A) OR MET-SILICONE PROBIOTIC-GELATIN ALGINATE COMPOSITES (2A). MEASUREMENTS FROM IN VITRO RELEASE EXPERIMENTS WILL BE USED TO DEVELOP AND TEST COMPUTATIONAL MODELS THAT PREDICT THE DELIVERY OF ANTIBIOTIC (1B) OR DUAL AGENTS (2B) IN A “VIRTUAL FEMALE REPRODUCTIVE TRACT” AND ULTIMATELY IN A MOUSE CO-INFECTION MODEL. WE WILL EVALUATE MET-SILICONE (1C) AND MET-SILICONE PROBIOTIC-GELATIN ALGINATE COMPOSITES (2C) FOR CYTOTOXICITY TO THE VAGINAL EPITHELIUM AND ABILITY TO STIMULATE SOLUBLE PROINFLAMMATORY MEDIATORS AND DOWNSTREAM HISTOPATHOLOGY. IN OUR MOUSE MODEL, WE WILL MEASURE LEVELS OF VIABLE GARDNERELLA AND PREVOTELLA RECOVERED FROM VAGINAL AND UTERINE TISSUES FOLLOWING TREATMENT WITH BLANK OR ACTIVE AGENT- CONTAINING 3D-PRINTED SCAFFOLDS. IF SUCCESSFUL, THIS PROJECT WILL SUPPORT THE DEVELOPMENT OF MULTIPURPOSE PLATFORMS TO PREVENT AND TREAT BV AS WELL AS OTHER FEMALE REPRODUCTIVE TRACT APPLICATIONS.

SYSTEMATIC IDENTIFICATION OF CARDIOTOXIC E-CIGARETTE FLAVORANTS - ABSTRACT THE USE OF E-CIGARETTES (E-CIGS) HAS INCREASED SUBSTANTIALLY SINCE THEY WERE FIRST INTRODUCED IN 2003. E-CIG DEVICES AEROSOLIZE E-LIQUIDS THAT TYPICALLY CONSIST OF HUMECTANTS WITH VARIABLE LEVELS OF NICOTINE AND FLAVORING CHEMICALS. ALTHOUGH THERE ARE THOUSANDS OF COMMERCIALLY AVAILABLE FLAVOR MIXTURES, THEY ROUTINELY OVERLAP IN INDIVIDUAL FLAVOR CHEMICALS (FLAVORANTS), WHICH ARE FAR FEWER IN NUMBER. MANY OF THESE FLAVORANTS BELONG TO COMMON CHEMICAL CLASSES AND ARE GENERALLY RECOGNIZED AS SAFE FOR INGESTION. HOWEVER, THEIR DIRECT AND INDIRECT CARDIAC EFFECTS FOLLOWING HEATING AND INHALATION, PARTICULARLY IN COMBINATION WITH NICOTINE, REMAIN MOSTLY UNKNOWN. DIRECT EXPOSURE TO NICOTINE ALONE DISTINCTLY AFFECTS THE CARDIAC ACTION POTENTIAL WAVEFORM, POTENTIALLY CONTRIBUTING TO THE HIGH INCIDENCE OF ARRHYTHMIAS AND SUDDEN CARDIAC DEATH AMONG SMOKERS. RECENT EVIDENCE ALSO SUGGESTS THAT NICOTINE IN E-CIGS MAY SIMILARLY PROMOTE ADVERSE CARDIAC OUTCOMES. YET, THE INFLUENCE OF FLAVORANTS ON THE CARDIAC EFFECTS OF E-CIG AEROSOLS REMAINS UNTESTED. IN OUR ONGOING WORK, WE FOUND THAT EXPOSURE TO NICOTINE- CONTAINING E-CIG AEROSOLS OF VARIOUS FLAVORS ACUTELY AND DIFFERENTIALLY ALTERED THE ELECTROCARDIOGRAM (ECG) IN MICE, VARIABLY INDUCING QT INTERVAL PROLONGATION, INCREASING HEART RATE, AND EVOKING ARRHYTHMIA. AS WELL, TWO SEPARATE E-LIQUIDS WITH THE SAME CHARACTERIZING FLAVORANT CONSISTENTLY INCREASED VENTRICULAR ARRHYTHMIAS. FURTHERMORE, WE OBSERVED IN CARDIOMYOCYTES THAT TREATMENT WITH SEVERAL FLAVORANTS COMMON TO E-CIGS DIRECTLY ALTERED CONTRACTILITY, RHYTHMICITY, AND ACTION POTENTIAL DURATION. NONETHELESS, IT REMAINS UNKNOWN HOW INDIVIDUAL FLAVORANTS IN E-CIG AEROSOLS EXERT DIRECT OR INDIRECT CARDIAC EFFECTS IN VIVO. CONSIDERING THE GROWING POPULARITY OF E-CIGARETTES AND THE URGENT NEED FOR STUDYING THE IN VIVO TOXICOLOGICAL PROFILE OF CONSTITUENTS IN THESE PRODUCTS, WE PROPOSE TO TEST THE HYPOTHESIS THAT E-CIGARETTE FLAVORANTS MODIFY THE EFFECTS OF E-CIG AEROSOL EXPOSURES ON CARDIAC ELECTROPHYSIOLOGY, LEADING TO ARRHYTHMIAS AND FUNCTIONAL REMODELING OF THE HEART. TO TEST THIS, WE WILL SYSTEMATICALLY IDENTIFY BOTH ACUTE AND LONG-TERM EFFECTS OF FLAVORANT EXPOSURE ON CARDIAC ELECTROPHYSIOLOGY USING A COMBINATION OF STATE-OF-THE-ART IN VIVO, IN VITRO, AND EX VIVO APPROACHES. SPECIFICALLY, WE WILL: 1) IDENTIFY THE ACUTE EFFECTS OF FLAVORED E-CIG AEROSOL INHALATION ON CARDIAC ELECTROPHYSIOLOGY IN VIVO, 2) EXAMINE THE DIRECT IMPACT OF FLAVORANTS ON CARDIAC ELECTROPHYSIOLOGY IN VITRO AND EX VIVO, AND, 3) ELUCIDATE DELETERIOUS IMPACTS OF ACUTE AND CHRONIC FLAVORANT AEROSOL EXPOSURE ON CARDIAC ELECTROPHYSIOLOGY, STRUCTURE, AND FUNCTION. THESE STUDIES, WHICH ARE RESPONSIVE TO THE RESEARCH PRIORITIES OF THE FDA/CTP, WILL PROVIDE NEW DATA SHOWING HOW DIFFERENT FLAVOR CHEMICALS AFFECT CARDIAC EXCITABILITY AND POTENTIALLY PROMOTE ARRHYTHMOGENESIS. SUCH RESULTS WOULD AID IN FORMULATING POLICIES REGULATING THE MANUFACTURE, DISTRIBUTION AND MARKETING OF FLAVORED E-CIGARETTES.

P.GINGIVALIS INTERACTIONS WITH GINGIVAL EPITHELIAL CELLS

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

LONGITUDINAL PERSONALIZED DYNAMICS AMONG ANOREXIA NERVOSA SYMPTOMS, CORE DIMENSIONS, AND PHYSIOLOGY PREDICTING SUICIDE RISK - PROJECT SUMMARY/ABSTRACT ANOREXIA NERVOSA (AN) IS A SEVERE MENTAL ILLNESS WITH THE HIGHEST MORTALITY RATE OF ANY PSYCHIATRIC DISORDER, WITH SUICIDE AS THE SECOND LEADING CAUSE OF DEATH. DESPITE EXTREMELY HIGH RATES OF SUICIDE, RISK FACTORS FOR SUICIDAL IDEATION (SI) AND BEHAVIORS/ATTEMPTS (SA) IN THIS HIGH-RISK POPULATION ARE NOT WELL UNDERSTOOD. WHILE THERE IS EVIDENCE THAT THREAT REACTIVITY, STRESS-RESPONSE, OVER-AROUSAL, EMOTION DYSREGULATION, AND AGITATION CONTRIBUTE TO SUICIDE RISK, THE DYNAMIC RELATIONS AMONG THESE PROCESSES HAVE NOT BEEN CHARACTERIZED ON A COMPREHENSIVE, MOMENTARY BASIS. OUR SCIENTIFIC PREMISE, DEVELOPED FROM OUR PAST WORK, IS THAT THE APPLICATION OF IDEATION-TO-ACTION AND NETWORK THEORIES WILL ENABLE THE IDENTIFICATION OF DYNAMIC LONGITUDINAL INTERACTIONS AMONG CORE DIMENSIONS (E.G., AROUSAL, THREAT), AN SYMPTOMS, AND SI/SA BOTH BETWEEN AND WITHIN INDIVIDUALS. OUR STUDY GOALS ARE TO (1) IDENTIFY SYMPTOM AND DIMENSION RISK INTERACTIONS OF CO-OCCURRING AN AND SI/SA BETWEEN AND WITHIN PERSONS, (2) DIFFERENTIATE WHICH RISK FACTORS PREDICT SI VS SA AND (3) TEST IF THESE RISK FACTORS PREDICT ONSET OF SI/SA. THESE GOALS WILL ULTIMATELY IDENTIFY WHICH FACTORS SHOULD BE TARGETED IN NOVEL PREVENTION AND TREATMENT EFFORTS. WE WILL USE A MULTIPLE UNITS OF ANALYSIS APPROACH, COMBINED WITH NOVEL, CUTTING-EDGE ADVANCES IN SUICIDE AND NETWORK SCIENCE. WE WILL COLLECT INTENSIVE REAL-TIME DATA ON AN AND SUICIDE BEHAVIORS, ANXIETY, OVER-AROUSAL, EMOTION REGULATION, AND AGITATION USING MOBILE TECHNOLOGY, AS WELL AS PSYCHOPHYSIOLOGICAL ASSESSMENT OF EMOTION REGULATION (VIA HEART-RATE VARIABILITY) AND AROUSAL (VIA ELECTRODERMAL ACTIVITY CHARACTERIZING OVER-AROUSAL AND ACCELERATION CHARACTERIZING THE SLEEP-WAKE CYCLE), FROM 230 INDIVIDUALS WITH A DIAGNOSIS OF AN/ATYPICAL AN (AAN). AT 1-MONTH, 6-MONTH, AND ONE YEAR FOLLOW-UP WE WILL TEST IF INDIVIDUAL RISK FACTORS PREDICT SI/SA. WE EXPECT 35-58 PARTICIPANTS WILL HAVE SA ACROSS OUR STUDY PERIOD. SPECIFIC AIMS ARE TO (1) TEST WHICH SYMPTOMS AND DIMENSIONS ACROSS TIME AND BETWEEN-PERSONS MAINTAIN COMORBID SI/SA AND AN SYMPTOMS, (2) DEVELOP PERSONALIZED NETWORK MODELS TO IDENTIFY WHICH SUICIDE AND AN FEATURES PREDICT SI/SA WITHIN INDIVIDUALS AND AN EXPLORATORY AIM (3) TO TEST IF THERE ARE DIFFERENCES BETWEEN AN AND AAN. THE PROPOSED RESEARCH USES HIGHLY INNOVATIVE METHODS, COMBINING INTENSIVE LONGITUDINAL DATA COLLECTION METHODS, MEASUREMENT OF PHYSIOLOGICAL DATA VIA WEARABLE SENSOR TECHNOLOGY, AND NOVEL ADVANCES IN NETWORK SCIENCE TO ANSWER PREVIOUSLY UNRESOLVABLE QUESTIONS PINPOINTING WHICH INDIVIDUAL RISK FACTORS CONTRIBUTE TO SUICIDE OUTCOMES. THE PROPOSED RESEARCH HAS CLINICAL IMPACT. IF WE IDENTIFY PATTERNS THAT CONTRIBUTE TO SUICIDE RISK, THESE DATA WILL PROVIDE A MODEL OF PERSONALIZED MEDICINE FOR THE ENTIRE FIELD OF PSYCHIATRY, AS WELL AS PROVIDING NOVEL INTERVENTION TARGETS TO PREVENT AND TREAT AN SPECTRUM ILLNESSES. ADDITIONALLY, THE ALGORITHMS WE DEVELOP CAN BE USED IN BOTH (A) CLINICIAN FRIENDLY SOFTWARE TO IDENTIFY TREATMENT TARGETS TO PREVENT SI/SA AND (B) IN WEARABLE ALERT DEVICES THAT CAN DISRUPT SA BEFORE IT OCCURS.

NURSE EDUCATION, PRACTICE, QUALITY, AND RETENTION - INTERPROFESSIONAL COLLBORATIVE PRACTICE - THE PURPOSE OF THIS PROJECT IS TO DEVELOP AND IMPLEMENT AN INCREMENTAL, ACCELERATED LICENSED PRACTICAL NURSE TO BACHELOR OF SCIENCE IN NURSING (LPN-TO-BSN) PATHWAY TO IMPROVE THE DIVERSITY OF THE RN WORKFORCE IN MEDICALLY UNDERSERVED AREAS OF KENTUCKY. THE OBJECTIVES ARE TO:? 1) DEVELOP AND IMPLEMENT AN INCREMENTAL, ACCELERATED LPN-TO-BSN EDUCATIONAL PATHWAY TO PREPARE LPNS FOR SUCCESS ON THE NCLEX-RN© AND GAINFUL EMPLOYMENT POST-GRADUATION.? 2) INCREASE THE DIVERSITY OF THE RN WORKFORCE IN MEDICALLY UNDERSERVED AREAS IN KENTUCKY.? 3) GROW THE NUMBER OF QUALIFIED DIVERSE NURSING FACULTY IN KENTUCKY.? 4) EXPAND ACADEMIC-CLINICAL PARTNERSHIPS IN MEDICALLY UNDERSERVED AREAS.? THIS GRANT WILL FUND THE: (1) CREATION OF AN INCREMENTAL, ACCELERATED LPN-TO-BSN PATHWAY, (2) ENHANCEMENT OF THE LPN-TO-BSN CURRICULUM, (3) RECRUITMENT AND RETENTION OF DIVERSE LPN-TO-BSN STUDENTS AND NURSING FACULTY, AND (4) FINANCIAL, ACADEMIC, AND SOCIAL SUPPORT FOR LPN-TO-BSN PATHWAY STUDENTS. THE PROGRAM IS A COLLABORATIVE EFFORT BETWEEN THE UNIVERSITY OF LOUISVILLE SCHOOL OF NURSING (ULSON) AND THE KENTUCKY COMMUNITY AND TECHNICAL COLLEGE SYSTEM AND WILL ALIGN CURRICULA OF THE ESTABLISHED LPN-TO-RN BRIDGE PROGRAM AND THE RN-TO-BSN PROGRAM TO CREATE AN LPN-TO-BSN PATHWAY. SITES: THE PROJECT FOCUS AREAS ARE: (1) MEDICALLY UNDERSERVED COUNTIES IN NORTH CENTRAL KENTUCKY, (2) RURAL SOUTHEASTERN KENTUCKY COUNTIES SERVED BY MOUNTAIN COMPREHENSIVE HEALTH CORPORATION, AND (3) RURAL WESTERN KENTUCKY COUNTIES SERVED BY OWENSBORO HEALTH, INC. NEED: THE US IS PROJECTED TO HAVE A SHORTAGE OF NEARLY 100,000 RNS BY 2025, WITH RURAL AREAS PROJECTED TO HAVE A LARGER SHORTAGE. DESPITE THIS NEED, ENROLLMENT IN KENTUCKY’S ADN AND BSN PROGRAMS HAS DECLINED SINCE 2019 WITH AN ANTICIPATED REDUCTION OF NEW RNS ENTERING THE WORKFORCE. HOWEVER, THE NUMBER OF STUDENTS PURSUING LPN EDUCATION IS INCREASING, INDICATING INTEREST IN NURSING, BUT ALSO THE DESIRE FOR EXPEDITED WORKFORCE ENTRY. RNS EDUCATED AT THE BACCALAUREATE LEVEL ARE BEST PREPARED TO PROVIDE SAFE AND EFFECTIVE CARE, ESPECIALLY IN COMMUNITY SETTINGS. TO PREPARE THE RN WORKFORCE TO MEET THE COMPLEX HEALTH NEEDS OF KENTUCKY, EQUAL ACCESS TO RN TRAINING PROGRAMS THROUGHOUT THE STATE IS PARAMOUNT. THIS IS ESPECIALLY CRUCIAL IN RURAL SETTINGS, WHERE THERE IS LIMITED ACCESS TO BSN PROGRAMS. WE WILL OFFER AN ACCELERATED LPN-TO-BSN PATHWAY IN RURAL, UNDERSERVED AREAS AND WILL ADDRESS THE ACADEMIC, SOCIAL, AND FINANCIAL BARRIERS TO STUDENT SUCCESS WITH A HOLISTIC SUPPORT PROGRAM. TO ENSURE GRADUATES ARE PREPARED TO PROVIDE CARE FOR DIVERSE PATIENT POPULATIONS, THE CURRICULUM WILL FOCUS ON DIVERSITY, EQUITY, AND INCLUSION THROUGH INFUSING PRINCIPLES OF SOCIAL DETERMINANTS OF HEALTH (SDOH), HEALTH EQUITY, AND HEALTH LITERACY THROUGHOUT THE BSN PATHWAY. METHODOLOGY: WE WILL DEVELOP RECRUITMENT MATERIALS THAT SPECIFICALLY FOCUS ON PROSPECTIVE STUDENTS WHO ARE DIVERSE OR ARE FROM UNDERSERVED COMMUNITIES. THE APPLICATION PROCESS WILL BE REVIEWED AND REVISED TO BE MORE HOLISTIC. FACULTY WILL BE TRAINED TO SUPPORT CULTURALLY AND LINGUISTICALLY DIVERSE STUDENTS. A SDOH CURRICULUM SPANNING THE FULL PROGRAM LENGTH WILL MOVE STUDENTS FROM FOUNDATIONAL KNOWLEDGE TO APPLICATION. THE SON’S STRONG RELATIONSHIPS WITH CLINICAL PARTNERS WILL PROVIDE FOR RECRUITMENT OF DIVERSE STUDENTS AND FACULTY AND INCREASED CLINICAL PLACEMENT OPPORTUNITIES IN RURAL AND MEDICALLY UNDERSERVED AREAS. OUTCOMES MEASURES INCLUDE BUT ARE NOT LIMITED TO: NUMBER OF DIVERSE STUDENTS AND NEW FACULTY; PROGRAM COMPLETION RATE; STUDENT EXPERIENCE WITH MEDICALLY UNDERSERVED POPULATIONS, AND PERCENTAGE OF GRADUATES WORKING IN MEDICALLY UNDERSERVED AREAS. WE REQUEST FUNDING PREFERENCE, “QUALIFICATION 2: SUBSTANTIALLY BENEFIT UNDERSERVED POPULATIONS,” AS CLINICAL EXPERIENCES WILL OCCUR AT SITES DESIGNATED AS MEDICALLY UNDERSERVED AREAS.

PROPRIOPSINAL NEURON FUNCTION IN NORMAL AND POST-SCI LOCOMOTION - ABSTRACT: DESPITE THE MORE THAN 100 YEARS SINCE THE RECOGNITION OF INTRINSIC SPINAL LOCOMOTOR CIRCUITS, MANY OF THE FUNCTIONAL DETAILS OF THOSE CIRCUITS AND THEIR CONTRIBUTIONS TO RECOVERY FOLLOWING SPINAL CORD INJURY (SCI) REMAIN TO BE DETERMINED. RECENT DEVELOPMENT OF POWERFUL MOLECULAR TOOLS ENABLES FUNCTIONAL DISSECTION OF NEURAL CIRCUITRY VIA REVERSIBLY SILENCING NEUROTRANSMISSION AND TRANS-SYNAPTIC LABELING. WE WILL COMBINE THESE TOOLS WITH SOPHISTICATED GAIT AND KINEMATIC ANALYSES, THAT INCLUDES THE FULL REPERTOIRE OF SPEED DEPENDENT GAITS, TO PROVIDE THE FUNCTIONAL AND ANATOMICAL INFORMATION NECESSARY FOR BUILDING AND REFINING AN ADVANCED NEURO- BIOMECHANICAL COMPUTER MODEL OF THE RAT SPINAL CORD, BODY AND LIMBS. WE WILL FOCUS ON TWO CLASSES OF SPINAL CORD INTERNEURONS, THE LONG ASCENDING (LAPNS) AND DESCENDING (LDPNS) PROPRIOSPINAL NEURONS, THAT INTERCONNECT THE FORELIMB AND HINDLIMB CIRCUITS AND CENTRAL PATTERN GENERATORS IN THE TWO ENLARGEMENTS, AND INVESTIGATE THEIR ROLE IN THE INTACT SPINAL CORD AND AFTER SCI USING BOTH HEMISECTION AND CONTUSION MODELS. OUR PRELIMINARY DATA SHOW THAT THESE LAPNS/LDPNS ARE ESSENTIAL COMPONENTS INVOLVED IN SPEED-DEPENDENT GAIT EXPRESSION. SILENCING THESE NEURONS PARTIALLY DECOUPLES THE RIGHT AND LEFT LIMBS AT EACH GIRDLE. SURPRISINGLY, SILENCING THESE NEURONS AFTER AN INCOMPLETE CONTUSION INJURY RESULTS IN BETTER OVERGROUND LOCOMOTION, A RESULT THAT IS HARD TO RECONCILE BASED ON CURRENT KNOWLEDGE AND OBSERVATIONS IN UNINJURED ANIMALS. USING VIRAL-BASED TRANS-SYNAPTIC LABELING WE WILL DETERMINE THE SENSORY, DESCENDING AND PROPRIOSPINAL INPUTS ONTO BOTH LAPNS AND LDPNS. WE WILL UTILIZE BOTH EXISTING AND NEW PHYSIOLOGICAL AND BIOMECHANICAL DATA (AIM 1) AS WELL AS NEW ANATOMICAL DATA (AIM 2) TO BUILD AND REFINE OUR COMPUTATIONAL MODEL (AIM 3). THEN, IN VIVO EXPERIMENTS AND COMPUTER MODELING WILL BE PERFORMED IN PARALLEL (AIM 4) TO DETERMINE THE ROLES THAT IPSILATERAL AND COMMISSURAL LAPNS AND LDPNS PLAY IN LOCOMOTOR BEHAVIOR, INCLUDING THE FULL RANGE OF LOCOMOTOR GAITS, AND IN RECOVERED FUNCTION AFTER HEMISECTION AND INCOMPLETE CONTUSION INJURIES. WE SUGGEST THAT A DEEPER UNDERSTANDING OF LONG PROPRIOSPINAL NEURONS REPRESENTS AN IMPORTANT STEP TOWARDS THE DEVELOPMENT OF NEW THERAPEUTIC TOOLS FOR RECOVERY AFTER SCI.

CYBERCORPS SCHOLARSHIP FOR SERVICE: CYBERSECURITY TALENT DEVELOPMENT IN KENTUCKY -THE SECURITY AND PROSPERITY OF THE UNITED STATES HAVE BECOME INCREASINGLY DEPENDENT ON ITS TECHNOLOGICAL SUPERIORITY AND COMPETITIVENESS IN THE CYBERSPACE. THE UNIVERSITY OF LOUISVILLE?S CYBERCORPS?: SCHOLARSHIP FOR SERVICE (SFS) PROGRAM WILL PREPARE 20 DIVERSE MASTER?S STUDENTS WITH SUPERIOR CYBERSECURITY SKILLS FOR ENTRY INTO THE GOVERNMENT WORKFORCE. TO ENSURE DIVERSITY, THIS PROJECT WILL ACTIVELY RECRUIT STUDENTS FROM CURRENTLY UNDERREPRESENTED GROUPS IN THE CYBERSECURITY WORKFORCE, INCLUDING WOMEN, MINORITIES, AND LOW-INCOME STUDENTS. AS THE FIRST SFS PROGRAM IN KENTUCKY, THIS PROJECT WILL MAKE ADVANCED CYBERSECURITY EDUCATION AND FINANCIAL, ACADEMIC, AND STUDENT SUPPORT MORE ACCESSIBLE TO DIVERSE STUDENTS IN KENTUCKY AND BEYOND. THIS PROJECT BUILDS ON THE EXISTING GRADUATE CERTIFICATE IN CYBERSECURITY PROGRAM, WHICH IS DESIGNATED BY THE NATIONAL SECURITY AGENCY AND DEPARTMENT OF HOMELAND SECURITY AS A NATIONAL CENTER OF ACADEMIC EXCELLENCE IN CYBER DEFENSE EDUCATION, TO PROVIDE STUDENTS WITH RIGOROUS TRAINING IN ADVANCED CYBERSECURITY KNOWLEDGE AND SKILLS TO DEFEND AGAINST CURRENT AND EMERGING CYBERATTACKS. SCHOLARSHIP RECIPIENTS WILL ALSO PARTICIPATE IN A VARIETY OF ACADEMIC AND STUDENT SUPPORT ACTIVITIES, SUCH AS PERSONALIZED CURRICULUM PLANNING AND MENTORING, COHORT-BASED PEER MEETINGS AND ADVISING, A FEDERAL INTERNSHIP PROGRAM, AND OTHER PROFESSIONAL DEVELOPMENT ACTIVITIES TO PROMOTE THEIR SUCCESS IN THE PROGRAM. ADDITIONALLY, THIS PROJECT WILL HELP THE UNIVERSITY OF LOUISVILLE BROADEN PARTICIPATION IN CYBERSECURITY EDUCATION AND STRENGTHEN PARTNERSHIPS WITH GOVERNMENT AGENCIES IN CYBERSECURITY. THIS PROJECT IS SUPPORTED BY THE CYBERCORPS? SCHOLARSHIP FOR SERVICE (SFS) PROGRAM, WHICH FUNDS PROPOSALS ESTABLISHING OR CONTINUING SCHOLARSHIP PROGRAMS IN CYBERSECURITY AND ALIGNS WITH THE U.S. NATIONAL CYBER STRATEGY TO DEVELOP A SUPERIOR CYBERSECURITY WORKFORCE. FOLLOWING GRADUATION, SCHOLARSHIP RECIPIENTS ARE REQUIRED TO WORK IN CYBERSECURITY FOR A FEDERAL, STATE, LOCAL, OR TRIBAL GOVERNMENT ORGANIZATION FOR THE SAME DURATION AS THEIR SCHOLARSHIP SUPPORT. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

LOW DENSITY NEUTROPHILS LINK INFLAMMATION AND COAGULOPATHY IN COVID-19 - PROJECT SUMMARY CORONAVIRUS DISEASE 2019 (COVID-19) IS A POTENTIALLY LIFE THREATENING DISEASE CAUSED BY THE NOVEL VIRAL PATHOGEN, SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2). APPROXIMATELY 20% OF COVID-19 PATIENTS EXPERIENCE SEVERE DISEASE, TYPICALLY PRESENTING WITH BILATERAL PNEUMONIA, AND ABOUT 5% PROGRESS TO ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). ARDS RESULTS FROM A COMBINATION OF VIRALLY INDUCED LUNG INJURY AND THE RAPID INFLUX OF IMMUNE CELLS THAT RELEASE INFLAMMATORY MEDIATORS LEADING TO A HYPER-ACTIVATED STATE KNOWN AS CYTOKINE STORM. COVID-19 ARDS IS FURTHER EXACERBATED BY A UNIQUE DIFFUSE COAGULOPATHY LEADING TO THROMBUS FORMATION IN THE VENOUS AND ARTERIAL CIRCULATIONS AND MICROTHROMBI IN CAPILLARIES OF THE LUNGS. PREDISPOSING FACTORS FOR THIS COAGULOPATHY INCLUDE INCREASED FIBRINOGEN, ACTIVATED COAGULATION CASCADE, PLATELET ACTIVATION, HYPER- INFLAMMATION, NEUTROPHIL EXTRACELLULAR TRAP (NET) FORMATION, AND ENDOTHELIAL CELL DAMAGE. UNDERSTANDING THE PATHOPHYSIOLOGY OF COVID-19 COAGULOPATHY AND ARDS IS CRITICAL TO FINDING EFFECTIVE THERAPEUTIC INTERVENTIONS. ACCUMULATING EVIDENCE INDICATES CRITICAL ROLES OF NEUTROPHILS IN BOTH ARDS AND IMMUNOTHROMBOSIS IN COVID-19. OUR PRELIMINARY STUDIES IDENTIFIED A NOVEL POPULATION OF LOW-DENSITY NEUTROPHILS (LDN) WHICH EXPRESSES INTERMEDIATE LEVELS OF CD16 (CD16INT LDN) IN COVID-19 PATIENTS. THE NUMBER OF CD16INT LDN CORRELATED WITH DISEASE SEVERITY, LEVELS OF INFLAMMATORY CYTOKINES IL-6/TNF-A, D-DIMER LEVELS, AND CLINICAL OUTCOMES. IN ADDITION, CD16INT LDN SHOWED SPONTANEOUS NET FORMATION AND EVIDENCE OF IN VIVO PLATELET ACTIVATION AND GRANULE EXOCYTOSIS. BASED ON THESE FINDINGS, WE POSTULATE THAT CD16INT LDN PLAY A CRITICAL ROLE IN THE INDUCTION OF COAGULOPATHY AND PULMONARY INFLAMMATION IN SEVERE AND CRITICAL COVID-19 PATIENTS. THREE SPECIFIC AIMS ARE PROPOSED TO FURTHER DISSECT THE UNDERLYING MECHANISMS. AIM 1 WILL COMPREHENSIVELY CHARACTERIZE LDN SUBSETS USING PROTEOMICS AND TRANSCRIPTOMICS APPROACHES. THE INFORMATION GAINED FROM THOSE STUDIES WILL BE USED TO REFINE OUR CYTOF ANTIBODY PANEL. WE WILL USE THIS PANEL TO TRACK DIFFERENTIAL NEUTROPHIL CLUSTERS IN LONGITUDINAL PATIENT SAMPLES. AIM 2 WILL DETERMINE LDN SUBSETS FUNCTIONAL CHANGES DURING DISEASE PROGRESSION AND THEIR CONTRIBUTIONS TO DYSREGULATED INFLAMMATORY RESPONSE AND COAGULOPATHY IN SEVERE AND CRITICAL COVID- 19 PATIENTS. NEUTROPHIL DEGRANULATION, NET FORMATION, PHAGOCYTOSIS, CHEMOTAXIS, APOPTOSIS, AND CYTOKINE RELEASE WILL BE EXAMINED. WE WILL ALSO DETERMINE IF LDN PROMOTE COAGULOPATHY IN COVID-19 PATIENTS. AIM 3 WILL DETERMINE WHETHER INHIBITION OF NEUTROPHIL GRANULE EXOCYTOSIS USING OUR NOVEL TAT-FUSION PROTEIN INHIBITORS PREVENTS ACTIVATED NEUTROPHIL-MEDIATED FUNCTIONAL CHANGES AND HYPERCOAGULATION. WE WILL ALSO USE A HACE2 TG MOUSE MODEL TO DETERMINE THE IN VIVO EFFICACY OF TAT-FUSION PROTEINS ON LUNG INFLAMMATION AND IMPAIRED FUNCTION. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL PROVIDE NOVEL INSIGHTS INTO COVID-19 PATHOPHYSIOLOGY BY DEFINING THE ROLE OF A UNIQUE SUBSET OF NEUTROPHILS AND BY ESTABLISHING NEUTROPHIL DEGRANULATION AS A THERAPEUTIC TARGET FOR INHIBITING INFLAMMATORY LUNG INJURY AND IMMUNOTHROMBOSIS IN COVID-19.

ABIN1 DYSFUNCTION IN LUPUS NEPHRITIS - PROJECT SUMMARY LUPUS NEPHRITIS (LN) IS A COMMON AND SEVERE COMPLICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AND CURRENT THERAPIES ARE TOXIC AND FREQUENTLY INEFFECTIVE. LN IS MORE PREVALENT AND MORE LIKELY TO CAUSE KIDNEY FAILURE IN AFRICAN AMERICAN PATIENTS [1-3]. SLE HAS STRONG GENETIC COMPONENTS, BUT THE RELATIONSHIP OF GENETIC SUSCEPTIBILITY TO PROGNOSIS IN AFRICAN AMERICANS IS POORLY UNDERSTOOD. PREVIOUS STUDIES SHOWED VARIANTS OF TNIP1 ARE ASSOCIATED WITH SLE AND LN SUSCEPTIBILITY [4-7]. WE REPORTED A STRONG ASSOCIATION FOR THE TNIP1 RS4958881 POLYMORPHISM WITH LN IN AFRICAN AMERICAN PATIENTS FROM A LARGE-SCALE SLE GENOTYPING STUDY [8]. OUR PRELIMINARY DATA SHOW AN ASSOCIATION OF THE RS4958881 VARIANTS WITH SEVERITY AND PROGRESSION OF LN IN AFRICAN AMERICANS. TNIP1 ENCODES THE PROTEIN ABIN1 THAT FUNCTIONS AS A PHYSIOLOGICAL INHIBITOR OF NF-B, A PROMINENT IMMUNE REGULATOR [9, 10]. WE REPORTED PREVIOUSLY THAT LOSS OF THE MOLECULAR FUNCTION OF ABIN1 IN MICE RESULTS IN SLE-LIKE AUTOIMMUNITY AND GLOMERULONEPHRITIS [8, 11, 12]. WHILE THERE IS EVIDENCE THAT ABIN1 REGULATION OF NF-B PLAYS A ROLE IN AUTOIMMUNITY AND DEVELOPMENT OF LN, A NUMBER OF CRITICAL GAPS IN KNOWLEDGE REMAIN. FIRST, WHAT MOLECULAR MECHANISMS MEDIATE ABIN1- DEPENDENT ENHANCED RISK OF LN, AND ARE THEY SPECIFIC FOR DIFFERENT IMMUNE CELL TYPES? SECOND, DOES ALTERED ABIN1 FUNCTION INDUCED BY TNIP1 POLYMORPHISMS PLAY A ROLE IN THE RACIAL DISPARITY OF LN? THIRD, DO TNIP1 POLYMORPHISMS HAVE DIFFERENT PATHOLOGIC, MOLECULAR, AND CELLULAR EFFECTS IN AFRICAN AMERICANS COMPARED WITH WHITE AMERICANS? THREE SPECIFIC AIMS ARE PROPOSED TO ADDRESS THESE SIGNIFICANT QUESTIONS. AIM 1: COMPARE THE ASSOCIATION OF THETNIP1 VARIANT RS4958881 ON LN IN WHITE AND AFRICAN AMERICANS. AIM 2: DETERMINE THE EFFECTS OF THE TNIP1 VARIANT RS4958881 ON MONOCYTE, NEUTROPHILS, AND B CELL ACTIVITY IN PATIENTS WITH LN. AIM 3. DETERMINE THE MECHANISMS BY WHICH LOSS OF ABIN1 MOLECULAR FUNCTION ALTERS MONOCYTE, NEUTROPHIL, AND B CELL FUNCTION USING ABIN1 TRANSGENIC MICE. THE ANIMAL EXPERIMENTS WILL BE INTERPRETED IN CONJUNCTION WITH SIMILAR EXPERIMENTS IN AIM 2 USING THE SAME CELLS ISOLATED FROM BLOOD OF LN PATIENTS WITH THE TNIP1 RS4958881 RISK VARIANT. THIS IS A MULTI-PI PROPOSAL WITH A CELL AND MOLECULAR BIOLOGIST/BIOCHEMIST (DR. DAVID W. POWELL) AND A CLINICAL NEPHROLOGIST/SCIENTIST (DR. DAWN J. CASTER). THESE INVESTIGATORS HAVE PUBLISHED MANY OF THE REPORTS PERTAINING TO TINIP1/ABIN1 FUNCTION IN LN VIA GENETIC AND ANIMAL STUDIES AND ARE NOW POISED WITH RECENT PRELIMINARY FINDINGS TO EVALUATE CAUSATIVE ROLES FOR A TNIP1 POLYMORPHISM IN SEVERITY AND PROGRESSION AND SPECIFIC CELLULAR AND MOLECULAR EVENTS IN HUMAN LN. THE TRANSLATIONAL AND POPULATION- TARGETED NATURE OF THESE STUDIES WILL PROVIDE IMPACTFUL INSIGHTS THAT WILL LEAD TO PRECISION DIAGNOSTICS AND THERAPEUTICS FOR HIGH-RISK AFRICAN AMERICAN LN PATIENTS.

UTILITY OF GENOMIC SEQUENCING IN COMMUNITY CARE CONTEXTS - PROJECT SUMMARY/ABSTRACT EFFORTS TO TRANSLATE GENOMIC SEQUENCING TECHNOLOGIES INTO CLINICAL CARE HAVE FACED ONGOING CHALLENGES DEFINING AND MEASURING UTILITY. EVALUATION OF UTILITY (AND DISUTILITY) IS PARTICULARLY DIFFICULT IN THE CONTEXT OF EFFORTS TO TRANSLATE GENOMIC SEQUENCING TECHNOLOGIES LIKE EXOME SEQUENCING (ES) AND GENOME SEQUENCING (GS) TO THE DIAGNOSIS OF CHILDREN WITH UNDIAGNOSED GENETIC CONDITIONS, SINCE THESE CONDITIONS ARE RARELY RESPONSIVE TO PHARMACOLOGICAL INTERVENTIONS AND PARENTS OFTEN EXPRESS A WIDE VARIETY OF REASONS FOR WANTING A GENOMIC DIAGNOSIS FOR THEIR CHILD. WE HYPOTHESIZE THAT PREVIOUS EFFORTS TO IDENTIFY THE EFFECTS (POSITIVE, NEGATIVE, AND NEUTRAL) OF ES AND GS HAVE MISSED IMPORTANT DIMENSIONS OF UTILITY THAT FALL IN THE “MIDDLE GROUND” BETWEEN CONVENTIONAL NOTIONS OF CLINICAL AND PERSONAL UTILITY. MOST OF THE CARE AND SERVICES THAT IMPROVE FUNCTIONING AND QUALITY OF LIFE FOR CHILDREN WITH COMPLEX GENETIC CONDITIONS OCCUR OUTSIDE DOCTORS’ OFFICES: PHYSICAL THERAPY; OCCUPATIONAL THERAPY; SPEECH-LANGUAGE PATHOLOGY; BEHAVIORAL INTERVENTION AND OTHER MENTAL HEALTHCARE; AND SPECIAL EDUCATION SERVICES. HOWEVER, IT IS UNKNOWN WHETHER RECEIVING A GENOMIC DIAGNOSIS CURRENTLY PROVIDES UTILITY OR DISUTILITY IN THESE COMMUNITY CONTEXTS, AND WHAT EVIDENCE MIGHT BE NEEDED TO INCREASE UTILITY AND MINIMIZE DISUTILITY. THIS PROJECT WILL ADDRESS THIS GAP THROUGH A RIGOROUS STUDY OF POTENTIAL AND ACTUAL EFFECTS THAT CHILDREN WITH UNDIAGNOSED GENETIC CONDITIONS MIGHT EXPERIENCE IN COMMUNITY SETTINGS AS A RESULT OF RECEIVING A GENOMIC DIAGNOSIS. THE OVERALL AIM OF THIS STUDY IS TO IDENTIFY (1) COMMUNITY-BASED UTILITIES CURRENTLY BEING REALIZED FOLLOWING GENOMIC DIAGNOSIS, (2) PERSPECTIVES OF COMMUNITY-BASED PROFESSIONALS REGARDING THE POTENTIAL UTILITY OF SUCH DIAGNOSES, AND (3) SOURCES OF INFORMATION (INCLUDING MEDICAL PROFESSIONALS, PARENT SUPPORT GROUPS, AND SOCIAL MEDIA) THAT MIGHT SUPPORT UTILITY FOR RARE GENETIC CONDITIONS.

COMMUNITY BASED DENTAL PARTNERSHIP

ALCOHOL MISUSE, GUT MICROBIAL DYSBIOSIS AND PREP CARE CONTINUUM: APPLICATION AND EFFICACY OF SBIRT INTERVENTION - PRE-EXPOSURE PROPHYLAXIS (PREP), A MEDICATION REGIMEN TO REDUCE HIV TRANSMISSION RISK AMONG HIV NEGATIVE INDIVIDUALS, HAS UTILITY IN HELPING TO REACH NATIONAL HIV PREVENTION GOALS. HOWEVER, CLINICAL SIDE EFFECTS, PARTICULARLY THOSE IMPACTING GASTROINTESTINAL (GI) (NAUSEA, VOMITING, LOSS OF APPETITE), HEPATIC AND RENAL INJURY OUTCOMES MAY INHIBIT PREP PERSISTENCE. IMPORTANTLY, ALCOHOL USE WHICH IS FREQUENT IN PREP USERS MAY INTERACT WITH PREP AND EXACERBATE PREP-ASSOCIATED ADVERSE GI EFFECTS AND CONSEQUENTLY AFFECT PREP PERSISTENCE. RECENT DATA IMPLICATES THAT THESE SIDE EFFECTS ARE LIKELY ASSOCIATED WITH CHANGES IN THE GUT MICROBIOME (DYSBIOSIS). DESPITE THE IMPORTANT RAMIFICATIONS THAT PREP, ALCOHOL, AND THEIR COMBINED USE MAY HAVE ON THE GUT DYSBIOSIS AND SUBSEQUENT PREP CONTINUANCE, THERE IS LITTLE RESEARCH TO ELUCIDATE THIS INTERACTION AND FEW ATTEMPTS TO ADDRESS IT. MOREOVER, THERE IS LITTLE RESEARCH EXPLORING DECISION-MAKING PROCESSES REGARDING ALCOHOL AND PREP UTILIZATION AND ADHERENCE AMONG PREP USERS. TO ADDRESS THESE GAPS IN RESEARCH, THIS STUDY WILL EMPLOY THE FOLLOWING AIMS. AIM 1: QUALITATIVELY EXPLORE MECHANISMS BY WHICH ALCOHOL USE IMPACTS MOVEMENT THROUGH THE PREP CONTINUUM AND UNDERSTAND HOW AN EARLY INTERVENTION AND TREATMENT APPROACH IMPACTS ALCOHOL USE AND PREP ADHERENCE. AIM 2: INVESTIGATE THE EFFECTIVENESS OF THE SBIRT INTERVENTION IN PREVENTING HAZARDOUS ALCOHOL USE AND ITS IMPACT ON GUT DYSBIOSIS IN PREP USERS. WITHIN THIS LONGITUDINAL COHORT STUDY, WE WILL IDENTIFY ALCOHOL IMPACTED PARTICIPANTS, WITH PATTERNS OF USE RANGING FROM EPISODIC TO LONG-TERM (ENGAGING IN RISKY OR HAZARDOUS USE). AIM 3: TO DETERMINE ALTERATIONS IN THE GUT MICROBIOME (DYSBIOSIS), INTESTINAL HOMEOSTASIS, SYSTEMIC INFLAMMATION, AND MARKERS OF LIVER DISEASE ASSOCIATED WITH HAZARDOUS ALCOHOL USE AMONG PREP USERS. RECRUITING FROM LOCAL PREP CLINICS, WE WILL DETERMINE ALTERATIONS IN THE GUT MICROBIOME, INTESTINAL HOMEOSTASIS, SYSTEMIC INFLAMMATION AND MARKERS OF LIVER DISEASE ASSOCIATED WITH ALCOHOL AND PREP USE. WE WILL ALSO EXECUTE A RANDOMIZED CONTROL TRIAL AMONG PREP USERS DEMONSTRATING HEIGHTENED ALCOHOL USE TO TEST THE EFFECTIVENESS OF THE SCREENING, BRIEF INTERVENTION, & REFERRAL TO TREATMENT (SBIRT) INTERVENTION TO REDUCE ALCOHOL USE AND EXAMINE SUBSEQUENT IMPACT ON THE GUT MICROBIOME COMPARED TO INDIVIDUALS RECEIVING TREATMENT AS USUAL AND PREP USERS NOT DEMONSTRATING ELEVATED ALCOHOL USE. FINALLY, WE WILL EMPLOY QUALITATIVE METHODS (IN-DEPTH INTERVIEWS) AND ANALYSIS TO UNDERSTAND DECISION-MAKING FACTORS INFLUENCING PREP ADHERENCE AND ALCOHOL USE OVER TIME. PRIORITY POPULATIONS, INCLUDING THOSE ENGAGING IN ALCOHOL USE, NEED TO INCREASE ENGAGEMENT IN THE PREP CARE CONTINUUM TO OPTIMIZE HIV PREVENTION. CLINICAL RESEARCH HAS YET TO FOCUS ON INTERACTIONS BETWEEN PREP, ALCOHOL USE AND GI ADVERSE EVENTS. THIS STUDY MAY HAVE IMPORTANT IMPLICATIONS FOR MITIGATING A SALIENT CHALLENGE TO PREP ADHERENCE AND PERSISTENCE (SIDE-EFFECTS) AND ELUCIDATING, FROM CLINICAL AND PUBLIC HEALTH STANDPOINTS, FACTORS PROMOTING MAINTENANCE IN THE PREP CARE CONTINUUM.

COMPREHENSIVELY DEFINING THE NOVEL ALPHAVIRAL CAPSID PROTEIN / IRAK1 INTERACTION - PROJECT SUMMARY / ABSTRACT ALPHAVIRUSES ARE MOSQUITO-BORNE PATHOGENS THAT ARE CAPABLE OF CAUSING SIGNIFICANT OUTBREAKS OF SEVERE CLINICAL DISEASE. CURRENTLY, FOR MANY ALPHAVIRUSES THERE ARE NO APPROVED ANTIVIRAL THERAPIES, OR SAFE AND EFFECTIVE VACCINES. THEREFORE, RESEARCH WHICH SEEKS TO DETERMINE THE MECHANISMS BY WHICH THE ALPHAVIRUSES EVADE OR DYSREGULATE THE HOST INNATE IMMUNE RESPONSE IS ESSENTIAL AND CRITICALLY IMPORTANT TO SYSTEMATICALLY DEFINING ALPHAVIRAL BIOLOGY AND THE DEVELOPMENT OF INNOVATIVE ANTIVIRAL STRATEGIES. THE OVERARCHING RESEARCH OBJECTIVE OF THIS PROPOSAL IS TO COMPREHENSIVELY DEFINE THE IMPACT OF A NOVEL INTERACTION BETWEEN THE ALPHAVIRAL CAPSID (CP) PROTEIN AND THE HOST IRAK1 PROTEIN. THE RATIONALE AND SCIENTIFIC PREMISES SUPPORTING THIS OBJECTIVE ARE BASED ON THE IMPORTANCE OF THE IRAK1 PROTEIN TO HOST INNATE IMMUNE AND INFLAMMATORY SIGNALING PATHWAYS, AND A ROBUST BODY OF PRELIMINARY EVIDENCE THAT INDICATES THAT THE CP/IRAK1 INTERACTION IS HIGHLY CONSERVED AMONGST THE MEMBERS OF THE GENUS ALPHAVIRUS, CRUCIAL TO LIMITING THE INDUCTION OF TYPE-I INTERFERON, AND ESSENTIAL TO SINDBIS (SINV) VIRUS NEUROPATHOGENESIS IN VIVO. NONETHELESS, THE PRECISE IMPACTS OF THE CP/IRAK1 INTERACTION ON ALPHAVIRAL INFECTION AND PATHOGENESIS REMAIN FULLY UNREALIZED, CONSTITUTING A CRITICAL GAP IN THE KNOWLEDGEBASE. THUS, WE PROPOSE THE FOLLOWING SPECIFIC AIMS- I) TO DELINEATE THE IMPACT OF THE CP/IRAK1 INTERACTION ON ALPHAVIRAL PATHOGENESIS IN VIVO; II) TO DEFINE THE MOLECULAR IMPACTS OF THE CP/IRAK1 INTERACTION ON HOST CELLULAR BIOLOGY; AND III) TO DETERMINE THE IMPACT AND CONSEQUENCES OF THE CP/IRAK1 INTERACTION ON THE ALPHAVIRAL CP PROTEIN. OVER THE COURSE OF THE FIRST AIM, WE WILL UTILIZE HIGHLY TRACTABLE MOUSE MODELS OF ALPHAVIRAL INFECTION AND PATHOGENESIS TO SPECIFICALLY PROBE THE ROLE OF THE CP/IRAK1 INTERACTION ON THE EVASION OF TOLL-LIKE RECEPTOR (TLR) SIGNALING AND INDUCTION OF AN INNATE IMMUNE RESPONSE, AND THE DYSREGULATION OF IL-1 FAMILY CYTOKINE SIGNALING. THE SECOND AIM USES ROBUST CELLULAR MODELS TO DISCERN THE MECHANISM BY WHICH THE CP/IRAK1 INTERACTION NEGATIVELY IMPACTS SIGNALING AND TO DEFINE THE PRECISE IMPACTS OF THE CP/IRAK1 INTERACTION ON THE HOST RESPONSE TO IL-1 STIMULATION. FINALLY, THE THIRD AIM USES ROBUST CELLULAR MODELS OF ALPHAVIRAL INFECTION TO RIGOROUSLY DETERMINE THE MOLECULAR CONSEQUENCES OF IRAK1-MEDIATED PHOSPHORYLATION OF THE CP PROTEIN. THIS PROPOSED WORK IS HIGHLY SIGNIFICANT IN THAT IT WILL COMPREHENSIVELY ASSESS THE IMPORTANCE OF THE NOVEL CP/IRAK1 INTERACTION TO ALPHAVIRAL INFECTION AND PATHOGENESIS. MOREOVER, THESE EFFORTS ARE CONCEPTUALLY, AND TECHNICALLY INNOVATIVE AS ROBUST TRIED-AND-TRUE AND STATE-OF-THE-ART APPROACHES, TECHNIQUES, AND MODELS OF INFECTION WILL BE USED TO RIGOROUSLY DEFINE THE BIOLOGICAL AND MOLECULAR IMPORTANCE OF THE CP/IRAK1 INTERACTION. THE SUCCESSFUL COMPLETION OF THESE EFFORTS WILL SERVE TO FUNDAMENTALLY EXPAND THE UNDERSTANDING OF ALPHAVIRAL BIOLOGY AND LAY THE FOUNDATION FOR THE DEVELOPMENT OF MEANINGFUL THERAPEUTIC INTERVENTIONS.

NUTRITION AND METABOLIC HEALTH CENTER (NMHC) COBRE - THE UNIVERSITY OF LOUISVILLE (UOFL) PROPOSES THE ESTABLISHMENT OF THE NUTRITION AND METABOLIC HEALTH CENTER (NMHC) AS A CENTER OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) TO ADDRESS THE PRESSING HEALTH CHALLENGES ASSOCIATED WITH MALNUTRITION, POOR DIET, AND METABOLIC DYSFUNCTION. THESE ISSUES CONTRIBUTE SIGNIFICANTLY TO THE GLOBAL BURDEN OF NONCOMMUNICABLE DISEASES, INCLUDING DIABETES, OBESITY, CARDIOVASCULAR DISEASE, AND LIVER DISORDERS. GIVEN THE CRITICAL ROLE OF NUTRITION IN REGULATING SYSTEMIC METABOLISM, IMMUNE FUNCTION, AND OVERALL ORGAN HEALTH, THE NMHC WILL SERVE AS A TRANSFORMATIVE INITIATIVE TO ADVANCE RESEARCH AND DEVELOP INNOVATIVE SOLUTIONS FOR DISEASE PREVENTION AND TREATMENT. THE CENTER IS PARTICULARLY TIMELY, AS KENTUCKY RANKS 41ST IN OVERALL HEALTH AND EXPERIENCES SOME OF THE NATION’S HIGHEST RATES OF CHRONIC METABOLIC DISEASES. BY LEVERAGING UOFL’S EXISTING EXPERTISE AND INTEGRATING WITH ONGOING NIH-FUNDED PROGRAMS, THE NMHC WILL ENHANCE INSTITUTIONAL RESEARCH CAPACITY, PROVIDE VITAL INFRASTRUCTURE, AND CREATE NEW OPPORTUNITIES FOR COLLABORATION IN METABOLISM AND NUTRITION SCIENCES. THE NMHC WILL BE SUPPORTED BY AN EXCEPTIONALLY STRONG INSTITUTIONAL COMMITMENT, INCLUDING $7.9 MILLION IN FUNDING AND DEDICATED SALARY LINES, MAKING IT THE MOST HIGHLY SUPPORTED COBRE INITIATIVE AT UOFL. THE CENTER WILL BE STRUCTURED AROUND AN ADMINISTRATIVE CORE (CORE A) AND THREE SPECIALIZED RESEARCH CORES: A MULTI-OMICS TECHNOLOGY DEVELOPMENT CORE (CORE B); A TRANSLATIONAL METABOLIC PHENOTYPING AND NUTRITION CORE (CORE C), AND A DATA MANAGEMENT, ANALYSIS, AND AI CORE (CORE D). THESE CORES WILL NOT ONLY PROVIDE ESSENTIAL RESOURCES AND EXPERTISE BUT ALSO FOSTER INTERDISCIPLINARY COLLABORATION TO DRIVE IMPACTFUL SCIENTIFIC DISCOVERIES. THE LEADERSHIP TEAM, LED BY DRS. CAVE AND HILL, BRINGS EXTENSIVE EXPERTISE IN BOTH BASIC AND CLINICAL SCIENCES, SPANNING METABOLISM, NUTRITION, CARDIOVASCULAR HEALTH, AND LIVER DISEASE. THEY WILL BE SUPPORTED BY A DISTINGUISHED GROUP OF MENTORS AND PROMISING EARLYCAREER INVESTIGATORS, ENSURING THE CENTER’S LONG-TERM SUSTAINABILITY AND SUCCESS. THE NMHC HAS THREE PRIMARY OBJECTIVES: (1) TO ESTABLISH A CENTER OF EXCELLENCE IN NUTRITION AND METABOLIC HEALTH RESEARCH BY EXPANDING RESEARCH CAPACITY AND FOSTERING INNOVATIVE STUDIES ACROSS BASIC, TRANSLATIONAL, AND CLINICAL DOMAINS; (2) TO SUPPORT THE DEVELOPMENT OF EARLY-CAREER INVESTIGATORS BY PROVIDING MENTORSHIP, RESEARCH FUNDING OPPORTUNITIES, AND HIGH-IMPACT PUBLICATION SUPPORT, THEREBY CULTIVATING FUTURE LEADERS IN THE FIELD; AND (3) TO CREATE SUSTAINABLE CORE FACILITIES THAT ENHANCE THE RESEARCH CAPABILITIES OF UOFL SCIENTISTS THROUGH ADVANCED METHODOLOGIES, TRAINING PROGRAMS, AND COLLABORATIVE OPPORTUNITIES. BY BUILDING EXPERTISE IN NUTRITION AND METABOLISM, THE NMHC WILL ACCELERATE SCIENTIFIC DISCOVERIES AND CONTRIBUTE TO IMPROVING HEALTH OUTCOMES IN KENTUCKY AND BEYOND. THROUGH ITS COMPREHENSIVE APPROACH, INCLUDING RECRUITMENT OF NEW INVESTIGATORS, DEVELOPMENT OF CUTTING-EDGE RESEARCH INFRASTRUCTURE, AND PROMOTION OF INTERDISCIPLINARY COLLABORATION, PHASE 1 OF THIS COBRE WILL ESTABLISH THE NMHC AS A NATIONALLY RECOGNIZED LEADER IN THE FIGHT AGAINST POOR NUTRITION AND METABOLIC DISEASE.

GLYCINE SUBUNIT SPECIFIC INHIBITION AND GANGLION CELL VISUAL RESPONSES

BMAL1/ARNTL PLAYS A CRITICAL, NON-CIRCADIAN ROLE IN SECONDARY TISSUE DAMAGE AFTER CONTUSIVE SCI