University Of Toledo

UNIVERSITY OF TOLEDO: CARES-INSTITUTIONAL PORTION OF THE HIGHER EDUCATION EMERGENCY RELIEF FUND

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

IMPORTANCE AND TIMELINESS OF MISSION EARTH THE MISSION EARTH PROPOSES A SYSTEMATIC EMBEDDING OF NASA ASSETS, INFUSED INTO GLOBE GLOBAL LEARNING AND O

NURTURES: NETWORKING URBAN RESOURCES WITH TEACHERS AND UNIVERSITY TO ENRICH EARLY CHILDHOOD SCIENCE

AREA HEALTH EDUCATION CENTERS POINT OF SERVICE MAINTENANCE AND ENHANCEMENT

CORAL: CLINICAL COORDINATING CENTER

CONTROL MECHANISMS OF CARDIAC PROTEINS AND ENZYMES

AREA HEALTH EDUCATION CENTERS POINT OF SERVICE MAINTENANCE AND ENHANCEMENT

PURPOSE: TO ADDRESS TWO MAJOR LIMITATIONS AT THE UNIVERSITY OF TOLEDO (UTOLEDO): [1] THE CURRENT BSL3/A-BSL3 IS TOO SMALL (2 ROOMS; 1099 FT2) TO RECRUIT NEW MICROBIOLOGY/INFECTIOUS DISEASE FACULTY OR TO ACCOMMODATE ADDITIONAL RESEARCH PROJECTS. FOR EXAMPLE, MMI VIROLOGISTS WERE DELAYED IN 2020 IN WORKING WITH SARS-COV-2, THE VIRUS THAT CAUSES COVID-19, BECAUSE OF BSL3 SPACE/EQUIPMENT LIMITATIONS AND PERSONNEL SECURITY CLEARANCE (FBI BACKGROUND CHECKS ARE NEEDED BECAUSE THE CURRENT BSL3/A-BSL3 IS CDC-DESIGNATED AS A TIER 1 SELECT AGENT FACILITY; MOST RESTRICTIVE FEDERAL REGULATIONS); [2] DLAR NEEDS TO RENOVATE EXISTING SPACES TO BE MORE EFFICIENT, PROVIDE ADDITIONAL HOUSING AND PROCEDURE ROOMS, AND CREATE ISOLATED ROOMS FOR SPECIALIZED RESEARCH NEEDS (E.G., MICROBIOME RESEARCH).ACTIVITIES TO BE PERFORMED: EXPAND THE UTOLEDO BSL3/A-BSL3 FACILITY INTO ADJACENT DLAR SPACE, CREATING 3 NEW BIOCONTAINMENT SUITES FOR TIER 1 SELECT AGENT BSL3/A-BSL3 RESEARCH, MORE THAN DOUBLING THE SIZE OF THE CURRENT BSL3/A-BSL3 FACILITY (1480 FT2 OF NEW BSL3/A-BSL3 SPACE). THESE 3 NEW SUITES WILL BE USED TO STUDY DISEASES LIKE PLAGUE, ANTHRAX, AND TULAREMIA. SEPARATE SUITES ARE IDEAL FOR BIOSECURITY, BIOCONTAINMENT, AND PERSONNEL SAFETY. THIS NEW TIER 1 SELECT AGENT SPACE WILL CONTAIN ITS OWN PASS-THROUGH AUTOCLAVE (ENHANCES BIOSAFETY BY PROVIDING A BACKUP TO THE EXISTING BSL3/A-BSL3 PASS-THROUGH AUTOCLAVE), DECONTAMINATION CHAMBER (FOR CHEMICAL DISINFECTION OF CONTAMINATED EQUIPMENT), AND SHARED EQUIPMENT SPACES.RENOVATE THE EXISTING BSL3/A-BSL3 SPACE (2 ROOMS; 1099 FT2) AND ASSOCIATED ENTRY/EXIT (2 ROOMS; 115 FT2) INTO 3 NEW BIOCONTAINMENT SUITES FOR NON-SELECT AGENT RESEARCH AND CREATE A NEW SHARED ENTRY/EXIT SPACE FOR BOTH SELECT AGENT AND NON-SELECT AGENT BSL3/A-BSL3 SPACES WITH GOWNING, DE-GOWNING, AND DECONTAMINATION SHOWER AREAS. THE CREATION OF THIS NEW NON-SELECT AGENT BSL3/A-BSL3 SPACE WILL ALLOW ANY UTOLEDO RESEARCHER (NO FBI BACKGROUND CHECKS REQUIRED), WITH INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) APPROVAL, TO RAPIDLY INITIATE PROJECTS ON EXISTING AND/OR EMERGING BSL3 PATHOGENS (E.G., COVID-19, INFLUENZA, TUBERCULOSIS, FUTURE PANDEMICS). THE SHARED ENTRY/EXIT SPACE WILL PROVIDE ENLARGED SPACES FOR PUTTING ON, TAKING OFF, AND DECONTAMINATING PERSONNEL PROTECTIVE EQUIPMENT (PPE). IN ADDITION TO THE 3 NEW SUITES, THE NON-SELECT AGENT BSL3/A-BSL3 WILL CONTAIN A PASS-THROUGH AUTOCLAVE (WILL RELOCATE THE EXISTING BSL3/A- BSL3 AUTOCLAVE) AND SHARED EQUIPMENT SPACES.REMODEL 21 EXISTING DLAR ROOMS, UNUSED/REDUNDANT HALLWAYS, AND UNDERUTILIZED SPACES (14,350 FT2 GROSS RENOVATION; 11,308 FT2 ROOM RENOVATIONS) INTO NEW MULTI-PURPOSE ROOMS FOR EITHER ANIMAL PROCEDURES AND/OR ANIMAL HOUSING, INCLUDING THE CREATION OF A NEW ISOLATION SUITE THAT COULD BE USED FOR GERM-FREE/MICROBIOME STUDIES. THESE DLAR RENOVATIONS ARE CRITICALLY NEEDED BECAUSE OF INCREASED UTOLEDO RESEARCH FUNDING, ASSOCIATED INCREASES IN ANIMAL RESEARCH, AND LIMITED AVAILABLE SPACE BUT WILL ADDRESS CURRENT AND PROJECTED UTOLEDO, PROVIDING MULTI-PURPOSE DLAR VIVARIUM SPACE FOR EXISTING BIOMEDICAL SCIENCE FACULTY AND ONGOING FACULTY RECRUITMENT EFFORTS AT UTOLEDO.EXPECTED OUTCOMES: ACROSS UTOLEDO, THE PROPOSED DLAR RENOVATIONS WILL DIRECTLY SUPPORT AND ENHANCE CURRENT RESEARCH, HELP RETAIN NATIONALLY-RECOGNIZED FACULTY, AND AID IN ONGOING EFFORTS TO RECRUIT THE BEST AND BRIGHTEST TALENT TO UTOLEDO. INTENDED BENEFICIARIES:AREAS OF RESEARCH EXCELLENCE AND RESEARCH CENTERS AND INSTITUTES, HUNDREDS OF UTOLEDO FACULTY, STAFF, AND STUDENT RESEARCHERS EXTENSIVELY USE DLAR SPACES FOR ANIMAL HOUSING (INCLUDING TELEMETRY FOR CONTINUOUS MONITORING), ANIMAL PROCEDURE ROOMS, AND SPECIALIZED OR ISOLATED HOUSING/PROCEDURE SPACES (E.G., LENTIVIRUS- OR ADENOVIRUS-TRANSFECTIONS; CANCER OR CHEMOTHERAPY STUDIES; GERMFREE ISOLATION ROOMS FOR MICROBIOME STUDIES).SUBRECIPIENT ACTIVITIES: NO SUBRECIPIENTS HAVE BEEN IDENTIFIED OR PROPOSED.

BIOCHEMISTRY AND GENETICS OF HYPERTENSION

LEADERS: LEADERSHIP FOR EDUCATORS: ACADEMY FOR DRIVING ECONOMIC REVITALIZATION IN SCIENCE

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

TOWARD LOW-COST, EFFICIENT AND STABLE PEROVSKITE THIN-FILM MODULES

TEACHER QUALITY ENHANCEMENT GRANTS FOR STATE AND PARTNERSHIPS - PARTNERSHIP GRANTS

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

STUDY OF EARLY BRAIN ALTERATIONS THAT PREDICT DEVELOPMENT OF CHRONIC PTSD

A PATH TOWARD AN ENVIRONMENTALLY SECURE FUTURE THROUGH ECOSYSTEM SCIENCE AND MONITORING

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

PPARG REGULATES OSTEOCYTE BIOENERGETICS AND FUNCTION DURING AGING - BONE LOSS AND IMPAIRMENT IN ENERGY METABOLISM WITH AGING PREVALENTLY LEAD TO FRACTURES AND DIABETES. AS AN ORGAN, THE SKELETON IS ONE OF THE LARGEST CONSUMERS OF ENERGY NEEDED FOR BONE REMODELING AND MAINTENANCE OF BONE HOMEOSTASIS. BONE REMODELING IS UNDER CONTROL OF OSTEOCYTES, WHICH CONSTITUTE 90-95% OF BONE CELLS, AND WHICH BIOENERGETIC PROGRAM IS LARGELY UNKNOWN. NEW EVIDENCE INDICATES THAT NUCLEAR RECEPTOR PPARG, WHICH IS A GLOBAL REGULATOR OF ENERGY METABOLISM AND PHARMACOLOGICAL TARGET TO TREAT HYPERGLYCEMIA, REGULATES OSTEOCYTE ENERGY METABOLISM AND THEIR FUNCTION INCLUDING PRODUCTION OF SCLEROSTIN, AN INHIBITOR OF WNT PATHWAY ACTIVITY AND A KEY PROTEIN REGULATING BONE REMODELING. RESEARCH PROPOSED IN THIS APPLICATION WILL PROVIDE AN INSIGHT INTO THE CONNECTION BETWEEN OSTEOCYTE BIOENERGETICS, ITS FUNCTION IN BONE METABOLISM AND SYSTEMIC ENERGY METABOLISM, AND WHETHER BONE ACTS AS THE BODY “ENERGOSTAT” VIA OSTEOCYTE ENDOCRINE ACTIVITIES. THE LEADING HYPOTHESIS IS THAT CHANGES IN PPARG ACTIVITY WITH AGING ALTER OSTEOCYTE FUNCTION AND BIOENERGETICS RESULTING IN SIMULTANEOUS DECREASE IN BONE FORMATION AND DECREASE IN ENERGY METABOLISM. THIS HYPOTHESIS WILL BE TESTED IN THREE SPECIFIC AIMS. AIM 1 WILL DETERMINE HOW FUEL CHOICE AND AGING AFFECT OSTEOCYTE FUNCTION AND WHETHER THESE PROCESSES ARE PPARG DEPENDENT. WITH THE USE OF AGED C57BL/6 AND OTKO MICE, BONE ORGAN CULTURES, AND OSTEOCYTE-LIKE MLO-Y4 CELLS WITH DOWN-REGULATED PPARG, IN COMBINATION WITH TRANSCRIPTOMICS, QUANTITATIVE PROTEOMICS, AND COCULTURE EXPERIMENTS, PPARG CONTRIBUTION TO OSTEOCYTE AGING WILL BE DEFINED. AIM 2 WILL CONTRAST THE PPARG PROTEIN INTERACTOME OF OSTEOCYTES WITH THE INTERACTOME OF ADIPOCYTES, IN RESPONSE TO EITHER FULL AGONIST ROSIGLITAZONE OR THE INVERSE AGONIST SR10171, IN ORDER TO DEFINE AN OPTIMAL PPARG MODULATOR FOR ITS BENEFICIAL EFFECTS ON BONE AND METABOLISM. THE ANALYSIS WILL BE DONE ON OSTEOCYTE- LIKE MLO-Y4 CELLS USING QUANTITATIVE TANDEM MASS TAG PROTEOMICS. AIM 3 WILL DEFINE DYNAMICS OF PPARG INTERACTOME ON PPRE SEQUENCES PRESENT IN SOST PROMOTER AS A FUNCTION OF AGING AND IN RESPONSE TO PHARMACOLOGICAL MODULATION OF PPARG ACTIVITY. THE PREMISE OF THIS APPLICATION IS TO SET A STAGE FOR PRECISE PHARMACOLOGIC MANIPULATION WITH PPARG ACTIVITIES IN OSTEOCYTES TO SIMULTANEOUSLY IMPROVE SKELETAL AND METABOLIC DYSFUNCTION IN ELDERLY.

INNOVATIVE MODELS FOR MECHANISTIC STUDIES OF NOVEL HYPERTENSION GENES

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

CROSS PLATFORM ANALYSIS OF DRUG TARGETS AND TOXICITY OF BATH SALTS - PROJECT SUMMARY/ABSTRACT THE UNITED STATES IS IN THE MIDST OF A SUBSTANCE ABUSE AND MENTAL HEALTH EPIDEMIC. OVER THE PAST DECADE, ABUSE OF PSYCHOSTIMULANT (AND SOMETIMES HALLUCINOGENIC) CATHINONES, OFTEN REFERRED TO AS “BATH SALTS”, AND VARIANTS SUCH AS ‘FLAKKA’, HAS BECOME INCREASING POPULAR IN AMERICA’S YOUTH. ALTHOUGH THERE HAS BEEN SUBSTANTIAL RESEARCH INTO THE MECHANISMS UNDERLYING THE ADDICTIVE AND ADVERSE EFFECTS OF SOME OF THESE AGENTS, SUCH AS 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA), A WIDE VARIETY OF VARIANTS ARE AVAILABLE FOR SALE ON THE INTERNET. FURTHERMORE, THESE REPRESENT ONLY A SMALL FRACTION OF CONCEIVABLE STRUCTURES WHICH CAN BE PRODUCED ON KILOGRAMS SCALE FOR SALE ONLINE. GAINING A MORE COMPLETE UNDERSTANDING OF THE DRUG TARGETS AND TOXICITY ASSOCIATED WITH THESE AGENTS IS AN IMPORTANT STEP TO TREAT SUBSTANCE ABUSE DISORDERS AND EPISODIC TOXICITY. THE OVER-ARCHING GOAL OF OUR WORK IS TO UNITE WHOLE SYSTEM LEVEL ANALYSIS INVOLVING THE NEUROBEHAVIORAL EFFECTS OF PSYCHOACTIVE AGENTS WITH THE STUDY OF BINDING PARTNERS AT THE MOLECULAR LEVEL. THE FOCUS OF THIS PROPOSAL IS TO IMPLEMENT A NOVEL IN VIVO PHOTOAFFINITY LABELING (PAL) APPROACH FOR CROSS PLATFORM ANALYSIS OF PSYCHOACTIVE AGENTS, WITH AN EMPHASIS ON STRUCTURES RELATED METHYLENEDIOXYPYROVALERONE (MDPV) AND A- PYRROLIDINOVALEROPHENONE (A-PVP). IN AIM 1 WE WILL SYNTHESIZE A CAREFULLY DESIGNED SET OF PROBES TO BE CATALOGED IN AIM 2 ASSAYS. THIS INCLUDES STEREOSELECTIVE SYNTHESIS OF PAL PROBES, STRUCTURE ACTIVITY RELATIONSHIP (SAR) CONTROLS, AND STABLE ISOTOPE LABELED STANDARDS FOR LC-MS STUDIES IN AIM 2C. THE SYNTHESIZED LIBRARY WILL BE ASSAYED FOR 1) RECEPTOR BINDING PROFILE; 2) EFFECT ON MONOAMINE UPTAKE AND RELEASE IN RAT SYNAPTOSOMES; AND 3) TOXICITY IN MULTIPLE CELL LINES HEPG2 (LIVER), SHSY-5Y (NEURONAL), AC16 (CARDIAC MYOCYTE) AND PC-12 (NEURONAL [RAT]). IN AIM 2C, ACTIVE COMPOUNDS (AND SELECT INACTIVE CONTROLS) WILL BE STUDIED IN AN ADULT ZEBRAFISH BEHAVIORAL PARADIGM UTILIZING THE NOVEL TANK TEST WITH CONCURRENT IN VIVO PAL. THE CONCENTRATION OF EACH DRUG WILL BE MEASURED BY LC-MS/MS TO CORRELATE TARGET TISSUE (BRAIN) DRUG EXPOSURE WITH BEHAVIORAL RESPONSES. SELECT COMPOUNDS WILL BE RE-EXAMINED IN THE AIM 2 ASSAYS USING PAL FOR SIDE-BY-SIDE COMPARISON OF BINDING INTERACTOME OF AIM 2 EXPERIMENTAL SYSTEMS VERSUS THE IN VIVO BINDING INTERACTOME. CHEMICAL BIOLOGY IN AIM 3 WILL UTILIZE CLICK CHEMISTRY TO VISUALIZE PROTEIN LABELING VIA FLUOROIMAGING OF SDS PAGE GELS. PROTEOMICS WILL DETERMINE PROTEIN IDENTIFICATION AFTER AFFINITY PURIFICATION TO DEFINE THE BINDING INTERACTOME OF EACH PROBE. A VARIETY OF COMPETITION EXPERIMENTS WILL BE PERFORMED TO CHARACTERIZE BACKGROUND PAL AND RECOGNIZE BONA FIDE TARGETS. BIOINFORMATICS WILL BE USED FOR NETWORK ANALYSIS TO PROVIDE AN UNBIASED COMPARISON OF THE BINDING INTERACTOMES FOR EACH EXPERIMENTAL SYSTEM TO PROPOSE POTENTIAL THERAPEUTIC TARGETS TO TREAT TOXICITY AND EPISODIC LETHALITY OF THESE AGENTS.

NURTURING STEM IN EARLY CHILDHOOD FOR MILITARY-CONNECTED FAMILIES (NURTURES).

THE GOAL OF THE PROPOSED PROJECT IS TO DEVELOP ACADEMIC AND TRAINING PROGRAMS AT UNIVERSITIES AND COMMUNITY COLLEGES IN NORTHERN OHIO WHICH WILL PREPARE THE WORKFORCE REQUIRED FOR THE HYDROGEN ECONOMY AND TO SUPPORT EFFORTS TO DECARBONIZE HEAVY INDUSTRY IN OHIO AND MICHIGAN. REGIONAL DECARBONIZATION EFFORTS, BOTH CURRENT AND IN THE NEAR FUTURE, INCLUDE THE PRODUCTION OF HYDROGEN FROM NUCLEAR AND SOLAR ENERGY VIA THE ELECTROLYSIS OF WATER, AND THE USE OF THIS GREEN HYDROGEN IN THE PRODUCTION OF STEEL, GLASS AND CHEMICALS, AND FOR FUEL-CELL POWERED BUSES, FORKLIFTS, AND MEDIUM-DUTY AND HEAVY-DUTY VEHICLES. SKILLED WORKERS WILL BE NEEDED TO SUPPORT THESE EFFORTS.

INTEGRATION OF NUTRIENT AND WATER RECYCLING FOR SUSTAINABLE ALGAL BIOREFINERIES

MINIMIZING ORGANIC CARBON LOSSES TO IMPROVE NET PRODUCTIVITY IN DIRECT AIR CAPTURE CULTIVATION

ASTROCYTE INSULIN RESISTANCE-INDUCED NEUROENDOCRINE DEFECTS IN PUBERTAL DELAY AND HYPOGONADOTROPIC HYPOGONADISM - ASTROCYTES ARE KNOWN TO PROVIDE SUPPORT TO GONADOTROPIN RELEASING HORMONE (GNRH) NEURONS THAT CONTROL THE REPRODUCTIVE AXIS, FOR EXAMPLE BY RELEASING PROSTAGLANDIN E2 (PGE2) REQUIRED FOR FERTILITY. ASTROCYTES MAY ALSO PLAY A CRITICAL ROLE IN THE BRAIN AS METABOLIC SENSORS. IN RESPONSE TO INSULIN, ASTROCYTES INCREASE GLUCOSE UPTAKE ACROSS THE BLOOD BRAIN BARRIER AND RELEASE METABOLITES AND GLIOTRANSMITTERS TO SUPPORT NEURONAL FUNCTION. WE HAVE RECENTLY DEMONSTRATED A UNIQUE BIOLOGICAL ROLE FOR ASTROCYTES IN COUPLING FERTILITY TO ENERGY AVAILABILITY. WE FOUND THAT THE ABSENCE OF INSULIN SIGNALING IN ASTROCYTES DELAYS PUBERTY, CAUSES HYPOGONADOTROPIC HYPOGONADISM, AND DRAMATICALLY REDUCES FERTILITY. THIS FINDING IS PARTICULARLY EXCITING SINCE NUMEROUS STUDIES HAVE SHOWN NEURONAL INSULIN SENSING IS UNNECESSARY FOR REPRODUCTION. WE HAVE ALSO FOUND THAT LOSS OF ASTROCYTE INSULIN SENSING REDUCES PGE2 SYNTHASE LEVELS, LEADING US TO HYPOTHESIZE THAT ASTROCYTE INSULIN SENSING FACILITATES GNRH RELEASE BY PROMOTING ASTROCYTE PGE2 RELEASE. NEW PRELIMINARY DATA SUGGEST THAT INSULIN SIGNALING VIA FOXO PATHWAYS ALTER THE TRANSCRIPTION OF ENZYMES IN THE PGE2 BIOSYNTHESIS PATHWAY, SUCH AS COX-2. WE WILL TEST OUR HYPOTHESIS BY PURSUING THREE SPECIFIC AIMS. AIM 1) DEFINE THE RELEVANT TEMPORAL & SPATIAL PARAMETERS OF ASTROCYTE INSULIN SIGNALING. USING THE TET-ON GENETIC TARGETING SYSTEM, WE WILL TEST WHETHER ASTROCYTES MUST SENSE INSULIN DURING ADULTHOOD OR PRIOR TO PUBERTY IN ORDER TO PERMIT NORMAL REPRODUCTIVE FUNCTION. ASTROCYTE-SPECIFIC VIRAL CRE ADMINISTRATION WILL ALSO DETERMINE THE IMPORTANCE OF ASTROCYTE INSULIN SENSING IN THE ARCUATE NUCLEUS AND THE ROSTRAL PREOPTIC AREA. AIM 2) DETERMINE THE IMPACT OF INSULIN SIGNALING ON ASTROCYTE PGE2 GLIOTRANSMITTER PRODUCTION PROXIMAL TO REPRODUCTIVE CIRCUITS. MEASUREMENT OF REGIONAL PGE2 PRODUCTION WILL BE COMPLEMENTED BY AAV TARGETED DISRUPTION OF COX-2 PRODUCTION BY ASTROCYTES TO DETERMINE ITS IMPORTANCE FOR FERTILITY. FINALLY, WE WILL DETERMINE WHETHER KISS1 NEURONS SENSE PGE2, LEADING TO ALTERED GNRH RELEASE. AIM 3) DETERMINE THE MOLECULAR ROLE OF THE INSULIN/ FOXO PATHWAY IN ASTROCYTE PGE2 SYNTHESIS. AN ASTROCYTE CELL LINE WILL BE USED TO SYSTEMATICALLY INVESTIGATE THE MAJOR ASPECTS OF INSULIN/FOXO/COX SIGNALING, INCLUDING PHOSPHORYLATION, LOCALIZATION, PROMOTER OCCUPANCY, AND QUANTITATIVE TRANSCRIPTIONAL ACTIVITY MEASUREMENTS. FINALLY, WE WILL ABLATE INSULIN SIGNALING PATHWAYS IN ASTROCYTES TO DETERMINE THEIR EFFECT ON FERTILITY AND PGE2 PRODUCTION. COLLECTIVELY, THESE STUDIES WILL IDENTIFY HOW INSULIN SIGNALING IN ASTROCYTES SUSTAINS REPRODUCTIVE CIRCUIT FUNCTION. THIS WORK WILL ELUCIDATE WHAT MAY BE THE DOMINANT MECHANISM IN THE MAMMALIAN BRAIN WHEREBY INSULIN PERMITS NORMAL FERTILITY AND PUBERTAL MATURATION. OUR RESULTS WILL ADVANCE OUR LONG-TERM GOAL OF FINDING TREATMENT TARGETS FOR IMPAIRED FERTILITY IN PATIENTS RECOVERING FROM ENERGY DEFICITS, OBESE AND DIABETIC POPULATIONS, AND OTHERS WITH IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM.

GENETIC, EPIGENETIC AND DIETARY SALT EFFECTS ON MICROBIOTA AND HYPERTENSION

GUT-BRAIN AXIS IN PARKINSON'S DISEASE

TARGETING EIF4A1 IN DRUG-RESISTANT BREAST CANCER STEM-LIKE CELLS - TARGETING EIF4A1 IN DRUG-RESISTANT BREAST CANCER STEM-LIKE CELLS THE OVERARCHING GOAL OF THIS PROJECT IS TO DELINEATE THE REGULATORY MECHANISMS BY WHICH THE HELICASE ACTIVITY OF EIF4A1 CONTROLS PLURIPOTENCY TFS AND ABC DRUG TRANSPORTERS AND HOW THIS CAN BE EXPLOITED TO OVERCOME DRUG RESISTANCE IN METASTATIC TNBC. CURRENTLY, DESPITE SIGNIFICANT IMPROVEMENTS IN THE SURVIVAL RATES OF PRIMARY BREAST CANCER PATIENTS, 90% OF THE MORTALITY IS DUE TO CHEMORESISTANCE FROM AGGRESSIVE TUMORS LEADING TO METASTASIS. NEOADJUVANT HEMOTHERAPY (NACT) IS THE MAINSTAY OF TREATMENT THOUGH POLY ADP-RIBOSE POLYMERASE (PARP) INHIBITORS ARE AVAILABLE ALONG WITH IMMUNOTHERAPY. THE PATHOLOGICAL COMPLETE RESPONSE (PCR) IS GENERALLY LOW IN TNBC PATIENTS. RESISTANCE TO NACT AND ALSO TO TARGETED THERAPY IS MAINLY DUE TO A SMALL POPULATION OF BREAST CANCER STEM-LIKE CELLS (BCSCS) OR TUMOR-INITIATING CELLS. BCSCS ARE INTRINSICALLY CHEMORESISTANT WITH HIGH PLASTICITY AND SELF-RENEWAL CAPABILITY. THEIR PROLIFERATIVE AND INVASIVE CAPACITY MEDIATES TUMORIGENESIS, IMMUNE EVASION AND METASTASIS. ACQUIRED RESISTANCE TO CHEMO- AND IMMUNOTHERAPY ALSO DEVELOPS DURING TREATMENT. FOLLOWING SUCH THERAPY, THE BULK TUMOR CELLS DIE BUT BCSCS SURVIVE AND CONSTITUTE THE MINIMAL RESIDUAL DISEASE (MRD). THE SURVIVING PLURIPOTENT BCSCS CAN UNDERGO MULTI-LINEAGE DIFFERENTIATION AND REPOPULATE THE ENTIRE HETEROGENEOUS TUMOR. THIS LEADS TO TUMOR RELAPSE WHICH ARE MORE AGGRESSIVE AND HIGHLY METASTATIC IN NATURE. TUMORS WITH HIGH EXPRESSION OF BCSC STEMNESS MARKERS (ALDH AND CD44) DEMONSTRATE WORST CLINICAL OUTCOMES IN TNBC PATIENTS. THUS, THERE IS AN UNMET NEED FOR IDENTIFYING NOVEL TARGETS AND STRATEGICALLY TARGET BCSCS TO OVERCOME CHEMORESISTANCE, ELIMINATE MRD AND ACHIEVE BETTER PCR IN METASTATIC TNBC (MTNBC). IN THIS STUDY, WE PROPOSE TO FIND THE MECHANISMS BY WHICH THE HELICASE ACTIVITY OF EIF4A1 REGULATES PLURIPOTENCY, ABC TRANSPORTERS THAT CONTRIBUTE TO CHEMORESISTANCE. WE PROPOSE IN AIM 1 TO DETERMINE THE ROLE OF THE HELICASE ACTIVITY OF EIF4A1 IN THE REGULATION OF PLURIPOTENCY AND ABC TRANSPORTERS IN VITRO. IN AIM2, WE WILL DETERMINE THE ROLE OF THE HELICASE ACTIVITY OF EIF4A1 IN THE REGULATION OF PLURIPOTENCY AND ABC TRANSPORTERS IN VIVO. IN AIM3 WE PROPOSE TO TRANSLATE THE FINDINGS IN AIM1 AND 2 TO PRECLINICAL PDX AND CDX MURINE MODELS. THIS WILL FACILITATE IN DEVELOPING NOVEL COMBINATION THERAPIES EFFECTIVE IN MTNBC AND HOPEFULLY TRANSLATE IT INTO HUMAN PHASE I TRIAL.

GRADUATE TEACHING FELLOWS IN STEM HIGH SCHOOL EDUCATION: AN ENVIRONMENTAL SCIENCE LEARNING COMMUNITY AT THE LAND-LAKE ECOSYSTEM INTERFACE

A COMPREHENSIVE STRATEGY FOR STABLE, HIGH PRODUCTIVITY CULTIVATION OF MICROALGAE WITH CONTROLLABLE BIOMASS COMPOSITION

MECHANISMS OF RAS-INDUCED NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA

METHODS TO SYNTHESIZE OLIGOSACCHARIDE-FUSION PROTEIN CONJUGATES AND ENHANCEMENT OF THEIR ANTIGENICITY

UPWARD BOUND

OHIO APPALACHIA EDUCATIONAL OPPORTUNITY CENTER

INVESTIGATION OF ACTIVE KINOME NETWORKS IN ALZHEIMER'S DEMENTIA. - SUMMARY THIS IS A REVISED R01 APPLICATION FROM A TEAM OF ESTABLISHED INVESTIGATORS WHO BRING COMPLEMENTARY EXPERTISE FOR A MULTI-OMICS, HYPOTHESIS GENERATING, SERIES OF EXPERIMENTS THAT HAVE THE OVERARCHING GOAL OF DEEPENING UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ALZHEIMER’S DEMENTIA (AD). TAKEN TOGETHER, THE PREVALENCE OF THIS DEVASTATING DISORDER, THE PAUCITY OF EFFICACIOUS TREATMENTS, AND THE VERY HIGH FAILURE RATE OF CLINICAL TRIALS FOR NEW AD TREATMENTS INDICATE A PRESSING NEED TO BETTER UNDERSTAND HOW THIS DISEASE BREAKS THE BRAIN. WE POSIT THAT MEASURES OF PROTEIN FUNCTION, RATHER THAN GENE EXPRESSION, ARE NEEDED TO DEVELOP A MORE SOPHISTICATED UNDERSTANDING OF AD PROGRESSION. PROTEIN FUNCTION CAN BE MEASURED IN MANY WAYS. GENETIC OR PHARMACOLOGICAL MANIPULATION PROVIDES COMPELLING INSIGHTS FOR CAUSAL RELATIONSHIPS BETWEEN PROTEINS. SUCH WORK RELIES ON ASSUMPTIONS ABOUT BIOLOGICAL FUNCTION THAT ARE LINEAR. HOWEVER, THE SUM OF THE PROPERTIES OF INDIVIDUAL COMPONENTS MAY NOT MODEL WHOLE SYSTEMS, AND ORCHESTRATION OF COMPLEX SYSTEMS MAY NOT BE EXPLAINED BY INDIVIDUAL COMPONENTS. THIS IS PARTICULARLY TRUE FOR PROTEIN KINASE SIGNALING, WHERE OVERLAP, CROSSTALK, AND REVERSIBILITY OF PHOSPHORYLATION EVENTS MAKES FOR NON-LINEAR NETWORKS. IN THIS PROPOSAL, WE EMBRACE THIS COMPLEXITY WITH A SERIES OF EXPERIMENTS DESIGNED TO ASSESS THESE TYPICALLY NON-LINEAR NETWORKS. WE PLAN TO ASSESS THE SERINE/THREONINE SUBKINOME USING AN UNBIASED PROTEIN KINASE ACTIVITY ARRAY APPROACH. COMBINED WITH BIOINFORMATICS TOOLS THAT YIELD PROTEIN KINASE NETWORKS AND NODES, WE HYPOTHESIZE THAT HIGHER ORDER INFORMATION REGARDING SIGNALING NETWORKS IN AD PROGRESSION WILL YIELD NOVEL INSIGHTS ABOUT THE DISEASE. THE BIOLOGICAL SUBSTRATES FOR THIS STUDY WILL INCLUDE POSTMORTEM BRAIN FROM CONTROL, MILD COGNITIVE IMPAIRMENT (MCI), AND AD SUBJECTS, AS WELL AS IPSC-DERIVED NEURONAL, ASTROCYTE, AND MICROGLIA CULTURES FROM SPORADIC (LATE ONSET) AND FAMILIAL AD CASES. AD PROGRESSION WILL BE ASSESSED WITH EARLY, INTERMEDIATE, AND LATE TIMEPOINTS IN AD IPSC CULTURES, AND BY COMPARING CONTROL VS MCI AND MCI VS AD POSTMORTEM SAMPLES. DELIVERABLES INCLUDE 1) IDENTIFICATION OF PROTEIN KINASES NETWORKS AND NODES ASSOCIATED WITH AD PROGRESSION, 2) VALIDATION OF PROTEIN KINASE NODES DURING AD PROGRESSION BETWEEN AND ACROSS POSTMORTEM AND IPSC SUBSTRATES, AND 3) ADVANCEMENT OF VALIDATED PROTEIN KINASE NODES FOR CAUSAL STUDIES IN HUMAN AD IPSCS. EFFECTS OF SEX WILL BE ASSESSED AS A SECONDARY OUTCOME, WITH EQUAL NUMBERS OF MALE AND FEMALE SAMPLES FOR EACH AD SUBSTRATE. LCMS DATASETS WILL BE GENERATED IN PARALLEL TO KINOME ARRAY DATASETS, PERMITTING MULTI-OMICS INTEGRATION. ALL DATASETS WILL BE INCORPORATED INTO AN R-SHINY PLATFORM THAT INTEGRATES BIOLOGICAL FEATURES OF PROTEIN KINASES. IMPORTANTLY, THE PRELIMINARY DATA FOR THIS PROPOSAL DEMONSTRATE THAT THIS PROJECT IS LOW-RISK, HIGH REWARD, AS WE HAVE PERFORMED A SERIES OF RIGOROUS STUDIES THAT IDENTIFY CANDIDATE PROTEIN KINASE NETWORK NODES AND CAREFULLY ADVANCE AND VALIDATE A CANDIDATE NODE PREVIOUSLY IMPLICATED IN AD THAT HAS NOT BEEN STUDIED IN HUMAN MODEL SYSTEMS. FOR THESE REASONS, WE BELIEVE THAT THIS PROJECT IS HIGHLY IMPACTFUL WITH A HIGH PROBABILITY OF SUCCESS.

NETWORKING URBAN RESOURCES WITH TEACHERS AND UNIVERSITY TO ENRICH EARLY CHILDHOOD SCIENCE (NURTURES) PHASE II: EXPANSION AND EVALUATION

DEVELOPMENT OF ATTENUATED FUROXANS AS NOVEL THERAPIES FOR ALZHEIMER'S DISEASE

MODEL STATE SUPPORTED AHEC PROGRAM

DEVELOPMENT OF 3-4 YEAR CONTROLLED RELEASE PZP CONTRACEPTIVE VACCINE FOR WILD HORSES

NOVEL GLT-1 ACTIVATORS FOR THE TREATMENT OF ALCOHOL DEPENDENCE: PRECLINICAL STUDIES - ABSTRACT: EMERGING EVIDENCE INDICATES THAT MANY ASPECTS OF ETHANOL (ETOH) AND DRUG DEPENDENCE INVOLVE CHANGES IN GLUTAMATE TRANSMISSION IN CENTRAL REWARD BRAIN REGIONS, INCLUDING THE NUCLEUS ACCUMBENS AND MEDIAL PREFRONTAL CORTEX. UPREGULATION OF GLUTAMATE TRANSPORTER 1 (GLT-1) IN THESE BRAIN REGIONS WITH I.P. INJECTIONS OF SEVERAL SS-LACTAMS, INCLUDING CEFTRIAXONE, ATTENUATED ETOH INTAKE AND ETOH RELAPSE BEHAVIORS IN ALCOHOL-PREFERRING RATS (P RATS). GLT-1 IS RESPONSIBLE FOR THE UPTAKE OF THE MAJORITY OF EXTRACELLULAR GLUTAMATE. IN ADDITION, CYSTINE/GLUTAMATE EXCHANGER (XCT) IS ANOTHER ASTROGLIAL PROTEIN INVOLVED IN REGULATING GLUTAMATE HOMEOSTASIS. THE PREMISE OF THIS WORK IS TO PURSUE A VERY EXTENSIVE PRECLINICAL STUDY THAT WILL INVESTIGATE THE NEUROPHARMACOLOGY OF NOVEL GLT- 1 UPREGULATORS, MC-100093, AND DERIVATIVES AS WELL AS A NON-ANTIBIOTIC FDA-APPROVED SS-LACTAM, CLAVULANIC ACID (CLAV), WHICH IS A SS-LACTAMASE INHIBITOR IN BOTH CONTINUOUS ETOH INTAKE AND ETOH RELAPSE BEHAVIOR. IN THIS STUDY, WE WILL INVESTIGATE NOVEL -LACTAMS (MC-100093 AND DERIVATIVES), WHICH DO NOT HAVE ANTIBIOTIC ACTION, ON THE EXPRESSION OF GLT-1 AND XCT, AND ANTI-INFLAMMATORY EFFECTS. THE EXPERIMENTAL GOALS ARE: (AIM 1) INVESTIGATE THE PHARMACOKINETICS.PHARMACODYNAMICS AND TARGET ENGAGEMENT OF MC-100093 AND, ITS DERIVATIVES AND CLAV TO DETERMINE DOSING, AND NOMINATE EFFICACY BIOMARKERS FOR SUBSEQUENT USE IN P RATS; (AIM 2) INVESTIGATE THE PHARMACOLOGICAL MECHANISMS OF ACTION OF MC-100093 AND ITS DERIVATIVES, AND CLAV INVOLVING THE UPREGULATION OF GLT-1 AND XCT, AND ATTENUATION OF NEUROINFLAMMATION IN P RATS. DATA GENERATED FROM THIS PROJECT WILL SHOW THAT NOVEL DRUGS CAN UPREGULATE GLT-1 EXPRESSION AND COULD HAVE SIGNIFICANT CLINICAL IMPLICATIONS FOR ALCOHOL DEPENDENCE AND OTHER NEUROPSYCHIATRIC DISORDERS CHARACTERIZED BY THE HYPERGLUTAMATERGIC STATE AS WELL AS MODULATING NEUROINFLAMMATION ASSOCIATED WITH AN INCREASE IN EXTRACELLULAR GLUTAMATE IN CENTRAL BRAIN REGIONS THAT REGULATE DRUG DEPENDENCE; AND (AIM 3) TO IDENTIFY OPTIMIZED, MORE LIPOPHILIC ANALOGS OF MC-100093 WITH DRUG-LIKE PROPERTIES AND PHARMACOKINETIC PROFILES THAT SUPPORT ONCE-DOSING.

THE ROLE OF PLATELETS IN PROTECTION AGAINST ORAL CANDIDIASIS

UPWARD BOUND

EVALUATION OF A STANDARD ACQUISITION CHARGE MODEL FOR KIDNEY PAIRED DONATION

UPWARD BOUND

MULTIFUNCTIONAL BONE PUTTY FOR CRANIOMAXILLOFACIAL BONE REPAIR

UNDERSTANDING HOW INTEGRATED COMPUTATIONAL THINKING, ENGINEERING DESIGN, AND MATHEMATICS CAN HELP STUDENTS SOLVE SCIENTIFIC AND TECHNICAL PROBLEMS IN CAREER TECHNICAL EDUCATION

INFLUENCE OF BONE MICROENVIRONMENT ON DRUG RESISTANCE IN PROSTATE CANCER BONE METASTASIS

COFILIN SIGNALING IN HEMORRHAGIC STROKE

UNDERSTANDING THE PROVIRAL ROLE FOR TRAF6 INTERACTION WITH THE VIRAL PROTEASE IN FLAVIVIRUS REPLICATION AND PATHOGENESIS

UPWARD BOUND PROGRAM

RESOURCE FOR RAT GENETIC MODELS OF AEROBIC CAPACITY

TRANSCRIPTIONAL REGULATION OF ANGIOTENSINOGEN GENE

SEP: EARTH-ABUNDANT THIN-FILM SOLAR CELLS AS A SUSTAINABLE SOLAR ENERGY PATHWAY

INTRAVITAL ASSESSMENT OF BORRELIA BURGDORFERI IMMUNE CLEARANCE IN SKIN

COUNTER REGULATORY MECHANISMS OF CARDIOTONIC STEROIDS IN CARDIO-RENAL SYNDROME

INHERITED GENETIC RISK FACTORS COMMON TO COPD AND LUNG CANCER.

ROLE OF COMPLEMENT REGULATOR PROPERDIN IN THE INTERACTION BETWEEN PLATELETS AND L

PRECLINICAL DEVELOPMENT OF A TULAREMIA VACCINE

CELL-SPECIFC ANALYSIS OF SUB-KINOMES IN SCHIZOPHRENIA

NA/K-ATPASE REDUCTION IN RENAL DISEASE-RELATED CARDIAC DYSFUNCTION

MECHANICAL CONTROL OF CORONARY ANGIOGENESIS IN MYOCARDIAL ADAPTATION TO ISCHEMIA

RYAN WHITE TITLE IV PROGRAM

INTEGRATION OF LEUKOTRIENE AND PROSTAGLANDIN RECEPTOR SIGNALING IN MAST CELL ACTIVATION AND PULMONARY INFLAMMATION DURING ASTHMA

PRE AND POST-SYNAPTIC PATHWAYS UNDERLYING THE STRESS RESPONSE IN THE ADRENAL MEDULLA - ABSTRACT THE “FIGHT-OR-FLIGHT” RESPONSE REFERS TO THE STATE OF HEIGHTENED PHYSIOLOGICAL AND MENTAL AROUSAL TRIGGERED BY A PHYSICAL THREAT, EMOTIONALLY CHARGED EVENT, OR METABOLIC DISTURBANCE. ALTHOUGH THE PRECISE REACTION TO EACH STRESSOR MAY VARY, ALL SHARE SOME BASIC CHARACTERISTICS OF SYMPATHETIC NERVOUS SYSTEM ACTIVATION. ADRENOMEDULLARY CHROMAFFIN CELLS ARE CORE EFFECTORS OF THE SYMPATHETIC RESPONSE IN THE PERIPHERY. WHEN ACTIVATED DURING STRESS, THEY DISCHARGE A COCKTAIL OF HORMONES INTO THE SUPRARENAL VEIN FOR CIRCULATION THROUGHOUT THE BODY. THESE HORMONES MODULATE CARDIAC, PULMONARY, AND METABOLIC FUNCTIONS IN WAYS THAT FAVOR SURVIVAL OR MAINTAIN INTERNAL CONDITIONS WHEN THEY ARE THREATENED. SECRETION FROM THE ADRENAL MEDULLA IS DEPENDENT ON INPUT FROM PREGANGLIONIC SPLANCHNIC FIBERS, WHICH RELEASE ACETYLCHOLINE (ACH) AND PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) ONTO CHROMAFFIN CELLS. WHAT REMAINS POORLY UNDERSTOOD IS HOW ACH AND PACAP TUNE HORMONE RELEASE TO ACCOMMODATE THE RANGE OF SPLANCHNIC FIRING FREQUENCIES ASSOCIATED WITH VARIATIONS IN SYMPATHETIC TONE. THREE SPECIFIC AIMS ARE PROPOSED TO FILL THIS GAP IN OUR UNDERSTANDING OF THE STRESS RESPONSE PATHWAY. THE AIMS WILL TEST THE OVERALL HYPOTHESIS THAT VARIATIONS IN PRESYNAPTIC SPLANCHNIC INPUT ARE TRANSLATED BY DIFFERENT RECEPTOR-COUPLED PATHWAYS IN CHROMAFFIN CELLS TO DYNAMICALLY REGULATE THE AMOUNT OF HORMONE OUTPUT. AIM 1 BUILDS ON RECENT PRELIMINARY DATA THAT SHOWS, FOR THE FIRST TIME, A ROLE FOR ANY SYNAPTOTAGMIN (SYT) AT THE SPLANCHNIC-CHROMAFFIN CELL SYNAPSE. PLANNED STUDIES, USING IN SITU SLICE ELECTROPHYSIOLOGY, WILL DEFINE THE ROLE OF CA2+ SENSING AT THIS SYNAPSE, AND EVALUATE THE IDEA THAT SYNAPTIC FACILITATION, REGULATED BY SYT7, AMPLIFIES HORMONE DISCHARGE FROM CHROMAFFIN CELLS WHEN SPLANCHNIC FIBERS DISCHARGE AT HIGH FREQUENCIES. AIM 2 IS MOTIVATED BY PRELIMINARY DATA THAT SHOWS PHOSPHOLIPASE C-EPSILON (PLC) IS REQUIRED FOR TRANSDUCING PACAP STIMULATION INTO CA2+ SIGNALS IN CHROMAFFIN CELLS THAT CAUSE EXOCYTOSIS. PACAP IS THOUGHT TO UNDERLIE CHROMAFFIN CELL SECRETION DURING STRESS. THIS HAS PROMPTED US TO POSIT THAT WITH INCREASED SPLANCHNIC FIRING FREQUENCIES THAT PRODUCE FACILITATION, PLC ACTIVITY IN CHROMAFFIN CELLS MUST BE “TURNED ON” TO SUSTAIN INCREASES IN HORMONE OUTPUT. AIM 3 BUILDS ON DATA WHICH SHOWS THAT PACAP STIMULATES EXOCYTOSIS IN CHROMAFFIN CELLS, BUT DOES SO WHILE PARADOXICALLY RESTRICTING THE RELEASE OF PEPTIDE HORMONES PACKAGED WITHIN A CHROMAFFIN GRANULE. RELEVANT FOR THE DIFFERENTIAL RELEASE OF BIOGENIC AMINES AND HORMONE PEPTIDES, WE WILL CHARACTERIZE THE PROPERTIES OF PACAP-STIMULATED FUSION PORES AND INVESTIGATE MECHANISMS BY WHICH THEY ARE CONSTRAINED. WE EXPECT THESE STUDIES WILL PROVIDE A COHERENT MOLECULAR AND PHYSIOLOGICAL FRAMEWORK FOR UNDERSTANDING HOW PRESYNAPTIC ACTIVITY, POSTSYNAPTIC RECEPTOR- COUPLED SIGNALING PATHWAYS, AND EXOCYTOSIS ARE MECHANISTICALLY LINKED TO REGULATE THE STRESS RESPONSE.

DEVELOPMENT OF ASPARTATE PATHWAY INHIBITORS AS NOVEL ANTIBIOTICS

: THE AR/TM4SF3 INTERACTION PROVIDES PROSTATE CANCER CELLS AN ENHANCED ABILITY TO SURVIVE, GROW, AND UNDERGO METASTASIS, ESSENTIAL STEPS FOR CASTRAT

MECHANISMS OF DEVELOPMENTAL REGULATION OF AFFECTIVE BEHAVIORS

MOLECULAR TARGETING THE TRANSLATIONAL CONTROL AXIS IN WNT/?-CATENIN SIGNALING PATHWAY

THE MELANOCORTINERGIC PATHWAY INGLOMERULAR DISEASE

UNIVERSITY TRANSPORTATION CENTER

DISSECTING CATALYTIC AND REGULATORY FUNCTIONS OF NONSEGMENTED NEGATIVE STRAND RNA VIRAL POLYMERASES

OPTOGENETIC AND CHEMOGENETIC DISSECTION OF CELL TRANSPLANTS

ENTIRELY CARBOHYDRATE VACCINE CONSTRUCTS AND THEIR APPLICATION IN PROBING GLYCOIM

EFFECTIVE TARGETING SURVIVIN DIMERIZATION INTERFACE WITH SMALL MOLECULE INHIBITORS

ATR ISOMERIZATION IN CELLULAR RESPONSES TO UV DAMAGE OF DNA

ROLE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) IN INFLAMMATORY BOWEL DISEASE - PROJECT SUMMARY IN 2020, APPROXIMATELY 1.6 MILLION AMERICANS WERE CONFIRMED TO HAVE INFLAMMATORY BOWEL DISEASE (IBD) AND IT IS EXPECTED THAT AS MANY AS 70,000 NEW CASES OF IBD ARE DIAGNOSED IN THE UNITED STATES EACH YEAR. IBD COMPRISES OF CHRONIC, RELAPSING INFLAMMATORY DISORDERS AFFECTING THE GASTROINTESTINAL (GI) TRACT, SUCH AS CROHN’S DISEASE AND ULCERATIVE COLITIS. AMONG VARIOUS IMMUNE CELLS THAT PARTICIPATE IN IBD, NEUTROPHILS ARE NOT ONLY THE FIRST RESPONDER CELL-TYPE TO INFLAMMATION, BUT ALSO INVOLVED IN LIMITING INFLAMMATION AND FACILITATING WOUND REPAIR. OF NOTE, THERE IS A DEARTH OF LITERATURE ON THE MUCOPROTECTIVE ROLE OF THE ENZYME PEPTIDYL ARGININE DEIMINASE-4 (PAD4), WHOSE PREDOMINANT FUNCTION IS TO FACILITATE THE GENERATION OF CITRULLINATED HISTONE 3 (H3CIT) AND THE RELEASE OF DNA AS NEUTROPHIL EXTRACELLULAR TRAPS (NETS). THE OVERALL GOAL OF THE RESEARCH IS TO STUDY THE ROLE PAD4 IN INFLAMMATORY BOWEL DISEASE (IBD). THIS PROPOSAL AIMS TO SYSTEMATICALLY ELUCIDATE THE ROLE OF PAD4- MEDIATED RELEASE OF H3CIT AND NETS DURING IBD. THREE SPECIFIC AIMS ARE PROPOSED, EACH OF WHICH INVESTIGATES THE MOLECULAR UNDERPINNINGS BY WHICH PAD4 INFLUENCE GUT HEALTH AND DISEASE. THE THREE AIMS ARE INTERRELATED, INDEPENDENTLY ACHIEVABLE AND WOULD SYSTEMATICALLY CHARACTERIZE: (I) THE ROLE OF NETS IN MURINE MODELS OF IBD, (II) THE ADVERSE CONSEQUENCE OF PAD4-DEFICIENCY IN POTENTIATING THE ‘SPILLOVER’ OF NEUTROPHIL GRANULE PROTEINS AND (III) THE SIGNIFICANCE OF NETS IN PREVENTING BACTERIAL ENCROACHMENT ON THE MUCOSA, THAT OTHERWISE CAN PERPETUATE INTESTINAL INFLAMMATION.

MALADAPTIVE NIGROVAGAL PATHOPHYSIOLOGY IN PARKINSONISM

ROLE OF GSK3BETA IN DIABETIC KIDNEY DISEASE - ABSTRACT DIABETIC KIDNEY DISEASE (DKD) IS THE LEADING CAUSE OF END-STAGE RENAL DISEASE WITH NO DEFINITIVE THERAPY YET AVAILABLE. EMERGING EVIDENCE SUGGESTS THAT DEFECTIVE INSULIN SIGNALING IN PODOCYTES PLAYS A KEY ROLE IN THE PATHOGENESIS OF DKD. IN ADDITION, THE “FINAL COMMON MOLECULAR PATHWAY” FOR GLOMERULAR DEGENERATION CONTRIBUTES TO DKD, INVOLVING OXIDATIVE DAMAGE AND STRESS-INDUCED PREMATURE SENESCENCE. GLYCOGEN SYNTHASE KINASE (GSK)3 IS A CRITICAL TRANSDUCER OF INSULIN SIGNALING, AND ALSO ACTS AS A CONVERGENT POINT FOR MYRIAD PATHWAYS IMPLICATED IN ORGAN INJURY, REPAIR, AND REGENERATION. IN RENAL GLOMERULI, GSK3SS RATHER THAN THE A ISOFORM IS PREDOMINANTLY EXPRESSED AND ENRICHED IN PODOCYTES. OUR LATEST STUDIES DEMONSTRATED THAT GSK3SS IS HYPERACTIVE IN GLOMERULAR PODOCYTES IN CLINICAL AND EXPERIMENTAL DKD, CORRELATING WITH THE SEVERITY AND PROGRESSION OF DKD AND ASSOCIATED WITH ACCELERATED PODOCYTE SENESCENCE. HOWEVER, THE ROLE OF GSK3SS IN DIABETIC NEPHROPATHY (DN) IS EXTREMELY CONTROVERSIAL BASED ON VERY FEW STUDIES SOLELY RELYING ON CHEMICAL INHIBITORS OR ACTIVATORS WITH SPECIFICITY CONCERNS. PRELIMINARY DATA REVEALED THAT GSK3SS CATALYZES PHOSPHORYLATION OF P53 AND P16INK4A, PIVOTAL MEDIATORS OF SENESCENCE SIGNALING IN PODOCYTES, AND THAT GSK3SS-REGULATED KEAP1-INDEPENDENT NRF2 ANTIOXIDANT DEFENSE IS A NEW ACTIONABLE TARGET FOR PODOCYTE PROTECTION. FURTHERMORE, GSK3SS INHIBITION PROMOTES THE EXPRESSION AND ACTIVITY OF RETINOIC ACID (RA) RECEPTOR (RAR)A, A KEY TRANSCRIPTION FACTOR DRIVING PODOCYTE DIFFERENTIATION AND REPAIR. BUILDING LOGICALLY ON PREVIOUS WORK, THIS PROJECT AIMS TO CONCLUSIVELY DEFINE THE EXACT ROLE OF GSK3SS IN DN AND TEST A NOVEL HYPOTHESIS THAT TARGETING GSK3SS IN PODOCYTES MIMICS OR SENSITIZES INSULIN SIGNALING, REINFORCES NRF2 ANTIOXIDANT RESPONSE, MITIGATES SENESCENCE, AND SYNERGIZES WITH RARA SIGNALING, RESULTING IN A BENEFICIAL EFFECT IN DN. AIM 1 WILL DEFINE THE MOLECULAR MECHANISM UNDERLYING GSK3SS REGULATION OF DIABETIC PODOCYTE INJURY. GSK3SS ACTIVITY WILL BE MANIPULATED IN PODOCYTES EXPOSED TO THE DIABETIC MILIEU AND ITS ROLE IN INSULIN SIGNALING, NRF2 RESPONSE AND ACCELERATED PODOCYTE SENESCENCE WILL BE DEFINED. AIM 2 WILL EXAMINE THE ROLE OF PODOCYTE-SPECIFIC GSK3SS IN DN. IN MICE WITH TYPE 1 DN ELICITED BY STREPTOZOTOCIN PLUS UNINEPHRECTOMY, OR IN DB/DB MICE WITH TYPE 2 DN, GSK3SS ACTIVITY WILL BE PROMOTED BY GSK3SS KNOCKIN OR PODOCYTE-SPECIFIC GSK3SS HYPERACTIVITY, OR INHIBITED BY INDUCIBLE CONDITIONAL KNOCKOUT (ICKO) OF GSK3SS. THE RESCUE EFFICACY OF SMALL MOLECULE INHIBITORS OF GSK3SS, INCLUDING MICRODOSE LITHIUM AND TIDEGLUSIB, ON ESTABLISHED DN WILL BE FURTHER EVALUATED. AIM 3 WILL TEST THE SYNERGISTIC EFFECT OF GSK3SS INHIBITION PLUS RA ON DN. MICE WITH ICKO OF GSK3SS AND RARA IN PODOCYTES WILL BE EMPLOYED TO DETERMINE IF RARA CONTRIBUTES TO GSK3SS REGULATION OF DN. THE ROLE OF GSK3SS IN REGULATING RARA ACTIVITY WILL BE DEFINED USING PODOCYTES WITH DIFFERING GSK3SS ACTIVITY AND VALIDATED IN GSK3SSICKO MICE WITH TYPE 1 OR 2 DN. THE SYNERGISTIC EFFECT OF RA PLUS GSK3SS INHIBITORS ON DN WILL BE TESTED. COLLECTIVELY, THESE STUDIES WILL PROVIDE A MECHANISTIC VIEW OF THE ROLE OF GSK3SS IN THE PATHOGENESIS OF DN AND PAVE THE WAY FOR TRIALS OF EXISTING OR NOVEL MEDICATIONS WITH GSK3SS INHIBITORY ACTIVITIES TO TREAT DKD IN MEN.

REGULATION OF MELANOCYTE DIFFERENTIATION BY SWI/SNF CHROMATIN REMODELING ENZYMES

VALIDATION OF A MULTI-GENE TEST FOR LUNG CANCER RISK

DEFECTIVE MELANOCORTIN SIGNALING UNDERLYING T2D-ASSOCIATED ERECTILE DYSFUNCTION

THE ROLES OF PRIMARY CILIA IN CARDIOVASCULAR SYSTEM

GENETICS OF HYPERTENSION

LOCOMOTION IN PARASITIC NEMATODES

INTERPLAY BETWEEN DIETARY FIBER AND GUT MICROBIOTA IN HEPATOCELLULAR CARCINOMA

THE MECHANISM OF CELL SIZE REGULATION BY POLYCYSTINS - THE MECHANISM OF MECHANOSENSING BY POLYCYSTINS DURING CELL GROWTH CYTOKINESIS IS THE LAST STAGE OF CELL DIVISION WHEN TWO DAUGHTER CELLS SEPARATE, BUT IT IS EQUALLY IMPORTANT FOR THE TRANSITION TO CELL GROWTH INCLUDING CELL SIZE EXPANSION. THE MECHANISM REGULATING SUCH A TRANSITION IS POORLY UNDERSTOOD. WE IDENTIFIED THE ROLE OF CALCIUM AND THE POLYCYSTIN CHANNEL PKD2P IN THIS PROCESS WHILE STUDYING CYTOKINESIS OF THE MODEL ORGANISM FISSION YEAST. PKD2P IS ESSENTIAL TO REGULATE THE CELL SIZE AND IT MEDIATES CALCIUM INFLUX. POLYCYSTINS ARE EVOLUTIONALLY CONSERVED ION CHANNELS. LOSS OF FUNCTION MUTATIONS OF HUMAN POLYCYSTINS LEAD TO THE GENETIC DISORDER, AUTOSOMAL POLYCYSTIC KIDNEY DISORDER (ADPKD). THE CELLULAR FUNCTION OF THIS HIGHLY CONSERVED FAMILY OF CHANNELS IS NOT WELL UNDERSTOOD. THIS STUDY WILL DETERMINE HOW PKD2P AND CALCIUM REGULATE THE TRANSITION TO CELL GROWTH. AIM 1. DETERMINE HOW THE HIPPO SIGNALING PATHWAYS REGULATE PKD2P. OUR GENETIC SCREEN HAS IDENTIFIED THE FISSION YEAST HIPPO PATHWAYS SIN AND MOR AS CRUCIAL FOR THE REGULATION OF PKD2P. BOTH ARE HIGHLY CONSERVED KINASE CASCADES THAT ARE ESSENTIAL FOR CELL PROLIFERATION. SIN ANTAGONIZES PKD2P ACTIVITY, WHILE MOR SYNERGIZES WITH PKD2P. HOWEVER, THE MECHANISM IS UNCLEAR. WE WILL 1) DETERMINE HOW MOR AND SIN REGULATE CELLULAR CALCIUM DURING CYTOKINESIS THROUGH CALCIUM-IMAGING. 2) DETERMINE HOW MOR AND SIN REGULATE PKD2P IN CELL SIZE EXPANSION. 3) DETERMINE HOW MOR PROMOTES THE CELL CYCLE-DEPENDENT LOCALIZATION OF PKD2P. 4) DETERMINE WHETHER PKD2P IS A DIRECT SUBSTRATE OF THE MOR KINASE ORB6P. AIM 2. DETERMINE HOW THE PKD2P CHANNEL IS ACTIVATED. PKD2 CHANNEL OPENS IN RESPONSE TO MECHANICAL FORCE IN VITRO, BUT THE MECHANISM IS UNCLEAR. WE WILL TEST THE PROPOSAL THAT PKD2P IS A CHANNEL SENSITIVE TO THE FORCE DRIVING THE YEAST CELL GROWTH. WE WILL 1) DETERMINE HOW PKD2P REGULATES CALCIUM WHEN THE CELLS ARE STIMULATED BY EXTERNAL FORCE. 2) PROBE HOW PKD2P SENSES OSMOTIC STIMULI AND THE LIPID ENVIRONMENT IN VITRO THROUGH A COLLABORATION WITH ALLEN LIU’S GROUP (UNIVERSITY OF MICHIGAN). 3) DETERMINE WHETHER PKD2P CHANNEL ALLOWS IONS OTHER THAN CALCIUM TO PASS THROUGH, USING PATCH CLAMP, THROUGH A COLLABORATION WITH DU JIANYANG’S GROUP (UNIVERSITY OF TENNESSEE). AIM 3 DETERMINE HOW PKD2P REGULATES THE ACTIN RE-ORGANIZATION DURING CYTOKINESIS. CALCIUM CAN ACTIVATE TWO HIGHLY CONSERVED MOLECULES CAM1P AND PPB1P. WE WILL DETERMINE HOW THEY CONTRIBUTE TO THE ROLE OF PKD2P IN CYTOKINESIS. WE WILL DETERMINE 1) HOW PKD2P REGULATES THE CAM1P-DEPENDENT ENDOCYTOSIS DURING CYTOKINESIS. 2) HOW PKD2P REGULATES THE CAM1P-DEPENDENT INTRACELLULAR TRANSPORT. 3) HOW PKD2P REGULATES THE ENZYMATIC ACTIVITY OF PPB1P. THROUGH THIS STUDY, WE EXPECT TO UNCOVER A NOVEL CELL SIZE REGULATION PATHWAY MEDIATED BY PKD2P CHANNEL. WE WILL DEMONSTRATE HOW BOTH INTERNAL SIGNALING PATHWAYS AND EXTERNAL ENVIRONMENT PLAY A VITAL ROLE IN ACTIVATING THIS CHANNEL IN CYTOKINESIS. WE WILL EMPLOY NOVEL IMAGING METHODS COMBINED WITH INNOVATIVE IN VITRO TECHNIQUES IN OUR STUDY. OUR WORKS SHALL HELP US BETTER UNDERSTAND THE CELLULAR FUNCTIONS OF THE HUMAN POLYCYSTINS.

THE MECHANISM OF PERICENTRIOLAR MATERIAL ASSEMBLY DURING CENTROSOME BIOGENESIS

ROLE OF JAK2-PAK1 INTERACTION IN PROLACTIN-DEPENDENT SIGNALING

CONJUGATED BILE ACIDS AS NUTRITIONALLY RE-PROGRAMMABLE ANTIHYPERTENSIVE METABOLITES - PROJECT SUMMARY HYPERTENSION IS THE SINGLE PROMINENT RISK FACTOR OF EPIDEMIC PROPORTIONS LEADING TO CARDIOVASCULAR DISEASE AND STROKE, WHICH COMPRISE THE TOP TWO REASONS FOR MORTALITY OF HUMANS IN THE MODERN AGE. GENETICS AND DIETARY SALT INTAKE ARE THE MOST INVESTIGATED FACTORS FOR SUSCEPTIBILITY TO HYPERTENSION. WE RECENTLY DISCOVERED A NOVEL LINK BETWEEN THE COMPOSITION OF GUT MICROBIOTA AND HYPERTENSION IN THE DAHL SALT-SENSITIVE (S) RAT, A RODENT MODEL OF HUMAN DISEASE. HOWEVER, EXCEPT FOR A FEW METABOLITES SUCH AS SHORT CHAIN FATTY ACIDS, THE MECHANISMS BY WHICH MICROBIOTA TRIGGER HYPERTENSION IS LARGELY UNKNOWN. MICROBIOTA COLLABORATES WITH THE HOST TO PRODUCE KEY METABOLITES REQUIRED FOR HOST HEALTH. CONJUGATED BILE ACIDS ARE ONE SUCH CLASS OF BILE ACIDS. THEY ARE GENERATED BY THE HOST IN THE LIVER AND DECONJUGATED BY MICROBIOTA IN THE GUT. A BILE ACID TARGETED METABOLOMICS STUDY LED US TO DISCOVER THAT CONJUGATED BILE ACIDS ARE SIGNIFICANTLY DEPLETED IN HYPERTENSION, RESCUING WHICH AMELIORATED HYPERTENSION. THUS, THE OVERARCHING HYPOTHESIS OF THIS PROPOSAL IS THAT CONJUGATED BILE ACIDS ARE NOVEL ANTIHYPERTENSIVE METABOLITES. TO TEST THIS HYPOTHESIS, EXPERIMENTS ARE PROPOSED TO ADDRESS TWO IMPORTANT QUESTIONS: FIRST, WHY ARE CONJUGATED BILE ACIDS DEPLETED IN HYPERTENSION? AIM 1 WILL ADDRESS THIS QUESTION. PRELIMINARY DATA SHOW THAT SPECIFIC GUT MICROBIOTA WHICH ARE KNOWN TO DECONJUGATE BILE ACIDS EXPAND DURING HYPERTENSION. WE PROPOSE TO INVESTIGATE WHETHER SUCH MICROBIOTA ARE THE CULPRITS RESPONSIBLE FOR DEPLETING THE CIRCULATING POOL OF CONJUGATED BILE ACIDS. USING NOVEL S RATS WHICH LACK GUT MICROBIOTA, STUDIES ARE PROPOSED TO INTRODUCE SPECIFIC MICROBIOTA TO TEST ITS EFFECT ON ENHANCING THE CIRCULATING LEVELS OF THE ANTIHYPERTENSIVE METABOLITES, CONJUGATED BILE ACIDS. AIM 2 WILL ADDRESS THE SECOND IMPORTANT QUESTION, ‘WHAT IS THE MECHANISM BY WHICH CONJUGATED BILE ACIDS PROVIDE PROTECTION AGAINST THE DEVELOPMENT OF HYPERTENSION?’ FOCUSING ON TAUROCHOLIC ACID, WHICH IS A SPECIFIC CONJUGATED BILE ACID DEPLETED DURING HYPERTENSION, AIM 2 WILL TEST THE HYPOTHESIS THAT TAUROCHOLIC ACID LOWERS HYPERTENSION BY TARGETING THE GUT FXR-CERAMIDE PATHWAY. SPECIFICALLY, TAUROCHOLIC ACID ANTAGONIZES THE BILE ACID RECEPTOR FARNESYL X RECEPTOR (FXR) IN THE GUT TO INHIBIT THE TRANSCRIPTION OF KEY GENES REQUIRED FOR THE SYNTHESIS OF THE KNOWN PROHYPERTENSIVE METABOLITE, CERAMIDE. A NOVEL VILLIN-CRE RAT KNOCK-IN RAT AND A SECOND NOVEL FXR KNOCKOUT RAT HAVE BEEN CONSTRUCTED AND PROPOSED AS TOOLS TO STUDY THIS GUT-SPECIFIC MECHANISM. OVERALL, THIS WORK EXPANDS OUR CURRENT LIMITED KNOWLEDGE BEYOND THE HOST FACTORS AND SHEDS IMPORTANT NEW LIGHT ON HOW MICROBIOTA CRITICALLY MODIFY BILE ACID BIOCHEMISTRY TO AMPLIFY HYPERTENSION. OUR PROPOSAL NOT ONLY IDENTIFIES THIS PROBLEM, BUT ALSO INTERROGATES A MEANS TO MITIGATE IT BY A SIMPLE SOLUTION OF ENHANCING CIRCULATING CONJUGATED BILE ACIDS AS A NOVEL PUTATIVE CLINICAL THERAPEUTIC STRATEGY TO LOWER HYPERTENSION.

ENGINEERING EXOSOME FOR PANCREATIC CANCER TARGETING THERAPIES - PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS ONE OF THE DEADLIEST CANCERS AND RANKS FOURTH IN CANCER- RELATED DEATHS IN THE UNITED STATES. THERAPIES FOR PANCREATIC CANCER ARE LARGELY HINDERED BY THE LACK OF AN EFFECTIVE DELIVERY SYSTEM. EXOSOMES ARE EMERGING AS A PROMISING TYPE OF NANOCARRIER FOR DRUG/GENE DELIVERY DUE TO THE UNIQUE PROPERTIES OF THESE NATURALLY DERIVED, NANOSCALE EXTRACELLULAR VESICLES AND THEIR INNATE ABILITY TO SHUTTLE PROTEINS, LIPIDS AND DNA/RNA BETWEEN CELLS. HOWEVER, MAJOR CHALLENGES EXIST, INCLUDING THEIR INABILITY TO TARGET TUMOR CELLS AND THEIR HIGH PROPORTION OF CLEARANCE BY THE MONONUCLEAR PHAGOCYTE SYSTEM (MPS) OF THE LIVER AND SPLEEN. OUR LONG-TERM GOAL IS TO DEVELOP INNOVATIVE NANOCARRIERS WITH LOW IMMUNOGENICITY, HIGH BIOCOMPATIBILITY, INCREASED STABILITY, LONGER CIRCULATION TIMES, AND HIGHLY ACTIVE TUMOR CELL TARGETING. USING NOVEL EXOSOMAL ENGINEERING TECHNIQUES, WE RECENTLY FOUND THAT (A) INCORPORATION OF A TUMOR-HOMING PEPTIDE (RGD) ONTO EXOSOMAL SURFACE MARKER CD9 (EXOCD9-RGD) RESULTS IN SPECIFIC BINDING TO AND UPTAKE BY INTEGRIN V3- EXPRESSING CANCER CELLS, AND (B) EXOSOMES OVEREXPRESSING CD47, A “DON’T EAT ME” SIGNAL, VIA ITS MINIMAL SELF- PEPTIDE (CD47P110-130), INTERACT WITH SIGNAL REGULATORY PROTEINS (SIRP, CD172A) ON MACROPHAGES TO SIGNIFICANTLY REDUCE LIVER AND SPLEEN CLEARANCE OF EXOSOMES. THESE FINDINGS LEAD TO OUR CENTRAL HYPOTHESIS THAT DISPLAYING RGD AND CD47P110-130 ON EXOSOMES THROUGH CD9 ENGINEERING WILL PERMIT EXOSOMES TO TARGET PDAC IN VIVO WHILE ALLOWING EXOSOMES TO EVADE MPS CLEARANCE. TOWARD THIS HYPOTHESIS, WE HAVE DEVELOPED “SMART EXOSOMES” BY CO-DISPLAYING RGD AND CD47P110-130 ON THE EXOSOME SURFACE (EXOSMART). THIS RESULTS IN ENHANCED RECEPTOR BINDING, THEREBY INCREASING ACCUMULATION AND CYTOTOXIC THERAPEUTIC EFFECTS IN 3D STROMA-RICH PDAC SPHEROID TUMOR MODELS. WITH THESE STRONG PRELIMINARY DATA, WE PROPOSE TO PURSUE THREE SPECIFIC AIMS TO CHARACTERIZE EXOSMART AND VALIDATE THE APPLICATION OF EXOSMART IN DRUG DELIVERY. (1) TO EVALUATE SMART EXOSOMES CO-EXPRESSING CD9- RGD AND CD9-CD47P110-130 (EXOSMART) FOR EXCLUSIVE ACTIVE PDAC TARGETING THERAPY USING HUMAN PDAC STROMA- RICH 3D SPHEROID MODELS, BOTH IN VITRO AND IN VIVO. (2) TO VALIDATE THE EFFICACY OF EXOSMART PDAC TARGETING CHEMOTHERAPIES IN A GENETICALLY ENGINEERED MOUSE PDAC TUMOR MODEL (KPC) AND CLINICALLY RELEVANT PATIENT- DERIVED XENOGRAFTED (PDX) PANCREATIC CANCER MICE MODELS. (3) TO EXTEND EXOSMART TO PERSONALIZED PDAC TARGETING BY OPTIMIZING MULTIPLE INSERTION SITES OF CD9 AND TUMOR-TARGETING PEPTIDES FOR OPTIMAL PDAC TARGETING. COLLECTIVELY, OUR PROPOSED RESEARCH WILL BROADLY IMPACT THE FIELD BY DEVELOPING INNOVATIVE NANOCARRIERS WITH OPTIMIZED CARGOS AND SURFACES FOR PRECISION PDAC TARGETING. THIS PROJECT HOLDS GREAT TRANSLATIONAL POTENTIAL FOR CANCER THERAPY WHILE PROVIDING A SOLID BASIS FOR FUTURE WORK UTILIZING NOVEL PEPTIDE-ENGINEERED EXOSOME STRATEGIES.

IN VIVO ROLE OF PLATELETS IN BACTERIAL BLOOD INFECTION

GENETICS OF HYPERTENSION

DISRUPTING AND MANAGING RIVERINE AND OTHER LARGE-SCALE FRESHWATER HARMFUL ALGAL BLOOMS

TAS::89 0321::TAS ADVANCED OFFSHORE WIND TURBINE/FOUNDATION CONCEPT FOR THE GREAT LAKES

DEVELOPMENT AND VALIDATION OF EARLY DETECTION AND SUSTAINED TREATMENT METHODS TO CONTROL HABS IN INLAND SOURCE WATERS IN OHIO

MECHANISMS DRIVING CORTICAL CYTOSKELETON DYNAMICS IN CANCER CELL INVASION

DYSREGULATION OF INNATE IMMUNE RESPONSES BY BORRELIA BURGDORFERI:A ROLE FOR IL-10

REGULATION OF EPITHELIAL JUNCTIONS AND LUMEN MORPHOGENESIS BY THE SCRIBBLE/SGEF/DLG1 COMPLEX

TRPC3 CHANNELS IN MOLECULAR AND CELLULAR EVENTS OF ATHEROGENESIS

IMMUNE RESPONSE TO PNEUMOCOCCAL VACCINATION IN HIV INFECTED ADULTS

HIGH-RATE FABRICATION OF A-SI-BASED THIN-FILM SOLAR CELLS USING LARGE-AREA VHF PECVD PROCESSES

UPWARD BOUND MATH SCIENCE PROGRAM

TRIP13 AAA-ATPASE OVEREXPRESSION IN CHROMOSOMAL INSTABILITY AND BREAST CANCER

CULTIVATING PERSISTENCE AND LEADERSHIP DEVELOPMENT IN SCIENCE MASTER TEACHERS -THIS PROJECT AIMS TO SERVE THE NATIONAL NEED OF PREPARING HIGH-QUALITY SCIENCE TEACHER LEADERS IN HIGH-NEED URBAN AND RURAL SCHOOL DISTRICTS. GIVEN THE CHALLENGES THAT EXIST IN THE RECRUITMENT AND RETENTION OF TEACHERS IN RURAL AND URBAN SCHOOL DISTRICTS, THIS PROJECT WILL DEVELOP ONE COHORT OF GRADE 6-12 MASTER TEACHING FELLOWS (MTFS) AS SCIENCE TEACHER LEADERS IN URBAN AND RURAL DISTRICTS IN KENTUCKY AND OHIO. THIS COHORT WILL BE COMPRISED OF 20 EFFECTIVE AND EXPERIENCED TEACHERS FROM MIDDLE AND HIGH SCHOOLS. THIS PROJECT WILL BUILD LEADERSHIP CAPACITY IN HIGH-NEED ENVIRONMENTS BY CREATING A COMMUNITY OF PRACTICE AND INCORPORATING THE USE OF VIDEO ANALYSIS TO IMPROVE PEDAGOGICAL AND CONTENT KNOWLEDGE RELATED TO IMPLEMENTATION OF THE NEXT GENERATION SCIENCE STANDARDS (NGSS). ADDITIONAL ELEMENTS OF THE PROGRAM WILL INCLUDE CLASSROOM OBSERVATIONS, TEACHER EXCHANGE PROGRAM, VIRTUAL BOOK STUDIES, AND MICRO-COURSES IN THE AREAS OF CULTURAL COMPETENCE, LEADERSHIP, AND NATIONAL BOARD PROFESSIONAL TEACHING STANDARDS. MTFS WILL BE IMMERSED IN RESEARCH-BASED TEACHER AND LEADERSHIP PROFESSIONAL DEVELOPMENT DESIGNED TO DEVELOP MASTERY OF THE KNOWLEDGE, SKILLS, AND DISPOSITIONS NECESSARY TO LEAD FROM THE CLASSROOM. THE PROJECT WILL ATTEMPT TO REDUCE THE EFFECTS OF ATTRITION-RELATED FACTORS THROUGH THE IMPLEMENTATION OF A STRUCTURED PROFESSIONAL DEVELOPMENT AND LEADERSHIP PROGRAM DESIGNED TO ADDRESS THESE RETENTION-RELATED FACTORS IN ORDER TO CULTIVATE TEACHER PERSISTENCE. THIS PROJECT AT THE UNIVERSITY OF TOLEDO WILL INCLUDE COLLABORATION BETWEEN THE PARTNERSHIP INSTITUTE FOR MATH AND SCIENCE EDUCATION REFORM (PIMSER), AND NINE HIGH NEED URBAN AND RURAL SCHOOL DISTRICTS: DEFIANCE, NELSONVILLE-YORK, TOLEDO, AND WASHINGTON SCHOOL DISTRICTS IN OHIO AND CARTER, FAYETTE, MADISON, PULASKI, AND ROCKCASTLE SCHOOL DISTRICTS IN KENTUCKY. PROJECT GOALS INCLUDE THE DEVELOPMENT OF MTFS WHO WILL EXHIBIT AN INCREASED ENGAGEMENT IN LEADERSHIP ACTIVITIES, AN INCREASED LEVEL OF CULTURAL COMPETENCE, AND ENGAGEMENT IN STRATEGIES DESIGNED TO INCREASE JOB SATISFACTION AND TEACHER PERSISTENCE. USING THE INITIAL AND REVISED COMMUNITY OF PRACTICE TEACHER LEADER IDENTITY MODEL (COPTLM) FRAMEWORK, THIS PROJECT WILL EXPLORE TEACHER LEADERSHIP IDENTITY DEVELOPMENT OF SECONDARY SCIENCE TEACHERS ACROSS URBAN AND RURAL CONTEXTS. SPECIFICALLY, THIS RESEARCH WILL EXPLORE THE FOLLOWING QUESTIONS: 1) WHAT ARE THE SHARED COMPETENCIES, PERFORMANCES, RECOGNITIONS, AND STRUCTURES NECESSARY TO FACILITATE TEACHER LEADERSHIP IDENTITY DEVELOPMENT ACROSS DIVERSE URBAN AND RURAL SPACES? 2) WHAT ARE THE UNIQUE COMPETENCIES, PERFORMANCES, RECOGNITIONS, AND STRUCTURES NECESSARY TO FACILITATE TEACHER LEADERSHIP IDENTITY DEVELOPMENT ACROSS DIVERSE URBAN AND RURAL SPACES? 3) HOW DOES TEACHER LEADERSHIP IDENTITY DEVELOP OVER TIME AND HOW IS IT INFLUENCED BY VARIATION ACROSS DIVERSE TEACHING CONTEXTS? THE DISSEMINATION PLAN INCLUDES SHARING PROFESSIONAL DEVELOPMENT MATERIALS, CAPSTONE PROJECTS, AND PROJECT RESULTS WITH ALL STAKEHOLDERS AT THE LOCAL, REGIONAL, STATE, AND NATIONAL LEVEL. THIS TRACK 3: MASTER TEACHING FELLOWSHIPS PROJECT IS SUPPORTED THROUGH THE ROBERT NOYCE TEACHER SCHOLARSHIP PROGRAM (NOYCE). THE NOYCE PROGRAM SUPPORTS TALENTED STEM UNDERGRADUATE MAJORS AND PROFESSIONALS TO BECOME EFFECTIVE K-12 STEM TEACHERS AND EXPERIENCED, EXEMPLARY K-12 TEACHERS TO BECOME STEM MASTER TEACHERS IN HIGH-NEED SCHOOL DISTRICTS. IT ALSO SUPPORTS RESEARCH ON THE EFFECTIVENESS AND RETENTION OF K-12 STEM TEACHERS IN HIGH-NEED SCHOOL DISTRICTS. 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.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

IMPROVEMENT IN PAIRED DONATION PROGRAM

ENHANCING CHEMOTHERAPEUTIC EFFICACY IN TRIPLE-NEGATIVE BREAST CANCER VIA DSTYK SILENCE - PROJECT ABSTRACT BREAST CANCER, THE MOST PREVALENT CANCER IN WOMEN, IS RESPONSIBLE FOR MORE THAN 15% OF NEW CANCER CASES AND ABOUT 6.9% OF ALL CANCER-RELATED DEATH IN THE US. A MAJOR CAUSE OF THERAPEUTIC FAILURE IN BREAST CANCER IS THE DEVELOPMENT OF RESISTANCE TO CHEMOTHERAPY, ESPECIALLY FOR TRIPLE- NEGATIVE BREAST CANCER (TNBC), A TYPE OF BREAST CANCER CONSIDERED TO BE MORE AGGRESSIVE AND HAVE A POORER PROGNOSIS THAN OTHER TYPES OF BREAST CANCER. THEREFORE, HOW TO OVERCOME CHEMORESISTANCE IS THE MAJOR CHALLENGE TO IMPROVE THE LIFE EXPECTANCY OF TNBC PATIENTS. PRELIMINARY DATA DEMONSTRATE THAT TNBC CELLS SURVIVING FROM THE CHRONIC TREATMENT OF CHEMOTHERAPEUTIC DRUGS SHOW SIGNIFICANTLY HIGHER EXPRESSION OF A SPECIAL PROTEIN KINASE, DUAL SERINE/THREONINE AND TYROSINE PROTEIN KINASE (DSTYK), THAN PARENTAL CELLS WITHOUT TREATMENT. ADDITIONALLY, FROM BOTH IN VITRO AND IN VIVO RESULTS, WE FOUND THAT BOTH THE KNOCKOUT OF DSTYK AND EXOSOME-MEDIATED DSTYK SILENCE CAN LEAD TO THE APOPTOSIS OF CHEMORESISTANT CELLS UPON DRUG TREATMENT. THIS NOVEL FINDING SUGGESTS THAT DSTYK EXERTS A PREVIOUSLY UNKNOWN AND IMPORTANT ROLE IN PROMOTING CHEMORESISTANCE. THE OBJECTIVE OF THIS PROPOSAL IS TO ELUCIDATE THE NOVEL ROLE AND THE UNDERPINNING MECHANISM OF DSTYK IN REGULATING CHEMORESISTANCE IN TNBC CELLS AND FURTHER EXPLORE THE POTENTIAL OF EXOSOME-MEDIATED DSTYK SILENCE IN TNBC CHEMOTHERAPY WITH PRECLINICAL MODELS. WE HYPOTHESIZE THAT DSTYK IS A NOVEL TARGET FOR CHEMOTHERAPY TO INDUCE TNBC CELL DEATH. WE WILL TEST OUR HYPOTHESIS WITH THREE SPECIFIC AIMS. IN AIM 1, WE WILL INVESTIGATE THE MECHANISM BY WHICH DSTYK PROMOTES CHEMORESISTANCE IN TNBC CELLS. IN AIM 2, WE WILL ESTABLISH DSTYK AS A PROGNOSTIC BIOMARKER IN CLINICAL TNBC. IN AIM 3, WE WILL EVALUATE THE THERAPEUTIC BENEFIT OF DSTYK-SIRNA-EXOSOMES IN CHEMOTHERAPY. WE ENGINEERED EXOSOMES CONTAINING SIRNA AGAINST DSTYK THAT CAN SPECIFICALLY TARGET TNBC CELLS. WE FOUND THESE ENGINEERED EXOSOMES CAN SIGNIFICANTLY PROMOTE TUMOR REGRESSION AND INHIBIT METASTASIS IN BOTH CELLULAR AND ORTHOTOPIC MODELS TREATED WITH DRUGS. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL PROVIDE FUNDAMENTAL INSIGHTS INTO THE ROLE OF DSTYK IN CHEMORESISTANCE IN TNBC CELLS AND WILL LAY THE ESSENTIAL FOUNDATION FOR THE DEVELOPMENT OF AN EXOSOME-MEDIATED STRATEGY TARGETING DSTYK TO SIGNIFICANTLY IMPROVE CLINICAL TNBC CHEMOTHERAPY.

ACTIVE EARLY DETECTION AND DIAGNOSIS OF HABS WITH SCALABLE BIOLOGICAL TREATMENT STRATEGIES

THIS PROJECT SUPPORTS THE GREAT LAKES RESTORATION INITIATIVE AND THE GREAT LAKES WATER QUALITY AGREEMENT, PURSUANT TO PUBLIC LAW 11210. UNIVERSITY O

TRIO STUDENT SUPPORT SERVICES

BUILDING A KIDNEY MONITORING PANEL TO GUIDE THERAPY IN RESISTANT HYPERTENSION - PROJECT SUMMARY HYPERTENSION (HTN) IS THE MOST COMMON RISK FACTOR FOR CARDIOVASCULAR DISEASE (CVD) AND CAUSES MULTIPLE HEALTH PROBLEMS INCLUDING STROKE, HEART FAILURE, KIDNEY FAILURE, MYOCARDIAL INFARCTION, AND DEATH. RESISTANT HTN IS DEFINED BY FAILURE TO REACH BLOOD PRESSURE (BP) GOAL DESPITE THE USE OF 3 OR MORE HTN MEDICATIONS. AMONG THE MOST CHALLENGING POPULATIONS WITH RESISTANT HTN TO TREAT ARE PERSONS WITH RENAL ARTERY STENOSIS (RAS) SINCE HTN TREATMENT IN RAS OFTEN CAUSES CHANGES IN CREATININE (CR). FURTHERMORE, THESE INDIVIDUALS HAVE EXTREMELY HIGH CVD RISK, SO ACHIEVING BP CONTROL IS ESPECIALLY IMPORTANT. A MAJOR CHALLENGE THAT IMPAIRS HTN TREATMENT IS THE PERCEPTION OF WORSENING KIDNEY FUNCTION OR ACUTE KIDNEY INJURY (AKI) BASED ON CREATININE (CR) CHANGES DURING HTN TREATMENT. BLOOD PRESSURE LOWERING IS OFTEN ACCOMPANIED BY CHANGES IN CR, WHICH IN TURN, TYPICALLY LEADS TO INTERRUPTION OR CESSATION OF EFFECTIVE HTN MEDICATIONS; THIS CLINICAL RESPONSE IS HARMFUL TO PATIENTS BECAUSE THESE ELEVATIONS IN CR ARE TYPICALLY CAUSED BY BENIGN ACCOMMODATIONS TO HEMODYNAMIC CHANGES RATHER THAN ACUTE KIDNEY INJURY (AKI). THE GOAL OF THIS PROPOSAL IS TO DEVELOP A BETTER KIDNEY HEALTH MONITORING SYSTEM, A URINE-BASED KIDNEY TUBULE HEALTH PANEL (KTHP), THAT CAN ADJUDICATE AKI VS. BENIGN CR CHANGES DURING HTN TREATMENT, AND THUS ADDRESS A CRITICAL UNMET NEED. IN AIM 1, WE WILL DETERMINE WHETHER KTHP BIOMARKERS PREDICT THE MAGNITUDE OF BP LOWERING DURING TREATMENT WITH A COMPREHENSIVE AND STRUCTURED BP LOWERING INTERVENTION. IN AIM 2, WE WILL DETERMINE IF THE MAGNITUDE OF BP LOWERING IS ASSOCIATED WITH CHANGES IN KTHP MARKERS AT 1-YEAR; AND, WE WILL EVALUATE ASSOCIATIONS OF DECREASES IN EGFR WITH THE CHANGES IN THE INTRINSIC KIDNEY DAMAGE MARKERS (KTHP) AT 1-YEAR. THESE STUDIES WILL PROVIDE CRITICAL INSIGHTS INTO THE COMPARATIVE UTILITY OF KTHP BIOMARKERS VS. CREATININE DURING BP LOWERING. IN AIM 3, WE WILL EVALUATE ASSOCIATIONS OF BOTH BASELINE AND CHANGES IN 1-YEAR KTHP WITH CVD EVENTS. THESE AIMS WILL BE ACCOMPLISHED BY UTILIZING THE RICH AND DETAILED CLINICAL PHENOTYPING OF THE CARDIOVASCULAR OUTCOMES IN RENAL ATHEROSCLEROTIC LESIONS (CORAL) TRIAL, INCLUDING ADJUDICATED CLINICAL EVENTS. THE CORAL TRIAL BIOSPECIMEN BANK HAS BASELINE AND 1 YEAR URINE SPECIMENS THAT WILL ALLOW FOR KTHP BIOMARKER ASSESSMENT. THE METHODS IN THIS PROPOSAL WILL BUILD ON OUR PRIOR WORK IN THE SPRINT TRIAL AND WILL VALIDATE THE KTHP BIOMARKERS IN A HIGH-RISK HTN COHORT WITH FREQUENT CHANGES IN CR DURING BP LOWERING TREATMENT. TOGETHER, THESE STUDIES WILL PROVIDE DETAILED INVESTIGATION OF URINE KTHP BIOMARKERS FOR MONITORING DURING TREATMENT OF RESISTANT HTN. OVERALL, WE AIM TO IMPROVE OR REPLACE THE CURRENT CR-BASED KIDNEY HEALTH MONITORING SYSTEM, AND TO PROVE THE ACCURACY AND UTILITY OF THE PROPOSED KTHP BIOMARKERS FOR MONITORING DURING BOTH RESISTANT AND GENERAL HTN TREATMENT.

DORMANCY MIMICKING TO INHIBIT PROSTATE CANCER METASTASIS AND RECURRENCE

GREENHOUSE NURSERIES OHIO

SHAWNEE STATE UNIVERSITY UPWARD BOUND MATH AND SCIENCE CENTER PROPOSAL

THE ROLE OF COMPLEMENT PROTEINS IN CARDIOVASCULAR DISEASE

STUDENT SUPPORT SERVICES PROGRAM

UPWARD BOUND MATH & SCIENCE

PREPARATION OF LEADERSHIP PERSONNEL

DEVELOPMENTAL PYRETHROID EXPOSURE IN THE PRAIRIE VOLE AS A MODEL OF ENVIRONMENTAL RISK FOR AUTISM - PROJECT SUMMARY THE PREVALENCE OF AUTISM AND OTHER NEURODEVELOPMENTAL DISORDERS (NDDS) IS AT AN ALL-TIME HIGH, WITH 17% OF CHILDREN DIAGNOSED WITH A DEVELOPMENTAL DISABILITY AND 1 IN 44 DIAGNOSED WITH AUTISM. MANY OF THESE DISORDERS HAVE FEW OR NO ESTABLISHED BIOMARKERS, FEW OR NO MEDICAL TREATMENTS, AND CAN ONLY BE DIAGNOSED BEHAVIORALLY, EMPHASIZING THE NEED FOR RESEARCH INTO CAUSES AND TREATMENTS. ONE RISK FACTOR FOR AUTISM AND NDDS IS EXPOSURE DURING PREGNANCY TO PYRETHROID PESTICIDES, WHICH ARE PRESENT IN 70-80% OF BLOOD SAMPLES FROM THE GENERAL PUBLIC AND ARE IMPLICATED IN RISK FOR AUTISM AND DEVELOPMENTAL DELAY. THERE IS A CRITICAL KNOWLEDGE GAP REGARDING THE MAXIMUM SAFE EXPOSURE TO PYRETHROIDS DURING DEVELOPMENT. TO ADDRESS THIS KNOWLEDGE GAP, I PROPOSE TO USE TO EXPLORE THE MAXIMUM SAFE DEVELOPMENTAL DOSE RELATIVE TO BEHAVIORAL AND MOLECULAR OUTCOMES USING DEVELOPMENTAL DELTAMETHRIN EXPOSURE (DPE) IN THE PRAIRIE VOLE. PRAIRIE VOLES ARE HAMSTER-SIZED RODENTS INDIGENOUS TO THE MIDWEST THAT ARE STUDIED IN BEHAVIORAL NEUROSCIENCE FOR THEIR UNIQUE COMPLEX SOCIAL BEHAVIORS, INCLUDING MONOGAMOUS BONDING, BIPARENTAL CARE, AND EMPATHY- BASED CONSOLING. PRAIRIE VOLES HAVE OTHER SPECIES-SPECIFIC ADVANTAGES, SUCH AS DIURNAL CYCLES, CIRCADIAN AND ULTRADIAN RHYTHMS, AND THE FACT THAT THEY SHARE AN ENVIRONMENT WITH HUMANS AND ARE CO-EXPOSED TO PESTICIDES. THESE FACTORS MAKE THE PRAIRIE VOLE THE IDEAL MODEL FOR EXPLORING ENVIRONMENTAL EFFECTS OF PESTICIDE EXPOSURE. OUR CENTRAL HYPOTHESIS IS THAT DPE CAUSES DOSE-DEPENDENT CHANGES IN NDD-RELEVANT OUTCOMES IN PRAIRIE VOLE, INCLUDING DISRUPTED CIRCADIAN/ULTRADIAN MOVEMENT, HYPERACTIVITY, REPETITIVE BEHAVIORS, DECREASED VOCALIZATIONS, LEARNING DEFICITS, NATURAL WILD BEHAVIORS. WE ALSO HYPOTHESIZE THAT DEVELOPMENTALLY EXPOSED PRAIRIE VOLES WILL SHOW DOSE-DEPENDENT, MULTI-MODAL CHANGES IN MOLECULAR FUNCTION OF THE SUPRACHIASMATIC NUCLEUS (SCN), THE MASTER CONTROL REGION FOR BIOLOGICAL RHYTHMS IN THE BRAIN. TO TEST THESE HYPOTHESES, WE WILL EXPOSE PRAIRIE VOLE MOTHERS TO DELTAMETHRIN AT FOUR DOSES (0, 0.03, 0.3, 3 MG/KG) DURING PREGNANCY AND LACTATION, AND LOOK FOR DEVELOPMENTAL EFFECTS IN THE SUBSEQUENT OFFSPRING. AIM 1 WILL ASSESS DOSE-DEPENDENT EFFECTS IN CONTROLLED LABORATORY ASSAYS TO LOOK FOR TASK-SPECIFIC DOSE-RESPONSE CURVES AND THE MAXIMUM DOSE AT WHICH NO ADVERSE EFFECTS ARE OBSERVED. IN AIM 2, WE WILL RELEASE DPE PRAIRIE VOLES INTO NATURAL OUTDOOR ENCLOSURES WITH ADVANCED TRACKING TECHNOLOGY AND MEASURE DOSE-DEPENDENT CHANGES TO NATURAL SOCIAL AND SURVIVAL BEHAVIORS. IN AIM 3, WE WILL USE A SPLIT-SAMPLE MULTIOMICS APPROACH TO LOOK FOR DOSE-DEPENDENT MULTIMODAL MOLECULAR CHANGES IN THE SCN AND STRIATUM, FOCUSING ON BULK AND CELL TYPE-SPECIFIC GENE TRANSCRIPTION, KINOME ARRAY PROFILING, AND MULTIOMICS INTEGRATION ANALYSES. SUCCESSFUL COMPLETION OF THESE AIMS WILL PROVIDE THE BROADEST POSSIBLE VIEW OF DOSE-DEPENDENT CHANGES IN BRAIN AND BEHAVIOR, INCLUDING THE DOSES RELEVANT TO EACH BEHAVIORAL OUTCOME AND TASK, AND THE FULL RANGE OF EXPOSURE-INDUCED CHANGES IN THE SCN.

METABOLISM AS THE ACHILLES HEEL IN PROSTATE CANCER

NOVEL CYSTEINYL LEUKOTRIENE RECEPTOR SIGNALING IN REGULATING CELLULAR, AND MOLECULAR EVENTS IN LUNG INFLAMMATION - PROJECT SUMMARY: CYSTEINYL LEUKOTRIENES (CYS-LTS; LTC4, LTD4, AND LTE4) PLAY AN IMPORTANT ROLE IN ASTHMA, ALLERGY, AND INFLAMMATORY BOWEL DISEASES VIA THEIR RECEPTORS, CYSLT1R AND CYSLT2R. HOWEVER, THE ROLE OF CYS-LTS IN REGULATING THE INFLAMMATORY AND PROLIFERATIVE PHENOTYPES OF MACROPHAGES (MФ) OR THEIR ROLE IN MФ-MEDIATED LUNG INFLAMMATION IS NOT WELL DEFINED. OUR PRELIMINARY WORK REVEALED A PREVIOUSLY UNIDENTIFIED ROLE FOR CYSLT1R IN BALANCING MФS’ INFLAMMATORY POTENTIAL, METABOLIC FUNCTION, AND PROLIFERATION IN VITRO, AND A ROLE IN DRIVING LPS- MEDIATED LUNG INFLAMMATION IN VIVO. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT THE PRESENCE OF CYSLT1R DRIVES THE INFLAMMATORY STATE OF MФS AND LUNG INFLAMMATION IN RESPONSE TO LPS. FURTHER, SINCE CYSLT1R AND CYSLT2R ANTAGONIZE EACH OTHER, CYSLT1R MAY ACT AS A MOLECULAR BRAKE FOR MФ HYPER-PROLIFERATION VIA BINDING TO AND INHIBITING CYSLT2R. WE PROPOSE TO TEST THIS HYPOTHESIS IN THREE AIMS. IN AIM 1, WE WILL DETERMINE THE MECHANISTIC ASPECTS OF HOW CYSLT1R PROMOTES THE HYPER-INFLAMMATORY MФ PHENOTYPE IN VITRO AND ANALYZE HOW CYSLT1R INFLUENCES THE RESIDENT AND RECRUITED IMMUNE POPULATION IN THE LUNG IN RESPONSE TO ACUTE LUNG INJURY (ALI). IN AIM 2, WE WILL ELUCIDATE HOW CYSLT1R SUPPRESSES MФ PROLIFERATION, AND METABOLISM, AND WE WILL EXPLORE ITS ANTAGONISM TOWARDS CYSLT2R IN DECIDING THE MФ ACTIVATION STATE. FINALLY, IN AIM 3, WE WILL DETERMINE THE PATHOPHYSIOLOGICAL SIGNIFICANCE OF MYELOID CYSLT1R SIGNALING IN MEDIATING LUNG INFLAMMATION IN MURINE ALI MODELS. FURTHER, WE WILL EXPLORE THE THERAPEUTIC POTENTIAL OF BLOCKING CYSLT1R USING MK571/SINGULAIR, AN FDA- APPROVED ASTHMA DRUG. ALTHOUGH A FEW REPORTS HAVE SUGGESTED THE BENEFITS OF SINGULAIR IN REDUCING PULMONARY INFLAMMATION DURING LPS-ALI AND COVID-19, NEITHER THE MECHANISTIC ASPECTS, NOR ITS PROPHYLAXIS VS THERAPEUTIC EFFECT ON ALL ALI PARAMETERS, WERE PREVIOUSLY ADDRESSED. THE SUCCESSFUL COMPLETION OF OUR PROJECT WILL UNRAVEL THE PREVIOUSLY UNKNOWN UNIQUE ROLES OF CYSLTR IN INFLUENCING MФ FUNCTION AND ITS ROLE IN LUNG INFLAMMATION/INJURY.

IMPROVED CDTE PV MODULES BY ATMOSPHERIC PRESSURE VAPOR DEPOSITION

STUDENT SUPPORT SERVICES PROGRAM

DISSECTING MOLECULAR MECHANISMS OF TUMOR-INDUCED MYELOID-MEDIATED IMMUNE SUPPRESSION IN TRIPLE-NEGATIVE BREAST CANCER - PROJECT SUMMARY BREAST CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED MORTALITY IN WOMEN WORLDWIDE. DESPITE CONSIDERABLE PROGRESS IN THE TREATMENT OF EARLY-STAGE DISEASE, A SIGNIFICANT FREQUENCY OF PATIENTS WILL DEVELOP RECURRENCE WITH DISTANT METASTASES. TRIPLE-NEGATIVE BREAST CANCER (TNBC) IS THE MOST AGGRESSIVE SUBTYPE WITH A DISMAL PROGNOSIS; IT LACKS THE ESTROGEN RECEPTOR, PROGESTERONE RECEPTOR, AND HER2 EXPRESSION AND, THEREFORE, IS RESISTANT TO TREATMENTS TARGETING THOSE PATHWAYS. INTERESTINGLY, HARNESSING THE IMMUNE SYSTEM THROUGH IMMUNOTHERAPY WITH IMMUNE CHECKPOINT INHIBITORS (ICIS) HAS IMPROVED SURVIVAL RATES; ALBEIT MODESTLY, WHEN USED IN COMBINATION WITH STANDARD-OF-CARE CHEMOTHERAPY. THUS, TNBC REMAINS A NEOPLASTIC DISEASE WITH UNMET CLINICAL CHALLENGES. NEW PRELIMINARY DATA IN OUR LABORATORIES INDICATE THAT LOSS-OF-FUNCTION OF TAZ, THE KEY COMPONENT IN THE HIPPO SIGNALING PATHWAY, INHIBITS TUMOR PROGRESSION IN MOUSE MODELS OF TNBC IN IMMUNE COMPETENT, BUT NOT IMMUNE DEFICIENT MICE, INDICATING THAT TUMOR TAZ EXPRESSION PLAYS AN UNDERAPPRECIATED EXTRINSIC ROLE IN TNBC BIOLOGY. MASS CYTOMETRY ANALYSIS SUGGESTED THAT TUMOR TAZ EXPRESSION ACTS EXTRINSICALLY TO REGULATE THE RECRUITMENT AND/OR FUNCTION OF MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) AND, PERHAPS, TUMOR- ASSOCIATED MACROPHAGES (TAMS), AND REGULATORY T CELLS (TREGS). ADDITIONAL MECHANISTIC STUDIES SHOWED THAT TAZ KNOCKDOWN IN PRECLINICAL TNBC MODELS LED TO A REDUCTION IN MDSCS, AS WELL AS A REDUCTION IN THE EXPRESSION OF SEVERAL CYTOKINES/CHEMOKINES, PARTICULARLY CCL20, POTENTIALLY LINKED TO THE MOBILIZATION OF MDSCS. THUS, THESE FINDINGS IMPLICATED A PREVIOUSLY UNRECOGNIZED BIOLOGY OF TUMOR-INTRINSIC TAZ EXPRESSION IN REGULATING TNBC PROGRESSION VIA ITS ACTIONS ON THE IMMUNE-TUMOR MICROENVIRONMENT (TME), NOTABLY MDSC TRAFFICKING. THE OVERALL OBJECTIVES OF THIS PROPOSAL ARE TO UNDERSTAND THE UNDERLYING MOLECULAR MECHANISMS BY WHICH TAZ EXPRESSION REGULATES THE ACCUMULATION OF IMMUNE SUPPRESSIVE CELLS LIKE MDSCS IN THE TME OF TNBC. OUR CENTRAL HYPOTHESIS IS THAT TAZ EXPRESSION IN TNBC REGULATES THE TME LANDSCAPE VIA CANCER CELL NON-AUTONOMOUS-DRIVEN MECHANISMS. OUR LONG-TERM GOALS ARE TO DECIPHER THE CROSSTALK BETWEEN TAZ EXPRESSION IN TNBC AND THE IMMUNE CONTEXTURE OF THE TME TO UNCOVER NEW PROGNOSTIC OR THERAPEUTIC TARGETS IN TNBC BIOLOGY. TO ACHIEVE THESE GOALS, WE PROPOSE THE FOLLOWING THREE AIMS: 1) DETERMINE THE IMPACT OF TUMOR-INTRINSIC TAZ EXPRESSION ON THE IMMUNE-TUMOR MICROENVIRONMENT IN PRECLINICAL MODELS OF TNBC; 2) DETERMINE THE MOLECULAR MECHANISMS BY WHICH TUMOR-INTRINSIC TAZ EXPRESSION RECRUITS MDSCS TO THE TME; AND 3) DETERMINE THE RELATIONSHIP BETWEEN TUMOR TAZ EXPRESSION AND THE IMMUNE-TUMOR MICROENVIRONMENT IN PATIENTS WITH TNBC. A MAJOR IMPACT OF THIS STUDY IS TO IDENTIFY PREVIOUSLY UNDESCRIBED TAZ-MEDIATED MECHANISMS THAT WILL UNVEIL NEW BIOMARKERS OR INFORM NOVEL THERAPEUTIC INTERVENTIONS FOR ADVANCED OR METASTATIC TNBC.

IMPROVED CDTE PV MODULES BY ATMOSPHERIC PRESSURE VAPOR DEPOSITION

THE ROLE OF GLT1 IN THE MODULATION OF ALCOHOL-DRINKING BEHAVIOR IN P RATS.

BEHAVIORAL DYNAMICS OF LANGERHANS CELLS IN SKIN

OXIDATIVE STRESS AND VASCULAR HO IN DIABETES

USING MICROCYSTIN DEGRADING BACTERIA AND THEIR ENZYMES FOR WATER TREATMENT

MOLECULAR BASIS AND TARGETING OF FASN IN EXPANDING PARPI UTILITY FOR TNBC - SUMMARY WHILE TARGETED THERAPIES AND IMMUNOTHERAPIES HAVE IMPROVED OUTCOMES FOR SOME CANCERS, PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER (TNBC) HAVE SEEN LIMITED BENEFITS FROM THESE ADVANCES AND OFTEN SUFFER FROM THE TOXICITIES OF INEFFECTIVE CHEMOTHERAPEUTICS, INCLUDING PLATINUM-BASED DRUGS. THIS HIGHLIGHTS A CRITICAL UNMET NEED IN TNBC TREATMENT. ALTHOUGH PARP INHIBITORS (PARPI’S) INCLUDING OLAPARIB AND TALAZOPARIB HAVE BEEN APPROVED FOR TREATING HER2-NEGATIVE BREAST CANCERS WITH BRCA MUTATIONS, MOST TNBC PATIENTS DO NOT BENEFIT FROM THIS NEW TREATMENT AND PARPI RESISTANCE FREQUENTLY DEVELOPS, FURTHER LIMITING THE BENEFITS OF PARPI’S. RECENT FINDINGS INDICATED THAT FATTY ACID SYNTHASE (FASN) REGULATES BOTH NHEJ AND HR REPAIR OF DOUBLE STRAND DNA BREAKS AND, THUS, MAY AFFECT CELLULAR RESPONSE TO PARPI. FASN IS THE SOLE CYTOSOLIC ENZYME RESPONSIBLE FOR DE- NOVO SYNTHESIS OF PALMITATE. GIVEN THE ABUNDANT DIETARY INTAKE OF FREE FATTY ACIDS IN A MODERN WESTERN DIET, NORMAL CELLS, EXCEPT THOSE IN LIPOGENIC TISSUES, DO NOT RELY ON FASN. IN CONTRAST, BREAST CANCER CELLS EXHIBIT HIGH FASN LEVELS AND THEIR SURVIVAL AND PROLIFERATION REQUIRE DE-NOVO FATTY ACID SYNTHESIS. TARGETING FASN TO INHIBIT LIPOGENESIS INDUCES APOPTOSIS SELECTIVELY IN CANCER CELLS BOTH IN VITRO AND IN VIVO WITH MINIMAL EFFECT ON NORMAL CELLS. FURTHERMORE, HIGH FASN EXPRESSION CORRELATES WITH POOR PROGNOSIS, METASTASIS, AND RECURRENCE IN BREAST CANCER, MAKING IT AN IDEAL TARGET FOR DRUG DISCOVERY. OUR RECENT WORK DEMONSTRATED THAT PROTON PUMP INHIBITORS (PPIS) EFFECTIVELY INHIBIT HUMAN FASN. RETROSPECTIVE ANALYSES OF ELECTRONIC MEDICAL RECORDS REVEALED THAT PPI USAGE SIGNIFICANTLY IMPROVES OVERALL SURVIVAL OF BREAST CANCER PATIENTS INCLUDING THOSE WITH TNBC. A PHASE II CLINICAL TRIAL FURTHER CONFIRMED THAT PPIS INHIBIT FASN FUNCTION, BENEFITING TNBC PATIENTS. OUR PRELIMINARY STUDIES SUGGEST THAT FASN CONTRIBUTES TO PARPI RESISTANCE BY REGULATING PARP1 AND BRCA1 EXPRESSION. MOREOVER, PPIS NOT ONLY INHIBIT TNBC CELL SURVIVAL BUT ALSO SYNERGIZES WITH PARPI’S, REGARDLESS OF BRCA STATUS. THUS, WE HYPOTHESIZE THAT (1) FASN CONTRIBUTES TO PARPI RESISTANCE BY UPREGULATING PARP1 AND BRCA1 EXPRESSION TO INCREASE NHEJ AND HR REPAIR OF DSB, AND (2) PPIS SYNERGIZE WITH PARPI BY TARGETING FASN TO OVERCOME PARPI RESISTANCE AND CREATE AN ARTIFICIAL SYNTHETIC LETHALITY IN BRCA PROFICIENT TNBC CELLS. TO THIS END, WE WILL ACCOMPLISH THREE SPECIFIC AIMS TO (1) DETERMINE THE MOLECULAR BASIS OF PPI INHIBITION OF FASN, (2) DETERMINE THE MOLECULAR MECHANISM OF FASN ACTION IN PARPI RESISTANCE, AND (3) DETERMINE THE SYNERGISM OF PPI COMBINATION WITH PARPI IN BOTH BRCA1 MUTANT AND WILD-TYPE TNBC CELLS. THE SUCCESSFUL OUTCOME OF THIS STUDY WILL HELP ESTABLISH FASN OVEREXPRESSION IN TNBC CELLS AS A MECHANISM OF PARPI RESISTANCE AND REPURPOSE PPIS TO OVERCOME PARPI RESISTANCE BY TARGETING FASN. FURTHERMORE, IT WILL PROVIDE SUPPORTING EVIDENCE AND SCIENTIFIC BASIS FOR A CLINICAL TRIAL TESTING SYNERGISTIC COMBINATION OF PPI WITH PARPI, OFFERING A NOVEL TREATMENT OPTION FOR TNBC PATIENTS IRRESPECTIVE OF THEIR BRCA STATUS AND POTENTIALLY TRANSFORMING THE TNBC TREATMENT LANDSCAPE.

THE UNIVERSITY OF TOLEDO UT3 NOYCE SCHOLARSHIP PROGRAM

JAVITS GIFTED AND TALENTED STUDENTS EDUCATION GRANT PROGRAM - JAVITS GIFTED AND TALENTED STUDENTS EDUCATION ACT

BACTERIA, SIGNALING & LEUKOCYTE TRANSCRIPTION ACTIVATION

AFFORDABLE CARE ACT: EXPANSION OF PHYSICIAN ASSISTANT TRAINING PROGRAM

PROJECT PREPARE

IN THIS PROJECT, WE PROPOSE TO DEVELOP ALL-PEROVSKITE TANDEM PHOTOELECTRODES (ACTIVE AREA OF 1 CM2) AND PANELS (ACTIVE AREA OF 25 CM2) TO ACHIEVE LOW-COST, HIGH STH (SOLAR-TO-HYDROGEN) EFFICIENCY (UP TO 18%) AND LONG-TERM STABLE (>500 HOURS) UNASSISTED PHOTOELECTROCHEMICAL (PEC) WATER SPLITTING SYSTEMS. THE OBJECTIVE FOR BUDGET PERIOD 1 IS TO DEMONSTRATE AN ALL-PEROVSKITE TANDEM PHOTOELECTRODE BASELINE FOR A SMALL-AREA DEVICE WITH AN ACTIVE AREA OF 0.1 CM2. THE OBJECTIVE FOR BUDGET PERIOD 2 IS TO DEVELOP SCALABLE PRODUCTION METHODS AND DEMONSTRATE LARGE-AREA ALL-PEROVSKITE TANDEM PHOTOELECTRODES WITH AN ACTIVE AREA OF 1 CM2. THE OBJECTIVE FOR BUDGET PERIOD 3 IS TO DEVELOP AND DEMONSTRATE ALL-PEROVSKITE TANDEM PHOTOELECTRODE PANELS WITH AN ACTIVE AREA OF 25 CM2 AND SHOW AN STH EFFICIENCY OF >18% AND RETAIN 80% OF THEIR INITIAL EFFICIENCY FOR MORE THAN 500 HOURS UNDER ONE SUN OPERATION.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

3D SKIN MODEL TO TEST TOXIC AND SENSITIZING POTENTIALS OF ENVIRONMENTAL CHEMICALS

GREATER EQUITY, ACCESS, AND READINESS FOR SUCCESS IN ENGINEERING AND TECHNOLOGY: PATHWAY TO AND THROUGH ENGINEERING

EXPLORATIONS: EXPERIENTIAL LEARNING OPPORTUNITIES IN MECHATRONICS IN TOLEDO, OHIO -THIS THREE-YEAR EXPLORATIONS PROJECT ENGAGES APPROXIMATELY 150 HIGH SCHOOL STUDENTS FROM DIVERSE SOCIOECONOMIC BACKGROUNDS IN EXPERIENTIAL OPPORTUNITIES TO LEARN ABOUT ELECTRIC VEHICLES WITH THE LARGER AIM OF REVITALIZING THE ADVANCED MANUFACTURING WORKFORCE IN NORTHWEST OHIO. THIS COLLABORATIVE EFFORT AT REVITALIZATION ALSO ADDRESSES BARRIERS THAT UNDERREPRESENTED YOUTH FACE WHEN ATTEMPTING TO ACCESS STEM WORKFORCE TRAINING AND CAREER ENTRY. PROJECT PARTNERS INCLUDE THE UNIVERSITY OF TOLEDO, TOLEDO PUBLIC SCHOOLS, OWENS COMMUNITY COLLEGE, AND DANA INCORPORATED. HIGH SCHOOL STUDENTS BEGIN LEARNING ABOUT ELECTRONIC VEHICLES THROUGH AN AFTER-SCHOOL EXPERIENTIAL MECHATRONICS CLUB AT TOLEDO HIGH SCHOOLS. TO DEVELOP STUDENTS? SKILLS, EACH PARTICIPANT RECEIVES AN INDUSTRY-STANDARD PROGRAMMABLE LOGIC CONTROLLER (PLC) AND FREE SOFTWARE. THROUGH A COMPREHENSIVE SERIES OF HYBRID, GAMING-CENTERED, AND EXPERIENTIAL ACTIVITIES, YOUTH BECOME ABLE TO APPLY THEIR SKILLS IN THE CONTEXT OF AN ANNUAL TEAM-BASED COMPETITION. INDUSTRY PARTNER DANA PROVIDES MECHATRONICS CLUB MEMBERS WITH MENTORING BY ITS ENGINEERS FOCUSED ON CAREER READINESS AND LIFE SKILLS, WHILE PROVIDING EXPOSURE TO PROFESSIONAL AND SKILLED TRADE EMPLOYMENT OPPORTUNITIES AT ITS TECHNOLOGY CENTERS AND MANUFACTURING FACILITIES. THE PROJECT?S GOAL IS TO EQUIP YOUTH WITH THE INTERESTS, CONFIDENCE AND SKILLS NEEDED TO PURSUE VARIOUS CAREER ON-RAMPS, INCLUDING IMMEDIATE EMPLOYMENT AS PLC TECHNICIANS, OR ADDITIONAL FORMAL EDUCATION VIA SCHOLARSHIPS OFFERED BY THE PARTNERING TWO- AND FOUR-YEAR INSTITUTIONS. HYBRID OPTIONS ARE ALSO AVAILABLE. FOR EXAMPLE, STUDENTS WHO ENROLL AT THE COMMUNITY COLLEGE CAN EARN STACKABLE MECHATRONICS CERTIFICATES WHILE WORKING PART-TIME IN THE INDUSTRY AND EARN AN ASSOCIATE DEGREE BY COMBINING THREE STACKABLE CERTIFICATES. TO ACHIEVE ITS POTENTIAL FOR BROADER IMPACTS, ALL EDUCATION MATERIALS WILL BE HOUSED AT HYBRIDPLC.ORG UNDERSCORING THE HYBRID LEARNING MODEL. TUTORIAL VIDEOS, TEXTBOOKS, LAB MANUALS, CODES, MODELS, AND EXERCISES PROVIDE THE LEARNERS, IN A ?IPPED CLASSROOM, WITH A SERIES OF BASIC AND ADVANCED COMPETENCIES. THE PROJECT CONTRIBUTES TO THE LITERATURE ON WORKFORCE TRAINING AND ENGINEERING EDUCATION BY EMPLOYING A RIGOROUS EVALUATION OF THE PROJECT ACTIVITIES INCLUDING ATTENTION TO ITS RECRUITMENT AND RETENTION EFFORTS, ANALYSIS OF ARTIFACTS CREATED BY STUDENTS, AND FOLLOW-UP ASSESSMENTS INCLUDING EMPLOYER SURVEYS AND CERTIFICATE COMPLETION RATES. THIS PROJECT IS SUPPORTED IN PART BY THE DISCOVERY RESEARCH PREK-12 PROGRAM (DRK-12) WHICH SEEKS TO SIGNIFICANTLY ENHANCE THE LEARNING AND TEACHING OF SCIENCE, TECHNOLOGY, ENGINEERING AND MATHEMATICS (STEM) BY PREK-12 STUDENTS AND TEACHERS, THROUGH RESEARCH AND DEVELOPMENT OF INNOVATIVE RESOURCES, MODELS AND TOOLS. PROJECTS IN THE DRK-12 PROGRAM BUILD ON FUNDAMENTAL RESEARCH IN STEM EDUCATION AND PRIOR RESEARCH AND DEVELOPMENT EFFORTS THAT PROVIDE THEORETICAL AND EMPIRICAL JUSTIFICATION FOR PROPOSED PROJECTS.? 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.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

MECHANISMS OF SYMPATHETIC NEURON DEVELOPMENT

TRAINING IN MOLECULAR AND TRANSLATIONAL CELL DYNAMICS - ABSTRACT THIS IS A MULTIDISCIPLINARY TRAINING PROGRAM UNDER THE GRADUATE RESEARCH TRAINING INITIATIVE FOR STUDENT ENHANCEMENT MECHANISM AT THE UNIVERSITY OF TOLEDO (UT), AND INVOLVES TEN PARTICIPATING PROGRAMS. THE OVERARCHING GOAL OF THE PROGRAM IS TO TRAIN A SIGNIFICANT NUMBER OF DIVERSE PROFESSIONALS WITH THE SKILLS AND LEADERSHIP REQUIRED FOR CAREERS IN BIOMEDICAL RESEARCH. THIS GOAL IS ALIGNED WITH THE MISSIONS OF THE NIH AND THE UNIVERSITY OF TOLEDO STRATEGIC PLAN. THE PROGRAM WILL BROADEN THE PIPELINE OF CANDIDATES AND UTILIZE EFFECTIVE MULTIPRONG MECHANISMS TO RECRUIT TRAINEES FROM TRADITIONALLY UNDERSERVED COMMUNITIES. TO ACHIEVE THIS OBJECTIVE, PARTNERSHIPS HAVE BEEN ESTABLISHED WITH EIGHT MINORITY-SERVING UNDERGRADUATE INSTITUTIONS WITH NIGMS-SUPPORTED RESEARCH TRAINING PROGRAMS, INCLUDING THE REBUILDETROIT PROGRAM, AS WELL AS WITH DISABILITY-SERVING PROGRAMS. SCHOLARS WILL PARTICIPATE IN A SUMMER BRIDGE PROGRAM PRIOR TO MATRICULATION AND RECEIVE INTENSIVE TRAINING AND MENTORSHIP TO FORM NETWORKS, ENHANCE SOCIAL INTEGRATION AND PERSEVERANCE. A MULTIFACETED INNOVATIVE AND EVIDENCE-BASED PROGRAM WILL BE IMPLEMENTED IN SUPPORTIVE ENVIRONMENTS TO INCREASE TRAINEES SUCCESS RATES, SHARPEN LEADERSHIP, SCIENTIFIC RIGOR, AND COMMUNICATION SKILLS. TRAINING WILL LEVERAGE THE RESOURCES AND INTELLECTUAL ENVIRONMENT OF THE UT MEDICAL CAMPUS TO EXPOSE TRAINEES TO TRANSLATIONAL RESEARCH IN HEALTH DISPARITIES AND BIOMARKER DISCOVERY TO BETTER-EQUIP THEM FOR CAREERS WITH SIGNIFICANT IMPACTS ON THE UNIQUE HEALTH-RELATED RESEARCH NEEDS OF UNDERSERVED COMMUNITIES AND THE NATION. IN CONJUNCTION WITH THE PH.D. DEGREES, SCHOLARS WILL RECEIVE TRAINING IN BIOINFORMATICS AND EARN A CERTIFICATE IN BIOMARKER AND BIOINFORMATICS TO POSITION THEM WELL FOR CAREERS IN THE FOREFRONT OF BIOMEDICINE. THROUGH VARIOUS ACTIVITIES, THE PROGRAM WILL GUIDE AND ENGAGE THE TRAINEES IN IDENTIFYING AND PURSUING A RANGE OF POTENTIAL CAREER OPTIONS IN BASIC SCIENCES. AT THE END OF THE FIVE-YEAR GRANT PERIOD, THIS PROGRAM WILL PRODUCE FORTY-EIGHT SKILLFUL BIOMEDICAL RESEARCHERS WHO WILL ENHANCE THE DIVERSITY OF THE BIOMEDICAL WORKFORCE AND POSITIVELY IMPACT THE LOCAL ECONOMY. THE PROGRAM WILL HAVE WIDER IMPACTS BY ENRICHING THE EDUCATIONAL CURRICULA AND THE CULTURAL ENVIRONMENT AT UT, BY ENGAGING THE LOCAL COMMUNITIES THROUGH THE NUMEROUS TARGETED ACTIVITIES OF OUR TRAINEES, AND BY CONTRIBUTING TO MAINTAINING THE COMPETITIVENESS OF THE U.S. IN THE GLOBAL ECONOMY

MRI-R2: ACQUISITION OF A SUITE OF ANALYTICAL INSTRUMENTATION ESSENTIAL FOR INVESTIGATING FUEL CHEMICAL AND POLYMER PRODUCTION FROM BIOMASS

SEP COLLABORATIVE: ALKALIPHILIC MICROALGAE-BASED SUSTAINABLE & SCALABLE PROCESSES FOR RENEWABLE FUELS AND PRODUCTS

BONE LOSS WITH AGING OCCURS DUE TO INCREASED PPAR-G ACTIVITY IN MARROW STEM CELLS

MASTERS DEGREES

DISCOVERY AND CHARACTERIZATION OF NOVEL HALOGENASES FROM THE HUMAN MICROBIOME - PROJECT SUMMARY/ABSTRACT FLAVIN-DEPENDENT HALOGENASES (FDHS) ARE BIOSYNTHETIC ENZYMES FROM BACTERIA AND FUNGI THAT CATALYZE REGIOSELECTIVE C-X BOND FORMATION (X=CL, BR, I) WITH VARIOUS AROMATIC SUBSTRATES. THEIR REGIOSELECTIVITY AND ENVIRONMENTALLY FRIENDLY REACTION CONDITIONS MAKE FDHS ATTRACTIVE CANDIDATES FOR GREEN SYNTHESIS OF ARYL HALIDES TO BE USED IN TRANSITION METAL CATALYZED CROSS- COUPLING REACTIONS. THE PROPOSED PROJECT WILL EXPAND OUR UNDERSTANDING OF REGIOSELECTIVE ARYL HALIDE FORMATION BY FDHS THROUGH THE IDENTIFICATION AND STRUCTURAL AND ENZYMATIC CHARACTERIZATION OF NOVEL MEMBERS OF THIS FAMILY OF ENZYMES, EXPANDING THE FDH TOOLKIT BY ADDING NEW MEMBERS WITH DIFFERENT SUBSTRATE AND HALIDE SELECTIVITIES TO THE CURRENTLY CHARACTERIZED ENZYMES. IN AIM 1 OF THIS PROJECT, WE WILL FULLY CHARACTERIZE THE EXTENDED SUBSTRATE SCOPE OF ABEH AND BORH, TWO FDHS FROM SOIL BACTERIA METAGENOMES THAT WE HAVE SHOWN CAN CHLORINATE AND BROMINATE TRYPTOPHAN TO PRODUCE TWO DIFFERENT REGIOISOMERS. AIMS 2 AND 3 ARE BASED ON OUR HYPOTHESIS THAT FDHS ARE ALSO PRODUCED BY THE BACTERIA OF THE HUMAN MICROBIOME, WHERE THEY COULD POTENTIALLY GENERATE SECONDARY METABOLITES THAT PLAY A ROLE IN CHEMICAL COMMUNICATION BETWEEN BACTERIA AND HUMAN CELLS. THIS HYPOTHESIS IS SUPPORTED BY THE FACT THAT A SIMPLE BIOINFORMATIC SEARCH OF THREE SEQUENCE FILES FROM HUMAN MICROBIOME METAGENOME SHOTGUN SEQUENCING PROJECTS YIELDED FIVE ORFS PREDICTED TO ENCODE NOVEL FDHS. PRELIMINARY INVESTIGATIONS OF THE FIRST OF THE FIVE HYPOTHETICAL FDH GENES HAS VERIFIED THAT IT ENCODES A PROTEIN WITH THE ABILITY TO HALOGENATE INDOLE. AIM 2 WILL INVOLVE THE FULL CHARACTERIZATION OF THE ENZYMATIC ACTIVITY, SUBSTRATE AND HALIDE SCOPE, AND CRYSTAL STRUCTURES OF THESE FIVE PUTATIVE MICROBIOME FDHS. AIM 3 WILL ESTABLISH A TRAINING PROGRAM IN BIOINFORMATICS, ENZYMOLOGY, AND STRUCTURAL BIOLOGY FOR UNDERGRADUATE BIOCHEMISTRY MAJORS, WHO WILL MINE HUMAN MICROBIOME METAGENOME SEQUENCES FOR ADDITIONAL PUTATIVE FDH GENES, EXPRESS AND PURIFY THE GENE PRODUCTS IN E. COLI, AND CHARACTERIZE THEIR STRUCTURES AND ACTIVITIES.

NA,K-ATPASE AS AN INTEGRATOR OF THE CALCIUM-SIGNALING MACHINERY

DEVELOPMENT OF AN ATTENUATED VACCINE FOR THE PREVENTION OF LYME DISEASE

TRIO - STUDENT SUPPORT SERVICES - STUDENT SUPPORT SERVICES PROGRAM

ANDROGEN AND SOLUBLE GUANYLYL CYCLASE SIGNALING IN PROSTATE CANCER

REGIO- AND ENANTIOSELECTIVE ALKENE DIFUNCTIONALIZATIONS FOR THE SYNTHESIS OF BIOACTIVE MOLECULES.

INCREMENTAL FUNDING INCREMENTAL FUNDING

NIOSH TRAINING PROJECT GRANT (TPG): INDUSTRIAL HYGIENE UNIVERSITY OF TOLEDO

FUNDAMENTAL PRINCIPLES INITIATIVE

ELDERLY IMMUNE RESPONSE TO PNEUMOCOCCAL POLYSACCHARIDE

ULTRA-HIGH EFFICIENCY AND STABLE ALL-PEROVSKITE TANDEM SOLAR CELLS

MONITORING AGRICULTURAL SEWAGE SLUDGE APPLICATION, OH

MACHINE LEARNING AND NETWORK SCIENCE FOR PREDICTING KIDNEY TRANSPLANT SURVIVAL

COMPUTED TOMOGRAPHY & DIGITAL RADIOGRAPHY BASED RESEARCH FOR AEROSPACE MATERIALS

STRESS RESPONSE MECHANISMS IN VIBRIO -STRESS LEADS TO PROFOUND CHANGES IN BACTERIAL BEHAVIOR AND PHYSIOLOGY. SOME OF THESE CHANGES HAVE ECONOMIC AND HEALTH IMPLICATIONS, AS STRESS RESPONSES HAVE BEEN LINKED TO THE FORMATION OF STRESS-RESISTANT BIOFILMS, VIRULENCE, ANTIBIOTIC TOLERANCE/RESISTANCE AND PERSISTENCE. THE OVERALL GOAL OF THIS PROJECT IS TO CHARACTERIZE THE VIBRIO CHOLERAE SIPA PATHWAY, WITH AN EMPHASIS ON UNDERSTANDING HOW THE PATHWAY HELPS THIS PATHOGEN AND OTHER BACTERIA SURVIVE IN THE PRESENCE OF STRESSORS SUCH AS ANTIMICROBIAL PEPTIDES. THIS PROJECT WILL SUPPORT THE TRAINING OF A PH.D. STUDENT WHO IS INTERESTED IN SCIENCE EDUCATION. IN ADDITION, SCIENCE EDUCATION GRADUATE STUDENTS, HIGH SCHOOL SCIENCE TEACHERS AND HIGH SCHOOL SCIENCE CLASSES WILL PARTICIPATE IN THE PROJECT. VIBRIO SPECIES MUST DETECT AND RESPOND APPROPRIATELY TO STRESSES THEY ENCOUNTER TO SURVIVE IN THE DIVERSE ENVIRONMENTS THEY INHABIT. SIPA IS A HIGHLY CONSERVED STRESS-RESPONSIVE PROTEIN THAT PLAYS A MAJOR ROLE IN V. CHOLERAE SURVIVAL IN THE PRESENCE OF SEVERAL STRESS-INDUCING AGENTS. DEDICATED REGULATORS OF SIPA EXPRESSION AND PROTEIN INTERACTION PARTNERS HAVE BEEN IDENTIFIED, BUT LITTLE ELSE IS KNOWN ABOUT THIS ESSENTIAL STRESS RESPONSE MECHANISM. DUE TO THE CONSERVATION OF SIPA, IT MAY BE A KEY STRESS RESPONSE PROTEIN IN NUMEROUS BACTERIA. THEREFORE, THE GOALS OF THIS PROPOSAL ARE TO FULLY CHARACTERIZE THE REGULATION OF THIS STRESS RESPONSE SYSTEM, ESTABLISH THE MECHANISM(S) BY WHICH SIPA CONTRIBUTES TO STRESS SURVIVAL, AND DETERMINE HOW THIS SYSTEM IS INTEGRATED WITH OTHER BIOLOGICAL PROCESSES IN V. CHOLERAE. OTHER STRESS RESPONSE MECHANISMS IN ENVIRONMENTAL VIBRIOS OF ECOLOGICAL IMPORTANCE WILL ALSO BE CHARACTERIZED AS A PART OF THE EDUCATIONAL GOALS OF THIS PROPOSAL. THERE ARE LIKELY TO BE SIGNIFICANT DIFFERENCES AMONG THESE GENETICALLY DIVERSE ENVIRONMENTAL SPECIES AND THIS WORK WILL DISTINGUISH BETWEEN BROADLY-CONSERVED AND SPECIES-SPECIFIC SURVIVAL MECHANISMS. 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.

COMBINED PRIORITY FOR PERSONNEL PREPARATION

YAP1, NEOINTIMA FORMATION, AND BLOOD PRESSURE REGULATION - PROJECT SUMMARY    VASCULAR SMOOTH MUSCLE CELL (VSMC) PHENOTYPIC MODULATION IS CENTRAL TO THE ETIOLOGIES OF MULTIPLE VASCULAR WALL  DISEASES.  IN  POST-­ANGIOPLASTY  RESTENOSIS  AND  ATHEROSCLEROSIS,  VSMCS  ACQUIRE  A  PROLIFERATIVE/MIGRATORY  PHENOTYPE  LEADING  TO  NEOINTIMA  FORMATION.  IN  CONTRAST,  HYPERTENSION  IS LARGELY  CAUSED  BY  INCREASED  VASCULAR  RESISTANCE THAT IS ATTRIBUTED TO EXAGGERATED VSMC CONTRACTION AND VASCULAR REMODELING. IDENTIFICATION OF THE KEY  PLAYERS  THAT  REGULATE  VSMC  PROLIFERATION  AND  CONTRACTION  IS  CRITICAL  FOR  FURTHER  UNDERSTANDING  OF  THE  UNDERLYING  MECHANISMS OF VSMC-­DRIVEN VASCULAR WALL DISEASES AND ALSO FOR DEVELOPING NOVEL THERAPEUTIC APPROACHES. WE  HAVE PREVIOUSLY DEMONSTRATED THAT THE TRANSCRIPTION CO-­FACTOR YES-­ASSOCIATED PROTEIN 1 (YAP1) PROMOTES VSMC  PROLIFERATION.  YET,  THE  ROLE  AND  UNDERLYING  MECHANISMS  OF  YAP1  IN  NEOINTIMA  FORMATION  IN  VIVO  REMAIN  UNCLEAR.  FURTHERMORE,  RECENT  GENOME-­WIDE  ASSOCIATION  STUDIES  (GWAS)  HAVE  IDENTIFIED  A  LOSS-­OF-­FUNCTION  SINGLE  NUCLEOTIDE  POLYMORPHISM  (SNP)  IN  YAP1  GENE  LOCUS  THAT  WAS  UNEXPECTEDLY  ASSOCIATED  WITH  LOWER  BLOOD  PRESSURE, SUGGESTING A NOVEL ROLE OF YAP1 IN BLOOD PRESSURE REGULATION. THE OVERARCHING GOAL OF THIS PROPOSAL IS  TO  DETERMINE  THE  ROLE  OF  YAP1  IN  REGULATING  BOTH  VSMC  PROLIFERATION  AND  CONTRACTION/HYPERTENSION.  NOVEL  PRELIMINARY  DATA  IN  THIS  PROPOSAL  INCLUDE  1)  YAP1  EXPRESSION  IS  UPREGULATED  AFTER  ARTERIAL  INJURY  AND  CORRELATES  WITH VSMC PROLIFERATION IN VIVO,  2) YAP1, IN ASSOCIATION WITH TEA DOMAIN TRANSCRIPTION FACTOR 1 (TEAD1), INDUCES  PLATELET-­DERIVED GROWTH FACTOR RECEPTOR BETA (PDGFRB), A PUTATIVE NOVEL YAP1 TARGET GENE THAT REGULATES VSMC  PHENOTYPE, 3) SM-­SPECIFIC YAP1 KNOCKOUT MICE EXHIBIT A HYPOTENSIVE PHENOTYPE AND AN ATTENUATED RESPONSE TO  VASOCONSTRICTORS IN ISOLATED VESSELS, AND 4) SILENCING YAP1 IN VSMCS INHIBITED PROTEIN KINASE C ALPHA (PRKCA)  SIGNALING  AND  IMPAIRED  ACTIN  POLYMERIZATION,  WHICH  ARE  KEY  FOR  VSMC  CONTRACTION.  THREE  SPECIFIC  AIMS  ARE  PROPOSED TO TEST THE CENTRAL HYPOTHESIS THAT YAP1 INDUCES VSMC PROLIFERATION AND CONTRACTION TO DRIVE NEOINTIMA  FORMATION  AND  HYPERTENSION,  RESPECTIVELY.  K99  AIM  1.   TEST  THE  HYPOTHESIS  THAT  YAP1  INDUCES  PDGFRB  TO  PROMOTE  VSMC  PROLIFERATION  AND  ENHANCE  INJURY-­INDUCED  NEOINTIMA  FORMATION  IN  VIVO.  R00  AIM  2.  TEST  THE  HYPOTHESIS  THAT  YAP1  ACTIVATES  PRKCA  SIGNALING  AND  PROMOTES  ACTIN  POLYMERIZATION  TO  ENHANCE  VSMC  CONTRACTION. R00 AIM 3. TEST THE HYPOTHESIS THAT VSMC-­EXPRESSED YAP1 UNDERLIES EXPERIMENTAL HYPERTENSION.  COMPLETION OF THE PROPOSED STUDIES WILL PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS REGULATING VSMC PHENOTYPIC  MODULATION AND BLOOD PRESSURE REGULATION AND WILL DETERMINE IF INHIBITING YAP1 IS AN ATTRACTIVE NOVEL THERAPEUTIC  STRATEGY  FOR  AMELIORATING  BOTH  OCCLUSIVE  VASCULAR  DISEASES  AND  HYPERTENSION.  ADDITIONAL  CONCEPTUAL  AND  EXPERIMENTAL  TRAINING  IN  HYPERTENSION-­RELATED  RESEARCH DURING  THE  K99  PHASE  WILL  HELP THE APPLICANT  PURSUE  AN  INDEPENDENT CAREER AND TRANSFORM THIS PROPOSAL INTO AN R01 APPLICATION DURING THE R00 PHASE.

MONITORING AGRICULTURAL SEWAGE SLUDGE, 2009

NUCLEAR RECEPTOR CHAPERONES IN SIGNALING AND METABOLISM

ANTIOXIDANT-PPARALPHA INTERACTION AND HYPERTENSION

POST-HYPOXIC REGULATION OF GABA-A RECEPTOR FUNCTION

SYNTHESIS OF GLYCOPEPTIDE-BASED CANCER ANTIGEN VACCINES

HIGH-RATE FABRICATION OF A-SI-BASED THIN-FILM SOLAR CELLS USING LARGE AREA VHF PECVD PROCESSES

GREAT START FOR HIGHER EDUCATION (GSHE)

PEROVSKITE/PEROVSKITE TANDEM PHOTOELECTRODES FOR LOW-COST UNASSISTED PHOTOELECTROCHEMICAL WATER SPLITTING

INSULIN RESISTANCE IN THE PATHOGENESIS OF NASH

NSF/DOE SOLAR HYDROGEN FUEL: NEW METAL OXIDES FOR EFFICIENT HYDROGEN PRODUCTION VIA SOLAR WATER SPLITTING

BEHAVIORAL AND NEUROLOGICAL EFFECTS OF DEVELOPMENTAL PYRETHROID EXPOSURE IN RODENTS

IMPACT OF THE INTERFERON REGULATED PROTEINS XAF1 AND ZNF313 ON INNATE IMMUNITY

HYPOTHALAMIC LEPTIN AND INSULIN SIGNALS ALIGNING METABOLIC STATE AND FERTILITY

IDENTIFICATION OF NOVEL INHIBITORS OF A VIBRIO CHOLERAE STRESS RESPONSE PATHWAY

PHASE II IUCRC AT THE UNIVERSITY OF TOLEDO: CENTER FOR DISRUPTIVE MUSCULOSKELETAL INNOVATIONS (CDMI)

EFFECTS OF BAYSHORE POWERPLANT ON ECOSYSTEM FUNCTION IN MAUMEE BAY, WESTERN LAKE ERIE

CAREER: THE LIFE CYCLE OF STAR CLUSTERS: NEW WINDOWS INTO STAR FORMATION AND GALAXY EVOLUTION

DETERMINANTS OF RNA VIRUS EVOLUTION

ROLE OF KDM4A AS AN EPIGENETIC REGULATOR WITH ONCOGENIC AND IMMUNOSUPPRESSIVE FEATURES IN MALIGNANT PLEURAL MESOTHELIOMA

COLLABORATIVE RESEARCH: GATEWAY OR GATEKEEPER: UNDERSTANDING WHY BLACK STUDENTS CHOOSE ENGINEERING TECHNOLOGY OR ENGINEERING, AND THE IMPLICATIONS OF THIS CHOICE -THIS PROJECT WILL CONTRIBUTE TO THE DEVELOPMENT OF A MORE DIVERSE ENGINEERING WORKFORCE BY HIGHLIGHTING THE ACADEMIC PATHWAYS TO AND THROUGH COLLEGE OF A GROUP OF DEGREED AND TRAINED WORKERS, BLACK ENGINEERING TECHNOLOGY (ET) GRADUATES, WHO ARE OFTEN OVERLOOKED IN CONVERSATIONS AROUND THE STATED DIVERSITY, EQUITY, AND INCLUSION GOALS FOR THE ENGINEERING PROFESSION. WHILE ET GRADUATES OFTEN WORK ALONGSIDE ENGINEERS AND THERE MAY BE LITTLE DISTINCTION BETWEEN THEIR ENTRY-LEVEL JOB DESCRIPTIONS, MANY ENCOUNTER BARRIERS TO CAREER ADVANCEMENT IN THE HIERARCHICAL ENGINEERING FIELD BECAUSE OF THEIR CHOSEN DEGREE PATH. IN ADDITION, THE DISPROPORTIONATELY LARGE NUMBER OF BLACK STUDENTS IN SOME ENGINEERING TECHNOLOGY PROGRAMS COMPARED TO ENGINEERING DIRECTLY IMPACTS THE NUMBER OF BLACK STUDENTS WHO LATER HAVE THE DEGREE CREDENTIALS OFTEN REQUIRED TO ENTER TO THE ENGINEERING PROFESSORATE, ENGINEERING RESEARCH CAREERS, AND LEADERSHIP POSITIONS IN INDUSTRY. THIS STUDY WILL CENTER ON THE VOICES, EXPERIENCES, AND KNOWLEDGE OF BLACK ET STUDENTS THROUGH FOCUS GROUP INTERVIEWS AND SURVEYS IN ORDER TO GAIN INSIGHT INTO THE FACTORS THAT LED THEM TO THEIR CHOSEN MAJOR AND THEIR EXPERIENCES AS BLACK STUDENTS IN ET. THE PROJECT WILL ALSO COMPARE THE ENGINEERING AND ET PROGRAMS AT THE COLLABORATING INSTITUTIONS AND EXAMINE WHETHER THERE ARE CERTAIN ENGINEERING MAJORS THAT ARE LESS ACCESSIBLE THAN OTHERS, AND WHETHER BLACK STUDENTS ARE CONCENTRATED IN SOME ET MAJORS MORE THAN OTHERS. THE OVERARCHING GOAL OF THIS WORK IS TO CONTRIBUTE TO THE IDENTIFICATION AND REMOVAL OF SYSTEMIC AND STRUCTURAL BARRIERS AND RACIAL INEQUITIES IN ET UNDERGRADUATE EDUCATION. THE LONG-TERM GOAL IS THAT THE FINDINGS OF THE RESEARCH WILL BE USED TO INFORM INTERVENTIONS AND POLICY CHANGES. INVESTIGATING THE REASONS WHY THERE IS A DISPROPORTIONATELY HIGH PERCENTAGE OF BLACK STUDENTS IN ET COMPARED TO ENGINEERING WILL SHED LIGHT ON THE COMPLEX SOCIAL TERRAIN THAT BLACK STUDENTS MUST NAVIGATE TO COMBAT THE STRUCTURAL BARRIERS IN EDUCATION TO ACHIEVE AN UNDERGRADUATE COLLEGE DEGREE GENERALLY, AND AN ENGINEERING-RELATED DEGREE SPECIFICALLY, WITH ALL OF THE PROFESSIONAL BENEFITS A DEGREE CONFERS. THE SPECIFIC RESEARCH QUESTIONS OF THE PROJECT ARE AS FOLLOWS: 1. WHAT ROLE DO HIGH SCHOOL COUNSELORS, COLLEGE COUNSELORS/RECRUITERS, AND FACULTY PLAY IN BLACK STUDENTS? CHOICE OF ET VERSUS ENGINEERING? 2. WHAT ARE THE ACADEMIC AND STRUCTURAL BARRIERS THAT EFFECT BLACK STUDENTS? ADMITTANCE TO ENGINEERING? 3. WHAT ARE THE STRUCTURAL BARRIERS AND AFFORDANCES THAT ENABLE OR PREVENT BLACK STUDENTS TO TRANSFER FROM ET TO ENGINEERING (AND VICE VERSA) FROM DURING AN UNDERGRADUATE PROGRAM? 4. HOW DO BLACK ET STUDENTS PERCEIVE THEIR FUTURE CAREER OPPORTUNITIES? 5. TO WHAT EXTENT DO BLACK ET STUDENTS IDENTIFY WITH THE ENGINEERING AND/OR ET DOMAIN AND HOW IS THIS RELATED TO CONTEXTUAL SALIENCE OF STEREOTYPE THREAT AND BELONGINGNESS TO THE PROGRAM? 6. HOW DO STUDENTS? PERCEPTIONS OF THEIR EXPERIENCES IN ET AND THE INTERPRETATION OF THESE EXPERIENCES RELATE TO THEIR SELF-SCHEMAS INCLUDING THEIR EXPECTATIONS OF SUCCESS, PERSONAL, CULTURAL, AND PROFESSIONAL IDENTITIES, AND THEIR CAREER GOALS? THIS PROJECT WILL CONTRIBUTE TO EFFORTS TO DEVELOP A MORE DIVERSE STEM WORKFORCE BY EXAMINING HOW THESE COMPLEXITIES INFLUENCE STUDENT CHOICE OF MAJOR AND SUGGESTING SOLUTIONS TO LESSEN THEIR IMPACTS. THIS COLLABORATIVE PROJECT IS FUNDED THROUGH THE RACIAL EQUITY IN STEM EDUCATION PROGRAM (EDU RACIAL EQUITY). THE PROGRAM SUPPORTS RESEARCH AND PRACTICE PROJECTS THAT INVESTIGATE HOW CONSIDERATIONS OF RACIAL EQUITY FACTOR INTO THE IMPROVEMENT OF SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) EDUCATION AND WORKFORCE. AWARDED PROJECTS SEEK TO CENTER THE VOICES, KNOWLEDGE, AND EXPERIENCES OF THE INDIVIDUALS, COMMUNITIES, AND INSTITUTIONS MOST IMPACTED BY SYSTEMIC INEQUITIES WITHIN THE STEM ENTERPRISE. THIS PROGRAM ALIGNS WITH NSF?S CORE VALUE OF SUPPORTING OUTSTANDING RESEARCHERS AND INNOVATIVE THINKERS FROM ACROSS THE NATION'S DIVERSITY OF DEMOGRAPHIC GROUPS, REGIONS, AND TYPES OF ORGANIZATIONS. PROGRAMS ACROSS EDU CONTRIBUTE FUNDS TO THE RACIAL EQUITY PROGRAM IN RECOGNITION OF THE ALIGNMENT OF ITS PROJECTS WITH THE COLLECTIVE RESEARCH AND DEVELOPMENT THRUSTS OF THE FOUR DIVISIONS OF THE DIRECTORATE. 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.

CAREER: THE REGULATION OF CYTOKINESIS BY CALCIUM

EDUCATIONAL ACHIEVEMENT/ATTAINMENT

NEUROPROTECTIVE EFFECT OF GINKGO BILOBA AND ITS BIOACTIVE COMPONENTS ISCHEMIA

PARAPROFESSIONAL PRESERVICE PROGRAM IMPROVEMENT GRANTS

CAREER: INVESTIGATION OF INTRON CELLULAR ROLES

HYBRID SOLID AND GAS PHASE DEPOSITION OF HYDROGENATED SILICON FOR PHOTOVOLTAICS

JIQUAN CHEN/ THE UNIVERSITY OF TOLEDO INTERACTIVE CHANGES OF ECOSYSTEMS AND SOCIETIES ON THE MONGOLIAN PLATEAU: FROM COUPLED REGULATIONS OF LAND US

ASSEMBLY, DISASSEMBLY AND FUNCTION OF THE MITOTIC CHECKPOINT COMPLEX

OHIO PHOTOVOLTAIC MATERIALS AND MODULE TEST FACILITY DEVELOPMENT OF PHOTOVOLTAIC CAPACITY AT PLUM B

HIGH-THROUGHPUT HIGH-RESOLUTION MICROSCOPY FOR PHENOTYPIC DRUG DISCOVERY APPLICATIONS - ABSTRACT: MULTIDRUG RESISTANCE (MDR) IS A MAJOR CAUSE OF CHEMOTHERAPY FAILURE IN CANCER AND A MAJOR PUBLIC HEALTH CONCERN. OFTEN, MDR CANCERS ARE AGGRESSIVE, METASTATIC, AND HAVE POOR PROGNOSES. IN ADDITION, MDR CANCER IS HIGHLY RESISTANT TO TREATMENTS THAT INDUCE CONVENTIONAL PROGRAMMED CELL DEATH, SUCH AS CHEMOTHERAPY AND RADIATION. FOR THE PURPOSE OF COMBATING APOPTOSIS MEDIATED MDR, NEW DRUG DISCOVERIES ARE BEING DIRECTED TOWARDS THERAPIES THAT INDUCE APOPTOSIS-INHIBITING PROCESSES, SUCH AS NECROPTOSIS, AUTOPHAGY, PARAPTOSIS, METHUOSIS, AND FERROPTOSIS. WHEN OPTIMIZING NEW CHEMICAL MOLECULES DURING THE EARLY PHASES OF DRUG DISCOVERY, TWO KEY QUESTIONS NEED TO BE ADDRESSED: A) THE ABILITY OF THE DRUG TO KILL CANCER CELLS, AND B) THE MECHANISM BY WHICH THE DRUG KILLS CANCER CELLS. AT PRESENT, CONVENTIONAL BIOCHEMICAL ASSAYS AND HIGH-DEFINITION IMAGING ARE THE ONLY METHODS FOR STUDYING THESE PROCESSES, BUT THEY ARE TIME CONSUMING, COSTLY, AND REQUIRE SKILLED EXPERTS, THUS LIMITING THEIR UTILITY TO A SMALL NUMBER OF LABORATORIES. WE PROPOSE A PARADIGM-ALTERING PHENOTYPIC SCREENING TOOL THAT IDENTIFIES CELL DEATH MECHANISMS IN REAL TIME USING HIGH-RESOLUTION WIDEFIELD MICROSCOPY COUPLED WITH DEEP LEARNING. FIRST, WE PROPOSE TO DEVELOP A LOW-COST WIDEFIELD HOLOGRAPHIC MICROSCOPE, WITH MULTI-WAVELENGTH ILLUMINATION, INCLUDING ULTRAVIOLET (UV), TO ENABLE HIGH CONTENT SCREENING WITHOUT EXTERNAL LABELING, AT HIGH RESOLUTION THAT EXCEEDS THE DIFFRACTION LIMIT. WE WILL ACHIEVE THIS BY INTEGRATING LENS-LESS HOLOGRAPHIC MICROSCOPY WITH MICROPARTICLE ARRAY-BASED IMAGING SUBSTRATES THAT WILL ALLOW US TO IMAGE THOUSANDS OF LIVE CELLS PER TEST. UV ILLUMINATION MAY PROVIDE EXTRA INFORMATION ABOUT NUCLEI AND OTHER ORGANELLES OF CELLS, EVEN THOUGH IT IS USED SPARINGLY. USING TIME LAPSE IMAGES OF CANCER CELLS, A 3D- CONVOLUTIONAL NEURAL NETWORK WILL BE TRAINED TO IDENTIFY DIFFERENT MORPHOLOGICAL FEATURES, SUCH AS SHRINKING, BLEBBING, VACUOLES AND MEMBRANE RUPTURES, ASSOCIATED WITH DIFFERENT CELL DEATH PROCESSES. DURING THE INCUBATION STEP, RESULTS WILL BE OBTAINED IN REAL TIME, USING THE PRE-TRAINED NETWORK FOR AUTOMATED CLASSIFICATION OF THE CELL DEATH PROCESS. USING THIS APPROACH, NEW ANTI-CANCER DRUG MOLECULES AND THEIR INTERMEDIATES CAN BE SCREENED AT HIGH-THROUGHPUT WITHOUT REQUIRING ANY FURTHER PROCESSING OR LABELING. A SUCCESSFUL COMPLETION OF THIS PROJECT WILL RESULT IN AN AFFORDABLE, COMPACT, HIGH-CONTENT SCREENING TOOL THAT CAN BE USED FOR MANY DIFFERENT APPLICATIONS, IN ADDITION TO PHENOTYPIC SCREENING. IN PARTICULAR, DURING THIS COVID-19 CRISIS, WHICH HAS HIGHLIGHTED THE NEED FOR HIGH THROUGHPUT DIAGNOSTICS, DRUG SCREENING, AND THERAPY TOOLS. BY IMPLEMENTING THIS AREA AWARD, WE WILL SIGNIFICANTLY STRENGTHEN UNIVERSITY OF TOLEDO'S RESEARCH CLIMATE AND PROVIDE UNDERGRADUATE STUDENTS WITH A UNIQUE INTERDISCIPLINARY TRAINING EXPERIENCE IN BIOPHYSICS, MICROSCOPY, IMAGING, DEEP LEARNING, CELL BIOLOGY, AND PHARMACOLOGY.

CAREER: EXPANDING THE TOOLBOX FOR OLEFIN FUNCTIONALIZATION AND DIFUNCTIONALIZATION REACTIONS

RESONANT MICROWAVE PLASMA SOURCES TO IMPROVE THE EFFICIENCY OF COMPACT PLASMA-BASED ACCELERATORS

ADVANCE & I-CORPS JOINT PROGRAM

COLLABORATIVE RESEARCH: MSB: MICROBIAL CONTROL OF LITTER DECAY AT THE CELLULOSE-LIGNIN INTERFACE

CAREER: DIRECT TESTS OF BLACK HOLE ACCRETION RATE PRESCRIPTIONS -A GALAXY CAN BE COMPLETELY TRANSFORMED BY A BLACK HOLE, THE HUGE ENERGY SOURCE AT ITS CENTER. COMPUTER SIMULATIONS HELP US UNDERSTAND THE PHYSICS THAT SHAPES GALAXIES. HOWEVER, EVEN THE MOST COMPLEX SIMULATIONS TODAY NEED TO GUESS WHAT IS GOING ON AT VERY SMALL SCALES. THIS PROJECT USES NEW STATE-OF-THE-ART OBSERVATIONS TO LOOK AT THOSE SMALL SCALES. THESE OBSERVATIONS WILL TEST THE EQUATIONS USED TO DESCRIBE HOW BLACK HOLES GROW. UNDERSTANDING THIS ASPECT OF BLACK HOLES WILL SHOW HOW THEY CHANGE THEIR HOST GALAXIES. THE INVESTIGATOR WILL ALSO LEAD EFFORTS TO RECRUIT MINORITY STUDENTS INTO PHYSICS AND ASTRONOMY BY PARTNERING WITH EXISTING BRIDGE PROGRAMS. THIS PROGRAM WILL ALSO SUPPORT CURRENT STUDENTS THROUGH MENTORSHIP AND A NEW COURSE ON BASIC PHYSICS, MATH, AND LOGIC SKILLS. BY COMBINING NEAR-INFRARED ADAPTIVE OPTICS-ASSISTED INTEGRAL FIELD SPECTROSCOPY AND LONG-BASELINE INTERFEROMETRY, USING NSF?S ALMA TELESCOPE, TO OBTAIN HIGH RESOLUTION IMAGES, THIS PROGRAM WILL MEASURE KEY PROPERTIES AT SUB-10PC RESOLUTION AROUND A BROAD RANGE OF ACTIVE BLACK HOLES. THE INTERFEROMETRIC OBSERVATIONS WILL MEASURE THE DISTRIBUTION OF CARBON MONOXIDE, CO, WHICH TRACES COLD GAS IN THIS REGION. THESE MEASUREMENTS PROVIDE THE INPUTS FOR STANDARD SUB-GRID PRESCRIPTIONS RELATING TO BLACK HOLE ACCRETION RATES, ALLOWING PREDICTIONS OF, FOR A GIVEN BLACK HOLE, WHAT THE ACCRETION RATE WOULD BE IF THAT PRESCRIPTION WERE THE DOMINANT ONE. THESE SYSTEMS ALSO HAVE EXISTING HARD-X-RAY OBSERVATIONS AND MODELING TO PROVIDE THE ACTUAL ACCRETION RATE. PUTTING THESE TWO TOGETHER WILL IDENTIFY WHICH BLACK HOLE ACCRETION RATE PRESCRIPTIONS ARE REASONABLE IN WHICH REGIMES, AND PRODUCE RECOMMENDATIONS FOR GALAXY EVOLUTION SIMULATIONS. 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.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

BENZODIAZEPINE-INDUCED GLUTAMATE RECEPTOR PLASTICITY