Creighton University

TRANSLATIONAL HEARING CENTER - PROJECT SUMMARY/ABSTRACT OVERALL PLAN FOR THE TRANSLATIONAL HEARING CENTER THIS CENTER OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) APPLICATION IS TO ESTABLISH THE TRANSLATIONAL HEARING CENTER, ADMINISTERED BY CENTRALLY-LOCATED CREIGHTON UNIVERSITY, WITH BOYS TOWN NATIONAL RESEARCH HOSPITAL (BTNRH) AND THE UNIVERSITY OF NEBRASKA MEDICAL CENTER (UNMC), AS INSTITUTIONAL PARTNERS. OUR OVERALL GOAL IS TO BUILD A CRITICAL MASS OF ACADEMIC TRANSLATIONAL RESEARCHERS DEVELOPING THERAPEUTIC INTERVENTIONS TO PRESERVE OR RESTORE HEARING AND VESTIBULAR FUNCTION FROM A WIDE RANGE OF ETIOLOGIES THAT CAUSE HEARING LOSS AND VESTIBULAR DEFICITS. HEARING LOSS IN INFANTS AND CHILDREN RESULTS IN DELAYED ACQUISITION OF LISTENING AND SPOKEN LANGUAGE SKILLS CRITICAL FOR ACADEMIC ACHIEVEMENT AND MAXIMAL CAREER TRAJECTORIES OF AFFECTED INDIVIDUALS. IN THE AGING POPULATION, HEARING LOSS AND VESTIBULAR DEFICITS WITHOUT APPROPRIATE REHABILITATION ACCELERATES AGING AND COGNITIVE DECLINE. AIM 1: DEVELOP THE INFRASTRUCTURE AND EXPERTISE BASE FOR TRANSLATIONAL AUDITORY AND VESTIBULAR RESEARCH. COBRE FUNDING WILL ENABLE AN ADMINISTRATIVE CORE WITHIN THE CENTER TO PROVIDE A UNIQUE, TRANSFORMATIONAL RESEARCH ENVIRONMENT FOR JUNIOR INVESTIGATORS TO TRANSLATE THEIR BASIC SCIENCE DISCOVERIES INTO THERAPEUTIC STRATEGIES THAT PRESERVE OR RESTORE HEARING AND VESTIBULAR FUNCTION. THIS WILL ESTABLISH A BROADER NONCLINICAL RESEARCH PROGRAM. THE ADMINISTRATIVE CORE WILL COORDINATE INTERACTIONS BETWEEN PROJECT LEADERS WITH THEIR MENTORS, AND AN EXTERNAL ADVISORY COMMITTEE. THE ADMINISTRATIVE CORE WILL DEVELOP A DRUG DISCOVERY AND DELIVERY CORE THAT WILL COORDINATE NECESSARY DRUG SCREEN ASSAYS AND PRODUCTION OF DERIVATIVES OF LEAD COMPOUNDS AND THEIR DELIVERY TO THE INNER EAR AND ASSOCIATED CENTRAL NEURAL PATHWAYS, AS WELL AS AN AUDITORY VESTIBULAR TECHNOLOGY CORE TO VALIDATE THE EFFICACY OF LEAD CANDIDATE OTOTHERAPEUTICS HITS. AIM 2: BUILD A CRITICAL MASS OF FUNDED INVESTIGATORS LEADING TRANSLATIONAL AUDITORY AND VESTIBULAR RESEARCH. WE WILL EXAMINE BOTH PERIPHERAL AND CENTRAL MECHANISMS OF HEARING LOSS AND VESTIBULAR DYSFUNCTION, AND IDENTIFY PHARMACOTHERAPEUTIC STRATEGIES PRESERVE OR RESTORE HEARING AND VESTIBULAR FUNCTION, WITH MULTIPLE LEVELS OF RESEARCH FUNDING FOR INVESTIGATORS. WE ALSO HAVE AN OUTSTANDING MENTORING PLAN FOR PROJECT LEADERS, COMPLEMENTING THEIR EXPERTISE WITH SENIOR INVESTIGATIONS AS INTERNAL MENTORS AND BIOSTATISTICAL SUPPORT, AS WELL AS OUTSIDE INVESTIGATORS WITH TRANSLATIONAL AND CLINICAL EXPERTISE AS EXTERNAL MENTORS. ADDITIONAL MENTORING IS PROVIDED BY RESEARCH CORE STAFF, GRANTSMANSHIP CLASSES AND MOCK STUDY SECTIONS OF PROPOSALS PRIOR TO REVIEW. EVALUATIONS OF RESEARCH PROGRESS, AND ALL OTHER CENTER ACTIVITIES, ARE ALSO KEY TO OPTIMIZE CENTER SUCCESS. THE CENTER WILL ALSO BENEFIT FROM THE BURGEONING TRANSLATIONAL RESEARCH ENVIRONMENT IN OMAHA, NEBRASKA. FUTURE PLANS CALL FOR CONTINUED EXPANSION OF THE CENTER TO INCLUDE SUBMISSION OF INVESTIGATIONAL NEW DRUG APPLICATIONS, SAFETY AND EFFICACY STUDIES AND CLINICAL TRIALS IN PARTNERSHIP WITH PATIENT POPULATIONS SERVED BY CREIGHTON UNIVERSITY’S ACADEMIC MEDICAL CENTER, CATHOLIC HEALTH INITIATIVES (CHI) HEALTH SYSTEM, BTNRH AND UNMC.

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND/INSTITUTION - CREIGHTON UNIVERSITY

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND - CREIGHTON UNIVERSITY

HAIR CELL RESPONSES TO OTOTOXIC DRUGS

CLINICAL TRIAL OF VITAMIN D3 TO REDUCE CANCER RISK IN POSTMENOPAUSAL WOMEN

A STUDY OF REDUCED BONE QUALITY AS A CAUSE OF FRACTURES

MESENCHYMAL STEM CELLS IN THE PREVENTION OF THROMBOSIS AND NEOINTIMAL HYPERPLASIA

A STUDY OF RELATIVISTIC HEAVY ION COLLISIONS

EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS

VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE

BIOPHYSICS AND DEVELOPMENT OF COCHLEAR HAIR CELLS

COMMUNITY HEALTH WORKER TRAINING PROGRAM - SERVICE AREA: NEBRASKA TARGET POPULATIONS: AFRICAN AMERICANS, LATINX/HISPANICS, NATIVE AMERICANS, SUDANESE, SOMALI, AND KAREN IMMIGRANTS, INDIVIDUALS EXPERIENCING HOMELESSNESS OR LOSS OF EMPLOYMENT, AND INDIVIDUALS IN PUBLIC HOUSING. PARTNERS: DOUGLAS COUNTY HEALTH DEPARTMENT, ONE WORLD COMMUNITY HEALTH CENTERS, CHARLES DREW COMMUNITY HEALTH CENTERS, CYNCHEALTH, INC., NE CENTER FOR HEALTHY FAMILIES, LEE BROWN AND ASSOCIATES, HEARTLAND WORKFORCE SOLUTIONS, INTERNATIONAL ADVANCED DEVELOPMENT, AND RESEARCH CORPORATION: INARC REQUEST AMOUNT: $2,996,074 PROJECT OVERVIEW: CHW-TAPP WILL INCREASE THE NUMBER OF LAY INDIVIDUALS TO SERVE AS COMMUNITY HEALTH WORKERS (CHWS) BY (1) INCREASING THE NUMBER OF PERSONS TRAINED AS CHWS, AND (2) STRENGTHENING THE CHW WORKFORCE PIPELINE. THE PROJECT IS GUIDED BY THREE GOALS AND SUPPORTING OBJECTIVES: GOALS/OBJECTIVES: GOAL 1: TO DEVELOP, TEST, AND REFINE A COLLABORATIVE FRAMEWORK THAT EFFECTIVELY RECRUITS, SUPPORTS, TRAINS, AND PLACES AN INCREASING NUMBER OF INDIVIDUALS IN CAREERS AS COMMUNITY HEALTH WORKERS (CHWS). OBJ. 1.1: TO RECRUIT 240 INDIVIDUALS (OR 80 PER YEAR) INTO THE CHW-TAPP PROGRAM FOR EDUCATION, TRAINING, AND PREPARATION FOR CAREERS AS COMMUNITY HEALTH WORKERS; OBJ. 1.2: TO PROVIDE PARTICIPANTS UP TO $7,500 IN ASSISTANCE AND SUPPORTS TO MINIMIZE BARRIERS AND ENHANCE COMPLETION OF THE CHW TRAINING PROGRAM; OBJ. 1.3: TO PLACE 45 PARTICIPANTS IN REGISTERED APPRENTICESHIPS OPPORTUNITIES. GOAL 2: TO EDUCATE AND INFORM HEALTH CARE ADMINISTRATORS AND HEALTHCARE TEAM MEMBERS ABOUT CHWS' ROLES, TRAINING AND PLACEMENTS, AND HOW CHWS CAN BEST PROMOTE HEALTH INSTITUTIONAL OBJECTIVES. OBJ. 2.1: TO INFORM COMMUNITY HEALTH STAKEHOLDERS ABOUT THE CPHHE CHW APPRENTICESHIP PROGRAM; OBJ 2.2: TO EDUCATE HEALTHCARE ADMINISTRATORS REGARDING CURRENT NATIONAL EVIDENCE ABOUT HOW HEALTH INSTITUTIONS WORK WITH CHWS; OBJ 2.3: TO FOSTER CONNECTIONS BETWEEN HEALTHCARE EMPLOYERS AND CHWS IN THE APPRENTICESHIP PROGRAM; OBJ. 2. 4: TO COMMUNICATE EVIDENCE ABOUT HOW CHWS CAN COMPLEMENT HEALTHCARE TEAMS AND RECOMMENDATIONS FOR BEST PRACTICES. GOAL 3: TO REDUCE HEALTH DISPARITIES THAT NEBRASKA'S MOST MEDICALLY-UNDERSERVED POPULATIONS EXPERIENCE. OBJ. 3.1: TO INCREASE HEALTH CARE ACCESS; OBJ. 3.2: TO IMPROVE PERCEIVED HEALTH STATUS; OBJ. 3.3: TO INCREASE HEALTH INSURANCE COVERAGE RATES; OBJ. 3.4: TO REDUCE THE PREVALENCE OF CHRONIC HEALTH CONDITIONS HOW PROJECT WILL BE ACCOMPLISHED: CHW-TAPP WILL EDUCATE CHWS ABOUT STRATEGIES TO LINK INDIVIDUALS AND FAMILIES WITH RELEVANT MEDICAL, BEHAVIORAL HEALTH, AND SOCIAL SERVICES. CHWS WILL LEARN TO FACILITATE COMMUNITY MEMBER ACCESS TO DIVERSE SERVICES THROUGH ADVOCACY, OUTREACH, REFERRAL, COMMUNITY AND INDIVIDUAL/FAMILY EDUCATION, INFORMAL MENTORING, AND SOCIAL SUPPORT. CHW-TAPP WILL ALSO PREPARE CHWS TO ATTAIN CAREERS IN HEALTHCARE FIELDS AS COMMUNITY AND HEALTH LIAISONS THROUGH JOB READINESS, TECHNOLOGY/APPLICATION UPSKILLING, AND HEALTHCARE FIELD TRAINING. THE CHW-TAPP EDUCATION COURSE WILL STRESS DEVELOPING EFFECTIVE COMMUNICATION SKILLS, BUILDING COLLABORATIVE RELATIONSHIPS WITH CLIENTS AND COMMUNITY PROVIDERS, AND PROMOTING HEALTHY LIFESTYLES. CPHHE CURRENTLY HAS AN EXISTING CERTIFICATION PROGRAM FOR CHWS THAT HAS TRAINED OVER 50 INDIVIDUALS AND HAS DEVELOPED STRATEGIC PARTNERSHIPS TO EFFECTIVELY DEPLOY AND UTILIZE CHWS IN SOME OF THE REGION'S MOST MEDICALLY-UNDERSERVED NEIGHBORHOODS. THE PROJECT WILL RESULT IN SEVERAL POSITIVE OUTCOMES AND DELIVERABLES INCLUDING (1) AN INCREASE IN THE NUMBER OF CERTIFIED CHWS, (2) HEIGHTENED AWARENESS OF THE ROLES OF CHWS IN ADDRESSING HEALTH DISPARITIES, (3) THE ESTABLISHMENT OF AN EDUCATION/TRAINING-APPRENTICESHIP MODEL THAT SUPPORTS THE PLACEMENT OF CHWS INTO EMPLOYMENT, AND (4) A STRENGTHENED CAREER PIPELINE FOR CHWS. FUNDING PREFERENCE: FUNDING PREFERENCE 1: CPHHE HAS SERVED 50% OR MORE FROM DISADVANTAGED BACKGROUNDS.

GENE AND STEM CELL THERAPY IN CORONARY ARTERY BYPASS GRAFT

CREIGHTON UNIVERSITY UPWARD BOUND PROGRAM

MYCOTOXINS AND BIRTH DEFECTS: A GLOBAL HEALTH CONCERN?

CENTER FOR PROMOTING HEALTH AND HEALTH EQUITY-RACIAL AND ETHNIC APPROACHES TO COMMUNITY HEALTH 2 (CPHHE-REACH 2)

MECHANISMS OF PRION STRAIN SELECTION

UPWARD BOUND

UPWARD BOUND PROGRAM

CREIGHTON UNIVERSITY UPWARD BOUND PROGRAM

HEALTH CAREERS OPPORTUNITY PROGRAM

MECHANISMS OF PRION SPREAD AND ESTABLISHMENT OF INFECTION

GENE THERAPY WITH SOCS-3 IN INTIMAL HYPERPLASIA AND IN-STENT RESTENOSIS

TAS::89 0321::TAS CREIGHTON UNIVERSITY TRAINING & RESEARCH IN SOLAR POWER

EFFICACY OF OPTIMAL LEVELS OF DIETARY DAIRY ON MODULATION OF ADOLESCENT WEIGHT

GENETIC CONTROL OF CELLULAR CONVERSION IN THE MATURE COCHLEA

CREIGHTON UNIVERSITY TALENT SEARCH

CLINICAL FACTORS IN AMINOGLYCOSIDE-INDUCED OTOTOXICITY

TALENT SEARCH PROGRAM

LONG-ACTING ANTIRETROVIRAL NANOPARTICLES FOR HIV PROPHYLAXIS

MECHANISMS OF BIOLOGICAL AGING OF COCHLEAR HAIR CELLS

MECHANISMS OF PRION STRAIN DYNAMICS

A PROTEOMIC AND BIOCHEMICAL STUDY OF HIV-1 NUCLEOPROTEIN COMPLEXES

TGF-BETA, CHLORIDE CHANNELS AND MIGRATION OF EOSINOPHILS

AUTORESUSCITATION AND SUDEP - PROJECT SUMMARY APPROXIMATELY 30% OF PEOPLE WITH EPILEPSY ARE REFRACTORY TO CURRENT ANTI-SEIZURE MEDICATIONS AND SUDDEN UNEXPECTED DEATH IN EPILEPSY (SUDEP) OCCURS IN ~1:150 PER YEAR FOR INDIVIDUALS WITH SEVERE REFRACTORY GENERALIZED CONVULSIVE SEIZURES (GCS). THE LONG-TERM GOALS OF OUR RESEARCH PROGRAM ARE TO IDENTIFY NOVEL MOLECULAR TARGETS WITH DISEASE-MODIFYING EFFECTS THAT MAY INCREASE LONGEVITY IN THOSE SUSCEPTIBLE TO SUDEP. EVIDENCE FROM THE MULTI- CENTER MORTEMUS STUDY ON SUDEP INDICATES THAT PATIENTS EXPERIENCED A SERIES OF EVENTS PROMOTING HYPOXIC AND HYPERCAPNIC (HH) FLUCTUATIONS IN BLOOD GASES, FROM WHICH THEY WERE UNABLE TO AUTORESUSCITATE AND SUCCUMBED TO TERMINAL APNEA. HOWEVER, THE RELATIONSHIP BETWEEN SUDEP RISK AND THE EFFICACY OF THE AUTORESUSCITATION RESPONSE IS UNKNOWN. THE OBJECTIVE OF THE PROPOSED PROJECT IS TO ELUCIDATE MECHANISMS OF AUTORESUSCITATION FAILURE IN RELATION TO SUDEP RISK. THE CENTRAL HYPOTHESIS IS THAT ALTERATIONS IN THE NETWORK OF CHEMOSENSITIVE CARDIORESPIRATORY NEURONS INCREASES THE PROBABILITY OF AUTORESUSCITATION FAILURE AND SUDEP RISK. OUR RATIONALE IS THAT SUDEP IS OFTEN ASSOCIATED WITH A PRECEDING GCS, BUT DEMISE HAS ALSO BEEN ASSOCIATED WITH PRONE POSITIONS WITH NO EVIDENCE OF SEIZURE. A VARIABLE OR DECLINE IN AUTORESUSCITATION EFFICACY MAY EXPLAIN SUCCUMBING TO ONE GCS AND NOT PREVIOUS SEIZURES OR FAILING TO AROUSE IN SITUATIONS OF CHANGING AIR SUPPLY. OUR SPECIFIC AIMS WILL TEST THE HYPOTHESES THAT MALADAPTIVE MODULATORY CONTROL OF KEY CENTRAL AUTORESUSCITATION CENTERS DISINTEGRATES THE NETWORK CHEMORESPONSE, CAUSING DETERIORATION OF THE RESPONSE AND THE AUTORESUSCITATION RESPONSE TO FAIL. UPON CONCLUSION, WE WILL HAVE DELINEATED MECHANISMS UNDERLYING AUTORESUSCITATION FAILURE IN THE CONTEXT OF EPILEPSY IN A CLINICALLY RELEVANT ANIMAL MODEL OF SUDEP. THIS INFORMATION WILL OFFER NEW RESEARCH AVENUES FOR UNDERSTANDING SUDEP, ASSESSING RISK AND IDENTIFYING THERAPEUTIC OPPORTUNITIES.

STUDENT SUPPORT SERVICES

SKELETAL EFFECTS OF TYPE 1 DIABETES

ROLE OF MICRORNAS IN MAMMALIAN EAR DEVELOPMENT AND NEUROSENSORY SPECIFICATION

CONTRIBUTIONS OF PRION STRAINS AND SUBSTRAINS TO PRION ZOONOTIC POTENTIAL AND EVOLUTION - PRIONS ARE INFECTIOUS PROTEIN-ONLY ZOONOTIC AGENTS THAT CAN RAPIDLY EVOLVE IN A NEW REPLICATION ENVIRONMENT. PRION STRAINS ARE ENCODED BY STRAIN-SPECIFIC CONFORMATIONS OF PRPSC, THE INFECTIOUS FORM OF THE HOST-ENCODED PRION PROTEIN, PRPC. COLLINGE AND CLARKE HYPOTHESIZED THAT PRION STRAINS ARE A MIXTURE OF A DOMINANT PRION STRAIN AND SUBSTRAINS. IN SUPPORT OF THIS HYPOTHESIS, WE AND OTHERS HAVE SHOWN: I) TREATMENT OF PRIONS WITH ANTI-PRION DRUGS CAN RESULT IN THE EMERGENCE OF A DRUG RESISTANT STRAIN, II) PHYSICAL METHODS (E.G. THERMOSTABILITY) THAT PARTIALLY INACTIVATE PRIONS CAN SELECT FOR PRIONS WITH ALTERED STRAIN PROPERTIES, AND III) STRAINS WITHIN A GIVEN HOST SPECIES CAN HAVE DIFFERENT HOST RANGES. DESPITE THESE DATA, DIRECT EVIDENCE FOR THE EXISTENCE OF PREEXISTING SUBSTRAINS IS LACKING AND, CONSEQUENTLY, THE CONTRIBUTIONS OF SUBSTRAINS TO PRION EVOLUTION HAS NOT BEEN EXPLORED. THE LONG-TERM GOAL OF THIS WORK IS TO PREVENT PRION EVOLUTION TO A NEW REPLICATIVE ENVIRONMENT. THE OVERALL OBJECTIVE OF THIS APPLICATION IS TO DETERMINE THE RELATIVE CONTRIBUTIONS OF THE DOMINANT PRION STRAIN AND SUBSTRAINS TO INTERSPECIES TRANSMISSION OF PRIONS. IN THIS APPLICATION WE WILL TEST THE HYPOTHESIS IS THAT PRION SUBSTRAINS DRIVE PRION TRANSMISSION TO A NEW PRP GENOTYPE. THE HYPOTHESIS IS BASED ON OUR NEW DISCOVERY THAT SELECTIVE REDUCTION OF PRPSC FROM THE BIOLOGICALLY CLONED HAMSTER-ADAPTED DROWSY (DY) STRAIN OF TRANSMISSIBLE MINK ENCEPHALOPATHY (TME), USING TWO MECHANISTICALLY DIFFERENT METHODS, ALLOWS FOR THE EMERGENCE AND ISOLATION OF A PREEXISTING SUBSTRAIN THAT IS DISTINCT FROM DY. MOREOVER, THIS SUBSTRAIN UNEXPECTEDLY HAS A DIFFERENT HOST RANGE THAN DY TME. TO TEST OUR HYPOTHESIS, WE WILL FIRST EXPLORE THE FREQUENCY AND DIVERSITY OF PREEXISTING SUBSTRAINS FROM STABLE AND UNSTABLE PRION STRAINS USING COMPLIMENTARY METHODS (CONFORMATIONAL STABILITY, PROTEASE DIGESTION, THERMOSTABILITY) TO SELECTIVELY DEPOPULATE THE DOMINANT STRAIN. THE FREQUENCY AND DIVERSITY OF SUBSTRAINS ISOLATED WILL BE DETERMINED USING COMPLEMENTARY IN VITRO PRION DETECTION METHODS AND ANIMAL BIOASSAY. SECOND, WE WILL EXPLORE THE WELL-STUDIED HAMSTER/MOUSE SPECIES BARRIER USING COMPLEMENTARY IN VITRO AND IN VIVO METHODS TO DETERMINE THE RELATIVE CONTRIBUTIONS OF THE DOMINANT STRAIN AND SUBSTRAINS TO INTERSPECIES TRANSMISSION. THE CONCEPT OF STRAIN INTERFERENCE BETWEEN THE DOMINANT STRAIN AND SUBSTRAINS WILL BE TESTED IN REGARDS INTERSPECIES TRANSMISSION. THESE STUDIES ARE SIGNIFICANT SINCE IT IS CRITICAL TO UNDERSTAND THE CONTRIBUTIONS OF SUBSTRAINS TO PRION EVOLUTION AS CURRENT PRION TREATMENT METHODS IN DEVELOPMENT (VACCINATION, ANTI-PRION DRUGS, ENVIRONMENTAL MITIGATION PROCEDURES) TARGET THE DOMINANT STRAIN. IT IS THEREFORE POSSIBLE THAT THESE METHODS WILL INADVERTENTLY RESULT IN THE EMERGENCE OF PREEXISTING PRION STRAINS WITH ALTERED ZOONOTIC POTENTIAL AND/OR INCREASED PATHOGENICITY. OVERALL, THESE STUDIES WILL DIRECTLY TEST THE COLLINGE AND CLARK MODEL OF PRION STRAIN DYNAMICS AND WILL ALLOW FOR A MORE PRECISE EVALUATION POTENTIAL OF PRION STRAINS TO ADAPT TO A NEW REPLICATION ENVIRONMENT (E.G., CHRONIC WASTING DISEASE TRANSMISSION TO HUMANS).

UPWARD BOUND MATH AND SCIENCE

TARGETING ABERRANT ANTI-APOPTOTIC SIGNALING FOR PREVENTION OF SKIN CANCER

DETERMINING THE OTOTOXIC POTENTIAL OF COVID-19 THERAPEUTICS USING MACHINE LEARNING AND IN VIVO APPROACHES - PROJECT SUMMARY/ABSTRACT THERE ARE OVER 900 DRUGS AND DRUG COMBINATIONS CURRENTLY IN CLINICAL TRIALS FOR COVID-19. WHILE THIS PACE OF DRUG DEVELOPMENT IS NECESSARY, IT ALSO COMES WITH INCREASED RISK OF PRODUCING THERAPIES WITH SIGNIFICANT SIDE- EFFECTS. ONE LIKELY SIDE-EFFECT OF SOME COVID-19 DRUGS IS HEARING LOSS. THE POTENTIAL OF DRUGS TO CAUSE HEARING LOSS IS TYPICALLY UNASSESSED DURING DRUG DEVELOPMENT OR CLINICAL TESTING. OUR RESEARCH WILL RAPIDLY ASSESS COVID-19 DRUGS FOR OTOTOXIC POTENTIAL, AS PER NOT-DC-20-008 TO DETERMINE THE “POTENTIAL OTOTOXICITY FROM THERAPEUTICS OR VACCINATION RELATED TO COVID-19.” OUR GOAL IS TO PROMOTE THE DEVELOPMENT OF SAFE COVID-19 DRUGS WITH MINIMAL SIDE EFFECTS. SOME DRUGS IN CLINICAL TRIALS FOR COVID-19 ARE ASSOCIATED WITH HEARING LOSS BUT THE OTOTOXIC POTENTIAL FOR THESE DRUGS IS BASED ON INDIVIDUAL CASE REPORTS OR IN VITRO EXPERIMENTS SO THE TRUE OTOTOXIC BURDEN IS LARGELY UNKNOWN. WE SHOULD NOT USE PATIENTS AS A TESTBED FOR A LIFE-ALTERING NEGATIVE SIDE- EFFECT WHEN THERE ARE RAPID LOW-COST ALTERNATIVES AVAILABLE. THE OBJECTIVE OF THIS PROPOSAL IS TO RAPIDLY IDENTIFY THE OTOTOXIC POTENTIAL OF COVID-19 THERAPEUTICS USING BOTH IN SILICO AND IN VIVO APPROACHES. WE WILL ACHIEVE THIS OBJECTIVE WITH THREE SPECIFIC AIMS: 1) PREDICT OTOTOXIC POTENTIAL OF COVID-19 THERAPIES WITH MACHINE LEARNING (ML), 2) DETERMINE THE RELATIVE HAIR CELL TOXICITY OF COVID-19 THERAPIES IN THE ZEBRAFISH LATERAL LINE, AND 3) DETERMINE THE DEGREE TO WHICH PREDICTED OTOTOXINS CAUSE HEARING LOSS IN RATS. OUR INNOVATIVE ML MODEL CORRECTLY CATEGORIZES OTOTOXINS VS. NON-OTOTOXINS WITH 87% ACCURACY. IN THIS PROJECT WE WILL EMPLOY OUR CURRENT MODEL FOR IMMEDIATE OTOTOXICITY DETECTION AND FURTHER OPTIMIZE THE MODEL FOR BETTER PREDICTIVE ACCURACY. IN PARALLEL WITH THE ML MODEL, WE WILL SCREEN COVID-19 THERAPEUTICS IN THE LARVAL ZEBRAFISH LATERAL LINE, WHICH IS AN EXCELLENT MODEL FOR RAPID OTOTOXICITY SCREENING. PRIOR WORK BY OUR GROUP AND OTHERS DEMONSTRATES THE VALIDITY OF THE LATERAL LINE AS A PLATFORM FOR EFFECTIVE OTOTOXIN DISCOVERY. FINALLY, WE WILL VALIDATE PREDICTED OTOTOXINS FROM AIMS 1 AND 2 IN RATS USING BOTH PHYSIOLOGICAL AND MORPHOLOGICAL ASSAYS. OUR RESEARCH IS SIGNIFICANT BECAUSE WE WILL DETERMINE THE OTOTOXIC POTENTIAL OF NEW OR REPURPOSED THERAPEUTICS FOR COVID-19, WHICH CAN INFORM EFFORTS TO 1) ADVANCE EFFECTIVE CANDIDATES THAT ARE NOT OTOTOXIC, 2) MODIFY SUCCESSFUL YET OTOTOXIC COVID-19 DRUGS AND/OR DEVELOP OTOPROTECTIVE CO-THERAPIES TO PRESERVE THERAPEUTIC EFFICACY WHILE MINIMIZING OTOTOXIC SIDE- EFFECTS, AND 3) DETERMINE WHICH PATIENTS REQUIRE AUDIOMETRIC MONITORING DUE TO THE DRUGS THEY RECEIVE. OUR TEAM INCLUDES EXPERTS IN OTOTOXICITY, MEDICINAL CHEMISTRY, BIOSTATISTICS, MACHINE LEARNING, AND CLINICAL EXPERTISE IN LARGE-SCALE HUMAN TRIALS FOR COVID-19 THERAPIES. OUR RESEARCH IS HIGHLY LIKELY TO IDENTIFY OTOTOXIC COVID-19 DRUGS, FACILITATING DEVELOPMENT OF SAFER PHARMACOTHERAPIES TO COMBAT THIS DEADLY PANDEMIC. FURTHER, MANY DRUGS IN CLINICAL TRIALS FOR COVID-19 ARE ALREADY APPROVED FOR OTHER INDICATIONS. OUR RESEARCH WILL THEREFORE PROVIDE IMPORTANT DATA ABOUT DRUGS IN CLINICAL USE FOR NON-COVID-RELATED DISEASE, ADDING ADDITIONAL VALUE.

TALENT SEARCH PROGRAM

PPARGAMMA, EPILEPSY AND THERAPEUTICS

DISCOVERY OF IN VIVO SMALL MOLECULES FOR HEARING PROTECTION AGAINST CISPLATIN AND NOISE

MECHANISMS OF UV-INDUCED SKIN CARCINOGENESIS

APOPTOSIS OF SMOOTH MUSCLE CELLS IN CAROTID PLAQUES

EPITHELIAL EXOSOMES AND TLR-MEDIATED MUCOSAL DEFENSE

ADENOSINE, HYPOCRETIN AND SLEEP DISORDER COMORBIDITIES ASSOCIATED WITH EPILEPSY

REGULATORY MECHANISMS GOVERNING BUBR1 PROTEIN STABILITY DURING STRESS AND AGING - ABSTRACT: BUBR1 IS A KEY REGULATOR OF AGING THROUGH SUPPRESSING CELLULAR SENESCENCE AND IS A CRITICAL TUMOR SUPPRESSOR THROUGH ITS ROLE IN MAINTAINING GENOME INTEGRITY BY SUSTAINING FIDELITY IN CHROMOSOMAL SEGREGATION DURING MITOSIS THROUGH CONTROL OF THE SPINDLE ASSEMBLY CHECKPOINT. IMPORTANTLY, BUBR1 LEVELS DECLINE WITH AGE PUTTING IT AT THE INTERSECTION OF AGING AND AGE-RELATED DISEASES SUCH AS CANCER. LOSS OF BUBR1 WITH AGE IS ATTRIBUTED, IN PART, THROUGH ITS INCREASED UBIQUITIN-PROTEASOMAL MEDIATED DEGRADATION, WHICH CAN BE BLOCKED BY INCREASING THE ACTIVITY OF THE NAD+-DEPENDENT DEACETYLASE SIRT2. HOWEVER, THE E3 UBIQUITIN LIGASE(S) INVOLVED IN PROMOTING THE DECLINE IN BUBR1 WITH AGE AND UNDER CONDITIONS OF STRESS REMAIN ELUSIVE. WE IDENTIFIED THE SKP1-CULLIN-F-BOX (SCF) E3 UBIQUITIN LIGASE SUBSTRATE RECOGNITION SUBUNIT -TRCP1 AS AN INTERACTOR OF BUBR1, WHICH TARGETS BUBR1 FOR UBIQUITINATION AND DEGRADATION. BUBR1 CONTAINS A PUTATIVE BINDING DOMAIN FOR -TRCP1 (KNOWN AS A DEGRON MOTIF), WHICH LIES ADJACENT TO THE ACETYLATED LYSINE CONTROLLED BY SIRT2 SUGGESTING A CROSS TALK BETWEEN SIRT2-REGULATED ACETYLATION AND UBIQUITINATION OF BUBR1 BY - TRCP1. FURTHERMORE, -TRCP1 IS INVOLVED IN UBIQUITINATION AND DEGRADATION OF KEY REGULATORS OF GENOME STABILITY AND CANCER SUCH AS CHK1 AND CYCLIN D1 IN RESPONSE TO CELLULAR STRESS, INCLUDING NUTRIENT DEPRIVATION. SIMILARLY, BUBR1 PROTEIN LEVELS ARE DESTABILIZED IN RESPONSE TO GLUCOSE DEPRIVATION, SUGGESTING A PUTATIVE ROLE FOR -TRCP1 IN REGULATING BUBR1 UNDER PHYSIOLOGICAL STRESS CONDITIONS AS WELL AS DURING THE NATURAL AGING PROCESS. BASED ON THESE OBSERVATIONS, WE HYPOTHESIZE THAT -TRCP1 IS A KEY REGULATOR OF BUBR1 PROTEIN STABILITY TO CONTROL AGING AND DISEASE. TO TEST THIS HYPOTHESIS, WE DEVELOPED TWO SPECIFIC AIMS. IN AIM 1 WE WILL DEFINE THE POSTTRANSLATIONAL REGULATION OF BUBR1 BY -TRCP1 AT THE MOLECULAR LEVEL, AND ITS IMPACT ON CELLULAR SENESCENCE AND ORGANISMAL LIFESPAN. THESE STUDIES WILL INVESTIGATE THE UPSTREAM AND DOWNSTREAM PATHWAYS BY WHICH -TRCP REGULATES BUBR1 PROTEIN STABILITY, AND ITS INVOLVEMENT IN THE PROMOTING THE DECLINE OF BUBR1 WITH AGE. IN AIM 2 WE WILL DETERMINE THE ROLE OF -TRCP1-MEDIATED PROTEIN DEGRADATION OF BUBR1 UNDER CONDITIONS OF CELLULAR STRESS INCLUDING GLUCOSE DEPRIVATION BY DELINEATING THE MOLECULAR MECHANISMS LINKING CELLULAR SENSING OF NUTRIENT STRESS TO UBIQUITIN-PROTEASOMAL MEDIATED DEGRADATION OF BUBR1. IN ADDITION, WE WILL ASSESS THE CONSEQUENCES OF ALTERING BUBR1 AND OTHER REGULATORS OF GENOME STABILITY IN THE CELLULAR RESPONSE TO GLUCOSE RESTRICTIVE CONDITIONS. FINALLY, WE WILL ELUCIDATE THE ROLE OF -TRCP1 IN PROTEOME REMODELING DURING THE CELLULAR RESPONSE TO GLUCOSE RESTRICTION CONDITIONS USING AN UNBIASED PROTEOMICS-BASED INTERACTION SCREEN. THE OVERALL GOAL OF THIS PROPOSAL IS TO ELUCIDATE AT THE MOLECULAR AND CELLULAR LEVEL THE ROLE OF -TRCP IN CONTROLLING KEY REGULATORS OF GENOMIC STABILITY INCLUDING BUBR1 DURING CELLULAR STRESS IN AGING AND DISEASE, WHICH WILL PROVIDE THE IMPETUS TO DEVELOP NOVEL THERAPEUTIC INTERVENTIONS FOR AGING AND AGE-RELATED DISEASES THROUGH STABILIZATION OF BUBR1.

CREIGHTON RESEARCH INFRASTRUTURE PROGRAM TO ACHIEVE SUSTAINABILITY PROJECT

A STUDY OF ULTRA-RELATIVISTIC HEAVY ION COLLISIONS

STUDENT SUPPORT SERVICES PROGRAM

EDRN: CLINICAL EPIDEMIOLOGY & VALIDATION CENTERS

MEETING PATIENTS AND STUDENTS WHERE THEY ARE - VIRTUAL REALITY AND OTHER ENGAGING TECHNOLOGIES

SMOOTH MUSCLE CELL PROLIFERATION IN HUMAN CORONARY ARTERY BYPASS GRAFTS

DYSREGULATION OF RGS2 PROTEIN AND AIRWAY HYPERRESPONSIVENESS IN ASTHMA

CHARACTERISTICS OF PRION ENTRY AND NEUROINVASION FOLLOWING NASAL CAVITY INFECTION

STUDENT SUPPORT SERVICES PROGRAM

SMALL MOLECULE THERAPEUTICS FOR HAIR CELL REGENERATION AFTER NOISE DAMAGE

EDUCATIONAL OPPORTUNITY CENTERS PROGRAM

CREIGHTON UNIVERSITY UPWARD BOUND MATH & SCIENCE

UPWARD BOUND MATH & SCIENCE

CREIGHTON UNIVERSITY EDUCATIONAL OPPORTUNITY CENTER FY 2021 GRANT PROPOSAL

CENTER FOR PROMOTING HEALTH AND HEALTH EQUALITY - RACIAL AND ETHNIC APPROACHES TO COMMUNITY HEALTH (CPHHE-REACH).

A NOVEL THERAPEUTIC STRATEGY TARGETING NEUROINFLAMMATION FOR GLOBAL CEREBRAL ISCHEMIA ASSOCIATED WITH CARDIAC ARREST - PROJECT SUMMARY/ABSTRACT EACH YEAR, OVER 200,000 AMERICANS SUFFER FROM GLOBAL CEREBRAL ISCHEMIA ASSOCIATED WITH CARDIAC ARREST LEADING TO COGNITIVE DEFICITS OR DEATH. WHILE EMERGENCY TREATMENTS OF CARDIAC ARREST FOCUS ON RESTORING CARDIAC FUNCTION AND BLOOD FLOW, AN EFFECTIVE THERAPEUTIC TREATMENT FOR NEURODEGENERATION AND COGNITIVE DEFICITS ASSOCIATED WITH GLOBAL CEREBRAL ISCHEMIA IS A CRUCIAL UNMET MEDICAL NEED. ALTHOUGH THE ENTIRE BRAIN IS DEPRIVED OF OXYGEN, GLOBAL ISCHEMIA CAUSES SELECTIVE, DELAYED DEATH OF HIPPOCAMPAL CA1 PYRAMIDAL NEURONS, WHICH IN TURN INDUCES SEVERE DEFICITS IN HIPPOCAMPUS-DEPENDENT COGNITIVE FUNCTION. ALTHOUGH THE MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF GLOBAL ISCHEMIA ARE UNCLEAR, THE LONG DELAY BETWEEN INSULT AND NEURONAL DEATH IS CONSISTENT WITH A ROLE FOR TRANSCRIPTIONAL CHANGES. IN PRELIMINARY STUDIES, WE PERFORMED RNA-SEQ USING NEXT GENERATION MASSIVELY PARALLEL SEQUENCING TO INVESTIGATE ALTERATIONS OF GENE EXPRESSION IN POST-ISCHEMIC HIPPOCAMPAL CA1 IN RATS. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED THAT `TRIGGERING RECEPTOR EXPRESSED IN MYELOID CELLS 1 (TREM1) SIGNALING' AND `NEUROINFLAMMATION' ARE THE TOP CANONICAL PATHWAYS. TREM1 IS AN INFLAMMATORY TYPE I MEMBRANE RECEPTOR EXPRESSED IN MYELOID LINEAGE AND KNOWN TO MAGNIFY THE PROINFLAMMATORY INNATE IMMUNE RESPONSE. EVIDENCE IMPLICATES A PROINFLAMMATORY ROLE OF TREM1 IN INFLAMMATORY DISEASES, CANCER, AND OTHER BRAIN DISEASES, HOWEVER, THE ROLE OF TREM1 IN GLOBAL CEREBRAL ISCHEMIA ASSOCIATED WITH CARDIAC ARREST REMAINS UNKNOWN. OUR PRELIMINARY CONFOCAL IMAGING SHOWED THAT TREM1 IS ACTIVATED IN CD11B POSITIVE IMMUNE CELLS BUT NOT IN NEURONS OR ASTROCYTES IN HIPPOCAMPAL CA1 AFTER GLOBAL ISCHEMIA. IPA ANALYSIS FURTHER IDENTIFIED BRD4 AND P300 AS UPSTREAM EFFECTORS WHICH ARE RECENTLY REPORTED AS EPIGENETIC REGULATORS OF TREM1 IN INFLAMMATORY RELATED DISEASES. WE ALSO VALIDATED BOTH PROTEINS ARE INCREASED IN TREM1 POSITIVE CELLS IN POST-ISCHEMIC HIPPOCAMPAL CA1 AND UPREGULATED TREM1 EXPRESSION WAS RESCUED BY A BRD4 INHIBITOR. IMPORTANTLY, OUR PRELIMINARY DATA SHOWED THAT TREM1 PEPTIDE INHIBITORS LR12 AND GJ073, AND BRD4 INHIBITOR JQ1 ATTENUATE GLOBAL ISCHEMIA- INDUCED NEURONAL DEATH. THE OVERALL OBJECTIVES OF THIS PROPOSAL ARE TO DETERMINE THE PATHOLOGICAL IMPORTANCE OF TREM1 AND MECHANISMS OF TREM1-MEDIATED NEUROINFLAMMATION IN GLOBAL ISCHEMIA-INDUCED NEURONAL DEATH, AND ESTABLISH INHIBITORS OF TREM1 AND ITS UPSTREAM BRD4 AS NOVEL THERAPEUTIC AGENTS TO IMPROVE OUTCOMES IN GLOBAL ISCHEMIA. THE CENTRAL HYPOTHESIS IS THAT GLOBAL ISCHEMIA ACTIVATES NEUROINFLAMMATION BY EPIGENETIC REGULATION OF TREM1 IN HIPPOCAMPAL CA1 AND THAT INHIBITION OF TREM1 SIGNALING RESCUES NEURONS AGAINST GLOBAL ISCHEMIC INSULTS. WE SEEK TO TEST THIS HYPOTHESIS AS DESCRIBED IN THE FOLLOWING SPECIFIC AIMS; AIM 1. DETERMINE THE PATHOLOGICAL IMPORTANCE OF TREM1 IN GLOBAL CEREBRAL ISCHEMIA. AIM 2. DETERMINE THE MECHANISM BY WHICH GLOBAL ISCHEMIA ACTIVATES TREM1 MEDIATED NEUROINFLAMMATION. AIM 3. EVALUATE THE ABILITY OF TREM1 AND BRD4 INHIBITORS AS POTENTIAL THERAPEUTIC AGENTS TO RESCUE NEURONS AGAINST GLOBAL ISCHEMIC INSULTS.

REDOX REGULATION OF DKSA-DEPENDENT BORRELIA BURGDORFERI INFECTIVITY - PROJECT SUMMARY BORRELIA BURGDORFERI, THE ETIOLOGIC AGENT OF LYME DISEASE, IS A MAJOR SOURCE OF ILLNESS IN THE UNITED STATES WITH OVER 476,000 CASES PER YEAR. LIKE OTHER VECTOR-BORNE PATHOGENS, B. BURGDORFERI MUST OVERCOME A WIDE VARIETY OF ENVIRONMENTAL STRESSES DURING ITS INFECTIOUS CYCLE IN TICKS OF THE GENUS IXODES, AND VARIOUS MAMMALIAN HOSTS. AMONG THE CHALLENGES FACED BY B. BURGDORFERI ARE SHIFTS IN PH, TEMPERATURE, OSMOLARITY, NUTRIENT AVAILABILITY, REACTIVE OXYGEN SPECIES (ROS) ALONG WITH NITRIC OXIDE (NO) AND ITS CONGENERS [REACTIVE NITROGEN SPECIES (RNS) (E.G., NO, NO2-, N2O3 AND ONOO-)]. OF THESE, THE ROLES OF TEMPERATURE AND PH ON B. BURGDORFERI VIRULENCE GENE EXPRESSION AND INFECTIVITY HAVE BEEN THE BEST CHARACTERIZED. PREVIOUSLY PUBLISHED WORK FROM OUR LABORATORY AND OTHERS HAVE DEMONSTRATED THAT B. BURGDORFERI ENCOUNTERS BIOLOGICALLY SIGNIFICANT AMOUNTS OF ROS AND RNS DURING INFECTION OF ITS TICK VECTOR IXODES SCAPULARIS AND MAMMALIAN HOSTS. WE HAVE ALSO SHOWN THAT CYSTEINE THIOLS OF PROTEINS INVOLVED IN GENE REGULATION, ANTIOXIDANT DEFENSES, AND CENTRAL METABOLISM ARE TARGETS OF ROS AND RNS, ALTHOUGH THE IMPACT OF THESE MODIFICATIONS ON B. BURGDORFERI INFECTIVITY HAVE YET TO BE DETERMINED. OUR PREVIOUSLY PUBLISHED WORK SHOWED THE DNAK SUPPRESSOR PROTEIN (DKSA) IS A GLOBAL REGULATOR OF GENE EXPRESSION IN B. BURGDORFERI AND COORDINATES THE STRINGENT RESPONSE DURING PERIODS OF NUTRIENT LIMITATION. WE NOW HAVE PRELIMINARY DATA SUPPORTING A ROLE FOR DKSA IN REGULATING VIRULENCE GENE EXPRESSION REQUIRED FOR COMPLETION OF ITS INFECTIOUS CYCLE IN I. SCAPULARIS AND MAMMALIAN HOSTS. DESPITE THIS, THERE ARE SUBSTANTIAL GAPS IN OUR KNOWLEDGE ABOUT HOW DKSA SENSES CHANGES WITHIN ITS VECTOR AND MAMMALIAN HOSTS TO DIRECT B. BURGDORFERI GENE EXPRESSION. IN THIS APPLICATION, WE PROPOSE TO TEST OUR CENTRAL HYPOTHESIS THAT DKSA SENSES TICK-BORNE ROS/RNS TO COORDINATE THE TRANSCRIPTIONAL RESPONSES OF B. BURGDORFERI REQUIRED FOR THE COMPLETION OF ITS INFECTIOUS CYCLE. THIS PROPOSAL IS PARTICULARLY INNOVATIVE AND WILL IMPACT THE FIELD OF TICK-BORNE DISEASES BY DETERMINING THE MECHANISMS UNDERLYING THE ABILITY OF B. BURGDORFERI TO SENSE CHANGES IN ITS ENVIRONMENT TO REGULATE GENE EXPRESSION. SINCE THIS AREA OF RESEARCH IS VIRTUALLY UNINVESTIGATED FOR TICK-BORNE DISEASES, OUR FINDINGS WILL UNDOUBTEDLY PROVIDE INSIGHT TO THE FIELD AND INFORM FUTURE STRATEGIES TO PREVENT TICK-BORNE INFECTIONS.

EDUCATIONAL OPPORTUNITY CENTERS PROGRAM

A NOVEL APPROACH TO TARGET NEUTROPHILIC AIRWAY INFLAMMATION AND AIRWAY HYPERRESPONSIVENESS IN THERAPY-RESISTANT (REFRACTORY) ASTHMA. - AIRWAY HYPERRESPONSIVENESS (AHR) AND AIRWAY INFLAMMATION ARE HALLMARKS OF ASTHMA. REFRACTORY ASTHMA MANIFESTS WITH PERSISTENT SYMPTOMS DESPITE USE OF HIGH-DOSE ORAL CORTICOSTEROIDS AND LONG-ACTING SS2-AGONIST BRONCHODILATORS AND POSES A MAJOR HEALTHCARE CHALLENGE. UNDERSTANDING THE MECHANISMS AND DEVELOPING STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE POSES A SIGNIFICANT UNMET NEED. AIRWAY SMOOTH MUSCLE (ASM) HYPERCONTRACTION IS A KEY FACTOR OF AHR, AND T-HELPER 17 (TH17) CELLS PROMOTE STEROID-INSENSITIVE NEUTROPHILIC AIRWAY INFLAMMATION (NAI). WE FOUND P63RHOGEF, A RHOA ACTIVATOR, PLAYS CRUCIAL ROLES IN REFRACTORY ASTHMA. WE ALSO DEVELOPED CXN-8, A SMALL MOLECULE INHIBITOR OF P63RHOGEF. OBJECTIVE: TO DETERMINE THE IMPORTANCE AND MECHANISMS BY WHICH P63RHOGEF MODULATES THE ASTHMA DIATHESIS AND IF CXN-8 INHIBITS P63RHOGEF TO AMELIORATE AHR AND NAI. LONG-TERM GOAL: TO DEVELOP NEW THERAPIES FOR REFRACTORY ASTHMA. FINDINGS: 1) P63- RHOGEF IS SELECTIVELY UPREGULATED IN ASTHMATICS AND PLAYS A CRITICAL ROLE IN RHOA ACTIVATION THAT CONTROLS ASM HYPERCONTRACTION AND TH17 CELL DIFFERENTIATION. 2) CXN-8 INHIBITS ASM CONTRACTION AND INDUCES RELAXATION OF AIRWAY. 3) CXN-8 AMELIORATES AHR AND NAI IN MURINE ASTHMA MODELS. 4) CXN-8 INTERACTS WITH P63RHOGEF TO BLOCK RHOA ACTIVATION. HYPOTHESIS: TARGETING P63RHOGEF-STIMULATED ASM HYPERCONTRACTILITY AND TH17 CELL DIFFERENTIATION WITH CXN-8 AMELIORATES AHR AND NAI AND THAT CXN-8 THERAPY REPRESENTS A NOVEL STRATEGY FOR REFRACTORY ASTHMA. WE WILL TEST THIS HYPOTHESIS IN VITRO AND IN VIVO. AIM 1. TO DEFINE THE MECHANISM UNDERLYING P63RHOGEF AND CXN-8 REGULATION OF AHR. WE WILL USE RNAI AND INHIBITORS TO DETERMINE THE PIVOTAL ROLE AND MECHANISM OF P63RHOGEF IN HYPERCONTRACTILITY OF ASTHMATIC HUMAN ASM (HASM) CELLS. WE WILL ANALYZE CXN- 8 REGULATION OF RHOA ACTIVITY, CA2+ SIGNALING, CONTRACTION/RELAXATION OF SS2-AGONIST-SENSITIVE/INSENSITIVE HASM CELLS. WE WILL COMBINE RNAI, MUTAGENESIS, AND SURFACE PLASMON RESONANCE TO ELUCIDATE THE SPECIFICITY AND MECHANISM FOR CXN-8 REGULATION OF P63RHOGEF. WHETHER P63RHOGEF LOSS AMELIORATES AHR AND REDUCES THE EFFECTS OF CXN-8 WILL BE EXAMINED IN A HOUSE DUST MITE (HDM)-DRIVEN MURINE MODEL OF ASTHMA. AIM 2. TO ELUCIDATE THE MECHANISM UNDERLYING P63RHOGEF AND CXN-8 REGULATION OF NAI. WE WILL EXAMINE THE EFFECTS OF CXN-8 ON TH17 CELL DIFFERENTIATION. WE WILL SILENCE RHOA OR EXPRESS AN ACTIVE RHOA MUTANT TO ESTABLISH ITS IMPORTANCE IN CXN-8 INHIBITION OF TH17 CELL DIFFERENTIATION. WE WILL ALSO DETERMINE IF LOSS OF P63RHOGEF ATTENUATES RHOA ACTIVATION AND TH17 DIFFERENTIATION IN CELLS AND HDM-INDUCED NAI IN MICE AND REDUCES CXN-8 INHIBITORY EFFECTS IN VITRO AND IN VIVO. AIM 3. TO EXAMINE THE THERAPEUTIC POTENTIAL OF CXN-8 IN MURINE MODELS OF REFRACTORY ASTHMA. WE WILL DETERMINE IF INHALED CXN-8 IS AN ACUTE AND EFFECTIVE BRONCHODILATOR IN A MURINE MODEL OF SS2-AGONIST INSENSITIVE AHR. WE WILL TEST LUNG TARGETED, LONG-ACTING CXN-8 MICROPARTICLES TO ALLEVIATE AHR/NAI WITH LIMITED SYSTEMIC SIDE-EFFECTS IN A MURINE MODEL OF CORTICOSTEROID-INSENSITIVE ASTHMA. THE IMPACT OF P63RHOGEF LOSS ON AHR/NAI AND THERAPEUTIC EFFECTS OF CXN-8 WILL ALSO BE EXAMINED IN THESE STUDIES.

TALENT SEARCH PROGRAM

ROLE OF VPRBP IN B CELL DEVELOPMENT AND V(D)J RECOMBINATION

NATURAL-BASED THERAPIES FOR SENSORY DISORDERS - PROJECT SUMMARY HEARING LOSS IS A MAJOR HEALTH CONCERN IN OUR SOCIETY, AFFECTING OVER 400 MILLION PEOPLE WORLDWIDE. AMINOGLYCOSIDE THERAPY CAUSES PERMANENT HEARING LOSS IN 40-60% OF TREATED PATIENTS. TO DATE, NO DRUGS HAVE BEEN APPROVED BY THE FOOD AND DRUG ADMINISTRATION FOR PROTECTION FROM AMINOGLYCOSIDE- RELATED HEARING LOSS (AGIHL). MOST CANDIDATE COMPOUNDS CURRENTLY IN PRE-CLINICAL AND CLINICAL TRIALS ARE RELATED TO ANTIOXIDANTS, VITAMINS, AND GLUTATHIONE METABOLISM. WE HAVE CONDUCTED A HIGH-THROUGHPUT SCREENING OF BIOACTIVE NATURAL COMPOUNDS EMPLOYING ZEBRAFISH AS OUR PLATFORM FOR AMINOGLYCOSIDE OTOTOXICITY AND IDENTIFIED PIPERLONGUMINE, AN ALKALOID EXTRACTED FROM THE LONG PEPPER PIPER LONGUM L., AS AN IMPORTANT THERAPEUTIC MOLECULE FOR AMINOGLYCOSIDE-INDUCED HAIR CELL DEATH. PREVIOUS STUDIES HAVE SHOWN THAT PIPERLONGUMINE CAN ALLOSTERICALLY MODULATE THE TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1) CHANNEL AT HIGH DOSES. OUR OWN STUDIES IN A MOUSE MODEL FOR AGIHL DEMONSTRATED THAT PIPERLONGUMINE CAN PARTIALLY PROTECT HEARING FUNCTION WHEN GIVEN AS A SINGLE DOSE FOR 17 CONSECUTIVE DAYS. THE MORPHOLOGICAL ASSESSMENT DEMONSTRATED THAT PIPERLONGUMINE PROTECTS HAIR CELLS AND THEIR SYNAPSES. GIVEN THAT TRPV1 IS UPREGULATED IN THE INNER EAR DURING INFLAMMATION, IN THIS PROPOSAL WE WANT TO 1) DESIGN, SYNTHESIZE AND TEST PIPERLONGUMINE DERIVATIVES WITH A BETTER FIT FOR TRPV1 ALLOSTERIC POCKET; 2) CHARACTERIZE THE PHARMACOLOGICAL AND PHYSICOCHEMICAL PROPERTIES AND DISTRIBUTION OF THE TOP LEAD CANDIDATES; 3) ESTABLISH EFFICACY AND THERAPEUTIC WINDOW OF THE TOP CANDIDATES IN AN ANIMAL MODEL THAT RECAPITULATES AGHIL AND ENDOTOXEMIA; 4) ESTABLISH THE TRPV1-MEDIATED MECHANISM(S) OF ACTION OF THE PIPERLONGUMINE DERIVATIVES, AND 5) CONFIRM THAT PIPERLONGUMINE DERIVATIVES DO NOT ANTAGONIZE WITH AMINOGLYCOSIDE ANTI-BACTERIAL ACTIVITY. BY COMPLETING THESE STUDIES, WE WILL BE ABLE TO OBTAIN THE NECESSARY INFORMATION TO MOVE PIPERLONGUMINE DERIVATIVES FORWARD TOWARD FUTURE CLINICAL TRIALS. WE HAVE ALREADY ESTABLISHED CONVERSATIONS WITH FUTURE COLLABORATORS INVOLVED IN CLINICAL RESEARCH WITH CYSTIC FIBROSIS PATIENTS AND NEWBORN INTENSIVE CARE UNIT PATIENTS. MOREOVER, I AM ONE OF THE INVENTORS ON A PATENT FOR THE USE OF PIPERLONGUMINE TO TREAT HEARING LOSS FILED BY TING THERAPEUTICS LLC AS A PATENT COOPERATION TREATY. THUS, THIS PROPOSAL HAS THE POTENTIAL TO BE A SIGNIFICANT STEP FORWARD FOR THE TREATMENT OF AGIHL IN PATIENTS WITH SEVERE GRAM-NEGATIVE BACTERIAL INFECTIONS.

ALTERNATIVE ENERGY FOR HIGHER EDUCATION

TRIO - STUDENT SUPPORT SERVICES - STUDENT SUPPORT SERVICES PROGRAM

UPWARD BOUND MATH AND SCIENCE COMPETITION

HEALTH CAREERS OPPORTUNITY PROGRAM

EDUCATIONAL OPPORTUNITY CENTERS PROGRAM

MOLECULAR REGULATION OF OCULAR GLAND DEVELOPMENT

CREIGHTON UNIVERSITY HEALTH SCIENCES AND MEDICAL SCHOOL-PHOENIX CAMPUS

HPSL - PHARMACY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

HEALTH CARE AND OTHER FACILITIES

REGULATION OF THE MICROGLIAL NEUROIMMUNE RESPONSE BY LONG NON-CODING RNAS - PROJECT SUMMARY/ABSTRACT SYSTEMIC INFLAMMATION DUE TO VIRAL OR BACTERIAL INFECTION IS A DIRECT CAUSE OF DYSREGULATED NEUROIMMUNE RESPONSES AND IS LINKED TO SEVERAL NEURODEGENERATIVE PATHOLOGIES SUCH AS MULTIPLE SCLEROSIS (MS). MICROGLIA PARTICIPATE IN INNATE IMMUNE PROCESSES OF PATHOGEN CLEARANCE CONTRIBUTING TO BOTH NEURORECOVERY AND NEUROTOXICITY. PROPER MICROGLIAL IMMUNE FUNCTION SUPPORTS NEUROGENESIS AND SYNAPSE DEVELOPMENT, REGULATES HOMEOSTATIC NEURONAL AND GLIAL ACTIVITY, AND PROVIDES HOST DEFENSE AGAINST PATHOGENS AND INJURY. DYSREGULATION MICROGLIAL IMMUNE FUNCTION IS LIKELY TO CONTRIBUTE TO NEUROINFLAMMATORY PROCESSES THAT CAUSE NEUROTOXICITY. THE MECHANISMS GOVERNING MICROGLIAL FUNCTIONAL PLASTICITY AND WHETHER MICROGLIAL IMMUNE RESPONSES ARE NEUROPROTECTIVE OR NEUROTOXIC ARE NOT WELL UNDERSTOOD. LONG INTERGENIC NON-CODING RNAS (LINCRNAS) ARE PRIME CANDIDATES FOR REGULATING MICROGLIAL PLASTICITY BECAUSE MANY LINCRNAS ARE EARLY-PRIMARY RESPONSE GENES WHOSE EXPRESSION IS STIMULATED BY ENVIRONMENTAL SIGNALS. LINCRNAS ARE ASSOCIATED WITH HUMAN INFLAMMATORY DISEASE AND NEUROPATHOLOGIES SUCH AS MS. OUR COLLABORATIVE WORK HAS IDENTIFIED LINCRNAS THAT REGULATE PRO-INFLAMMATORY GENE EXPRESSION IN TLR4-STIMULATED MACROPHAGES AND MICROGLIA THROUGH MODULATION OF CHROMATIN REMODELING. BASED ON THESE STUDIES, WE HYPOTHESIZE THAT DIFFERENTIAL EXPRESSION OF LINCRNAS ACT AS REGULATORS OF GENE TRANSCRIPTION TO CONTROL MICROGLIAL EXPRESSION OF NEUROPROTECTIVE OR NEUROTOXIC PHENOTYPES. FURTHER, WE PROPOSE THAT DIFFERENTIAL EXPRESSION OF LINCRNAS WILL CONTRIBUTE TO WHETHER MICROGLIAL RESPONSES ARE EFFECTIVE IN CLEARING PATHOGENS AND PROMOTING NORMAL FUNCTION OR CAUSING NEUROTOXICITY AND PROMOTING NEURODEGENERATION. TO ADDRESS THIS HYPOTHESIS, WE MINED WHOLE-TRANSCRIPTOME DATA AND USED AN IN VITRO MODEL SYSTEM TO IDENTIFY LINCRNAS THAT ARE INVERSELY EXPRESSED IN MICROGLIAL PRO- INFLAMMATORY NEUROTOXIC (TLR4-STIMULATED) AND ANTI-INFLAMMATORY NEUROTROPHIC (IL-4-STIMULATED) FUNCTIONAL STATES. OUR RECENTLY PUBLISHED WORK SHOWS THAT LINCRNAS ARE DIFFERENTIALLY EXPRESSED IN MICROGLIAL NEUROINFLAMMATORY AND NEUROTROPHIC STATES AND THAT SILENCING NEUROINFLAMMATORY LINCRNAS CAN REDUCE NEUROTOXICITY. PRELIMINARY EVIDENCE SHOWS THAT SPECIFIC LINCRNAS ARE OVEREXPRESSED IN DEGENERATING CORTICAL TISSUE OF A MOUSE MODEL FOR PROGRESSIVE, CHRONIC MS. THE OBJECTIVES OF THIS PROPOSAL ARE TO INVESTIGATE THE MECHANISMS BY WHICH LINCRNAS MEDIATE A PROINFLAMMATORY STATE IN MICROGLIA (AIM 1) AND TO DETERMINE WHETHER DIFFERENTIAL LINCRNA EXPRESSION UNDERLIES VIRAL-INDUCED ACUTE AND CHRONIC MOUSE MODELS OF MS (AIM 2). THIS PROPOSAL IS CONCEPTUALLY INNOVATIVE AS IT WILL PROVIDE INFORMATION ABOUT LINCRNA-REGULATED MECHANISMS OF NEUROIMMUNITY AND NEUROTOXICITY. THESE STUDIES ARE DIRECTLY APPLICABLE TO THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES FOR LIMITING THE NEURODEGENERATION ASSOCIATED WITH INFLAMMATORY NEUROPATHOLOGIES.

REGULATOR OF G-PROTEIN SIGNALING (RGS) PROTEINS IN PROSTATE CANCER

IDENTIFICATION AND CHARACTERIZATION OF NOVEL FUNCTIONS FOR THE USHER PROTEINS IN THE INNER EAR - ABSTRACT. AN ORGANISM’S PERCEPTION OF ITS SURROUNDING ENVIRONMENT DEPENDS ON THE SENSORY FUNCTION. NEUROSENSORY CELLS FROM THE INNER EAR ARE INVOLVED IN KEY BIOLOGICAL PROCESSES ASSOCIATED WITH HEARING AND BALANCE. TO BE ABLE TO ACHIEVE THEIR FUNCTION THESE CELLS DEPEND ON A COMPLEX ARRAY OF MEMBRANE RECEPTORS, ION CHANNELS, AND SIGNALING MOLECULES THAT ARE CONCENTRATED AT EXTREMELY SOPHISTICATED STRUCTURES POSITIONED AT THE APICAL (HAIR CELL BUNDLE AND KINOCILIUM) AND BASAL (RIBBON SYNAPSES) POLES. DISRUPTION OF THIS NETWORK DUE, FOR EXAMPLE, TO MUTATIONS, RESULTS IN MORPHOLOGICAL AND FUNCTIONAL ABNORMALITIES AND FORMS THE BASES OF MANY HUMAN GENETIC DISORDERS. THIS PROPOSAL IS FOCUSED ON STUDYING THE ROLE OF THE PCDH15-ITGA8 (PROTOCADHERIN-15-INTEGRIN ALPHA8) COMPLEX DURING HAIR CELL (HC) DEVELOPMENT AND FUNCTION, AND THE DOWNSTREAM SIGNALING PATHWAYS ACTIVATED BY IT. OUR RECENTLY PUBLISHED WORK AND PRELIMINARY DATA SUGGEST THAT THE ABSENCE OF PCDH15-ITGA8 COMPLEX RESULTS IN HC BUNDLE ABNORMALITIES, INCREASE THE NUMBER OF OUTER HAIR CELLS, AND ALTERATIONS IN THE RHOA-ERM(EZRIN-RADIXIN-MOESIN)-YAP SIGNALING CASCADE. MOREOVER, ITGA8 HAIR CELL-SPECIFIC CONDITIONAL KNOCKOUT MICE HAVE PROGRESSIVE HEARING LOSS AND SENSIBILITY TO NOISE EXPOSURE. BASED ON THIS INFORMATION, OUR CENTRAL HYPOTHESIS IS THAT DURING INNER EAR DEVELOPMENT, ENVIRONMENTAL CUES ACTIVATE THE ITGA8-PCDH15 COMPLEX RESULTING IN THE MODULATION OF CYTOSKELETAL ELEMENTS THAT WILL ACTIVATE DOWNSTREAM SIGNALING CASCADES. LACK OF THE COMPLEX RESULTS IN INNER EAR ABNORMALITIES THAT OVER TIME CAN CAUSE PROGRESSIVE HEARING LOSS. WE WILL TEST THIS HYPOTHESIS WITH TWO SPECIFIC AIMS. IN THE FIRST AIM, WE WILL IDENTIFY THE ENVIRONMENTAL CUES THAT LEAD TO PCDH15-ITGA8 ACTIVATION AND THE FORMATION OF CYTOSKELETAL STRUCTURES. WE WILL ALSO IDENTIFY AND CHARACTERIZE THE COMPLEX’S MOLECULAR TARGETS. IN THE SECOND AIM, WE WILL INVESTIGATE THE CONTRIBUTION OF SUPPORTING CELLS AND SPIRAL GANGLION NEURONS TO THE PCDH15-ITGA8 COMPLEX PHENOTYPE AND THE SENSIBILITY TO NOISE. COLLECTIVELY THE STUDIES PROPOSED HERE WILL CLARIFY THE FUNCTIONAL ROLE(S) FOR THE PCDH15-ITGA8 COMPLEX DURING ORGAN OF CORTI DEVELOPMENT, INTRODUCING A DIRECT FUNCTIONAL LINK BETWEEN USHER SYNDROME AND AN INTEGRIN-DOWNSTREAM SIGNALING CASCADE.

DETERMINATION OF RDA FOR VITAMIN D IN CAUCASIAN AND AFRICAN AMERICAN WOMEN

TGF-BETA, CHLORIDE CHANNELS AND APOPTOSIS OF AIRWAY EPITHELIAL CELLS

EPIGENETIC REGULATION OF THE NEUROENDOCRINE AXIS IN BRAIN DEVELOPMENT AND BEHAVIOR - PROJECT SUMMARY LYSINE METHYLTRANSFERASE 5B (KMT5B) IS PART OF A GENE FAMILY THAT MODULATES THE METHYLATION STATE OF HISTONE 4 LYSINE 20 (H4K20) RESIDUES, AND H4K20 METHYLATION REGULATES GENE EXPRESSION BY ALTERING CHROMATIN COMPACTION. HETEROZYGOUS DISRUPTIVE VARIANTS IN KMT5B HAVE BEEN ASSOCIATED WITH HUMAN NEURODEVELOPMENTAL DISEASE–SPECIFICALLY, KMT5B HAS BEEN IDENTIFIED AS ONE OF THE MOST MUTATED GENES IN AUTISM SPECTRUM DISORDER (ASD), A HIGHLY PREVALENT AND LIFELONG CONDITION. PHENOTYPES REPORTED AMONG KMT5B PATIENTS AND IN OUR KMT5B MOUSE MODEL SUGGEST THAT KMT5B MAY HAVE A ROLE IN THE EPIGENETIC EXPRESSION OF THE INSULIN-LIKE GROWTH FACTOR (IGF) FAMILY, WHICH INCLUDES TWO MEMBERS–IGF1 AND IGF2. THESE HORMONES CAN BE EXPRESSED IN AN ENDOCRINE (CIRCULATING) OR PARACRINE (LOCAL) FASHION AND HAVE BEEN STRONGLY LINKED TO AUTISM. WE HYPOTHESIZE THAT KMT5B REGULATES THE EXPRESSION OF THE IGF GENES DRIVING THE PRIMARY NEURODEVELOPMENTAL PHENOTYPES OBSERVED. WE WILL TEST OUR CENTRAL HYPOTHESIS AND, THEREBY, ACCOMPLISH THE OVERALL OBJECTIVE OF THIS PROJECT THROUGH THREE SPECIFIC AIMS. FIRST, WE WILL SPECIFY THE ROLE THAT KMT5B PLAYS IN PARACRINE IGF PRODUCTION (I.E., LOCAL BRAIN EXPRESSION) USING BOTH CONSTITUTIVE AND BRAIN-SPECIFIC KNOCKOUT MODELS. SECOND, WE WILL DEFINE HOW ENDOCRINE IGF EXPRESSION (I.E., CIRCULATING AND EXPRESSED POSTNATALLY BY THE LIVER) CHANGES RELATIVE TO KMT5B EXPRESSION OVER TIME AND HOW THIS IMPACTS (1) BRAIN IGF EXPRESSION AND (2) KMT5B-LINKED BEHAVIORAL PHENOTYPES. WE WILL COMPARE THE RESULTS OF THESE TWO AIMS TO IDENTIFY WHETHER IGF1 AND IGF2 ARE DIFFERENTIALLY OR SIMILARLY REGULATED BY KMT5B AND WHETHER RESCUE CAN BE ACHIEVED BY TARGETING EITHER SYSTEM. FINALLY, WE WILL USE A COMBINATION OF ATAC SEQ AND RNA SEQ TO IDENTIFY CELL TYPES WHERE KMT5B REGULATES THE EXPRESSION OF IGFS AND WHETHER THESE EFFECTS CAN BE THERAPEUTICALLY RESCUED. OUR RESULTS WILL INCREASE OUR UNDERSTANDING OF HOW KMT5B INTERACTS WITH THE IGF AXIS, HOW IGFS ARE EPIGENETICALLY REGULATED, AND HOW IGF1 AND IGF2 ARE REGULATED IN DIFFERENT TISSUES OVER TIME. WE EXPECT THE OUTCOMES OF THIS STUDY TO DEFINE THE CONTRIBUTION OF KMT5B TO AUTISM CLINICAL FEATURES WHILE ILLUMINATING NOVEL DRUG TARGETS FOR THE TREATMENT OF THIS CLINICAL POPULATION.

HPSL - DENTISTRY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

ESTROGEN SIGNALING IN NORMAL AND TRANSFORMED CELL GROWTH

ANABOLIC ACTION OF WNT IN THE ADULT SKELETON

DEVELOPMENT OF ARTIFICIAL AGONISTS FOR A BACTERIAL RIBOSWITCH

SUBTHRESHOLD VESTIBULAR STIMULATION AS A STRATEGY FOR REHABILITATION - 1 PROJECT SUMMARY/ABSTRACT 2 IN INDIVIDUALS WITH BILATERAL VESTIBULAR HYPOFUNCTION (BVH), VESTIBULAR RESPONSES TO SELF-MOTION CUES ARE REDUCED 3 BILATERALLY, OFTEN WITHOUT A DEFINED CAUSE. THE PERSISTENT STATE OF DESENSITIZATION YIELDS SYMPTOMS OF BOUNCING OR 4 UNSTABLE VISION, DIZZINESS, IMBALANCE, AND FALLS; COLLECTIVELY, THESE SYMPTOMS LEAD TO A SUBSTANTIAL REDUCTION IN 5 QUALITY OF LIFE. HOWEVER, DESPITE THE SIZEABLE IMPACT OF BVH ON QUALITY OF LIFE, HEALTH CARE EXPENDITURES, AND FALLS, 6 INTERVENTIONS TAILORED TO THE SPECIFIC NEEDS OF PATIENTS WITH BVH, AS OPPOSED TO PATIENTS WITH UNILATERAL LESIONS, 7 HAVE YET TO BE DEVELOPED. THE OBJECTIVE OF THIS PROPOSAL IS TO INVESTIGATE A NOVEL STRATEGY FOR IMPROVING VESTIBULAR 8 FUNCTION IN INDIVIDUALS WITH BVH. THE NERVOUS SYSTEM POSSESSES A ROBUST CAPACITY TO REGULATE NEURAL ACTIVITY IN 9 THE FACE OF CHANGING ENVIRONMENTAL OR INTERNAL CONDITIONS. WHEN EXPOSED TO A WEAK SENSORY STIMULUS (E.G., SLOW 10 MOVEMENTS OF THE HEAD), A SPECIFIC TYPE OF NEURAL PLASTICITY, “HOMEOSTATIC PLASTICITY”, HAS BEEN SHOWN TO INCREASE 11 THE RESPONSIVENESS OF THE INVOLVED NEURONS TO SUBSEQUENT MOTION STIMULI. IN THIS PROJECT, WE AIM TO DETERMINE IF 12 SUCH MECHANISMS, PROMPTED BY PERIODS OF SUBTHRESHOLD (I.E., LOW AMPLITUDE) MOTION, MAY SERVE AS A POTENTIAL 13 STRATEGY FOR DRIVING PLASTICITY IN THE LESIONED VESTIBULAR SYSTEM. SPECIFICALLY, IN INDIVIDUALS DIAGNOSED WITH BVH 14 WE WILL (1) MEASURE CHANGES IN SENSITIVITY TO SELF-MOTION CUES IMMEDIATELY FOLLOWING A SUBTHRESHOLD MOTION 15 STIMULUS (AIM 1), (2) CHARACTERIZE CHANGES IN VESTIBULAR FUNCTION AFTER REPEATED EXPOSURE TO A SUBTHRESHOLD 16 MOTION STIMULUS (AIM 2), AND (3) DETERMINE IF THE ADDITION OF A SUBTHRESHOLD MOTION “PRIMER” CAN IMPROVE THE 17 OUTCOMES OF VESTIBULO-OCULAR REFLEX (VOR) ADAPTATION (AIM 3A) AND BALANCE TRAINING (AIM 3B). WE HYPOTHESIZE 18 THAT THE USE OF A SUBTHRESHOLD STIMULUS, SECONDARY TO ITS CAPACITY TO DRIVE PLASTIC CHANGES IN THE VESTIBULAR 19 SYSTEM, WILL LEAD TO AN INCREASED SENSITIVITY TO SELF-MOTION CUES, AS WELL AS POSITIVE CHANGES IN VESTIBULAR FUNCTION 20 (E.G., GAZE STABILITY, BALANCE), IN PATIENTS WITH BVH. IN ACCORDANCE WITH THE TOPIC OF THE PROPOSED RESEARCH PROJECT, 21 MY LONG-TERM CAREER GOAL IS TO ESTABLISH A RESEARCH LAB THAT FOCUSES ON DEVELOPING INNOVATIVE TREATMENTS FOR 22 VESTIBULAR DYSFUNCTION. TO ACHIEVE THIS GOAL, THE PROPOSED CAREER DEVELOPMENT PLAN FOCUSES ON ACQUIRING THE 23 SKILLS AND KNOWLEDGE REQUIRED TO DESIGN, IMPLEMENT, MONITOR, AND ANALYZE THE RESULTS OF CLINICAL TRIALS IN THE 24 REHABILITATION SCIENCES; MORE SPECIFICALLY, THIS INCLUDES (1) GAINING A BETTER UNDERSTANDING OF THE 25 NEUROPHYSIOLOGICAL PRINCIPLES UNDERLYING VESTIBULAR PLASTICITY/LEARNING, (2) LEARNING STATE-OF-THE-ART TECHNIQUES FOR 26 ANALYZING THE BEHAVIOR OF THE VOR, AND (3) LEARNING CURRENT METHODS FOR ADAPTING THE GAIN OF THE VOR. THE 27 MENTORED PHASE OF THE TRAINING PLAN WILL TAKE PLACE AT OHIO STATE UNIVERSITY IN THE LAB OF DR. DANIEL MERFELD, PHD. 28 CONSISTENT WITH THE TRANSLATIONAL NATURE OF THE PROJECT, THE MENTORSHIP TEAM WILL CONSIST OF CLINICIAN-SCIENTISTS AND 29 BASIC VESTIBULAR SCIENTISTS, BOTH AT OHIO STATE (DANIEL MERFELD, PHD & KEVIN KERBER, MD) AND AT EXTERNAL 30 INSTITUTIONS (MICHAEL SCHUBERT, PT, PHD, AND SOROUSH SADEGHI GHANDEHARI, MD, PHD). 31 32 33 34 35

CAREER: MAPPING PROTEIN INTERACTIONS THAT LINK DNA REPLICATION AND NUCLEOSOME ASSEMBLY

GLUTAMATE DELTA-1 RECEPTOR AND METABOTROPIC GLUTAMATE RECEPTOR INTERACTION

ALCOHOL MODULATES AIRWAY HYPERRESPONSIVENESS & INFLAMMATION IN ALLERGIC ASTHMA

PROSTATE GENETICS IN AFRICAN AMERICANS

MULTIVARIATE CART FOR SURVIVAL WITH DENTAL APPLICATIONS

REGULATION OF FOOD INTAKE & BODY ADIPOSITY BY PEPTIDE YY

MICRORNAS IN EPITHELIAL INNATE IMMUNITY TO C. PARVUM

NOVEL TRANSCRIPTION FACTORS FOR REGENERATION OF FUNCTIONAL OUTER HAIR CELLS AFTER NOISE INJURY

REGULATION OF FOOD INTAKE AND BODY WEIGHT BY GLP-1

THE USE OF NOVEL TECHNOLOGIES TO INVESTIGATE BONE HEALTH IN DIABETES MELLITUS

CHARACTERIZATION OF V(D)J CLEAVAGE AND REPAIR COMPLEXES

HEALTH CAREERS OPPORTUNITY PROGRAM

RELAPSE PREVENTION: LONG-ACTING ATYPICAL ANTIPSYCHOTICS

MECHANISMS CONTROLLING BUBR1 REGULATION OF CANCER AND AGING

ALPHA-2 ADRENOCEPTORS IN ANTIDEPRESSANT DRUG MECHANISMS

MICROXCT-200 HIGH RESOLUTION 3D X-RAY MICROSCOPE

NSL - BACCALAUREATE NURSING - OTHER ADMIN CHANGES

(DEPSCOR-RESEARCH COLLABORATION-FY21) "BUILDING A COMPUTATIONAL MODEL OF MOBS LEVERAGING SOCIAL SCIENCE THEORIES"

DEVELOPMENT OF AFFERENT AND EFFERENT INNERVATION IN THE INNER EAR

CAREER: INVESTIGATION OF SOL-GEL-DERIVED HYBRID COLLOIDS FOR NEW SILICA-GERMANIA GLASSES

UNDERSTANDING THE ROLE OF STRESS HORMONES IN MENIERE'S DISEASE - PROJECT SUMMARY HEARING LOSS AND VERTIGO ARE SYMPTOMS OF MENIERE'S DISEASE (MD). WHILE THE ETIOLOGY OF MD IS UNKNOWN, ENDOLYMPHATIC HYDROPS OBSERVED IN THE TEMPORAL BONE SPECIMENS OF MD PATIENTS POINT TO DISRUPTION OF ENDOLYMPH HOMEOSTASIS IN THE DISEASE. THE ENDOLYMPH IS AN EXTRACELLULAR PHYSIOLOGICAL FLUID IN THE INNER EAR THAT IS ESSENTIAL FOR HEARING AND BALANCE. CONSEQUENTLY, ANY FACTOR THAT PERTURBS THE ENDOLYMPH HOMEOSTASIS IS LIKELY TO AFFECT INNER EAR FUNCTION. HOWEVER, OUR UNDERSTANDING OF THE FACTORS THAT AFFECT ENDOLYMPH HOMEOSTASIS IS A WORK IN PROGRESS. FOR EXAMPLE, WE KNOW STRESS IS AN IMPORTANT FACTOR THAT EXACERBATES MD SYMPTOMS, BUT THE RELATIONSHIP (MOLECULAR CONNECTION) BETWEEN STRESS AND ENDOLYMPH HOMEOSTASIS IS UNKNOWN. HENCE, A DEEPER UNDERSTANDING OF THE FACTORS THAT AFFECT ENDOLYMPH HOMEOSTASIS WILL BE ESSENTIAL TO DEVELOP EFFECTIVE TREATMENTS. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT STRESS HORMONES AFFECT ENDOLYMPH PRODUCTION AND INNER EAR PHYSIOLOGY. SPECIFIC AIM 1 WILL FOCUS ON THE ROLE OF ADRENERGIC (STRESS) HORMONE RECEPTORS IN ENDOLYMPH HOMEOSTASIS. TO ELUCIDATE THE ACTION OF ADRENERGIC HORMONES ON ENDOLYMPH PRODUCTION, AIM 1A WILL FOCUS ON IN VIVO REGULATION OF THE ENDOLYMPH AND PERILYMPH BY ADRENERGIC HORMONE RECEPTORS IN MICE. WE WILL USE VARIOUS ELECTROPHYSIOLOGICAL MEASURES AND HISTOLOGICAL ANALYSIS TO ASSESS THE IMPACT OF THESE RECEPTORS ON ENDOLYMPH HOMEOSTASIS AND INNER EAR FUNCTION. IN AIM 1B, WE WILL USE EXPLANTS FROM THE MOUSE COCHLEA TO ANALYZE THE PHYSIOLOGIC RESPONSE (TO MELATONIN AND Β-ADRENERGIC HORMONES) ELICITED BY THE STRIA VASCULARIS IN THE COCHLEA AND DARK CELLS OF THE VESTIBULAR SYSTEM, THE EPITHELIA RESPONSIBLE FOR THE ENDOLYMPH PRODUCTION. THE PHYSIOLOGICAL RESPONSE WILL BE EVALUATED BY LIVE IMAGING OF ION LEVELS IN THE CELLS OF THE EXPLANTS. SPECIFIC AIM 2 WILL DETERMINE THE ACTION OF GLUCOCORTICOIDS ON ENDOLYMPH HOMEOSTASIS. THIS AIM IS IMPORTANT FOR TWO REASONS. GLUCOCORTICOID SECRETION IS A CLASSIC ENDOCRINE RESPONSE TO STRESS, AND INJECTION OF GLUCOCORTICOIDS IS A COMMON TREATMENT FOR MD. IN AIM 2, CONDITIONAL KNOCKOUT MICE WILL BE USED TO STUDY THE EFFECT OF (DISABLING) GLUCOCORTICOID RECEPTORS IN INTERMEDIATE CELLS OF THE STRIA VASCULARIS. THE OUTCOMES WILL BE ASSESSED BY METHODS USED IN AIM 1A. THE PROPOSED WORK WILL REVEAL THE MECHANISTIC RELATIONSHIP BETWEEN STRESS HORMONES, ENDOLYMPH HOMEOSTASIS, AND INNER EAR DYSFUNCTION. THE RESULTS WILL BE RELEVANT TO UNDERSTANDING THE CONTRIBUTIONS OF STRESS HORMONES TO MD SYMPTOMS AND DEVELOPING TREATMENTS TO MITIGATE THOSE SYMPTOMS. FURTHER, THIS AWARD WILL LAUNCH THE CANDIDATE TO PURSUE AN INDEPENDENT CAREER IN INNER EAR HOMEOSTASIS. CASE WESTERN RESERVE UNIVERSITY WILL BRING TOGETHER EXPERT PHYSIOLOGICAL RECORDING (DR. MOSS, CONSULTANT) AND ION LEVEL IMAGING (DR. STEPANYAN, CONSULTANT) TO ENHANCE THE CANDIDATE'S CAREER.

ABERRANTLY UPREGULATED P-REX1 PROMOTES CASTRATION-RESISTANT PROSTATE CANCER PROGRESSION

PFI: AN INTERDISCIPLINARY UNIVERSITY-BASED EDUCATION PARTNERSHIP TO SUPPORT BIOMEDICAL TECHNOLOGY COMMERCIALIZATION IN NEBRASKA

PRECLINICAL AND CLINICAL THERAPEUTICS FOR NOISE-INDUCED HEARING LOSS

BREAST CANCER STEM CELLS IN ANTIESTROGEN RESISTANCE

BRC-BIO: TRACING IMPACTS OF INVASIVE WOODY PLANTS ON LAKE FOOD WEBS -INVASIVE WOODY PLANTS THREATEN ECOSYSTEMS ACROSS NORTH AMERICA. SOME EURASIAN SPECIES, SUCH AS AMUR HONEYSUCKLE AND AUTUMN OLIVE, ARE RAPIDLY SPREADING, AND UNDERSTANDING THEIR RELATIVE IMPACTS IS ESSENTIAL FOR DEVISING MANAGEMENT PLANS THAT PRIORITIZE THOSE SPECIES THAT POSE THE GREATEST RISK. THIS PROJECT WILL EXAMINE HOW INVASIVE PLANTS AFFECT AQUATIC ECOSYSTEMS IN THE IOWA LOESS HILLS, A UNIQUE ECOREGION OF BLUFFS AND RAVINES CARVED FROM ONE OF THE WORLD?S DEEPEST SILT DEPOSITS. THE AREA?S LOWLAND PONDS AND STREAMS PROVIDE IMPORTANT HABITAT FOR VARIOUS SPECIES, INCLUDING SPORT FISH LIKE LARGEMOUTH BASS. EVERY AUTUMN, LEAF LITTER FROM SURROUNDING FORESTS ACCUMULATES IN THESE WATER BODIES, SERVING AS FOOD FOR AQUATIC ORGANISMS. HOWEVER, THE QUALITY OF THIS FOOD LIKELY DEPENDS ON THE PLANT SPECIES AND THEIR LEAF CHARACTERISTICS. IN THIS PROJECT, RESEARCHERS WILL QUANTIFY LEAF TRAITS FROM A VARIETY OF SPECIES AND TRACE THEIR RELATIVE CONTRIBUTIONS TO AQUATIC FOOD WEBS, WITH THE GOAL OF DETERMINING HOW THE UNIQUE CHARACTERISTICS OF INVASIVE WOODY PLANTS SHAPE THEIR IMPACTS. FURTHERMORE, THE PROJECT WILL ENGAGE NINE UNDERGRADUATE STUDENTS IN HANDS-ON RESEARCH, PROVIDING THEM WITH VALUABLE SKILLS FOR FUTURE CAREERS. FINALLY, PUBLIC INVOLVEMENT WILL BE PROMOTED THROUGH CITIZEN SCIENCE, ALLOWING LOCAL COMMUNITIES TO PARTICIPATE IN DATA COLLECTION AND GAIN INSIGHT INTO THE STUDY?S FINDINGS AND BROADER APPLICATIONS. TO ADDRESS THESE RESEARCH QUESTIONS, THE RESEARCHERS WILL (1) QUANTIFY THE RELATIVE INFLUENCE OF LEAF LITTER SUBSIDIES FROM NATIVE AND INVASIVE WOODY PLANTS ON FRESHWATER FOOD WEBS AND (2) EXPLAIN THESE DIFFERENCES IN TERMS OF LEAF LITTER TRAITS AND THE BIOTIC INTERACTIONS WITH AQUATIC INVERTEBRATES AND MICROBES WITHIN THE RECIPIENT COMMUNITIES. FIELD SURVEYS AND EXPERIMENTS WILL BE USED TO COMPARE INPUTS AND DECOMPOSITION RATES OF LEAF LITTER FROM NATIVE AND INVASIVE WOODY PLANTS IN THREE SMALL LAKES. FURTHERMORE, A COMBINATION OF BULK AND COMPOUND-SPECIFIC STABLE ISOTOPE ANALYSIS (?13C, ?15N, AND ?2H) WILL BE USED TO TRACE THE CONTRIBUTIONS OF ORGANIC MATERIAL FROM DIFFERENT PLANT SPECIES TO THE AQUATIC INVERTEBRATE COMMUNITY THAT SERVES AS THE BASIS FOR HIGHER TROPHIC LEVELS. THESE RESULTS WILL BE COMPLEMENTED BY COMPREHENSIVE MEASUREMENTS OF LEAF TRAITS TO EXPLAIN DIFFERENCES IN DECOMPOSITION, AND THEREBY ACCESSIBILITY, OF LEAF LITTER BETWEEN DIFFERENT SPECIES. FINALLY, LABORATORY MICROCOSM EXPERIMENTS WILL BE USED TO DETERMINE THE ROLES OF AQUATIC INVERTEBRATES AND MICROBES IN MEDIATING DECOMPOSITION OF LEAF LITTER FROM NATIVE AND INVASIVE WOODY PLANTS. 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.

EARMARKS

CENTER FOR PROMOTING HEALTH AND HEALTH EQUALITY - RACIAL AND ETHNIC APPROACHES TO COMMUNITY HEALTH (CPHHE-REACH).

IDENTIFYING NEURAL CIRCUITS THAT SUPPORT EFFORTFUL LISTENING - PROJECT SUMMARY/ABSTRACT CANDIDATE: MY LONG-TERM CAREER GOAL IS TO ESTABLISH AN INDEPENDENT RESEARCH PROGRAM FOCUSING ON THE NEURAL MECHANISMS OF LISTENING EFFORT, AND EXPLORE HOW ADOLESCENT HEARING LOSS ALTERS THIS MECHANISM. MY PREVIOUS TRAINING HAS PROVIDED ME WITH A STRONG FOUNDATION IN ACOUSTICS, AUDITORY PHYSIOLOGY, BEHAVIORAL NEUROSCIENCE, AND HEARING LOSS-INDUCED DEFICITS IN SENSORY PROCESSING AND PERCEPTION. I PROPOSE TO EXPAND MY SKILLSET WITH ADDITIONAL TRAINING IN COGNITIVE MECHANISMS OF AUDITORY PERCEPTION, AWAKE-BEHAVING RECORDINGS, PHARMACOLOGICAL AND CHEMOGENETIC ATTENUATION OF NEURAL ACTIVITY IN AWAKE-BEHAVING ANIMALS, AND PUPILLOMETRIC MEASURES. DURING THE K99 PHASE, I WILL CONTINUE WORKING TOWARDS INDEPENDENCE BY DEVELOPING THE INTELLECTUAL AND TECHNICAL SKILLS NEEDED FOR SUCCESS. THIS INCLUDES ATTENDING WORKSHOPS ON PUTTING TOGETHER A SUCCESSFUL JOB APPLICATION AND CHALK TALK, AND LEARNING EFFECTIVE STRATEGIES FOR THE JOB INTERVIEW AND LAB MANAGEMENT. BY THE END OF THE R00 PHASE, I WILL HAVE A STRONG PUBLICATION RECORD AND THE PRELIMINARY DATA NEEDED FOR A SUCCESSFUL R01 APPLICATION. ENVIRONMENT: THE K99 PHASE OF THE AWARD WILL TAKE PLACE IN THE CENTER FOR NEURAL SCIENCE AT NEW YORK UNIVERSITY (NYU), AN EXCELLENT ENVIRONMENT FOR THE PROPOSED TRAINING. MY PRIMARY MENTOR, DR. DAN SANES, HAS 30+ YEARS OF EXPERIENCE IN DEVELOPMENTAL AUDITORY NEUROSCIENCE. HE WILL PROVIDE HIS EXPERTISE AND MENTORSHIP IN ALL AREAS OF MY TRAINING, INCLUDING AUDITORY SENSORY PROCESSING, HEARING LOSS-INDUCED SENSORY AND COGNITIVE DEFICITS, AND AWAKE-BEHAVING METHODS. ADDITIONAL MENTORING WILL BE PROVIDED BY DR. MATTHEW MCGINLEY (BAYLOR COLLEGE OF MEDICINE), AN EXPERT ON ATTENTIONAL AUDITORY MECHANISMS AND RODENT PUPILLOMETRY, AND DR. MATTHEW WINN (UNIVERSITY OF MINNESOTA), AN EXPERT ON LISTENING EFFORT AND HEARING LOSS. RESEARCH: LISTENING TO SPEECH REQUIRES INTACT SENSORY AND COGNITIVE PROCESSING. FOR THOSE WITH HEARING LOSS, ADDITIONAL MENTAL EFFORT IS OFTEN REQUIRED, RESULTING IN COGNITIVE FATIGUE THAT CAN HAVE LONG-TERM NEGATIVE IMPLICATIONS FOR QUALITY OF LIFE. HOWEVER, THE NEURAL MECHANISMS UNDERLYING EFFORTFUL LISTENING, AND HOW HEARING LOSS ALTERS THIS MECHANISM, IS UNCERTAIN. THIS PROPOSAL WILL IDENTIFY A CORTICAL NETWORK THAT IS ENGAGED DURING AN EFFORT-BASED AUDITORY TASK, AND USE PERTURBATIONS OF NEURAL ACTIVITY TO DETERMINE WHETHER CANDIDATE REGIONS ARE REQUIRED FOR TASK PERFORMANCE DURING DIFFICULT LISTENING CONDITIONS (K99). NEXT, I WILL USE WIRELESS NEURAL RECORDINGS IN SENSORY AND NON-SENSORY CORTICAL AREAS, ALONG WITH PUPILLOMETRY APPROACHES, TO EXPLORE HOW ADOLESCENT HEARING LOSS DISRUPTS THIS CORTICAL MECHANISM (R00).

EXAMINATION OF ORNITHINE DECARBOXYLASE ANTIZYME RNA STRUCTURE AND FUNCTION FROM VARIOUS ORGANISMS FOR THE DEVELOPMENT OF ANTIBIOLOGICAL AGENTS - PROJECT SUMMARY NEARLY ALL ORGANISMS POSSESS THE CAPABILITY TO SYNTHESIZE THE NATURAL POLYAMINES - PUTRESCINE, SPERMIDINE AND SPERMINE - WHICH ARE ESSENTIAL FOR CELL GROWTH AND DIFFERENTIATION. DUE TO THE ABILITY OF POLYAMINES TO INTERACT WITH NEARLY EVERY BIOMOLECULE - DNA, RNA, PHOSPHOLIPIDS, PROTEINS AND ATP, TO NAME A FEW - THEY PLAY MANY ROLES WITHIN THE CELL IN ORDER TO SUPPORT CELL GROWTH. IT HAS BEEN WELL DOCUMENTED THAT POLYAMINE LEVELS IN MAMMALIAN CELLS CORRELATE WITH THE RATE OF CELL GROWTH, HIGH POLYAMINE CONCENTRATIONS HAVE BEEN OBSERVED IN RAPIDLY PROLIFERATING CELLS AND LOW CONCENTRATIONS HAVE BEEN MEASURED IN SLOW-GROWING OR QUIESCENT CELLS. NOT SURPRISINGLY, THE TRANSPORT AND METABOLISM OF POLYAMINES ARE HIGHLY REGULATED BY COMPLEX FEEDBACK MECHANISMS. ORNITHINE DECARBOXYLASE (ODC) IS THE KEY REGULATORY ENZYME IN POLYAMINE BIOSYNTHESIS. ODC HOMEOSTASIS AFFECTS CELL GROWTH AND CANCER DEVELOPMENT. ODC OVER-EXPRESSION HAS BEEN OBSERVED IN MANY TUMOR TYPES, INCLUDING PROSTATE, BREAST, AND SKIN CANCERS. BOTH ODC AND CELLULAR UPTAKE OF POLYAMINES IS INHIBITED BY ORNITHINE DECARBOXYLASE ANTIZYME (OAZ). THE MAKING OF ANTIZYME PROTEIN FROM OAZ MRNA REQUIRES TRANSLATIONAL FRAMESHIFTING AT A HIGHLY CONSERVED SITE TO BYPASS PREMATURE TERMINATION. MAMMALIAN OAZ MRNAS FURTHER POSSESS A PSEUDOKNOT (PK) RNA 3¢ TO THE FRAMESHIFT SITE THAT STIMULATES +1 FRAMESHIFTING. MOREOVER, FRAMESHIFTING IS STIMULATED BY POLYAMINES, THUS PROVIDING A FEEDBACK MECHANISM WHEREBY THE ACCUMULATION OF METABOLIC PRODUCTS INHIBITS BIOSYNTHESIS. ALTHOUGH THE ROLE OF THE OAZ PSEUDOKNOT RNA ELEMENT (FURTHER DESIGNATED OAZ-PK) IN POLYAMINE-DEPENDENT FRAMESHIFTING HAS BEEN INVESTIGATED, IT HAS NOT BEEN EXAMINED AS A DISTINCT POLYAMINE “SENSOR”. RIBOSWITCHES ARE ELEMENTS WITHIN NONCODING REGIONS OF MRNAS THAT DIRECTLY BIND TO CELLULAR METABOLITES AND MODULATE GENE EXPRESSION. MANY RIBOSWITCHES PROVIDE A MECHANISM OF FEEDBACK REGULATION FOR GENE PRODUCTS WITHIN THE BIOSYNTHETIC PATHWAY OF THE COGNATE METABOLITE. RIBOSWITCHES ARE WIDESPREAD AMONG BACTERIA, AND ONE CLASS FURTHER RESIDES IN FUNGI AND PLANTS, BUT NO RIBOSWITCHES HAVE BEEN FOUND IN ANIMALS. IT IS PROPOSED THAT THE OAZ-PK RNA FUNCTIONS AS A RIBOSWITCH, AND HEREIN EVIDENCE IS PROVIDED THAT THIS NONCODING RNA IS A POLYAMINE SENSOR. THIS RNA ELEMENT IS HIGHLY CONSERVED AMONG VERTEBRATE GENES REQUIRED FOR SPERMINE BIOSYNTHESIS. DEVELOPMENT OF DRUGS THAT TARGET PUTATIVE SPERMINE RIBOSWITCHES FROM DIFFERENT ORGANISMS MIGHT THEREFORE BE USED FOR WIDE-RANGING PURPOSES SUCH AS ANTICANCER AGENTS, ANTIFUNGAL AGENTS, OR PESTICIDES. THIS PROPOSAL WILL EXAMINE THE STRUCTURE AND FUNCTION OF THE OAZ-PK RNA FROM VARIOUS ORGANISMS, INCLUDING THOSE OF BIOMEDICAL RELEVANCE – HUMAN, PATHOGENIC FUNGI AND DISEASE HARBORING INSECTS - WITH THE FOLLOWING SPECIFIC AIMS: (1) EXAMINE THE SPECIFICITY AND AFFINITY OF POLYAMINE BINDING TO OAZ RNAS FROM VARIOUS ORGANISMS, (2) INVESTIGATE THE THREE-DIMENSIONAL STRUCTURE OF OAZ RNAS, AND (3) EXPLORE THE ROLE OF ANTIZYME OAZ RNAS FROM VARIOUS ORGANISMS IN CONTROL OF GENE EXPRESSION.

THE DEVELOPMENTAL EFFECTS OF ENVIRONMENTAL ENRICHMENT ON THE MINOR CANNABINOID DRUG REWARD AND CANNABINOID RECEPTOR LEVELS - PROJECT SUMMARY/ABSTRACT UNDERSTANDING INDIVIDUAL DIFFERENCES IN THE VULNERABILITY TO DRUG ABUSE IS AN IMPORTANT COMPONENT TO DEVELOPING BETTER PREVENTION AND TREATMENT STRATEGIES. EVIDENCE INDICATES THAT PERSONALITY TRAITS SUCH AS “NOVELTY-SEEKING” OR “SENSATION-SEEKING” CAN INFLUENCE DRUG USE. THE RODENT ENVIRONMENTAL ENRICHMENT PARADIGM HAS BEEN SHOWN TO RELIABLY INDUCE A BEHAVIORAL PHENOTYPE THAT MODELS THE INCREASED DRUG ABUSE VULNERABILITY SEEN WITH THE NOVELTY-SEEKING PERSONALITY TRAIT. IN THIS ENRICHMENT MODEL, RATS ARE RAISED IN ENVIRONMENTS WITH EITHER HIGH OR LOW LEVELS OF NOVELTY THROUGHOUT EARLY ADOLESCENCE AND THROUGH ADULTHOOD. RATS EXPOSED TO HIGH LEVELS OF NOVELTY (ENRICHED RATS) ARE CONSISTENTLY FOUND TO BE LESS SENSITIVE TO LOW DOSES OF VARIOUS DRUGS OF ABUSE COMPARED TO RATS EXPOSED TO LOW LEVELS OF NOVELTY (IMPOVERISHED RATS) WHEN TESTED IN YOUNG ADULTHOOD. WHEN USING THIS MODEL, THE ALTERED SENSITIVITY TO DRUGS OF ABUSE IS TRADITIONALLY NOT TESTED UNTIL THE ANIMALS REACH ADULTHOOD. A MORE SYSTEMATIC INVESTIGATION ON WHEN DURING ADOLESCENCE EXPOSURE TO HIGH- OR LOW-NOVELTY ENVIRONMENTS INDUCES THESE ALTERED BEHAVIORAL PHENOTYPES IS WARRANTED. THIS MAY BE PARTICULARLY IMPORTANT AS THE PEAK OF WHEN PEOPLE INITIATE CANNABIS USE IS DURING ADOLESCENCE. GIVEN THE POPULARITY OF CANNABINOID DRUGS, IT IS SURPRISING THAT THERE IS LITTLE TO NO RESEARCH INVESTIGATING WHETHER ENVIRONMENTAL ENRICHMENT CAN ALTER SENSITIVITY TO MARIJUANA. WHILE DELTA-9-TETRAHYDROCANNABINOL (DELTA-9-THC) IS CONSIDERED THE MAJOR PSYCHOACTIVE INGREDIENT OF MARIJUANA, THE PASSAGE OF THE 2018 “FARM BILL” HAS LED TO THE RISE IN THE POPULARITY OF MINOR CANNABINOIDS OF THE HEMP PLANT INCLUDING DELTA-8-TETRAHYDROCANNABINOL (DELTA-8-THC) AND CANNABIDIOL (CBD). PRODUCTS CONTAINING DELTA-8-THC HAVE RECENTLY SKYROCKETED IN POPULARITY, PARTICULARLY IN STATES WHERE DELTA-9-THC REMAINS FULLY ILLEGAL. A MAIN GOAL OF THE PROPOSED RESEARCH IS TO COMBINE NEW RESEARCH FROM OUR LAB LOOKING AT THE ABUSE LIABILITY OF VAPED OR PULMONARY ADMINISTRATION OF DELTA-8-THC AND CBD AND COMBINATIONS OF THESE COMPOUNDS USING A CONDITIONED PLACE PREFERENCE (CPP) PROCEDURE AND DETERMINE WHEN AND IF ADOLESCENT ENVIRONMENTAL ENRICHMENT EXPOSURE CAN ALTER THE SENSITIVITY TO THESE CANNABIS DRUGS. A SECOND GOAL IS TO DETERMINE WHEN AND IF ADOLESCENT ENVIRONMENTAL ENRICHMENT EXPOSURE MAY ALTER BRAIN CANNABINOID RECEPTOR DENSITIES IN KEY BRAIN STRUCTURES INVOLVED IN THE REWARDING AND BEHAVIORAL EFFECTS OF CANNABINOID DRUGS.

EXAMINATION OF ORNITHINE DECARBOXYLASE ANTIZYME RNA STRUCTURE AND FUNCTION FOR THE DEVELOPMENT OF ANTIBIOLOGICAL AGENTS

MICRORNAS AND RNA INTERFERENCE EFFECTS ON HAIR CELL TRANSDIFFERENTIATION

INTEGRASE INHIBITOR COMBINATION NANOMICROBICIDE FOR PREVENTION OF HIV INFECTION

REGULATION OF CHOROID PLEXUS EPITHELIAL FUNCTION BY KLOTHO - PROJECT SUMMARY AGE-RELATED CHANGES TO PROTEIN AND THUS CELLULAR FUNCTION OCCUR ACROSS THE BRAIN. INCREASED UNDERSTANDING OF WHEN AGE-RELATED EVENTS BECOME PATHOLOGICAL IS REQUIRED BOTH TO SUPPORT HEALTHY BRAIN AGING AND TO DEVELOP EARLY AND EFFICACIOUS NEURODEGENERATIVE DISEASE THERAPEUTICS. AMONG THE CELLS OF THE BRAIN TO EXPERIENCE AGE- RELATED IMPAIRMENT TO STRUCTURE AND FUNCTION, THE CHOROID PLEXUS EPITHELIAL CELLS STAND OUT AS A TISSUE WITH UNTAPPED POTENTIAL TO SUPPORT THE ENTIRE BRAIN PARENCHYMA. CHOROID PLEXUS EPITHELIAL CELLS EXPRESS HIGH LEVELS OF KLOTHO PROTEIN. INCREASING EXPRESSION OF KLOTHO ENHANCES BUT DECREASING EXPRESSION IMPAIRS NEURONAL MEMORY FUNCTION ACROSS SPECIES AND IN MODELS OF NEURODEGENERATIVE DISEASE. RECENT WORK DETERMINED THAT A COMMON HUMAN POLYMORPHIC VARIANT OF KLOTHO THAT INCREASES PROTEIN IS PROTECTIVE AGAINST ALZHEIMER’S DISEASE DEVELOPMENT AND PATHOLOGY. WHILE KLOTHO ACTION IN AND UPON CELLS OF THE BRAIN PARENCHYMA INDICATES ITS EFFECTS ARE BRAIN-WIDE, LITTLE IS KNOWN ABOUT THE PRIMARY SOURCE OF BRAIN KLOTHO, THE CHOROID PLEXUS EPITHELIAL CELLS. OUR PILOT DATA INDICATE THAT CELL-TYPE SPECIFIC KLOTHO-DEFICIENCY IMPACTS LONGEVITY, MEMORY, AND CHOROID PLEXUS CELL STRUCTURE AND FUNCTION. THESE DATA SUGGEST THAT KLOTHO MAY EFFECTS CELLS THROUGHOUT THE BRAIN BECAUSE IT IS CRITICAL TO CHOROID PLEXUS EPITHELIAL CELL ACTIVITIES. CHOROID PLEXUS EPITHELIAL CELLS PROVIDE PHYSICAL, NUTRIENT, AND SIGNAL TRANSDUCTION SUPPORT TO THE ENTIRE BRAIN. THEY ALSO FUNCTION AS A PHYSICAL PROTECTIVE BARRIER AND COMMUNICATION CENTER BETWEEN BODY AND BRAIN. THE LONG-TERM GOAL OF THE PROPOSED RESEARCH IS TO UNDERSTAND THE HEALTH-RELATED FUNCTIONAL CONSEQUENCES OF AGE-RELATED KLOTHO-DEFICIENCY FROM CHOROID PLEXUS EPITHELIAL CELLS. WE WILL USE MOUSE MODELS TO INTERROGATE THE CENTRAL HYPOTHESIS THAT KLOTHO-DEFICIENCY IMPAIRS BRAIN PARENCHYMA BY DISRUPTING THE FUNCTION OF THE CHOROID PLEXUS EPITHELIAL CELLS. IN SPECIFIC AIM ONE, WE WILL USE MOUSE MODELS TO DETERMINE THE ROLE OF CHOROID PLEXUS-SPECIFIC KLOTHO EXPRESSION ON MEMORY ACROSS LIFESPAN. USING ANIMAL MODELS AND CELLULAR AND MOLECULAR TECHNIQUES, AIM TWO WILL DETERMINE WHETHER CHOROID PLEXUS EPITHELIAL CELL STRUCTURE OR FUNCTION ARE ALTERED BY KLOTHO-DEFICIENCY. THE SIGNIFICANCE OF THE PROPOSAL LIES IN CONTRIBUTIONS TO UNDERSTANDING THE BASIC BIOLOGY OF KLOTHO AS A PROTEIN CRITICAL FOR THE NORMAL CHOROID PLEXUS EPITHELIAL CELL FUNCTIONS REQUIRED TO SUSTAIN AND SUPPORT HEALTHY BRAIN PARENCHYMA ACROSS LIFESPAN. WE ARE UNIQUELY SITUATED TO EXPOSE UNDERGRADUATE STUDENTS INTERESTED IN RESEARCH AND MEDICALLY FOCUSED CAREERS DISCOVERY NEUROSCIENCE RESEARCH USING ANIMAL MODELS. THE PROPOSAL IS INNOVATIVE IN ITS USE OF NOVEL ANIMAL MODELS TO ALLOW TARGETED MANIPULATION OF KLOTHO EXPRESSION AND, IN STUDYING THE CHOROID PLEXUS EPITHELIA, STUDIES A TISSUE-TYPE WITH UNREALIZED POTENTIAL TO SUPPORT BRAIN HEALTH ACROSS LIFESPAN.

CHOLINERGIC ANTHELMINTICS: TACHYPHYLAXIS MECHANISMS AND CONTROL IN A PARASITIC NEMATODE MODEL,BRUGIA MALAYI - PROJECT SUMMARY SOIL-TRANSMITTED HELMINTH INFECTIONS ARE A GLOBAL CONCERN FOR PUBLIC HEALTH AND AFFECT OVER 1 BILLION PEOPLE WORLDWIDE. INFECTIONS CAUSED BY ASCARIS LUMBRICOIDES, TRICHURIS TRICHIURA (WHIPWORMS), AND ANCYLOSTOMA DUODENALE (HOOKWORMS) AFFECT PEOPLE IN WARM AND MOIST CLIMATES OFTEN LACKING IN HYGIENE AND SANITATION AND IN TEMPERATE ZONES DURING WARMER MONTHS. INFECTED CHILDREN DEVELOP SEVERE MALNUTRITION AND SHOW SEVERE PHYSICAL AND COGNITIVE GROWTH. CONTROL OF THESE PARASITES DEPENDS ON THE ADMINISTRATION OF ANTHELMINTIC DRUGS LIKE BENZIMIDAZOLES LIKE ALBENDAZOLE, MACROCYCLIC LACTONE, IVERMECTIN, AND NICOTINIC AGONISTS LIKE LEVAMISOLE AND PYRANTEL. THE DEVELOPMENT OF RESISTANCE TO THESE ANTHELMINTICS POSES A GREAT CHALLENGE IN CONTROLLING THE TRANSMISSION OF THESE DISEASES. PARASITIC NEMATODES ARE COMPLEX ORGANISMS THAT ADOPT COMPLEX MECHANISMS TO RESIST EXPOSURE TO ANTHELMINTIC DRUGS. WE HAVE IDENTIFIED TACHYPHYLAXIS AS ONE MECHANISM THE PARASITE UTILIZES TO RESIST AND RECOVER MOTILITY IN THE CONTINUED EXPOSURE TO THE CHOLINERGIC ANTHELMINTIC LEVAMISOLE. THE ENDOPLASMIC RETICULUM RETENTION PROTEIN, NRA-2, IS ONE OF THE PROTEINS IMPLICATED IN MODULATING TACHYPHYLAXIS IN THE FEMALE BRUGIA MALAYI PARASITES. THE TRANSCRIPTION FACTOR, DAF-12 IS UPREGULATED IN TACHYPHYLACTIC WORMS AND COULD PLAY A KEY ROLE IN MEDIATING TACHYPHYLAXIS. MACROCYCLIC LACTONE, ABAMECTIN, HAS LIMITED EFFECT ON ITS OWN ON THE MOTILITY OF ADULT B. MALAYI BUT, WHEN APPLIED IN COMBINATION WITH LEVAMISOLE, PREVENTS TACHYPHYLAXIS AND RECOVERY OF MOTILITY. HERE, WE PROPOSE, AIM #1: TO TEST THE HYPOTHESIS THAT DAF-12 MEDIATES TACHYPHYLAXIS IN B. MALAYI. WE WILL KNOCKDOWN DAF-12 IN ADULT B. MALAYI TO DETERMINE ITS ROLE IN MEDIATING TACHYPHYLAXIS. WE WILL MEASURE TRANSCRIPT LEVELS OF NRA-2 IN DAF-12 KNOCKDOWN WORMS TO DETERMINE THE ROLE OF DAF-12 IN REGULATING THE EXPRESSION OF NRA-2. WE WILL ALSO TARGET DAF-12 USING AGONISTS TO PREVENT TACHYPHYLAXIS. AIM #2: TO TEST THE HYPOTHESIS THAT MUSCLE CALCIUM CONCENTRATIONS & CALCIUM RELEASE MECHANISMS PRODUCED BY LEVAMISOLE ARE CHANGED IN THE PRESENCE OF MACROCYCLIC LACTONES. WE WILL INVESTIGATE THE EFFECTS OF MACROCYCLIC LACTONES, ABAMECTIN, IVERMECTIN, AND MOXIDECTIN IN PROLONGING THE PARALYSIS INDUCED BY LEVAMISOLE. WE WILL EVALUATE THE CHANGE IN CALCIUM RELEASE MECHANISMS DUE TO MACROCYCLIC LACTONES BY PERFORMING RNAI OF THE RYANODINE AND THE IP3 RECEPTORS, UNC-68 AND ITR-1 IN B. MALAYI, AND PERFORMING IN VIVO CALCIUM IMAGING USING C. ELEGANS. AT THE END OF THESE EXPERIMENTS, WE WILL HAVE CHARACTERIZED DAF-12 AS A NOVEL ANTHELMINTIC TARGET THAT COULD HELP PREVENT CHOLINERGIC TACHYPHYLAXIS. WE WOULD HAVE AN INSIGHT INTO THE EFFECT OF MACROCYCLIC LACTONES ON LEVAMISOLE CALCIUM RELEASE MECHANISMS IN NEMATODE MUSCLE. THESE STUDIES WILL PROVIDE AN IMPROVED MECHANISTIC INSIGHT INTO CHOLINERGIC TACHYPHYLAXIS AND A RATIONAL AVENUE TO PREVENT WORM RECOVERY AND RESISTANCE.

NOVEL OCULAR HYPOTENSIVE AND NEUROPROTECTIVE MICROPARTICLE-BASED HYDROGEN SULFIDE DELIVERY SYSTEM - GLAUCOMA IS ONE OF THE LEADING CAUSES OF IRREVERSIBLE BLINDNESS WORLDWIDE. IN THE USA, GLAUCOMA IS PROJECTED TO INCREASE FROM 2.7 MILLION IN 2010 TO 6.3 MILLION BY 2050. GLAUCOMA IS CHARACTERIZED BY PROGRESSIVE DEGENERATION OF RETINAL GANGLION CELLS WITH CORRESPONDING IRREVERSIBLE DEFICITS IN VISUAL FUNCTION, AND IN A MAJORITY OF PATIENTS, ELEVATION IN INTRAOCULAR PRESSURE (IOP). WHILE CURRENT MEDICATION THERAPIES TARGET REDUCTION IN IOP, SO FAR, A CLINICALLY EFFECTIVE TREATMENT THAT EXERTS BOTH OCULAR HYPOTENSIVE AND RETINAL NEUROPROTECTIVE ACTIONS REMAIN ELUSIVE, PROMPTING INTENSE SEARCH FOR POTENTIAL THERAPEUTIC OPTIONS. THERE IS EVIDENCE THAT HYDROGEN SULFIDE (H2S), A COLORLESS ODORIFEROUS GAS, ATTENUATES IOP IN NORMOTENSIVE RABBITS AND EXERTS NEUROPROTECTION IN RETINAL NEURONS, SUGGESTING A POTENTIAL SUPERIOR APPLICATION IN MANAGEMENT OF GLAUCOMA. HOWEVER, THE FULL CLINICAL POTENTIAL OF H2S CANNOT BE REALIZED WITHOUT AN EFFICIENT METHOD FOR ITS DELIVERY INTO OCULAR TISSUES. INDEED, THE CONVENIENT AND CONVENTIONAL TOPICAL OCULAR DELIVERY APPROACHES (E.G. SOLUTIONS, SUSPENSIONS, EMULSIONS, OINTMENTS, ETC) ARE NOT APPROPRIATE BECAUSE OCULAR SURFACE IS PREDOMINANTLY AQUEOUS, AND MOST H2S- DONORS RELEASE THE GAS IN AQUEOUS MEDIUM. ADDITIONALLY, IT CANNOT PROVIDE A LOW SUSTAINED LEVEL OF H2S, A CRITICAL REQUISITE FOR THERAPEUTIC APPLICATION. THE MAIN OBJECTIVE OF THIS PROPOSAL, THEREFORE, IS TO DESIGN A NOVEL DRUG DELIVERY SYSTEM CAPABLE OF SUPPLYING H2S INTO THE ANTERIOR UVEA AND RETINA AT A SUSTAINED RATE. WE HYPOTHESIZE THAT SUBCONJUNCTIVAL INJECTION OF A NOVEL GYY4137 (H2S DONOR)-LOADED MICROPARTICLE-BASED IN SITU GELLING DELIVERY SYSTEM CAN RELEASE H2S AT A SUSTAINED RATE WITH CORRESPONDING REDUCTION IN IOP IN THE ANTERIOR SEGMENT AND PROTECTION OF RETINAL NEURONS IN THE POSTERIOR SEGMENT. THERE IS EVIDENCE THAT SOME SUBCONJUNCTIVALLY ADMINISTERED DRUGS CAN GAIN ACCESS TO THE POSTERIOR SEGMENT OF THE EYE, IN VIVO. THUS, DUE TO ITS GASEOUS NATURE, IT IS CONCEIVABLE THAT H2S RELEASED ON SUBCONJUNCTIVAL ADMINISTRATION CAN SIMULTANEOUSLY GAIN ACCESS INTO THE ANTERIOR SEGMENT FOR REDUCTION OF IOP AND THE POSTERIOR SEGMENT FOR RETINAL NEUROPROTECTION. EXPERIMENTS IN THIS PROJECT HAVE THEREFORE BEEN DESIGNED TO ADDRESS THE FOLLOWING QUESTIONS: (A) CAN GYY4137 LOADED MICROPARTICLE-BASED, IN SITU GEL FORMING DELIVERY SYSTEM SUSTAIN H2S IN THE ANTERIOR AND POSTERIOR SEGMENTS WITHIN A PHARMACOLOGICAL RANGE? (B) WHAT ARE THE RELEASE AND DISTRIBUTION PROFILES OF H2S FROM THE NOVEL FORMULATION IN OCULAR TISSUES, IN VITRO AND IN VIVO? (C) CAN THE NOVEL FORMULATION INDUCE AND SUSTAIN A REDUCTION IN IOP AND MITIGATE RETINAL NEURODEGENERATION FOLLOWING SUBCONJUNCTIVAL INJECTION? WE ANTICIPATE THAT SATISFACTORY COMPLETION OF THESE AIMS WILL NOT ONLY DEMONSTRATE THE POTENTIAL APPLICATION OF H2S IN OCULAR THERAPY AND REVEAL STRATEGIES TO OVERCOME BARRIERS TO DELIVERY OF A WIDE RANGE OF H2S-DONORS TO OCULAR TISSUES.

IMPACT OF ENDOGENOUS METABOLIC BIASES ON OTOTOXIC OXIDATIVE DAMAGE

ROLE OF SUPPORTING CELLS IN COCHLEAR HAIR CELL REGENERATION

ROLES OF REACTIVE OXYGEN AND NITROGEN SPECIES ON VECTOR COLONIZATION BY TICK-BORNE RELAPSING FEVER SPIROCHETES

CHARACTERIZATION OF A TEMPORALLY CONTROLLED DOMINANT-NEGATIVE RB1 MOUSE MODEL

REVERSING NON-ADHERENCE IN AMERICAN INDIANS WITH DIABETES MELLITUS TYPE TWO

A STUDY OF ULTRA PERIPHERAL COLLISIONS AT RHIC

DEVELOPMENT OF SMALL CHEMICAL-MOLECULE INHIBITORS OF QUORUM SENSING REGULATOR: A NOVEL TREATMENT FOR ANTIBIOTIC RESISTANT BACTERIAL INFECTIONS.

MATERIAL FUMONISIN EXPOSURE AND PREGNANCY OUTCOME: DECODING THE SPHINGOLIPID IMMU

NMDA RECEPTOR SUBTYPES IN BASAL GANGLIA

HETEROMERS AND L-TYPE CALCIUM CHANNELS: INCREASING THE POTENCY OF EMODEPSIDE IN FILARIAL NEMATODE MODEL, BRUGIA MALAYI - PROJECT SUMMARY FILARIAL NEMATODE INFECTIONS ARE A GLOBAL CONCERN FOR PUBLIC HEALTH. LYMPHATIC FILARIASIS, CAUSED BY FILARIAL NEMATODES LIKE WUCHERIA BANCROFTI, BRUGIA MALAYI, AND BRUGIA TIMORI, AFFECT OVER 120 MILLION PEOPLE IN TROPICAL COUNTRIES OF THE WORLD. LYMPHATIC FILARIASES ARE NOT USUALLY LIFE-THREATENING, BUT PEOPLE ARE OFTEN OSTRACIZED FROM SOCIETY DUE TO DISTORTED LIMBS AND SKIN LESIONS. CONTROL OF THESE PARASITIC NEMATODES DEPENDS SIGNIFICANTLY ON THE MASS DRUG ADMINISTRATION (MDA) OF ANTHELMINTIC DRUGS: BUT THERE ARE NO EFFECTIVE MACROFILARICIDES THAT KILL THE ADULT PARASITES IN THE HOST. THERE ARE CONCERNS THAT MASS DRUG ADMINISTRATION OF MICROFILARICIDE CHEMOTHERAPY WILL LEAD TO THE DEVELOPMENT OF RESISTANCE. EMODEPSIDE IS AN EMERGING ANTHELMINTIC THAT TARGETS NEMATODE LARGE CONDUCTANCE POTASSIUM CHANNELS SLO-1 AND IS THE ONLY DRUG THAT CAN KILL ADULT FILARIA. SINGLE DOSE EMODEPSIDE TREATMENTS COULD ALLOW A MAJOR ADVANCE OVER EXISTING MDA PROGRAMS. HOWEVER, THE IN VITRO EFFICACY OF EMODEPSIDE VARIES BETWEEN THE DIFFERENT FILARIAL SPECIES, THE SEX, AND THE LIFE CYCLE STAGES OF THE SAME PARASITE SPECIES. THERE IS ALSO A DISCONNECT BETWEEN THE IN VIVO AND IN VITRO EFFECT OF EMODEPSIDE ON THE SLO K CHANNELS. HERE, WE PROPOSE, AIM #1: TO CHARACTERIZE THE PHARMACOLOGY OF ENDOGENOUS SLO-1/2 CHANNELS. WE WILL USE ERG-28 MUTANTS IN C. ELEGANS TO INVESTIGATE THE PHARMACOLOGY OF THE ENDOGENOUS SLO-1/2 RECEPTORS FOR ACTIVATION BY EMODEPSIDE. WE WILL TEST FOR ACTIVATION AND POTENTIATION OF EMODEPSIDE RESPONSES BY OTHER BK CHANNEL AGONISTS LIKE ARACHIDONIC ACID AND NS11021. WE WILL PARASITIZE C. ELEGANS BY EXPRESSING BMA-SLO-1 AND BMA-SLO-2 AND ASSAY THE PHARMACOLOGY OF THE ENDOGENOUS FILARIAL SLO-1/2 HETEROMER. AIM #2: TO TEST THE HYPOTHESIS THAT EGL-19 CHANNELS MODULATE SLO-1 RESPONSES TO EMODEPSIDE. WE WILL KNOCK DOWN EGL-19 IN B. MALAYI AND INVESTIGATE THE POTENCY OF EMODEPSIDE INHIBITING THE MOTILITY OF THESE WORMS. WE WILL ALSO EVALUATE THE ROLE OF EGL-19 AGONISTS AND ANTAGONISTS IN POTENTIATING OR INHIBITING THE EMODEPSIDE RESPONSES IN WORM MOTILITY. WE WILL DETERMINE IF EGL- 19 MODULATES SLO-1 IN MICRODOMAINS USING CELL-ATTACHED PATCH-CLAMP EXPERIMENTS ON BRUGIA MUSCLE. ON COMPLETING THESE EXPERIMENTS, WE WILL HAVE ENHANCED INSIGHT INTO THE PHARMACOLOGY OF THE ENDOGENOUS SLO-1/2 HETEROMERIC CHANNELS AND AID THE DEVELOPMENT OF NEW AND MORE EFFECTIVE MACROFILARICIDES. WE WILL IMPROVE THE EFFICACY OF EMODEPSIDE BY USING DRUG COMBINATIONS THAT SELECTIVELY INCREASE CALCIUM IN MICRO-DOMAINS CLOSE TO SLO-1 CHANNELS. THE USE OF COMBINATION THERAPY CAN ENHANCE THE POTENCY AND EFFICACY OF EMODEPSIDE WHERE BIOAVAILABILITY OR ACTIVITY AGAINST PARTICULAR NEMATODES SPECIES MAY BE LOW.

ONCE MONTHLY ANTIRETROVIRAL NANOPARTICLES FOR HIV-1 TREATMENT

ROLE OF A RAG1-DCAF1(VPRBP)-EZH2 AXIS IN B CELL DEVELOPMENT - PROJECT SUMMARY B AND T LYMPHOCYTES FORM THE FOUNDATION OF OUR ADAPTIVE IMMUNE SYSTEM, WHICH IS BASED ON SPECIFIC RECOGNITION OF FOREIGN MOLECULES BY STRUCTURALLY DIVERSE SURFACE ANTIGEN RECEPTORS. STRUCTURAL DIVERSITY IN THESE RECEPTORS ORIGINATES FROM RAG (RECOMBINATION ACTIVATING GENE)-MEDIATED V(D)J RECOMBINATION THAT ASSEMBLES ANTIGEN RECEPTOR GENES DURING LYMPHOCYTE DEVELOPMENT. HOWEVER, V(D)J RECOMBINATION IS NOT ALWAYS BENIGN, AS ABERRANT REARRANGEMENT CAN CONTRIBUTE TO GENOMIC INSTABILITY AND CANCER IN LYMPHOCYTES. WE PREVIOUSLY SHOWED THAT THE AMINO-TERMINAL 215 RESIDUES OF RAG1, WHICH IS DISPENSABLE FOR RAG ENDONUCLEASE ACTIVITY, CONSTRAINS V(D)J RECOMBINATION BY RECRUITING VPR BINDING PROTEIN (VPRBP) AND ITS ASSOCIATED CULLIN4-DDB1- RBX1 (CRL4) E3 UBIQUITIN LIGASE COMPLEX TO MEDIATE TIMELY RAG1 DEGRADATION. INTERESTINGLY, VPRBP (ALSO CALLED DCAF1) WAS RECENTLY FOUND TO STABILIZE THE HISTONE-LYSINE N-METHYLTRANSFERASE ENHANCER OF ZESTE HOMOLOG 2 (EZH2), WHICH CATALYZES THE ADDITION OF METHYL GROUPS TO HISTONE H3 AT LYSINE 27 (H3K27) BY THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2). TRIMETHYLATION OF H3K27 (H3K27ME3) IS GENERALLY CONSIDERED TO PROMOTE GENE SILENCING. IN MICE, B LINEAGE-SPECIFIC LOSS OF EZH2 EXPRESSION ARRESTS B CELL DEVELOPMENT AT THE PRO-B TO PRE-B CELL TRANSITION, AND SELECTIVELY IMPAIRS REARRANGEMENT OF THE DISTAL IMMUNOGLOBULIN (IG) VHJ558 GENE FAMILY. THIS PHENOTYPE RESEMBLES THAT OBSERVED IN MICE LACKING VPRBP IN B CELLS. TRUNCATING THE FIRST 215 RESIDUES OF RAG1 IN MICE TO ELIMINATE THE VPRBP BINDING SITE (R1215 MICE) CONFERS A LESS SEVERE PHENOTYPE, BUT NEVERTHELESS IMPAIRS SHORT-RANGE IG D-J REARRANGEMENT FOR REASONS THAT REMAIN UNCLEAR. THESE OBSERVATIONS LEAD US TO HYPOTHESIZE THAT VPRBP STABILIZES EZH2 IN B CELLS TO PROMOTE PRC2 FORMATION, H3K27 METHYLATION, TRANSCRIPTIONAL PROGRAMS, AND IMMUNE REPERTOIRE IN EARLY B LINEAGE CELLS, AND THROUGH VPRBPS ASSOCIATION WITH FULL-LENGTH RAG1, SPECIFICALLY REGULATES H3K27 METHYLATION WITHIN THE IGH LOCUS TO REGULATE SHORT-RANGE IG D-J REARRANGEMENT. THIS HYPOTHESIS WILL BE TESTED BY EXPERIMENTS DESCRIBED IN TWO BROAD AIMS. IN AIM I OF THIS PROJECT, WE WILL: (A) ESTABLISH THE CONCORDANCE OF THE PHENOTYPES PRESENTED BY MICE LACKING VPRBP OR EZH2 IN THE B LINEAGE WHEN RESCUED BY ENFORCED BCL2 EXPRESSION; (B) COMPARE EZH2, TOTAL H3, AND H3K27ME3 PROTEIN LEVELS IN WILD-TYPE AND VPRBP-DEFICIENT B CELLS, USING EZH2-DEFICIENT B CELLS AS A NEGATIVE CONTROL; AND (C) ESTABLISH VPRBP-DEPENDENT EZH2 ASSOCIATION WITH PRC2 SUBUNITS EED AND SUZ12 IN PRIMARY B CELLS. IN AIM II OF THIS PROJECT, WE WILL USE RNA, IMMUNE REPERTOIRE, AND H3K27ME3 “CUT&RUN” SEQUENCING APPROACHES TO ANALYZE AND COMPARE THE TRANSCRIPTOME, IG GENE USAGE, AND LOCALIZATION OF H3K27ME3 MARKS IN SORTED PRO-B AND PRE-B CELLS FROM WILD-TYPE, VPRBP-DEFICIENT, EZH2-DEFICIENT, AND R1215-EXPRESSING B CELLS. ESTABLISHING THAT THE RAG1-VPRBP-EZH2-H3K27ME3 AXIS REGULATES V(D)J RECOMBINATION WOULD BE CONCEPTUALLY INNOVATIVE, AS IT PROVIDES A MEANS FOR THE RAGS TO LOCALLY MODIFY IG GENE ACCESSIBILITY AND EXPRESSION WITHIN ANTIGEN RECEPTOR LOCI BY RECRUITING VPRBP AND REGULATING EZH2 ACTIVITY.

MECHANISMS OF SUDEP: FAILURE TO AUTORESUSCITATE

ASSESSMENT OF GLUTAMATE DELTA-1 RECEPTOR IN MENTAL DISORDERS

NEURONAL P-REX1 REPRESSION: A KEY FACTOR IN EARLY-LIFE ENVIRONMENTAL CIGARETTE SMOKE EXPOSURE MEDIATED RISK OF ASTHMA

ROLE OF RACK1 IN RAG1 DEGRADATION AND B CELL DEVELOPMENT - PROJECT SUMMARY B AND T LYMPHOCYTES FORM THE FOUNDATION OF OUR ADAPTIVE IMMUNE SYSTEM, WHICH IS BASED ON SPECIFIC RECOGNITION OF FOREIGN MOLECULES BY STRUCTURALLY DIVERSE SURFACE ANTIGEN RECEPTORS. STRUCTURAL DIVERSITY IN THESE RECEPTORS ORIGINATES THROUGH SITE-SPECIFIC REARRANGEMENT OF THE ANTIGEN RECEPTOR GENES DURING LYMPHOCYTE DEVELOPMENT. THIS REARRANGEMENT PROCESS, CALLED V(D)J RECOMBINATION, IS INITIATED WHEN THE RAG1/2 PROTEINS INTRODUCE DNA DOUBLE-STRAND BREAKS (DSBS) AT ANTIGEN RECEPTOR GENE SEGMENTS, AND IS COMPLETED WHEN THE DSBS ARE SENSED AND REPAIRED BY NON-HOMOLOGOUS END-JOINING. THIS PROCESS IS SUBJECTED TO MANY LAYERS OF REGULATION, BUT AN ELEMENTARY MEANS TO CONSTRAIN V(D)J RECOMBINATION IS TO CONTROL THE LEVEL OF THE RAG PROTEINS THEMSELVES. WORK IN THIS LABORATORY SUGGESTS THAT RAG1 LEVELS ARE CONTROLLED BY A RAG1 INTERACTING PROTEIN WE IDENTIFIED CALLED VPR BINDING PROTEIN (VPRBP; ALSO CALLED DCAF1), WHICH EXERTS ITS CONTROL THROUGH TWO DIFFERENT MECHANISMS: FIRST, BY PROMOTING TIMELY PROTEASOME-DEPENDENT DEGRADATION OF RAG1 THROUGH VPRBP’S ASSOCIATION WITH A CUL4-DDB1 E3 UBIQUITIN LIGASE COMPLEX; AND SECOND, BY REGULATING RAG TRANSCRIPTIONAL INDUCTION UNDER CONDITIONS THAT STIMULATE V(D)J RECOMBINATION. THE MOLECULAR DETAILS UNDERLYING THESE MECHANISMS REMAIN UNCLEAR. WE HAVE RECENTLY PERFORMED MORE DETAILED INTERACTOME STUDIES, CONFIRMING VPRBP AND DDB1 ASSOCIATION WITH FULL-LENGTH RAG1 AND IDENTIFYING RECEPTOR OF ACTIVATED C KINASE 1 (RACK1) AS A PROMISING CO-FACTOR IN MEDIATING RAG1 DEGRADATION BASED ON PREVIOUS WORK ESTABLISHING IT AS AN ADAPTOR FOR OTHER MODULAR CULLIN E3 UBIQUITIN LIGASES. THESE FINDINGS LEAD US TO HYPOTHESIZE THAT RACK1 REGULATES RAG1 DEGRADATION AND V(D)J RECOMBINATION. TO TEST THIS HYPOTHESIS, WE WILL (I) ESTABLISH THE ROLE OF RACK1 IN REGULATING FULL-LENGTH RAG1 DEGRADATION IN VITRO AND IN CELL MODELS AND, BASED ON PREVIOUS STUDIES, ITS POTENTIAL FOR COMPETITIVE INHIBITION BY HSP90 AND MODULATION BY SIGNALING PATHWAYS INVOLVED IN ACTIVATING PROTEIN KINASE C; AND (II) ESTABLISH HOW LOSS OF RACK1 IN B CELLS AFFECTS B CELL DEVELOPMENT, RAG1 PROTEIN LEVELS, AND V(D)J RECOMBINATION. ESTABLISHING THE MOLECULAR BASIS FOR RACK1 INTERACTIONS WITH FULL-LENGTH RAG1 AND THE CUL4- DDB1 UBIQUITIN LIGASE COMPLEX, THE ROLE OF RACK1 (AND POTENTIALLY HSP90 AND RECEPTOR SIGNALING PATHWAYS) IN REGULATING RAG1 DEGRADATION, AND THE CONSEQUENCE OF LOSING RACK1 EXPRESSION IN B CELLS ON B CELL DEVELOPMENT, RAG1 PROTEIN LEVELS, AND V(D)J RECOMBINATION, WOULD DEFINE A NEW PHYSIOLOGICAL ROLE FOR RACK1 (AND HSP90) IN V(D)J RECOMBINATION, AND PROVIDE NEW INSIGHTS INTO SOURCES FOR ALTERED IMMUNE REPERTOIRE AND GENOMIC INSTABILITY CAUSED BY DYSREGULATED RAG1 EXPRESSION. THIS WORK WOULD ALSO EXTEND THE PARADIGM FOR RACK1 AS A MULTI-FUNCTIONAL ADAPTOR TO E3 UBIQUITIN LIGASES AND POTENTIALLY REVEAL NEW AVENUES TO THERAPEUTICALLY REGULATE RACK1-DEPENDENT PROTEIN TURNOVER.

PRO-NP PREVENTION OF UV-INDUCED SKIN CANCER

IMPLICATIONS OF B10-LIKE CELL EXPANSION IN A MODEL OF IMPAIRED RECEPTOR EDITING

MOLECULAR MECHANISM OF D-CYCLOSERINE ACTION

DETERMINATION OF METABOLIC STATE OF HAIR CELL MITOCHONDRIA BY FLIM

A NOVEL FORM OF LIGHT CHAIN GENE REPLACEMENT - PROJECT SUMMARY B AND T LYMPHOCYTES FORM THE FOUNDATION OF OUR ADAPTIVE IMMUNE SYSTEM, WHICH IS BASED ON SPECIFIC RECOGNITION OF FOREIGN MOLECULES BY STRUCTURALLY DIVERSE SURFACE ANTIGEN RECEPTORS. STRUCTURAL DIVERSITY IN THESE RECEPTORS ORIGINATES THROUGH SITE-SPECIFIC REARRANGEMENT OF ANTIGEN RECEPTOR GENES DURING LYMPHOCYTE DEVELOPMENT. THIS REARRANGEMENT PROCESS, CALLED V(D)J RECOMBINATION, IS INITIATED WHEN THE RAG1/2 PROTEINS CLEAVE ANTIGEN RECEPTOR GENE SEGMENTS AT RECOMBINATION SIGNAL SEQUENCES (RSS) THROUGH A NICK-HAIRPIN MECHANISM, AND IS COMPLETED WHEN THE DNA BREAKS ARE SENSED AND REPAIRED BY NON-HOMOLOGOUS END-JOINING. CLASSICALLY, B CELL REPERTOIRE DIVERSITY IS CONSIDERED RESTRICTED BY THE NUMBER OF FUNCTIONAL V, D, AND J GENE SEGMENTS IN THE IMMUNOGLOBULIN (IG) HEAVY AND LIGHT CHAIN GENE LOCI. HOWEVER, FORMS OF SECONDARY V(D)J REARRANGEMENT HAVE BEEN REPORTED IN WHICH AN UNREARRANGED IG HEAVY CHAIN V (VH) GENE SEGMENT REPLACES A REARRANGED VH GENE VIA RECOMBINATION WITH A CRYPTIC RSS EMBEDDED IN THE 3’ END OF THE VH GENE (CALLED VH GENE REPLACEMENT). MECHANISTIC INSIGHT INTO THIS PROCESS HAS BEEN HAMPERED BY THE LOW FREQUENCY OF THESE EVENTS AND, TYPICALLY, THE USE OF GERMLINE PRE-REARRANGED VH ALLELES. WHETHER SIMILAR EVENTS OCCUR IN THE LIGHT CHAIN LOCI REMAINS UNCLEAR. WE RECENTLY PERFORMED BULK LIGHT CHAIN REPERTOIRE SEQUENCING OF B CELLS FROM TRANSGENIC MICE EXPRESSING THE IG VH12 HEAVY CHAIN, SORTED BASED ON IMMUNOREACTIVITY TO PHOSPHATIDYLCHOLINE. INTERESTINGLY, OUR ANALYSIS UNCOVERED INFREQUENT, BUT RECURRENT, ENDOGENOUS HYBRID REARRANGED IG KAPPA V (KV) GENE SEQUENCES, IN WHICH THE 3’ END OF THE HIGHLY SELECTED KV4-91 GENE WAS REPLACED BY ANOTHER KV GENE. BASED ON THIS PRELIMINARY DATA, OUR WORKING HYPOTHESIS IS THAT THE RAG PROTEINS MEDIATE KV GENE REPLACEMENT IN VH12 MICE VIA CLEAVAGE OF A CRYPTIC RSS IDENTIFIED IN FRAMEWORK REGION 3 OF THE KV GENE (KV FR3 CRSS). THE PROPOSED PROJECT WILL EXTEND OUR PRELIMINARY FINDINGS TO CONFIRM KV GENE REPLACEMENT LEADS TO PRODUCTIVE ANTIBODY GENERATION IN SINGLE B CELLS, TEST WHETHER THE KV FR3 CRSS SUPPORTS RAG-MEDIATED CLEAVAGE AND REARRANGEMENT IN VITRO AND IN CELLS, AND ALSO EXCLUDE ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) AS AN ALTERNATIVE MECHANISM FOR KV GENE REPLACEMENT IN VH12 MICE. THIS PROJECT WILL CHALLENGE OUR CURRENT UNDERSTANDING OF THE THEORETICAL CONSTRAINTS ON ANTIBODY STRUCTURAL DIVERSITY, AND LEAD TO CONSIDERING KV GENE CHIMERAS FOR RATIONAL DESIGN OF THERAPEUTIC ANTIBODIES. THIS WORK WILL ALSO HIGHLIGHT AN IMPORTANT POTENTIAL CAVEAT OF AUTOMATED KV SEQUENCE ANALYSIS, BECAUSE SUCH EVENTS (REGARDLESS OF ORIGIN) MAY BE MISSED IN KV GENE CALLS OR BE MISTAKEN FOR SOMATIC HYPERMUTATION. THE POTENTIAL OF THIS PROJECT TO SHIFT EXISTING PARADIGMS PLACES THE PROJECT IN THE “HIGH RISK-HIGH REWARD” CATEGORY FOR WHICH THE R21 WAS DESIGNED.

REGENERATION OF STEREOCILIA OF COCHLEAR HAIR CELLS

INTERVENTION TO PREVENT DELAYED DIAGNOSIS OF ORAL CANCER

THE ROLE OF THE ADAPTIVE IMMUNE SYSTEM IN EPILEPSY - PROJECT SUMMARY THE LACK OF DRUG EFFECTIVENESS IN REFRACTORY EPILEPSY (~30% OF PEOPLW WITH EPILEPSY) IMPLIES THE EXISTENCE OF ADDITIONAL MECHANISMS OF HYPEREXCITABILITY AND HYPERSYNCHRONY THAT CURRENT ANTI-SEIZURE DRUGS DO NOT TARGET. THE LONG-TERM GOALS OF OUR RESEARCH PROGRAM ARE TO IDENTIFY NOVEL MOLECULAR TARGETS WITH DISEASE-MODIFYING EFFECTS FOR THE TREATMENT OF REFRACTORY EPILEPSY, WHICH MAY ALSO DECREASE CO-MORBIDITIES AND INCREASE LONGEVITY IN THOSE SUSCEPTIBLE TO SUDEP. IN THE PAST DECADE, INFLAMMATION HAS BEEN FOUND TO HAVE A DETRIMENTAL IMPACT ON EPILEPSY. A MINORITY OF STUDIES HAVE FOCUSED ON PERIPHERAL IMMUNE RESPONSES BUT HAVE FOUND THAT SEVERE HUMAN AND ANIMAL REFRACTORY EPILEPSIES EXHIBIT A CHRONIC CNS INFLAMMATORY STATE WITH ACTIVATION AND INFILTRATION OF PERIPHERAL ADAPTIVE IMMUNE CELLS INTO THE BRAIN. HOWEVER, THE RELATIONSHIP BETWEEN CHRONIC EPILEPSY AND THE PERIPHERAL ADAPTIVE IMMUNE SYSTEM IS UNKNOWN. THE OBJECTIVE OF THIS GRANT IS TO DETERMINE THE ROLE OF PERIPHERAL ADAPTIVE IMMUNE RESPONSE IN SEIZURE GENERATION, SEIZURE SEVERITY AND EPILEPTOGENESIS. THE CENTRAL HYPOTHESIS IS THAT EPILEPTIC SEIZURES CAUSE ACTIVATION OF THE PERIPHERAL ADAPTIVE IMMUNE RESPONSE AND THAT SEIZURE-INDUCED PERIPHERAL ADAPTIVE IMMUNE RESPONSES CONTRIBUTE TO WORSENING SEIZURES/EPILEPSY. OUR RATIONALE IS THAT DELINEATING THE NATURE OF THE RELATIONSHIP BETWEEN CHRONIC EPILEPSY AND THE PERIPHERAL ADAPTIVE IMMUNE SYSTEM WILL OFFER NEW RESEARCH AVENUES AND THERAPEUTIC OPPORTUNITIES. OUR SPECIFIC AIMS WILL TEST THE FOLLOWING HYPOTHESES: (AIM 1) SPONTANEOUS RECURRENT SEIZURES IN CHRONIC EPILEPSY ALTER THE PERIPHERAL IMMUNE RESPONSE RESULTING IN BRAIN INFILTRATION OF PERIPHERAL IMMUNE CELLS; AND (AIM 2) PERIPHERAL ADAPTIVE IMMUNE CELLS CONTRIBUTE TO THE AGE-DEPENDENT WORSENING OF SEIZURE SEVERITY IN EPILEPTIC MICE. UPON CONCLUSION, WE WILL UNDERSTAND SEIZURES IN THE SETTING OF PERIPHERAL INFLAMMATION. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE WE INVESTIGATE THE EFFECT OF SPONTANEOUS RECURRENT SEIZURES ON PERIPHERAL INFLAMMATORY SIGNALING AND VICE VERSA IN A DEVELOPMENTAL MODEL OF TEMPORAL LOBE EPILEPSY, A HERETOFORE-UNEXAMINED PROCESS.

DCAF1(VPRBP) REGULATES FOXO1 TO PROMOTE RAG TRANSCRIPTION

UNIVERSITY CENTER

RUI: DYNAMIC LIGHT SCATTERING TEST OF BOND MODEL PREDICTIONS FOR THE DYNAMICS OF NETWORK-FORMING LIQUIDS NEAR THE GLASS TRANSITION

NATURAL PRODUCT-BASED THERAPIES AGAINST NOISE-INDUCED HEARING LOSS

ANDROGEN RECEPTOR: A KEY REGULATOR OF TRAIL RESISTANCE IN BREAST CANCER

DISSECTING THE SENSORY HAIR CELL NUCLEUS: DEVELOPMENT OF A NOVEL METHOD FOR INVESTIGATING CHROMATIN INTERACTIONS (TN5-CAPTURE) IN SMALL CELL NUMBERS - PROJECT SUMMARY: CHROMATINS ARE PACKED INTO THE TINY NUCLEUS IN A WAY THAT DISTAL ENHANCERS INTERACT WITH TARGET GENE PROMOTERS IN 3D SPACE TO FACILITATE THE EXPRESSION OF THE TARGET GENES IN A CELL TYPE-SPECIFIC MANNER, THOUGH ENHANCERS AND PROMOTERS ARE SEPARATED BY SEVERAL KILOBASES OR SOMETIMES MEGABASES IN THE LINEAR FORMS OF CHROMATINS. THUS, UNDERSTANDING OF THE CHROMATIN INTERACTIONS IS IMPORTANT FOR US TO INTERPRET THE TRANSCRIPTION REGULATORY NETWORKS DICTATING CELL IDENTIFIES AND TO REVERSE OR CONVERT CELL FATE THROUGH TRANSCRIPTION MANIPULATIONS. HOWEVER, MILLIONS OF CELLS ARE REQUIRED TO PROFILE GENOME-WIDE CHROMATIN INTERACTIONS BY CONVENTIONAL PROXIMITY LIGATION-BASED CHROMATIN CONFORMATION CAPTURE METHODS, MAKING IT DIFFICULT TO INTERROGATE CHROMATIN INTERACTIONS IN SENSORY HAIR CELLS OF THE ORGAN OF CORTI. THE LACK OF ENHANCER-PROMOTER INTERACTION INFORMATION IN THE HAIR CELLS RESTRAINS OUR UNDERSTANDING OF THE REGULATORY NETWORKS GOVERNING HAIR CELL-SPECIFIC GENE EXPRESSION AND HINDERS THE IDENTIFICATION OF POTENTIAL TARGETS FOR HAIR CELL REGENERATION THROUGH EXPRESSION MANIPULATION. TO ADDRESS THIS NEED, WE ARE PROPOSING TO INVESTIGATE ENHANCER-PROMOTER INTERACTIONS IN SENSORY HAIR CELLS UTILIZING THE “CUT-AND-PASTE” TRANSPOSITION ACTIVITY OF TN5 TRANSPOSASE (TN5-CAPTURE). THE FEASIBILITY OF TN5- CATPURE TO DETECT ENHANCER-PROMOTER INTERACTIONS HAS BEEN DEMONSTRATED BY OUR PRELIMINARY STUDY, WE WILL START ENHANCER-PROMOTER INTERACTION ANALYSIS FOR A FEW ESSENTIAL TRANSCRIPTION FACTOR GENES USING TN5-CAPTURE FOLLOWED BY QPCR, AND THEN EXPAND THE ANALYSIS TO GENOME-WIDE SCALE BY COMBINING TN5-CAPTURE AND NEXT GENERATION SEQUENCING. FINALLY, WITH THE CRISPRI (CRISPR-DCAS9-EZH2) SYSTEM, WE WILL VALIDATE THE REGULATORY FUNCTIONS OF SELECTED ENHANCER-PROMOTER INTERACTIONS FOR ALREADY KNOWN AND NEWLY DISCOVERED ENHANCER-PROMOTER INTERACTIONS. THROUGH THIS PROJECT, WE WILL COLLECT DATASETS OF ENHANCER-PROMOTER INTERACTIONS IN HAIR CELLS, WHICH CAN BE INTEGRATED WITH AVAILABLE TRANSCRIPTOMIC AND EPIGENETIC DATA TO ESTABLISH HAIR CELL REGULATORY NETWORKS GOVERNING HAIR CELL-SPECIFIC GENE EXPRESSION AND TO IDENTIFY POTENTIAL TARGETS TO STIMULATE HAIR CELL REGENERATION. IMPLEMENTATION OF THE CRISPRI TECHNOLOGY IN THE INNER EAR SYSTEM ALSO PROVIDE A POWERFUL TOOL IN THE CONTEXT OF THERAPEUTICAL TREATMENT OF DEAFNESS. BESIDES, THE TN5-CAPTURE METHOD, A NEW CHROMATIN INTERACTION INTERROGATING TECHNIQUE, WILL HAVE BROAD APPLICATIONS IN RESEARCH OUTSIDE OF THE INNER EAR SYSTEM.

EXPLORING THE BENEFICIAL EFFECTS OF QUINOLINE DERIVATIVES AFTER NOISE-INDUCED DAMAGE

PHARMACOLOGIC REGULATION OF AUDITORY HAIR CELL REGENERATION

DISCOVERY OF NOVEL NONTUBERCULOUS INHIBITORS - PROJECT SUMMARY/ABSTRACT NON-TUBERCULOUS MYCOBACTERIA (NTM) ARE WIDESPREAD PATHOGENS FOUND IN THE ENVIRONMENT AND CAUSE PROGRESSIVE LUNG DISEASE AS WELL AS SKIN AND SOFT TISSUE, CENTRAL NERVOUS SYSTEM AND DISSEMINATED INFECTIONS. NTM INFECTIONS RATES ARE RISING GLOBALLY AND HAVE EMERGED AS IMPORTANT HUMAN PATHOGENS GLOBALLY. THE SPECIFIC PATHOGENS RESPONSIBLE FOR THESE INFECTIONS ARE PART OF ONE OF TWO SPECIES, I) MYCOBACTERIUM ABSCESSUS (M. ABSCESSUS) COMPLEX (MABSC) AND II) MYCOBACTERIUM AVIUM (M. AVIUM) COMPLEX. THE M. ABSCESSUS COMPLEX COMPRISES THE SUBSPECIES M. ABSCESSUS, M. MASSILIENSE AND M. BOLLETII, HAS EMERGED AS A SIGNIFICANT GLOBAL THREAT CAUSING AN INCREASING NUMBER OF PULMONARY INFECTIONS AMONG PATIENTS WITH STRUCTURAL LUNG DISEASE SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE, BRONCHIECTASIS AND CYSTIC FIBROSIS (CF). OF PARTICULAR CONCERN, PATIENTS WITH CF CO-INFECTED WITH AN MABSC PATHOGEN ARE OFTEN UNTREATABLE DESPITE YEARS OF COMBINATION THERAPY RESULTING IN 60-70% TREATMENT FAILURES. THEREFORE, NOVEL ANTI-NTM AGENTS WITH POTENT ACTIVITY AGAINST MABSC STRAINS THAT CAN SHORTEN TREATMENT TIME, DECREASE RESISTANCE RATES WITH IMPROVED EFFICACY ARE STRONGLY NEEDED. WE HAVE DISCOVERED A NOVEL SERIES OF INDOLE-2-CARBOXAMIDES (IC) THAT HAVE POTENT MINIMUM INHIBITOR CONCENTRATION (MIC) VALUES OF 0.0039 - 8 ΜG/ML AGAINST VARIOUS SLOW- AND FAST-GROWING NTM OF CLINICAL INTEREST, INCLUDING M. ABSCESSUS, M. MASSILIENSE, M. BOLLETII AND M. CHELONAE. IN ADDITION, ICS ARE EFFECTIVE IN VITRO AND IN MICE, DEMONSTRATING THEIR SAFE AND EFFECTIVE PROFILE. HOWEVER, ICS ARE LIPOPHILIC AND ARE POORLY WATER SOLUBLE RESULTING IN POOR ORAL ABSORPTION. TO CIRCUMVENT THIS POOR PHARMACOKINETIC PROPERTY, WE PROPOSE TO DESIGN NOVEL AMINO-ACID BASED IC ANALOGS AND DEVELOP DRUG-LOADED LIPOSOMES, WHICH ARE A SAFE AND EFFECTIVE OPTION TO FORMULATE POORLY SOLUBLE ICS. NOVEL ANALOGS WILL BE EVALUATED FOR ANTIMYCOBACTERIAL ACTIVITY AND ACTIVE COMPOUNDS WILL UNDERGO A SERIES OF ADMETOX ASSAYS TO DETERMINE PUTATIVE PK/PD ACTION. IC- AND IC-ANALOG- LOADED LIPOSOMES WILL BE DESIGNED FOR INHALATION ADMINISTRATION AND BE ENGINEERED TO BE PREFERENTIALLY TAKEN UP BY MACROPHAGES, WHERE NTM PATHOGENS RESIDE IN INFECTED PATIENTS. THIS WILL BE ACCOMPLISHED THROUGH SYNTHESIS OF ICS, PRODUCTION OF DRUG-LOADED LIPOSOMES AND CHARACTERIZATION OF DRUG RELEASE AND MACROPHAGE UPTAKE. LIPOSOMES WILL BE PRODUCED USING THIN FILM HYDRATION METHOD WITH SUBSEQUENT IC-LOADING USING PASSIVE TRAPPING METHODS. THE LAMELLARITY OF THE LIPOSOMES WILL BE MONITORED BY 31P NMR AND CONFIRMED WITH CRYO-TEM. DRUG-RELEASE STUDIES WILL BE PERFORMED TO ENSURE THERAPEUTIC IC CONCENTRATIONS ARE RELEASED (CONCENTRATIONS ABOVE MIC VALUES). FINALLY, IC-LOADED LIPOSOMES WITH OPTIMIZED DRUG-RELEASE WILL BE SUBJECTED TO MACROPHAGE UPTAKE STUDIES. THIS WILL BE PERFORMED USING A FLUORESCENT LABELED IC LOADED LIPOSOME AND MACROPHAGES EXPRESSING GFP TO VISUALIZE UPTAKE AND TEM.

TAMIFLU AS A THERAPEUTIC CANDIDATE FOR NOISE-INDUCED HEARING LOSS

DEFINING THE ROLE OF A NOVEL E3 UBIQUITIN LIGASE IN V(D)J RECOMBINATION

DIFFERENTIATION OF CENTRAL VERSUS PERIPHERAL FATIGUE IN PARKINSON'S DISEASE

THE ROLE OF LPA1 IN THE ETIOLOGY OF PERIODONTAL DISEASE

STUDENT SUPPORT SERVICES

THE NATURAL FACE OF NORTH AMERICA: A PUBLIC PORTAL TO THE MAXIMILIAN-BODMER COLLECTION AT JOSLYN ART MUSEUM [CREIGHTON UNIVERSITY, THE JOSLYN ART MUSEUM, AND THE NEBRASKA INDIAN COMMUNITY COLLEGE WILL IMPLEMENT A DIGITAL PORTAL TO INCREASE PUBLIC ACCESS AND INTERPRETATION OF MATERIALS RELATED TO MAXIMILIAN VON WIED AND KARL BODMER'S 1832-1834 EXPEDITION ACROSS NORTH AMERICA. STAFF WILL DIGITIZE, GEOCODE, AND MARKUP MAXIMILIAN'S JOURNAL AND BODMER'S ARTWORKS. USERS WILL BE ABLE TO BROWSE AND SEARCH THE COLLECTION OR FOLLOW THE EXPEDITION USING GEOREFERENCED MAPS, CREATING AN INTEGRATED DIGITAL EXPERIENCE THAT ALLOWS MULTIPLE ENTRY POINTS INTO TEXT AND IMAGE. THE PROJECT WILL ENRICH THESE RESOURCES WITH SCHOLARLY ESSAYS AND ENSURE ITS BROAD IMPACT THROUGH PUBLIC OUTREACH AND A K-12 CURRICULUM DEVELOPED IN COORDINATION WITH NATIVE AMERICAN COMMUNITIES. THE NATURAL FACE OF NORTH AMERICA WILL BE THE MOST COMPREHENSIVE PUBLIC RESOURCE FOR THE MAXIMILIAN-BODMER EXPEDITION, PROVOKING NEW AND INDIGENOUS-CENTERED UNDERSTANDINGS OF NINETEENTH-CENTURY AMERICA ON THE CUSP OF IMMENSE CULTURAL CHANGE.]

PHYSIOLOGICAL AND BIOMECHANICAL ANALYSES OF PARKINSONIAN RIGIDITY

UNIVERSITY CENTER

PHARMACOLOGY OF ANTIRETROVIRAL NANOPARTICLE MICELLES

RUI: COMPLEX DYNAMICS IN GLASS-FORMING OXIDE MELTS

CHARACTERIZING UPSTREAM REGULATORS OF GLUCOSYLCERAMIDE METABOLISM FOR PARKINSON'S DISEASE AND LEWY BODY DEMENTIA - PARKINSON’S DISEASE (PD)-ASSOCIATED DEMENTIA AND LEWY BODY DEMENTIA (LBD) INCIDENCE IS HIGH AMONG THE AGED POPULATION WITH 1% OF THOSE OVER 60 AND 4% OF THOSE OVER 80. MUTATIONS IN THE GBA GENE REPRESENT ONE OF THE MOST COMMON GENETIC RISK FACTORS FOR PD AND LBD. GBA ENCODES THE LYSOSOMAL ENZYME GLUCOCEREBROSIDASE (GCASE) WHICH CONVERTS GLUCOSYLCERAMIDE TO CERAMIDE AND GLUCOSE, AND PD PATIENTS WITH GBA MUTATIONS HAVE EARLIER ONSET OF DISEASE AND GREATER COGNITIVE DECLINE. MUTATIONS IN GBA LEADING TO PARKINSON’S LEAD TO A REDUCTION IN GCASE ACTIVITY, AND GCASE ACTIVITY IS ALSO SIGNIFICANTLY DECREASED IN THE SUBSTANTIA NIGRA AND ANTERIOR CINGULATE CORTEX IN SPORADIC PD AND LBD CASES, SUGGESTING A CRITICAL ROLE FOR GCASE ACTIVITY IN THE PATHOPHYSIOLOGY OF PD AND LBD. IMPORTANTLY, GLUCOSYLCERAMIDE HAS BEEN SHOWN TO PROMOTE AGGREGATION OF ALPHA-SYNUCLEIN, LEADING TO LEWY BODY FORMATION. WHILE THERE IS NO CURE OF PD OR LBD, TREATMENT IS TARGETED PRIMARILY TO IMPROVE SYMPTOMS, INCLUDING L-DOPA AND OTHER DOPAMINE AGONISTS. HOWEVER, AS NEURONAL LOSS WITHIN THE SUBSTANTIA NIGRA CONTINUES, THE EFFECTIVENESS OF DOPAMINE TARGETED THERAPIES IS GREATLY REDUCED. THEREFORE, IDENTIFYING MECHANISMS TO INCREASE GBA ACTIVITY MAY BE AN IDEAL METHOD FOR THERAPEUTIC INTERVENTION FOR THOSE PATIENTS HARBORING MUTANT GBA OR REDUCED GCASE ACTIVITY. HOWEVER, THE UPSTREAM MECHANISMS REGULATING GBA ACTIVITY REMAIN UNKNOWN. WE RECENTLY DISCOVERED THAT THE S- ADENOSYLMETHIONINE (SAM) SYNTHETASE MAT2A MAY NEGATIVELY REGULATE GBA ACTIVITY THEREBY SUGGESTING THAT INHIBITION OF MAT2A MAY SERVE AS A NOVEL MECHANISM TO UPREGULATE GCASE ACTIVITY AND PROVIDE A NEW TREATMENT STRATEGY FOR PD AND LBD. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE THAT MAT2A NEGATIVELY REGULATES GBA AND THEREFORE TARGETING MAT2A FOR INHIBITION MAY RESTORE GBA ACTIVITY IN INDIVIDUALS WITH PD AND LBD CARRYING MUTATIONS IN GBA. WE ANTICIPATE RESULTS IN THIS STUDY WILL DEFINE THE MOLECULAR MECHANISM BY WHICH MAT2A CONTROLS GBA TO INFLUENCE GLUCOSYLCERAMIDE LEVELS WHICH ARE INTIMATELY LINKED TO PD AND LBD, ASSESS WHETHER REDUCED GLUCOSYLCERAMIDE IN RESPONSE TO MAT2A INHIBITION WILL SUPPRESS ALPHA- SYNUCLEIN AGGREGATION AND TOXICITY, AS WELL AS TO IDENTIFY NEW CANDIDATE GENES INVOLVED IN THIS PATHWAY WHICH COULD SERVE AS ADDITIONAL POTENTIAL THERAPEUTIC TARGETS FOR PD AND LBD. THESE STUDIES WILL DETERMINE UPSTREAM REGULATORY MECHANISMS CONTROLLING GLUCOSYLCERAMIDE METABOLISM CONTRIBUTING TO PD AND LBD IN BOTH GBA-ASSOCIATED PD AS WELL AS PATIENTS WHO HAVE ALTERED GCASE ACTIVITY IN THE ABSENCE OF GBA MUTATIONS. FURTHERMORE, THESE STUDIES WILL WELL SERVE AS PROOF-OF-PRINCIPLE FOR TARGETING MAT2A AS A NOVEL PD AND LBD THERAPEUTIC STRATEGY.

FLT3-LIGAND, IMMUNOMODULATION AND THERAPY IN ASTHMA

OBSERVATIONS AND MODELING OF OROGRAPHIC CUMULUS DEVELOPMENT USING DATA COLLECTED DURING CUPIDO 2006

SINGLET O2 FROM VAN DER WAALS COMPLEXES AND THE COMPETITION BETWEEN PRODUCT CHANNELS -THIS PROJECT, JOINTLY FUNDED BY THE CHEMICAL STRUCTURE, DYNAMICS, AND MECHANISMS-A (CSDM-A) PROGRAM IN THE CHEMISTRY DIVISION AND THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR), PROVIDES SUPPORT FOR PROFESSOR BRADLEY PARSONS AND HIS RESEARCH GROUP AT CREIGHTON UNIVERSITY TO INVESTIGATE THE PRODUCTION OF EXCITED OXYGEN SPECIES FROM MOLECULAR CLUSTERS THAT ARE IRRADIATED WITH LIGHT. THE RESEARCH TEAM CREATES ISOLATED CLUSTERS CONSISTING OF AN OXYGEN MOLECULE AND AN ORGANIC OR BIOLOGICALLY RELEVANT MOLECULE. EXCITING THE CLUSTERS USING VISIBLE OR ULTRAVIOLET LASER LIGHT PRODUCES OXYGEN SPECIES THAT ARE DETECTED USING MASS SPECTROMETRY AND A TECHNIQUE CALLED VELOCITY MAP IMAGING (VMI) IN ORDER TO MEASURE THE ENERGY RELEASED DURING THE REACTION. BY ANALYZING THE EXPERIMENTAL DATA, THE TEAM SEEKS TO UNDERSTAND HOW THE ORGANIC MOLECULE INFLUENCES THE RATIO OF DIFFERENT OXYGEN SPECIES FORMED FROM THE IRRADIATED COMPLEXES, WITH A PARTICULAR EMPHASIS ON CLUSTERS LEADING TO HIGHLY REACTIVE OXYGEN MOLECULES FORMED IN THE LOWEST EXCITED STATE, CALLED SINGLET OXYGEN. SINGLET OXYGEN IS A POTENT OXIDIZING SPECIES THAT HAS APPLICATIONS IN THE TREATMENT OF CANCER USING PHOTODYNAMIC THERAPY (PDT) AND IN THE DISINFECTION OF WATER. THE BROADER IMPACTS OF THE WORK INCLUDE POTENTIAL IMPLICATIONS FOR THESE APPLICATIONS BASED ON NEW DEVELOPMENTS MADE POSSIBLE THROUGH A BETTER UNDERSTANDING OF SINGLET OXYGEN PRODUCTION USING VISIBLE LIGHT. ADDITIONALLY, THE PROJECT PREPARES UNDERGRADUATE RESEARCH STUDENTS FOR CAREERS IN SCIENCE BY GIVING THEM HANDS-ON TRAINING IN ADVANCED RESEARCH METHODS. THE PARSONS RESEARCH TEAM WILL USE SUPERSONIC EXPANSION TO FORM WEAKLY BOUND COMPLEXES BETWEEN MOLECULAR OXYGEN AND HIGH MOLECULAR-WEIGHT ORGANIC CHROMOPHORES. THE RESULTING SUPRAMOLECULAR COMPLEXES WILL BE EXCITED WITH LIGHT RANGING BETWEEN 213 AND 680 NM IN ORDER TO PROBE THE WAVELENGTH-DEPENDENT PHOTOCHEMICAL DECOMPOSITION MECHANISM. DEPENDING ON THE ENERGY OF THE TRIPLET STATE IN THE CHROMOPHORE AND THE EXCITATION ENERGY, THE PHOTOEXCITED COMPLEX MAY DISSOCIATE DIRECTLY TO FORM SINGLET OXYGEN MOLECULES, SINGLET O2, OR THROUGH COMPETING PRODUCT CHANNELS THAT RESULT IN THE FORMATION OF EITHER TRIPLET OXYGEN ATOMS, O(3P), OR SINGLET O2 DUE TO AN AVOIDED CROSSING BETWEEN TWO EXCITED STATES. THE TEAM WILL PROBE EITHER THE SINGLET O2 OR O(3P) PRODUCTS USING RESONANCE-ENHANCED MULTIPHOTON IONIZATION (REMPI) COUPLED WITH MASS SPECTROMETRY AND VELOCITY MAP ION IMAGING (VMI). THE COMBINATION OF REMPI SPECTROSCOPY AND VMI IDENTIFIES THE INTERNAL STATE OF THE OXYGEN PRODUCT. BY ANALYZING CHANGES IN BRANCHING BETWEEN PRODUCT CHANNELS DUE TO THE CHROMOPHORE TRIPLET-STATE ENERGY AND THE EXCITATION ENERGY, THE TEAM WILL EXAMINE THE SINGLET O2 FORMATION MECHANISM AND THE ROLE PLAYED BY A HYPOTHESIZED AVOIDED CROSSING. THE SCIENTIFIC BROADER IMPACT OF THE WORK IS EXPECTED TO INCLUDE A BETTER UNDERSTANDING OF FUNDAMENTAL REACTION DYNAMICS, AS WELL AS IMPLICATIONS FOR UNDERSTANDING THE MECHANISMS RESPONSIBLE FOR THE PRODUCTION OF SINGLET OXYGEN USING VISIBLE LIGHT. 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.

PROBIOTIC PROPHYLAXIS OF VENTILATOR-ASSOCIATED PNEUMONIA

WILDLIFE SERVICES PROTECTION OF NATURAL RESOURCES INITIATIVE - AWARD PURPOSE: IMPROVE THE MANAGEMENT OF WILD CERVID CWD-AFFECTED AREAS. ACTIVITIES TO BE PERFORMED: EVALUATING THE EFFECTIVENESS OF SORBENTS ON CWD PRION CONFINEMENT. ESTABLISHING COMPUTATIONAL SIMULATION FOR SORBENT EVALUATION AND SELECTION. DELIVERABLES AND EXPECTED OUTCOMES: THE OUTCOMES MAY RESULT IN RE-EVALUATION OF THE RISK OF ACCEPTING CERVID CARCASSES AND WASTES AND THE IMPACT OF THE CURRENT LANDFILLING MANAGEMENT BY REQUIRING CWD DIAGNOSIS BEFORE ACCEPTING THEM. IT MAY ALSO IMPACT CURRENT LEACHATE DISPOSAL BY MONITORING THE PRESENCE OF CWD PRIONS BEFORE TRANSFER TO WASTEWATER TREATMENT PLANTS, DISCHARGE TO WATER BODIES, OR REUSE. ADDITIONALLY, IT MAY IMPACT ON-FARM DISPOSAL PRACTICES IF THE CWD STATUS OF THE CARCASSES AND WASTES IS NOT AVAILABLE. INTENDED BENEFICIARY(IES): THE OUTCOMES OF THE PROJECT WILL DIRECTLY BENEFIT LANDFILL OWNERS AND MANAGERS, PROVIDING INFORMATION TO BETTER EVALUATE THE RISKS OF ACCEPTING CERVID CARCASSES AND WASTES, OR TO BETTER MANAGE THEM WITH ADDITIONAL PRACTICES AND MONITORING. IT WILL ALSO BENEFIT AGENCIES SUCH AS DNR, USDA, AND EPA FOR RELEVANT POLICY DEVELOPMENT OR MODIFICATION REGARDING SAFE DISPOSAL OF CERVID CARCASSES AND WASTES TO BETTER CONTROL CWD TRANSMISSION. SUBRECIPIENT ACTIVITIES: THE UNIVERSITY OF NEBRASKA-LINCOLN WILL BE RESPONSIBLE FOR TASKS IN OBJECTIVE 1 INCLUDING MUNICIPAL SOLID WASTE CREATION AND CHARAC TERIZATION, AND OPERATION OF LABORATORY SCALE REACTORS TO SIMULATE CWD BURIAL. THEY WILL COORDINATE LEACHATE COLLECTION ACTIVITIES FROM A LOCAL OPERATING LANDFILL AND DELIVER SAMPLES FOR PRION ANALYSIS TO CREIGHTON UNIVERSITY. AT MICHIGAN STATE UNIVERSITY WE WILL DIRECTLY PERFORM STUDIES IN OBJECTIVE 2. SPECIFICALLY, THEY WILL COMPUTATIONALLY SIMULATE THE BINDING OF CWD PRION STRUCTURES WITH MODEL SORBENT SURFACES USING MOLECULAR DYNAMICS. THEY WILL PRODUCE THE FREE ENERGIES OF BINDINGS AND REVEAL BINDING MECHANISMS BETWEEN CWD PRIONS AND REPRESENTATIVE SORBENT SURFACES. ALL RESULTS FROM OUR STUDIES WILL BE COMPLEMENTARY TO THE WORK IN OBJECTIVE 1 AND HELP TO SELECT THE MOST EFFECTIVE SORBENTS AND GENERALIZE THE EXPERIMENTAL RESULTS TO BROADER SETTINGS. THEY WILL BE REGULARLY DISSEMINATED TO ALL INVOLVED PARTICIPANTS OF THIS PROPOSAL.

COMPARISON OF NADH FLIM AND INTENSITY IMAGING TO ASSESS CELLULAR ENERGETICS

LIGHT SCATTERING & FLOURESCENCE STUDY OF SUGAR SOLUTIONS AS CRYOPROTECTIVE AGENTS

NURSE FACULTY LOAN PROGRAM

STANDARD GRANT: HEALTH PROFESSIONS EDUCATION STRATEGIES FOR BROADENING PARTICIPATION IN PHYSICAL THERAPY AND OCCUPATIONAL THERAPY -AFTER 1960, HEALTHCARE INSTITUTIONS AND SPECIALTIES EXPANDED RAPIDLY, BUT ACCESS TO HEALTH PROFESSIONS EDUCATION AND CAREERS REMAINED LIMITED FOR MANY AMERICANS. THE RESULTING LACK OF BROAD PARTICIPATION IN HEALTH PROFESSIONS CONTRIBUTED TO THE LIMITED AVAILABILITY AND QUALITY OF CARE FOR MANY MARGINALIZED POPULATIONS. THIS PROJECT EXAMINES THE HISTORY OF HEALTH PROFESSIONS, WITH A FOCUS ON PHYSICAL THERAPY AND OCCUPATIONAL THERAPY EDUCATION. EACH OF THESE FIELDS WAS HEAVILY INFLUENCED BY APPROACHES TO MEDICAL EDUCATION REFORMS STEMMING FROM THE FLEXNER REPORT (1910). BY CONTRAST, THE NURSING PROFESSION ADOPTED ALTERNATIVE MODELS, WHICH PROMOTED BROADER PARTICIPATION IN NURSING EDUCATION AND CAREER ADVANCEMENT. THESE APPROACHES HELPED TO MAKE THE NURSING PROFESSION MORE ACCESSIBLE TO PEOPLE FROM LESS PRIVILEGED EDUCATIONAL AND FINANCIAL BACKGROUNDS, AND EVENTUALLY LED TO NURSING BECOMING MORE DEMOGRAPHICALLY REPRESENTATIVE THAN OTHER US HEALTH FIELDS AT EVERY CAREER LEVEL. IN THIS HISTORY OF MEDICINE PROJECT, THE INVESTIGATORS EXPLORE PATTERNS OF PARTICIPATION IN PHYSICAL THERAPY AND OCCUPATIONAL THERAPY EDUCATION. SCIENCE AND TECHNOLOGY STUDIES SCHOLARS HAVE PRIMARILY FOCUSED ON MEDICAL EDUCATION, WITH A PARALLEL LITERATURE ON NURSING. IN COMPARISON, VERY LITTLE ATTENTION HAS BEEN GIVEN TO SMALLER AND LESS WELL-KNOWN HEALTH PROFESSIONS. THERE IS A GREAT NEED FOR WIDE-RANGING ANALYSES OF THE BROADER SYSTEM OF U.S. HEALTH PROFESSIONS, INCLUDING PHYSICAL THERAPY AND OCCUPATIONAL THERAPY. DRAWING ON ARCHIVAL SOURCES, PUBLISHED REPORTS, AND ORAL HISTORY INTERVIEWS, THE INVESTIGATORS EXAMINE INITIATIVES THAT SOUGHT TO ENHANCE EDUCATIONAL ACCESSIBILITY AND CAREER MOBILITY IN PHYSICAL THERAPY AND OCCUPATIONAL THERAPY, AND THE ROLE OF ACADEMIC AND PROFESSIONAL INSTITUTIONS IN CREATING BARRIERS TO THESE EFFORTS. AS PART OF THIS, THE INVESTIGATORS EXPLORE THE EVOLVING STATUS AND INSTITUTIONAL CHARACTERISTICS OF PHYSICAL THERAPY AND OCCUPATIONAL THERAPY EDUCATION SINCE 1960, AND THE CORRELATION BETWEEN INCREASED ACCESSIBILITY AND THE DEMOGRAPHIC REPRESENTATION ACROSS STUDENTS AND PRACTITIONERS IN THESE FIELDS. RESULTS FROM THIS RESEARCH WILL BE DIRECTLY SHARED WITH HEALTH PROFESSIONS EDUCATORS THROUGH A VARIETY OF ACADEMIC FORUMS. 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.

RUI:CAS:REACTION DYNAMICS OF ANDERSON-TYPE POLYOXOMETALATE IONS IN AQUEOUS SOLUTION: RELATING SOLID-STATE STRUCTURES WITH SOLUTION-STATE PROPERTIES -WITH SUPPORT FROM THE CHEMICAL STRUCTURE, DYNAMICS & MECHANISMS-B (CSDM-B) PROGRAM OF THE CHEMISTRY DIVISION AND THE ESTABLISHED PROGRAM TO STIMULATE COMPETITIVE RESEARCH (EPSCOR), ERIC VILLA OF THE DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY AT CREIGHTON UNIVERSITY IS FOCUSED ON DETERMINING HOW THE STRUCTURAL FEATURES OF SIMPLE POLYOXOMETALATE IONS (PREDOMINATELY-ANIONIC METAL-OXIDE CLUSTERS) AFFECT THEIR REACTIVITY IN AQUEOUS SOLUTION. THE RANGE OF APPLICATIONS FOR THESE POLYOXOMETALATE (POM) IONS IS WIDE, WITH PROPERTIES INCLUDING ANTIVIRAL/ANTITUMOR ACTIVITY, ACID CATALYSIS, WATER OXIDATION CATALYSIS, MRI CONTRAST AGENTS, LUMINESCENT AND MAGNETIC MATERIALS, AND POTENTIALLY RADIOACTIVE WASTE TREATMENT. THE GOAL OF THIS RESEARCH IS TO UNDERSTAND HOW POMS REACT IN AQUEOUS SOLUTION AND WHAT CONTROLS THEIR REACTIVITY IN SOLUTION. THE RESULTING DATA FROM THIS PROJECT WILL ALLOW FOR POMS TO BE BETTER TUNED FOR THESE IMPORTANT APPLICATIONS. THIS PROJECT ENGAGES UNDERGRADUATE STUDENTS IN FUNDAMENTAL RESEARCH AND GAINS THEM TRAINING IN INORGANIC CHEMISTRY, WHICH INCLUDES SEVERAL ANALYTICAL TECHNIQUES AND INSTRUMENTAL METHODS. UNDERGRADUATE STUDENTS WILL ALSO BE INVOLVED IN THE SET-UP AND DELIVERY OF A MIDDLE SCHOOL CHEMISTRY SUMMER CAMP FOCUSING ON INORGANIC CHEMISTRY. THIS PROJECT FOCUSES ON UNDERSTANDING THE STABILITY AND REACTIVITY OF ANDERSON-TYPE POM IONS (XMO6O24Z-) IN AQUEOUS SOLUTION. HERE, THE PRIMARY GOAL IS TO PINPOINT HOW CHANGES IN THE IDENTITY OF ATOM X ALTERS THE ION?S PROPERTIES IN AQUEOUS SOLUTION TO BE ABLE TO CORRELATE STRUCTURE-PROPERTY RELATIONSHIPS. THE ANDERSON-TYPE POM HAS ONLY THREE TYPES OF STRUCTURAL OXYGEN, MAKING IT AN IDEAL STRUCTURE FOR UNDERGRADUATE RESEARCHERS TO APPRECIATE THE COMPLEXITIES OF AQUEOUS SOLUTION REACTIVITY. IMPORTANTLY, THE GENERAL REACTIVITY TRENDS OF POMS IN AQUEOUS MEDIA HAVE NOT BEEN CLEARLY IDENTIFIED AND STILL HAVE MANY UNANSWERED QUESTIONS: 1) WHAT TYPES OF OXYGEN SITES EXCHANGE THE FASTEST? 2) WHAT AFFECTS ONLY A SINGLE SITE VERSUS WHAT AFFECTS THE ENTIRE UNIT? 3) WHAT STRUCTURAL PROPERTIES (BOND LENGTHS, CHARGE STATE OR PROTONATION) CORRELATE WITH REACTIVITY? 4) HOW GENERAL ARE THE TRENDS OBSERVED? 5) CRITICALLY, CAN THE REACTIVITY OF POMS IN WATER BE EASILY PREDICTED? 6) FINALLY, HOW DO SINGLE, TARGETED METAL SUBSTITUTIONS AFFECT THE ABILITY OF THE POM TO MAKE STABLE COMPLEXES WITH SURROGATES OF RADIOACTIVE CATIONS FOR REMEDIATION PURPOSES? THE SMALL ANDERSON-TYPE POMS WILL ALLOW UNDERGRADUATE RESEARCHERS TO CONFIDENTLY PROBE THE ABOVE QUESTIONS AND THE DATA COLLECTED WILL ALLOW FOR THE ABILITY TO BETTER TUNE THESE IONS TO THEIR IMPRESSIVE SET OF APPLICATIONS. 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.

LEAPS-MPS: COMPUTATIONAL MODELING OF METAL ION MEDIATED DNA ADSORPTION TO FUNCTIONALIZED SURFACES -THIS AWARD IS BEING FUNDED BY THE MPS-LEAPS (LAUNCHING EARLY-CAREER ACADEMIC PATHWAYS) PROGRAM AND MANAGED BY THE BROADENING PARTICIPATION (CHE-BP) PROGRAM IN THE DIVISION OF CHEMISTRY. PROFESSOR MAKENZIE LONG AND UNDERGRADUATE STUDENTS AT CREIGHTON UNIVERSITY WILL USE COMPUTER SIMULATIONS TO IDENTIFY HOW DIVALENT METAL IONS HELP DNA BIND TO A NEGATIVELY CHARGED SURFACE AND WHY DIFFERENT DIVALENT METAL IONS YIELD DIFFERENT RESULTS. THIS PROJECT IDENTIFIES HOW DIVALENT METAL IONS TUNE DNA BEHAVIOR, SUCH AS ITS ABILITY TO SELF-ASSEMBLE AND BIND TO OTHER NANOSCALE STRUCTURES. THE PHYSICAL INSIGHT GAINED FROM THIS PROJECT MAY BE USED TO IMPROVE THE PERFORMANCE OF DNA-BASED NANOTECHNOLOGY, WHICH HAS APPLICATIONS IN SENSING, IMAGING, AND MEDICINE. THE PROJECT ESTABLISHES A NANOSCIENCE SUMMER CAMP PROGRAM AT CREIGHTON UNIVERSITY FOR MIDDLE-SCHOOL STUDENTS. THIS PROJECT LEVERAGES PARTNERSHIPS WITH LOCAL NON-PROFIT ORGANIZATIONS TO RECRUIT SUMMER CAMP PARTICIPANTS AND TEACHING ASSISTANTS FROM DIVERSE STUDENT POPULATIONS, INCLUDING THOSE FROM GROUPS HISTORICALLY UNDERREPRESENTED IN THE MATHEMATICAL AND PHYSICAL SCIENCES. DR. LONG AND HER UNDERGRADUATE STUDENTS WILL USE CLASSICAL MOLECULAR DYNAMICS SIMULATIONS TO MODEL DNA ADSORPTION TO A CARBOXYLATE-TERMINATED MONOLAYER MEDIATED BY ALKALINE EARTH METAL IONS. PUBLISHED LENNARD-JONES POTENTIALS AND CHARGE-SCALING APPROACHES FOR MODELING ALKALINE EARTH METAL ION BINDING TO CARBOXYLATE GROUPS WILL BE SYSTEMATICALLY TESTED TO REPRODUCE BINDING FREE ENERGIES MEASURED USING ATOMIC FORCE MICROSCOPY. SIMULATIONS WILL BE ANALYZED TO IDENTIFY THE MECHANISM OF ALKALINE EARTH METAL ION MEDIATED DNA ADSORPTION AND THE ORIGIN OF ITS ION-SPECIFIC EFFECTS. THE SUMMER CAMP PROGRAM WILL BE ASSESSED IN ITS ABILITY TO INCREASE THE NUMBER OF STUDENTS FROM UNDERREPRESENTED GROUPS PARTICIPATING IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS (STEM) ACTIVITIES AND ITS EFFECT ON PARTICIPANTS? STEM IDENTITIES AND INTERESTS. 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.

REBUILDING THE ASTRONOMY CURRICULUM AROUND ROBOTIC TELESCOPE OBSERVATIONS AND ACTIVE LEARNING EXERCISES

NEBRASKA VICTIM ASSISTANCE ACADEMY

NOVEL TARGETS FOR TREATMENT OF PSEUDOMONAS AERUGINOSA

NOISE-INDUCED HEARING LOSS ALTERS EFFERENT CONTROL OF CENTRAL AUDITORY HYPERACTIVITY - PROJECT SUMMARY HEARING LOSS AFFECTS ~20% OF THE GLOBAL POPULATION, ALTERING BOTH PERIPHERAL AND CENTRAL AUDITORY SYSTEMS. IT IS CLOSELY LINKED TO AUDITORY DISORDERS SUCH AS TINNITUS AND HYPERACUSIS. WHILE EXTENSIVE RESEARCH HAS EXAMINED COCHLEAR AND ASCENDING PATHWAY DYSFUNCTION, THE AUDITORY EFFERENT SYSTEM – RESPONSIBLE FOR BRAIN-TO-EAR FEEDBACK – REMAINS UNDEREXPLORED. LATERAL OLIVOCOCHLEAR (LOC) NEURONS, THE MOST ABUNDANT EFFERENT NEURONS, PROMOTE HEARING PROTECTION AND RECOVERY AFTER NOISE EXPOSURE. THIS FUNCTION MAY BE RELATED TO THEIR INCREASED NEUROTRANSMITTER AND NEUROPEPTIDE EXPRESSION FOLLOWING NOISE-INDUCED HEARING LOSS (NIHL). HOWEVER, HOW THESE CHANGES INFLUENCE COCHLEAR FUNCTION DEPENDS ON ELECTROPHYSIOLOGICAL PROPERTIES OF LOC NEURONS, WHICH REMAIN POORLY UNDERSTOOD. WHETHER LOC SYSTEM CHANGES ARE ADAPTIVE OR PATHOLOGICAL FOR AUDITORY FUNCTION IS ALSO UNKNOWN. THIS PROPOSAL ADDRESSES THESE GAPS BY: (AIM 1) DETERMINING HOW NIHL ALTERS GENE EXPRESSION AND LOC NEURON ACTIVITY, AND (AIM 2) ASSESSING HOW NIHL-INDUCED LOC ALTERATIONS CONTRIBUTE TO CENTRAL HYPERACTIVITY. THE CENTRAL HYPOTHESIS IS THAT NIHL ELEVATES LOC ACTIVITY AND DRIVES CORRELATED CHANGES IN GENE EXPRESSION, WITH THE TWO PROCESSES ACTING INTERDEPENDENTLY TO DRIVE COMPENSATORY ADJUSTMENTS IN COCHLEAR OUTPUT AND MITIGATE CENTRAL HYPERACTIVITY. RECENTLY, I DISCOVERED A UNIQUE INFRA-SLOW BURST FIRING PATTERN OF ELECTRICAL ACTIVITY IN LOC NEURONS, DRIVEN BY CA2+ CHANNELS, WHICH MAY REGULATE NEUROPEPTIDE RELEASE ONTO SPIRAL GANGLION NEURON DENDRITES. HENCE, I PREDICT THAT NIHL-INDUCED NEUROPEPTIDE EXPRESSION INCREASE CORRESPONDS TO ALTERED BURST FIRING AND CA2+ CHANNEL GENE EXPRESSION IN LOC NEURONS. TO TEST THIS, PATCH-SEQ WILL CORRELATE GENE EXPRESSION WITH ELECTROPHYSIOLOGICAL PROPERTIES AT THE SINGLE-CELL LEVEL. IF ELEVATED LOC ACTIVITY PLAYS A COMPENSATORY ROLE FOLLOWING NIHL, LOSS OF SUCH ACTIVITY COULD EXACERBATE THE CENTRAL CONSEQUENCES OF NIHL. TO TEST THIS, IN VIVO SINGLE-UNIT RECORDINGS FROM THE INFERIOR COLLICULUS (IC) WILL ASSESS CENTRAL HYPERACTIVITY IN YOUNG ADULT MICE WITH INTACT OR ABLATED LOC SYSTEMS, TAKING ADVANTAGE OF RECENTLY-DEVELOPED GATA3FLPO;UCNCRE;ROSA26FLTG;MAPTDS-DTR MICE THAT ALLOWS SELECTIVE ABLATION OF LOC NEURONS BY DIPHTHERIA TOXIN (DTX) TREATMENT WITHOUT AFFECTING HEARING THRESHOLDS. I PREDICT THAT LOC-ABLATED MICE WILL SHOW HIGHER SPONTANEOUS IC FIRING FOLLOWING NIHL COMPARED TO LOC-INTACT MICE. AN ADDITIONAL BENEFIT OF THIS APPROACH IS THE ABILITY TO ASSESS LOC FUNCTION IN REGULATING CENTRAL GAIN WITHOUT NIHL; IC RECORDINGS IN ABLATED MICE ARE ALSO EXPECTED TO SHOW ELEVATED BASELINE FIRING RATES. THIS PROJECT WILL UNCOVER THE CELLULAR MECHANISMS DRIVING ALTERED EFFERENT ACTIVITY IN PATHOLOGICAL CONDITIONS, ESTABLISHING THE ROLE OF EFFERENTS IN CONNECTING HEARING LOSS TO HYPERACTIVITY-RELATED DISORDERS LIKE TINNITUS AND HYPERACUSIS, AND GUIDING NOVEL STRATEGIES FOR FUNCTIONAL RECOVERY.

CHARACTERIZATION OF INTERFERON EPSILON MEDIATED PROTECTION AGAINST TRICHOMONAS VAGINALIS AND ITS SUPPRESSION BY PARASITE EXTRACELLULAR VESICLES - PROJECT SUMMARY / ABSTRACT TRICHOMONAS VAGINALIS (TV) THE CAUSATIVE AGENT OF TRICHOMONIASIS IS THE MOST COMMON NON-VIRAL SEXUALLY TRANSMITTED INFECTION (STI) WITH APPROXIMATELY 150 MILLION NEW PEOPLE INFECTED ANNUALLY. THE CONTINUED EMERGENCE OF DRUG RESISTANT STRAINS OF TV, AND AN EMERGING APPRECIATION OF THE LINK BETWEEN ASYMPTOMATIC TV INFECTIONS WITH INFLAMMATION-DRIVEN PATHOLOGIES AND NEGATIVE EFFECTS ON REPRODUCTIVE HEALTH DEMANDS BETTER UNDERSTANDING OF THIS PREVALENT HUMAN INFECTION. CLINICALLY RELEVANT INFECTION MOST COMMONLY OCCURS IN FEMALE REPRODUCTIVE TRACT (FRT) WHERE IT MUST CONTEND WITH THE UNIQUE MUCOSAL IMMUNE ENVIRONMENT OF THE FRT. THUS, UNDERSTANDING HOW TV SUBVERTS THE HOST CELL IMMUNE RESPONSE, WITH A PARTICULAR FOCUS ON THE UNIQUE IMMUNE ENVIRONMENT OF THE FRT, WILL BE KEY IN ATTEMPTS TO PREVENT PATHOGENESIS BY THE PARASITE. EXTRACELLULAR VESICLES SECRETED BY TV (TVEVS) ARE NOW APPRECIATED AS ONE WAY THE PARASITE CAN ALTER PATHOGENESIS. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT TVEVS PLAY A MAJOR ROLE IN SUPPRESSING HOST CELL IMMUNE RESPONSES THAT WOULD OTHERWISE IMPEDE PARASITE-MEDIATED HOST CELL LYSIS A PROCESS CRITICAL FOR THE ACQUISITION OF NUTRIENTS BY THIS OBLIGATE EXTRACELLULAR PARASITE. TO TEST THIS, I WILL LEVERAGE PRELIMINARY TRANSCRIPTOMIC DATA SHOWING THAT TVEVS DOWN-REGULATE EXPRESSION OF A NON-CANONICAL, TYPE I INTERFERON, IFNΕ AND IN VITRO ASSAYS SHOWING THAT PRETREATMENT OF PROSTATE AND VAGINAL EPITHELIAL CELLS WITH IFNΕ IS PROTECTIVE AGAINST TV-MEDIATED KILLING. IN AIM 1, I WILL CHARACTERIZE THE MECHANISM BY WHICH IFNΕ PROTECTS HOST CELLS FROM TV-MEDIATED CYTOLYSIS. IN AIM 2, I WILL DETERMINE THE MECHANISM BY WHICH TVEVS DISRUPT THE TYPE I IFN PATHWAY. IN ADDITION TO THESE AIMS, I HAVE ESTABLISHED A CAREER DEVELOPMENT STRATEGY THAT SUPPORTS MY RESEARCH GOALS THROUGH A RIGOROUS SCHEDULE OF SCIENTIFIC COMMUNICATION WORKSHOPS AND TRAININGS ON GRANT WRITING, LABORATORY MANAGEMENT, AND LABORATORY MENTORSHIP. THESE ACTIVITIES ARE DESIGNED TO HELP ME SUCCESSFULLY TRANSITION FROM MY POSTDOCTORAL POSITION TO AN INDEPENDENT RESEARCHER STUDYING THE UNIQUE IMMUNE RESPONSE OF THE FRT TO TV.

HUMANITIES AND HEALTH JUSTICE PATHWAYS: FORMING FIRST-GENERATION PROFESSIONALS [THIS PROJECT PROPOSES CREATION OF NEW PATHWAYS (CURRICULAR AND CO-CURRICULAR) THAT INTEGRATE HUMANITIES CONCEPTS WITH THE FIRST-YEAR EXPERIENCE OF CREIGHTON AND ARIZONA STATE UNIVERSITY FIRST-GENERATION PRE-HEALTH UNDERGRADUATES. WITH A FOCUS ON HEALTH JUSTICE THAT PROVIDES CONTEXT FOR THE VALUE OF THE HUMANITIES, OUR APPROACH PREVENTS THE HUMANITIES FROM BECOMING AN AFTERTHOUGHT. BY INTEGRATING HUMANITIES CONTENT WITH THE FIRST YEAR AT CREIGHTON/ASU, STUDENTS WILL BE ON AN EARLY PATH TO BECOMING MORE JUST, HUMANISTIC CARE PROVIDERS. THIS PROVIDES AN ALTERNATIVE TO THE TYPICAL IMMEDIATE HEAVY FOCUS ON SCIENCE COURSES, WHICH CAN DERAIL FIRST-GENERATION STUDENTS WHO ARE DEALING WITH UNIQUE CHALLENGES ALREADY. WE EXPECT STUDENTS IN THIS PROGRAM TO HAVE STRONG RETENTION LEVELS DUE TO THIS OVERALL APPROACH DELIVERED THROUGH HIGH-IMPACT PRACTICES. WITH THIS EARLY FORMATIVE EXPERIENCE, STUDENTS WILL BE WELL-POSITIONED TO BECOME PROVIDERS WHO WILL PROMOTE GREATER HEALTH EQUITY.]

EFFECTIVENESS OF A 6-WEEK HIPPOTHERAPY PROGRAM IN CHILDREN WITH AUTISM SPECTRUM DISORDER

RURAL BUSINESS OPPORTUNITY GRANTS

TYPHOON 9140

STANDARD GRANT: EVOLVING NARRATIVES OF DEVELOPMENTAL DISABILITIES IN POSTWAR CLINICAL PROFESSIONS

COLLABORATIVE RESEARCH: EAGER: ESTABLISHING IMMORTALIZED CELL LINES FROM THE EUROPEAN HONEY BEE, APIS MELLIFERA

REPURPOSING FDA-APPROVED MEK INHIBITOR TRAMETINIB FOR PROTECTION AGAINST CISPLATIN-INDUCED HEARING LOSS - PROJECT SUMMARY/ABSTRACT HEARING LOSS CAUSED BY CISPLATIN OTOTOXICITY AFFECTS 40-60% OF CHEMOTHERAPY PATIENTS RESULTING IN DECREASED QUALITY-OF-LIFE AND DEBILITATING LANGUAGE BARRIERS, YET NO FOOD AND DRUG ADMINISTRATION (FDA)-APPROVED TREATMENT IS CURRENTLY AVAILABLE. CURRENT COMPOUNDS IN PRECLINICAL AND CLINICAL TRIALS PROVIDE ONLY PARTIAL PROTECTION OR ARE ASSOCIATED WITH LIFE-THREATENING SIDE EFFECTS, THUS THERE IS A CLEAR NEED ALTERNATIVE TREATMENT STRATEGY. RECENTLY, BRAF INHIBITOR DABRAFENIB WAS FOUND TO PROTECT FROM CISPLATIN TOXICITY IN VIVO WHEN ADMINISTERED AT CLINICALLY RELEVANT DOSES. ADDITIONAL INHIBITORS OF THE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) PATHWAY, INCLUDING MEK INHIBITOR TRAMETINIB, ALSO PROTECT FROM CISPLATIN TOXICITY IN COCHLEAR EXPLANT MODELS. IMPORTANTLY, A COMBINATION OF DABRAFENIB AND TRAMETINIB IS FDA-APPROVED FOR TREATMENT OF MELANOMA AND MAY BE FAST-TRACKED FOR TREATMENT CISPLATIN-INDUCED HEARING LOSS. THE COMPOUNDS ARE ALSO EFFECTIVE AGAINST BRAIN METASTASES, REVEALING THEY CROSS THE BLOOD-BRAIN BARRIER WHICH IS SIMILAR TO THE BLOOD-LABYRINTH BARRIER IN THE EAR. WE THEREFORE HYPOTHESIZE TRAMETINIB WILL PROTECT AGAINST CISPLATIN-INDUCED OTOTOXICITY IN VIVO AND PROVIDE ENHANCED PROTECTION IN COMBINATION WITH DABRAFENIB. IN AIM 1, WE WILL DETERMINE WHETHER MEK INHIBITOR TRAMETINIB CONFERS PROTECTION FROM CISPLATIN-INDUCED OTOTOXICITY IN MOUSE MODELS. WE WILL TEST WHETHER ORAL TRAMETINIB MITIGATES CISPLATIN OTOTOXICITY IN CBA MOUSE MODELS USING A CLINICALLY RELEVANT MULTI-DOSE, MULTI- CYCLE TREATMENT MODEL. HEARING LOSS WILL BE DETERMINED BY MEASURING AUDITORY BRAINSTEM RESPONSE (ABR) AND DISTORTION PRODUCT OTOACOUSTIC EMISSION (DPOAE) THRESHOLD SHIFTS, ALONG WITH MORPHOLOGICAL ANALYSIS OF COCHLEAR HCS, SUPPORTING CELLS, STRIA VASCULARIS, AND SGNS. VERIFICATION OF TRAMETINIB-MEDIATED MAPK PATHWAY INHIBITION WILL BE OBTAINED BY IMMUNOSTAINING OF ADULT MOUSE COCHLEAE. CONFIRMATION TRAMETINIB CROSSES THE BLOOD-LABYRINTH BARRIER ACHIEVED BY ABOVE MENTIONED IMMUNOSTAINING AND MASS SPECTROMETRY (LC-MS) OF PERILYMPH SAMPLES FROM TRAMETINIB TREATED MICE. IN AIM 2, DETERMINE IF A COMBINATION OF TRAMETINIB AND DABRAFENIB PROVIDE ENHANCED PROTECTION FROM CISPLATIN-INDUCED OTOTOXICITY WE WILL TEST THE DRUG COMBINATION’S PROTECTION FROM OTOTOXICITY, REGULATION OF THE MAPK PATHWAY, AND ABILITY TO CROSS THE BLOOD-LABYRINTH BARRIER AS DESCRIBED IN AIM 1. THIS STUDY WILL BE THE FIRST TO INVESTIGATE THE POTENTIAL OF TRAMETINIB, AND COMBINATION OF TRAMETINIB WITH DABRAFENIB, FOR PROTECTION AGAINST CISPLATIN-INDUCED HEARING LOSS AS WE SEEK TO PROVIDE A ROBUST THERAPEUTIC CANDIDATE FOR A DISORDER WITH NO CURRENT FDA-APPROVED TREATMENT. MOREOVER, CREIGHTON HOSTS 7 AUDITORY RESEARCH LABS WHO REGULARLY COLLABORATE ON PROJECTS, JOINT MEETINGS, AND SEMINARS. ADDITIONALLY, CREIGHTON’S TRANSLATIONAL HEARING CENTER HAS BEEN AWARDED AN NIH-AFFILIATED CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COBRE) GRANT TO TRANSLATE BASIC HEARING LOSS RESEARCH INTO PRACTICAL THERAPIES. IT WILL ALLOW FOR EXPANSION OF CORE FACILITY EQUIPMENT AS WELL AS RECRUIT NEW RESEARCH FACULTY. THUS, CREIGHTON PROVIDES AN EXCELLENT ENVIRONMENT AND SUPPORT FOR JUNIOR SCIENTISTS SEEKING TO BUILD A CAREER IN THE AUDITORY RESEARCH FIELD.

BRIDGING THE ACCESSIBLE TECHNOLOGY GAP: CONNECTING INDUSTRY AND COMPUTING FACULTY FOR THE ADOPTION OF EVIDENCE-BASED TEACHING OF ACCESSIBILITY CONCEPTS -THIS PROJECT AIMS TO SERVE THE NATIONAL INTEREST BY IMPROVING COMPUTER SCIENCE CURRICULA THROUGH INTEGRATION OF ACCESSIBLE TECHNOLOGY CONCEPTS IN FOUNDATIONAL COMPUTER SCIENCE COURSES. PROVIDING ACCESSIBILITY IN SOFTWARE APPLICATIONS AND WEB SITES TO ENABLE USE BY PEOPLE WITH DISABILITIES IS OFTEN AN AFTERTHOUGHT, AND INACCESSIBLE APPLICATIONS CAN DISADVANTAGE LARGE NUMBERS OF PEOPLE. THIS LEVEL II ENGAGED STUDENT LEARNING PROJECT INTENDS TO SCALE UP INSTRUCTION OF ACCESSIBLE TECHNOLOGY CONCEPTS BY ENGAGING FACULTY IN PEDAGOGY-FOCUSED DEVELOPMENT WORKSHOPS AND VIRTUAL SUPPORT SESSIONS THROUGHOUT THE YEAR. INTEGRATING INSTRUCTION ON ACCESSIBLE TECHNOLOGY CONCEPTS INTO EXISTING FOUNDATIONAL COURSES HAS THE POTENTIAL TO EXPAND THE NUMBER OF STUDENTS REACHED AND AID IN ADOPTION SINCE NEW COURSES WILL NOT NEED TO BE DEVELOPED. THIS IN TURN HAS THE POTENTIAL TO POSITIVELY IMPACT PREPARATION OF THE WORKFORCE TO DEVELOP TECHNOLOGY FOR A WIDE VARIETY OF PEOPLE. THE WORKSHOPS WILL BE OFFERED IN BOTH VIRTUAL AND IN-PERSON FORMATS TO MEET THE NEEDS OF A RANGE OF FACULTY FROM DIFFERENT TYPES OF INSTITUTIONS. THE PROJECT BUILDS ON PRIOR WORK BY THE PROPOSERS WHERE THEY DEVELOPED ACCESSIBLE TECHNOLOGY RELATED LEARNING OUTCOMES AND PROVIDED ONE-ON-ONE PROFESSIONAL DEVELOPMENT TO HELP FACULTY DEVELOP ASSIGNMENTS THAT INCORPORATE ACCESSIBLE TECHNOLOGY IN THEIR COURSES. AN IMPORTANT GOAL OF THIS PROJECT IS TO ALIGN LEARNING OBJECTIVES WITH INDUSTRY NEEDS THROUGH A DELPHI PANEL OF INDUSTRY EXPERTS. THE PROJECT TEAM WILL INVESTIGATE THREE RESEARCH QUESTIONS: WHETHER THE TECHNICAL ACCESSIBILITY LEARNING OUTCOMES ALIGN WITH INDUSTRY NEEDS; THE EFFICACY OF THE WORKSHOPS FOR DISSEMINATING KNOWLEDGE ABOUT, AND PEDAGOGIES FOR, TEACHING TECHNICAL ACCESSIBILITY CONCEPTS; AND WHETHER THE ASSIGNMENTS DEVELOPED THROUGH THEIR WORKSHOPS ACHIEVE DESIRED GAINS IN STUDENT LEARNING. THIS PROJECT WILL EMPLOY EMPIRICAL EVALUATION TO MEASURE FACULTY TRAINING EFFECTIVENESS AND ITS IMPACT ON STUDENT SUCCESS. THE NSF IUSE: EDU PROGRAM SUPPORTS RESEARCH AND DEVELOPMENT PROJECTS TO IMPROVE THE EFFECTIVENESS OF STEM EDUCATION FOR ALL STUDENTS. THROUGH THE ENGAGED STUDENT LEARNING TRACK, THE PROGRAM SUPPORTS THE CREATION, EXPLORATION, AND IMPLEMENTATION OF PROMISING PRACTICES AND TOOLS. 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.

LINCRNAS AND AR REACTIVATION AFTER ANDROGEN DEPRIVATION IN PROSTATE CANCER

REPURPOSING MOMELOTINIB FOR THE PREVENTION OF AMINOGLYCOSIDE-INDUCED OTOTOXICITY - PROJECT SUMMARY: AMINOGLYCOSIDE ANTIBIOTICS ARE CONSIDERED AN ESSENTIAL GROUP OF MEDICATIONS BY THE WORLD HEALTH ORGANIZATION. EACH YEAR, THOUSANDS OF CHILDREN AND ADULTS ARE PRESCRIBED AMINOGLYCOSIDES TO TREAT SEVERE GRAM-NEGATIVE BACTERIAL INFECTIONS. THIS IS ESPECIALLY PROMINENT IN THE NEONATAL INTENSIVE CARE UNITS, WHERE OVER 80% OF THE NEONATES ARE PRESCRIBED AMINOGLYCOSIDES. UNFORTUNATELY, ADMINISTRATION OF AMINOGLYCOSIDES CARRIES SUBSTANTIAL RISK FOR LIFE ALTERING SIDE EFFECTS, NAMELY IRREVERSIBLE HEARING LOSS. THIS IS ESPECIALLY EVIDENT IN THE FACT THAT 15 OUT OF EVERY 100 NEONATES WILL EXPERIENCE HEARING LOSS, AS COMPARED TO THE 1 TO 3 OUT OF EVERY 1,000 BABIES WHO ARE BORN FULL TERM. HEARING LOSS ALTERS AN INDIVIDUAL’S ABILITY TO COMMUNICATE AND IS ASSOCIATED WITH FEELINGS OF ISOLATION AND DEPRESSION. SUBSTANTIAL EFFORT IS STILL REQUIRED TO IDENTIFY THE FIRST FDA APPROVED THERAPEUTIC FOR PREVENTION OF AMINOGLYCOSIDE RELATED OTOTOXICITY. WE ARE PROPOSING THIS STUDY WITH THE LONG-TERM GOAL OF PROVIDING A THERAPEUTIC TO COMBAT THIS OTOTOXIC SIDE EFFECT. TO DATE, WE HAVE COLLECTED PROMISING PRELIMINARY DATA SUGGESTING MOMELOTINIB, A DRUG CURRENTLY WITH FDA FAST TRACK DESIGNATION, COULD BE REPURPOSED FOR THIS USE. IN AIM 1, WE WILL USE AN AMINOGLYCOSIDE TREATED SEPSIS MOUSE MODEL TO PROVIDE PRECLINICAL, FUNCTIONAL HEARING DATA ON THE ABILITY OF MOMELOTINIB TO PREVENT AMINOGLYCOSIDE INDUCED HEARING LOSS. IN OUR EXPERIMENTS PROPOSED IN AIM 2, WE WILL UTILIZE THE WELL-ESTABLISHED AND TRANSLATABLE ZEBRAFISH MODEL ORGANISM TO IDENTIFY THE ESSENTIAL TARGETS AND MECHANISMS OF HAIR CELL PROTECTION BY MOMELOTINIB. THIS PROJECT ADVANCES THE MISSION OF THE NIDCD TO PROMOTE INTERVENTIONS TO TREAT COMMUNICATION AND OTHER DISORDERS. SPECIFICALLY, OUR MECHANISTIC STUDIES IN AIM 2 ADDRESS PRIORITY AREA 2 IN HEARING AND BALANCE RESEARCH TO INCREASE THE UNDERSTANDING AND PATHOGENESIS OF OTOTOXICITY. IN ADDITION, OUR CHARACTERIZATION OF MOMELOTINIB AS A PROMISING PREVENTATIVE TREATMENT FOR AMINOGLYCOSIDE INDUCED HEARING LOSS ADVANCES PRIORITY AREA 3, TO IMPROVE THE DIAGNOSIS, TREATMENT, AND PREVENTION OF HEARING LOSS THROUGH THE DEVELOPMENT THERAPIES TO RESIST CELL DAMAGE. THIS PROJECT WILL BE COMPLETED AT CREIGHTON UNIVERSITY UNDER THE SPONSORSHIP OF THE WELL-ESTABLISHED AUDITORY SCIENTIST, DR. JIAN ZUO. CREIGHTON UNIVERSITY HAS A STRONG HISTORY OF AUDITORY RESEARCH. IT HOUSES A TRANSLATIONAL HEARING CENTER DEDICATED TO RESEARCH PURSUITS IN THE THERAPEUTIC PREVENTION OF HEARING LOSS AND HEARING RESTORATION THROUGH HAIR CELL REGENERATION. THE PHYSICIAN-SCIENTIST PROGRAM AT CREIGHTON UNIVERSITY PROVIDES A WELL-ROUNDED, INTEGRATED CURRICULUM AND TAILORS EDUCATIONAL AND CLINICAL EXPERIENCES TO EACH STUDENT AND THEIR CAREER ASPIRATIONS. SPECIFICALLY, THE GATEWAY PROGRAM AND LONGITUDINAL CLINIC PROVIDE GREAT OPPORTUNITIES FOR STUDENTS TO GAIN EXPOSURE TO THE FIELD THEY ARE GOING TO ENTER. THERE IS ALSO A CLINICAL REFRESHER COURSE OFFERED DURING THE LAST YEAR OF RESEARCH TRAINING, WHICH WILL EASE THE TRANSITION OF THE STUDENTS BACK INTO THE CLINIC. OVERALL, THE STRONG AUDITORY RESEARCH COMMUNITY, UNIQUE TRAINING ENVIRONMENT AND IMPACTFUL RESEARCH PROJECT, ENSURES THAT MY TIME AT CREIGHTON UNIVERSITY WILL FACILITATE MY DEVELOPMENT TO BECOME AN INDEPENDENT PHYSICIAN-SCIENTIST IN THE FIELD OF OTOLARYNGOLOGY.

DEVELOPMENT OF A LONG-TERM IBTRACS DATABASE FOR NEARSHORE TROPICAL CYCLONE ACTIVITY IN THE EASTERN NORTH PACIFIC