Midwestern University

LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

RELIEF AID FOR STUDENTS AND MIDWESTERN UNIVERSITY TO SUPPORT STUDENTS AFFECTED BY COVID-19 PANDEMIC AND EDUCATION INTERUPTION.

RELIEF AID FOR STUDENTS AND MIDWESTERN UNIVERSITY TO SUPPORT STUDENTS AFFECTED BY THE COVID-19 PANDEMIC.

SYSTEMS-BASED PHARMACOLOGIC MODELLING TO ELUCIDATE BETA-LACTAM CLINICAL PHARMACODYNAMICS AND DEFINE OPTIMAL DOSING REGIMENS IN SEVERE PNEUMONIA - PROJECT ABSTRACT HOSPITAL-ACQUIRED PNEUMONIA (HAP) CAUSED BY ANTIBIOTIC-RESISTANT PATHOGENS SUCH AS KLEBSIELLA AEROGENES, KLEBSIELLA PNEUMONIAE, AND PSEUDOMONAS AERUGINOSA ARE RESPONSIBLE TREATMENT FAILURE AND MORTALITY RATES UP TO 50% AND 30%, RESPECTIVELY. BETA-LACTAM ANTIBIOTICS ARE A MAINSTAY FOR THE TREATMENT OF HAP, BUT ANTIBIOTIC RESISTANCE CONTINUES TO ERODE THEIR CLINICAL EFFICACY. IMPORTANTLY, THE EFFICACY OF BETA- LACTAMS DEPENDS ON ACHIEVING ADEQUATE PHARMACOKINETIC-PHARMACODYNAMIC (PK/PD) EXPOSURES; HOWEVER, MANY PATIENTS WITH HAP EXPERIENCE INADEQUATE PK/PD BECAUSE OF CHANGES IN PK CAUSED BY CRITICALLY ILLNESS. PRECISION DOSING STRATEGIES CAN OVERCOME PK VARIABILITY CAUSED BY CRITICAL ILLNESS, BUT PRECISION DOSING REQUIRES ROBUST PK MODELS AND CLINICALLY VALIDATED PK/PD TARGETS; SUCH MODELS AND TARGETS ARE CURRENTLY LACKING FOR PATIENTS WITH HAP. WITHOUT ROBUST PK MODELS AND OPTIMAL PK/PD TARGETS FOR ANTIBIOTIC DOSING, HAP PATIENTS WILL CONTINUE TO EXPERIENCE HIGH RATES OF TREATMENT FAILURE AND DEATH. OUR PROPOSAL WILL ADAPT AND EXTEND THE EXISTING RESEARCH INFRASTRUCTURE OF THE SUCCESSFUL CLINICAL RESPONSE IN PNEUMONIA THERAPY (SCRIPT) SYSTEMS BIOLOGY CENTER TO ROBUSTLY ADDRESS THESE GAPS IN KNOWLEDGE. OUR LONG-TERM GOAL IS TO DEVELOP PRECISION DOSING STRATEGIES THAT OVERCOME PK VARIABILITY CAUSED BY SEVERE ILLNESS. THE PROJECT OBJECTIVE IS TO UTILIZE THE INFRASTRUCTURE, SAMPLES, AND DATA COLLECTED IN SCRIPT TO DEVELOP PK MODELS IN CRITICALLY ILL PATIENTS WITH HAP—THEREBY FACILITATING THE DEVELOPMENT AND VALIDATION OF HAP-SPECIFIC PK/PD MODELS. OUR CENTRAL HYPOTHESIS IS: (1) INADEQUATE BETA-LACTAM PK IS COMMON WITH STANDARD “ONE-SIZE-FITS ALL” HAP DOSING REGIMENS; WHICH (2) INCREASES THE RISK OF RE- INFECTION; THAT IN TURN (3) INCREASES THE LIKELIHOOD OF CLINICAL TREATMENT FAILURE IN HAP. IN AIM 1, WE WILL DEVELOP AND EVALUATE PK MODELS FOR USE IN PRECISION DOSING OF BETA-LACTAMS FOR HAP. IN AIM 2, WE WILL EVALUATE THE IMPACT OF ALVEOLAR BETA-LACTAM PK/PD ON OUTCOMES IN HAP INCLUDING (A) TREATMENT SUCCESS AND (B) PATHOGEN REINFECTION. IN AIM 3, WE WILL IDENTIFY PATIENTS WHO EXPERIENCE ALVEOLAR-PLASMA PK PROFILE DISCORDANCE—MAKING PLASMA A POOR SURROGATE FOR ALVEOLAR CONCENTRATIONS AND PLACING THESE PATIENTS AT RISK OF UNDERDOSING FOR PNEUMONIA TREATMENT—AND DETERMINE CLINICAL RISK FACTORS FOR SUCH DISCORDANCE. OUR STUDY WILL PROVIDE CLINICALLY VALIDATED TOOLS WHICH WILL FACILITATE THE ACTUALIZATION OF PRECISION DOSING FOR PATIENTS WITH HAP. OUR STUDY WILL HAVE A POSITIVE CLINICAL IMPACT BY PROVIDING OPTIMAL PK SAMPLING TIMES, GENERALIZABLE PK MODELS, HAP-SPECIFIC PK/PD TARGETS, AND VALIDATED RISK FACTORS FOR ALVEOLAR- PLASMA PK DISCORDANCE, ALL OF WHICH CAN BE APPLIED AT THE BEDSIDE FOR PATIENTS WITH HAP. THIS RESEARCH IS SIGNIFICANT BECAUSE IT WILL PROVIDE THE TOOLS REQUIRED TO ACHIEVE PRECISION DOSING IN HAP, WHICH WILL ADVANCE THE NIH MISSION TO PROTECT AND IMPROVE THE HEALTH OF PATIENTS AFFECTED BY RESISTANT PATHOGENS.

ORAL INFLAMMATION AND FUNCTIONAL GASTROINTESTINAL DISORDERS: A PRACTICE-BASED RESEACH APPROACH - PROJECT SUMMARY: THE OVERARCHING GOAL OF THIS PROJECT IS TO DEVELOP ORGANIZED, SUSTAINABLE CLINICAL RESEARCH PROGRAMS THAT ENABLE FACULTY AND STUDENTS TO CONDUCT PRACTICE-BASED RESEARCH AT THE MIDWESTERN UNIVERSITY COLLEGES OF DENTAL MEDICINE. IT IS EXPECTED THAT ONCE STUDENTS GRADUATE FROM THESE TWO DENTAL SCHOOLS, THEY WILL BE ADEQUATELY TRAINED TO FULLY PARTICIPATE IN THE NATIONAL DENTAL PBRN. TO ACCOMPLISH THIS GOAL, THIS PROJECT WILL FORM A PARTNERSHIP BETWEEN THE TWO INDEPENDENTLY OPERATED DENTAL SCHOOLS THAT ARE PART OF MIDWESTERN UNIVERSITY (MWU) COLLEGES OF DENTAL MEDICINE (THE COLLEGE OF DENTAL MEDICINE-AZ IN GLENDALE, AZ, AND THE COLLEGE OF DENTAL MEDICINE-IL IN DOWNERS GROVE, IL)) AND AN INTER-INSTITUTIONAL PARTNER: THE UNIVERSITY OF CHICAGO (UC) BIOLOGICAL SCIENCES DIVISION CENTER FOR HEALTH AND THE SOCIAL SCIENCES PROGRAM IN ORAL HEALTH (CHESS POH). IN APPROACH AREA 1, WE WILL LEVERAGE THE EXPERTISE AND RESOURCES OF THE UC CHESS POH TO PROVIDE FOUNDATIONAL CLINICAL RESEARCH TRAINING TO CLINICAL FACULTY AND STUDENT TEAMS AT BOTH DENTAL SCHOOLS. CONCURRENTLY, MWU WILL DEVELOP AN INFRASTRUCTURE OF VIDEO RECORDED TRAINING MATERIALS AND A MENTOR NETWORK OF RESEARCH-ORIENTED FACULTY TO PROVIDE SUSTAINABILITY TO THIS PROGRAM BY MAKING CLINICAL RESEARCH TRAINING A FUNDAMENTAL COMPONENT OF THE INSTITUTION AND DENTAL STUDENT EDUCATION. IN APPROACH AREA 2, WE WILL BUILD UPON THE EXISTING INTRA-INSTITUTIONAL COLLABORATION BETWEEN BOTH MWU DENTAL SCHOOLS, WHICH ALREADY SHARE A COMMON RESEARCH TEAM COMPRISED OF RESEARCH-ORIENTED FACULTY AND LABORATORY TECHNICIANS. WE WILL EXPAND THIS TEAM TO INCLUDE CHESS POH MEMBERS AS INTER-INSTITUTIONAL PARTNERS AND WORK COLLABORATIVELY TO MENTOR CLINICAL FACULTY AND STUDENTS IN THE CONDUCT OF PRACTICE-BASED RESEARCH. IN APPROACH AREA 3, WE WILL EXPAND THE CURRENT FACULTY MENTOR-DENTAL STUDENT PAIRING THAT OCCURS AT BOTH DENTAL SCHOOLS WHEN STUDENTS ENTER THEIR THIRD YEAR OF EDUCATION. EACH INCOMING 3RD-YEAR STUDENT IS PAIRED WITH A 4TH-YEAR STUDENT ALREADY WORKING IN THE CLINIC. THESE TWO STUDENTS WORK FOR THE REMAINDER OF THE YEAR AS CLINICAL COLLEAGUES UNDER THE DIRECT SUPERVISION OF A SPECIFIC CLINICAL FACULTY MEMBER. BY TRAINING A COHORT OF STUDENTS EACH YEAR TO CONDUCT CLINICAL RESEARCH UNDER THE MENTORSHIP OF A RESEARCH-TRAINED FACULTY MEMBER, THE PROGRAM WILL PRODUCE COMPETENT CLINICAL RESEARCHERS ENTERING THE WORKFORCE AS WELL AS A RESEARCH MENTOR NETWORK THAT FOSTERS CLINICAL RESEARCH ACTIVITIES IN BOTH SCHOOLS. IN APPROACH AREA 4, WE WILL PROVIDE PRACTICAL EXPERIENCE FOR THE FACULTY/STUDENT RESEARCH MENTOR SYSTEM BY CONDUCTING A PRACTICE-BASED RESEARCH PROJECT WHEREIN WE SYSTEMATICALLY MEASURE LONGITUDINAL RELATIONSHIPS BETWEEN ORAL INFLAMMATION AND FUNCTIONAL GASTROINTESTINAL DISORDERS. THIS MULTISITE, NONINTERVENTIONAL PROSPECTIVE CLINICAL STUDY WILL PROVIDE APPLIED TRAINING IN DAY-TO-DAY STUDY OPERATIONS, INCLUDING CONSENTING, ENROLLING, AND DATA COLLECTION. UPON SUCCESSFUL COMPLETION OF THIS PROJECT, WE WILL HAVE BUILT A SUSTAINABLE, ENDURING CLINICAL TRAINING PROGRAM THAT WILL PRODUCE APPROXIMATELY 32 PRACTICE-BASED RESEARCH TRAINED NEW DENTAL PRACTITIONERS EVERY YEAR.

MICRORNA AS A NOVEL THERAPEUTIC TARGET FOR PAIN IN SICKLE CELL DISEASE - OUR LONG-TERM GOAL IS TO DEVELOP EFFECTIVE PHARMACOLOGICAL INTERVENTIONS THAT CAN ALLEVIATE SICKLE CELL PAIN AND IMPROVE THE QUALITY OF LIFE FOR PATIENTS WITH SICKLE CELL DISEASE (SCD). APPROXIMATELY 100,000 AMERICANS– PRIMARILY AFRICAN OR HISPANIC BACKGROUND–SUFFER FROM SCD, FEATURED WITH RECURRENT EPISODES OF ACUTE VASO- OCCLUSION, HEMOLYTIC ANEMIA, AND PROGRESSIVE ORGAN DAMAGE. PATIENTS WITH SCD ENDURE FREQUENT EPISODES OF ACUTE CRISIS PAIN, AS WELL AS PERSISTENT, INTRACTABLE CHRONIC PAIN THROUGHOUT THEIR LIVES. CHRONIC PAIN IN SCD IS REFRACTORY TO CURRENT MEDICATIONS AND REPRESENTS A SIGNIFICANT UNMET MEDICAL CHALLENGE. THERE REMAINS A CRITICAL AND URGENT NEED TO IDENTIFY NOVEL THERAPEUTIC TARGETS FOR EFFECTIVE PAIN MANAGEMENT IN SCD. WITH A GROWING APPRECIATION FOR ITS FUNCTIONAL CAPACITY, MICRORNA (MIRNA) IS NOW RECOGNIZED AS ONE OF THE MAJOR EPIGENETIC REGULATORS THAT CONTROLS TARGET GENE EXPRESSION AT THE POST-TRANSCRIPTIONAL LEVEL. OUR GROUP HAS DEDICATED SIGNIFICANT RESEARCH EFFORT TO INVESTIGATE THE FUNCTIONAL ROLE OF MIRNA IN CHRONIC PAIN CONDITIONS, WITH A FOCUS ON LET-7 FAMILY MICRORNA (MIRNA). AS A DEVELOPMENTAL TIMING REGULATOR, LET-7 MIRNA HAS BEEN IMPLICATED IN THE FETAL-TO-ADULT HEMOGLOBIN SWITCH– A CRITICAL EVENT ASSOCIATED WITH THE ONSET OF SICKLE CELL PAIN. MEANWHILE, RESULTS FROM OUR PRELIMINARY EXPERIMENTS HAVE DEMONSTRATED MARKEDLY INCREASED EXPRESSION OF NEURONAL AND CIRCULATING EXOSOMAL LET-7 MIRNA IN MOUSE MODELS OF SCD, AS WELL AS PATIENTS WITH SCD. PRIOR TO OUR STUDY, IT WAS NOT KNOWN WHETHER TARGETING LET-7 MIRNA COULD ALLEVIATE CHRONIC PAIN IN SCD. STRIKINGLY, WE HAVE SINCE GENERATED PRELIMINARY DATA THAT SPINAL LET-7 KNOCKDOWN SIGNIFICANTLY REVERSED PERSISTENT PAIN BEHAVIORS IN A HUMANIZED MOUSE MODEL OF SCD. MOREOVER, WE HAVE ESTABLISHED ROBUST METHODOLOGIES TO ASSESS DIFFERENT PAIN TYPES IN MICE WITH SCD. OUR STUDIES HAVE REVEALED THE PRESENCE OF EVOKED HYPERSENSITIVITY (TACTILE ALLODYNIA, COLD AND HEAT HYPERALGESIA) AND, MORE IMPORTANTLY, ONGOING SPONTANEOUS PAIN IN MULTIPLE MOUSE MODELS OF SCD. DESPITE BEING THE CHIEF COMPLAINT REPORTED BY PATIENTS WITH SCD, MECHANISTIC UNDERSTANDING OF ONGOING SPONTANEOUS PAIN ASSOCIATED WITH SCD REMAIN LARGELY UNEXPLORED. BASED ON OUR PRELIMINARY FINDINGS AND THE INTRIGUING PROPERTIES OF LET-7 MIRNA, WE WILL TEST THE HYPOTHESIS THAT LET-7 FAMILY MIRNA CAN BE A NOVEL THERAPEUTIC TARGET FOR CHRONIC PAIN IN SCD. BY IDENTIFYING MOLECULAR AND EPIGENETIC MECHANISMS OF LET-7 MIRNA IN SICKLE CELL PAIN, SPECIFIC TARGETING OF THESE MECHANISMS HOLDS GREAT PROMISE OF DESIGNING EFFECTIVE PAIN THERAPIES THAT CAN BENEFIT PATIENTS WITH SCD. SUCCESSFUL COMPLETION OF THE STUDY WILL NOT ONLY CHARACTERIZE THE ROLE OF LET-7 MIRNA AS A MECHANISM, BIOMARKER, AND THERAPEUTIC TARGET FOR CHRONIC PAIN IN SCD, BUT ALSO BUILD UP A STRONG SCIENTIFIC FRAMEWORK FOR FUTURE STUDIES THAT MAY ULTIMATELY LEAD TO ADDITIONAL TRANSLATIONAL RESEARCH.

MECHANISM(S) OF CD8 T CELL-MEDIATED CHLAMYDIA-INDUCED REPRODUCTIVE PATHOLOGY

COMBINED PRIORITY FOR PERSONNEL DEVELOPMENT

THE ROLE OF SAM POLYMERIZATION IN POLYCOMB-DEPENDENT CHROMATIN STRUCTURES

PHYSICIAN ASSISTANT TRAINING IN PRIMARY CARE

TRANSLATIONAL ADAPTED GROUPS: COMMUNITY BUILDS CAPACITY FOR SCHOOL SLPS

INTRINSIC PRIMARY AFFERENT NEURONS IN REGULATION OF INTESTINAL NUTRIENT SENSING AND OBESITY - PROJECT SUMMARY INTESTINAL NUTRIENT SENSING IS DYSREGULATED IN OBESITY AND ASSOCIATED COMORBIDITIES INCLUDING TYPE 2 DIABETES (T2D) WHICH FEED INTO THE VICIOUS CYCLE OF MALADAPTIVE RESPONSE AND NUTRIENT EXCESS. WHILE ENTEROENDOCRINE MEDIATED NUTRIENT SENSING HAS BEEN STUDIED, THE ROLE OF GUT’S NEURAL PLAYERS IN REGULATING THIS PHENOMENON AND UNDERLYING MECHANISMS REMAIN UNKNOWN. OUR DATA DEMONSTRATE THAT INTESTINAL SENSORY INTRINSIC PRIMARY AFFERENT NEURONS (IPANS) MODULATE NUTRIENT SENSING IN A MANNER THAT PRIMES TOWARDS WEIGHT GAIN. IPANS ARE A UNIQUE CLASS OF ENTERIC NEURONS THAT ORCHESTRATE NEURAL REFLEXES FOR OPTIMIZING NUTRIENT UPTAKE AND EFFICIENT PROCESSING OF MEALS. IN THE GUINEA PIG, EVIDENCE POINTS TOWARD NEUROPLASTICITY MECHANISMS THAT ENABLE IPANS TO ADAPT TO CHANGING HORMONAL AND NEURAL STIMULI IN THE GUT. USING INTESTINE-SPECIFIC CHEMO GENETIC TARGETING STRATEGY, WE FOUND THAT IPAN ACTIVATION IN THE PROXIMAL SMALL INTESTINE INDUCED OBESITY IN LEAN MICE ON A STANDARD CHOW DIET. MECHANISMS UNDERLYING THIS NOVEL AND INTRIGUING PHENOMENON ARE UNKNOWN, BUT OUR FINDINGS POINT TOWARDS ALTERATIONS IN NOT JUST INTESTINAL GLUCOSE AND LIPID UPTAKE BUT VAGAL AFFERENT ACTIVITY INFLUENCING REWARD REINFORCEMENT AND FOOD SEEKING BEHAVIOR. WE HYPOTHESIZE THAT IPAN ACTIVITY REGULATES WEIGHT GAIN BY MODULATING INTESTINAL GLUCOSE AND LIPID UPTAKE, AND VAGAL MEDIATED GUT-BRAIN REWARD REINFORCEMENT. TOWARD THIS GOAL, WE AIM TO: (1) UNCOVER THE ROLE OF IPANS IN MODULATING ENTEROCYTIC GLUCOSE ABSORPTION, LYMPHATIC LIPID TRANSPORT, AND VAGAL MEDIATED REWARD REINFORCEMENT, AND (2) ELUCIDATE THE MOLECULAR MACHINERY DRIVING IPAN FIRING, TO UNDERSTAND HOW HYPERACTIVITY TRIGGERS THE OBESE PHENOTYPE. COMBINATION OF MOLECULAR, BEHAVIORAL, AND ELECTROPHYSIOLOGICAL APPROACHES WILL BE EMPLOYED TO STUDY IPAN ACTIVITY IN THE LEAN AND OBESE LANDSCAPE, USING THE RECENTLY CHARACTERIZED AND VALIDATED NEUROMEDIN (NMU)-DRIVEN CRE MOUSE MODEL THAT SPECIFICALLY TARGETS IPANS. OUR STUDIES WILL REVEAL NOVEL FUNCTIONS OF A PREVIOUSLY UNKNOWN PLAYER IN NUTRIENT SENSING AND ABSORPTION, AND THE CROSSTALK BETWEEN ENTERIC SENSORY NEURONS AND VAGAL AFFERENT TERMINALS TO INFLUENCE COMMUNICATION OF LUMINAL SIGNALS TO THE BRAIN. WE WILL THEN EVALUATE WHETHER TARGETED BLUNTING OF INTESTINAL IPAN ACTIVITY SLOWS OR INHIBITS WEIGHT GAIN IN DIET-INDUCED OBESE MICE AND COULD AMELIORATE METABOLIC OUTCOMES, INCLUDING HYPERGLYCEMIA, HYPERTRIGLYCERIDEMIA, AND SYSTEMIC GLUCOSE AND LIPID HANDLING. COMPLETION OF THE PROPOSED WORK WILL REVEAL DIRECT ROLES OF ENTERIC NEURONS IN NUTRIENT SENSING, CONTRARY TO THE PARADIGM, AND DEEPEN OUR UNDERSTANDING OF HOW THE DEEPER LAYERS OF GUT’S NEURONAL CIRCUITRY INFLUENCE METABOLISM AND OBESITY.

TIERED OCCUPATIONAL THERAPY (TOT) GRANT: PREPARING OCCUPATIONAL THERAPISTS TO SERVE ON SCHOOL MENTAL HEALTH TEAMS

UNRAVELING THE ANATOMICAL AND MOLECULAR ADAPTATIONS OF PRIMATE TOUCH -TOUCH IS A FUNDAMENTAL WAY THAT HUMANS AND OTHER ANIMALS NAVIGATE AND INTERACT WITH THEIR WORLD. PRECISION TOUCH, WHICH ALLOWS US TO USE OUR HANDS TO DETECT TEXTURE, SHAPE, VIBRATION, AND MOVEMENT, IS VITALLY IMPORTANT FOR HUMAN AND PRIMATE SENSORY BIOLOGY AND HEALTH. WHILE PRECISION TOUCH IS CRITICAL FOR TASKS LIKE DETECTING FRUIT RIPENESS, LOCOMOTION, AND MAKING AND USING TOOLS, IT IS STILL POORLY UNDERSTOOD RELATIVE TO OTHER SENSES. THIS PROJECT USES A MULTIDISCIPLINARY APPROACH TO INVESTIGATE VARIATION IN, AND THE ROLE OF, PRECISION TOUCH ACROSS PRIMATES AND OTHER MAMMALS. THE RESULTS OF THIS WORK AIM TO IDENTIFY ECOLOGICAL FACTORS ASSOCIATED WITH VARIATION IN PRECISION TOUCH AND CONTRIBUTE TO OUR UNDERSTANDING OF THE ROLE OF TOUCH IN PRIMATE AND HUMAN SENSORY BIOLOGY, ECOLOGY, AND EVOLUTION. THIS PROJECT CAN INCREASE PUBLIC UNDERSTANDING OF SENSORY SYSTEMS AND SCIENCE THROUGH AN INTERACTIVE EXHIBIT AT THE ARIZONA MUSEUM OF NATURAL HISTORY. FURTHERMORE, THE PROJECT SUPPORTS AND EXPANDS INTERNATIONAL RESEARCH COLLABORATIONS AND STEM RESEARCH TRAINING TO UNDERGRADUATE AND GRADUATE STUDENTS. CRITICALLY, THE RESEARCH TEAM LEVERAGES A UNIQUE SAMPLING OPPORTUNITY TO GENERATE A BIOBANK OF TISSUES AND RNA FROM WILD MAMMAL SPECIES, MANY OF WHICH ARE ENDANGERED AND POORLY STUDIED, AND MAKE THE DATA AVAILABLE TO THE GLOBAL RESEARCH COMMUNITY. THIS MULTIDISCIPLINARY PROJECT ADDRESSES FOUR AIMS: (1) IDENTIFY GENOTYPE-PHENOTYPE RELATIONSHIPS FOR PRECISION TOUCH; (2) QUANTIFY THE EFFECTS OF DIET, MANUAL DEXTERITY, AND TOOL USE ON PRECISION TOUCH; (3) QUANTIFY THE EFFECTS OF ARBOREALITY VS. TERRESTRIALITY ON PRECISION TOUCH, AND (4) EVALUATE CLAIMS THAT THE PRIMATE ORDER IS UNIQUELY DERIVED FOR PRECISION TOUCH. THE PROJECT AIMS TO ADDRESS LONG-STANDING EVOLUTIONARY QUESTIONS REGARDING SELECTIVE FACTORS DRIVING THE ORIGIN OF EARLY PRIMATE FEATURES AS WELL AS QUESTIONS ABOUT THE EVOLUTION OF HIGHLY SENSITIVE PRECISION TOUCH IN THE HUMAN LINEAGE. THE RESEARCH TEAM USES TRANSCRIPTOME SEQUENCING, HISTOLOGY, AND MORPHOMETRICS TO COMPARE THE EXPRESSION OF TOUCH-RELATED GENES WITH ESTIMATES OF TOUCH RECEPTOR CELL (I.E., MECHANORECEPTOR) DENSITIES AND MORPHOLOGY IN DIFFERENT TISSUES WITHIN INDIVIDUALS AND BETWEEN SPECIES. THE PROJECT FOCUSES ON PRIMATE SPECIES THAT SPAN TAXONOMIC CLADES (STREPSIRRHINES, PLATYRRHINES, CERCOPITHECOIDS, HOMINOIDS) AND ECOLOGIES (DIET, ACTIVITY PATTERN, SUBSTRATE USE, TOOL USE), AND COMPARES THESE TO NON-PRIMATE MAMMALIAN MODELS TARGETED TO INVESTIGATE THE CONVERGENT EVOLUTION OF PRIMATE TRAITS. THE RESEARCH TEAM COLLECTS TISSUE SAMPLES FROM INDIVIDUALS ACROSS 18 MAMMAL SPECIES IN COLLABORATION WITH VETERINARIANS. THE TEAM ALSO COLLECTS BEHAVIORAL DATA ON HOW THE STUDY SPECIES USE PRECISION TOUCH TO INTERACT WITH FOOD ITEMS AND MOVE ABOUT THEIR ENVIRONMENT. ADDITIONALLY, THE RESEARCH TEAM LEVERAGES PUBLICLY-AVAILABLE GENOMIC DATABASES IN ORDER TO INVESTIGATE THE HISTORY OF NATURAL SELECTION ACTING ON TOUCH GENES ACROSS MAMMALS. THIS PROJECT IS JOINTLY SUPPORTED BY THE BIOLOGICAL ANTHROPOLOGY (SBE) AND PHYSIOLOGICAL MECHANISMS AND BIOMECHANICS (BIO) PROGRAMS. 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.

METHODS DEVELOPMENT: INVESTIGATING THE ROLE OF HOST FACTORS IN THE SUSCEPTIBILITY OF ELK TO CHRONIC WASTING DISEASE

DISSECTING THE ROLE OF LRH1 IN PHTHALATE-RELATED REPRODUCTIVE IMPAIRMENTS: A CELLULAR AND MOLECULAR APPROACH - PROJECT SUMMARY/ABSTRACT THE WORLD HEALTH ORGANIZATION REPORTS THAT APPROXIMATELY 20% OF COUPLES WORLDWIDE EXPERIENCE INFERTILITY. PHTHALATES, WIDELY UTILIZED AS PLASTICIZERS OR SOLVENTS IN A VAST ARRAY OF CONSUMER PRODUCTS, HAVE BEEN IMPLICATED IN REPRODUCTIVE DISTURBANCES, AS EVIDENCED BY HUMAN EPIDEMIOLOGICAL STUDIES AND RODENT RESEARCH. THIS PROPOSAL IS DEDICATED TO OFFERING COMPREHENSIVE MENTORSHIP AND CAREER DEVELOPMENT IN REPRODUCTIVE TOXICOLOGY RESEARCH FOR PRE-DOCTORAL HEALTH PROFESSIONALS AND GRADUATE STUDENTS. THE PROJECT IS CENTERED ON THE PREMISE THAT EXPOSURE TO PHTHALATES AT ENVIRONMENTALLY RELEVANT CONCENTRATIONS DURING CRITICAL DEVELOPMENTAL WINDOWS FOR THE TESTIS (FROM EMBRYONIC DAY 15.5 TO POSTNATAL DAY 3) ADVERSELY AFFECTS SPERMATOGENESIS. THIS IS HYPOTHESIZED TO OCCUR THROUGH THE DISRUPTION OF LRH1 SIGNALING IN SERTOLI CELLS, CRUCIAL FOR GERM CELL DEVELOPMENT. OUR APPROACH COMPRISES TWO INNOVATIVE AIMS: THE FIRST AIMS TO ELUCIDATE HOW PHTHALATES MAY IMPAIR GERM CELL DEVELOPMENT BY DISRUPTING LRH1-MEDIATED REGULATION OF STEROIDOGENESIS AND METABOLISM IN MOUSE SERTOLI CELLS. THE SECOND SEEKS TO DETERMINE THE EFFECTS OF PHTHALATES ON THE FUNCTIONAL CAPACITIES OF BOTH MOUSE AND HUMAN SERTOLI CELLS (USING PRIMARY CELLS AND CELL LINES) IN VITRO BY TARGETING LRH1. THE SUCCESSFUL COMPLETION OF THESE OBJECTIVES WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF THE MOLECULAR DYNAMICS THROUGH WHICH PHTHALATES INFLUENCE GONADAL FUNCTION AND GERM CELL MATURATION. GAINING INSIGHT INTO THE SEX-SPECIFIC EFFECTS OF PHTHALATES WILL FACILITATE THE DEVELOPMENT OF TAILORED HEALTHCARE INTERVENTIONS FOR DISEASES RELATED TO DEVELOPMENT, REPRODUCTION, AND ENDOCRINE FUNCTION. THIS RESEARCH, ALONGSIDE THE CAREER DEVELOPMENT ACTIVITIES PROPOSED, WILL EMPOWER PRE-DOCTORAL HEALTH PROFESSIONALS AND GRADUATE STUDENTS PURSUING CAREERS IN HEALTHCARE, SETTING THE STAGE FOR PIVOTAL BREAKTHROUGHS IN MEDICAL SCIENCE. ULTIMATELY, THIS PROJECT ALIGNS WITH THE NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES (NIEHS) GOAL TO EXPLORE THE CONSEQUENCES OF ENVIRONMENTAL EXPOSURES ON HUMAN HEALTH, MARKING A CRITICAL STEP FORWARD IN ENVIRONMENTAL AND REPRODUCTIVE HEALTH RESEARCH.

SL - VETERINARY MEDICINE - OTHER ADMIN CHANGES

IDENTIFICATION OF SIGNALING MOLECULES THAT FUNCTION AT FERTILIZATION - PROJECT SUMMARY/ABSTRACT DURING FERTILIZATION, THE PREVIOUSLY QUIESCENT EGG IS ACTIVATED TO BEGIN EMBRYONIC DEVELOPMENT. ONE OF THE ROLES OF THIS ACTIVATION IS TO INITIATE THE PATHWAYS THAT LEAD TO CELL CYCLE PROGRESSION AND THE EVENTUAL ACTIVATION OF THE ZYGOTIC GENOME. HOWEVER, THE MOLECULAR MECHANISMS THROUGH WHICH SPERM- EGG INTERACTION LEADS TO THESE EVENTS ARE NOT COMPLETELY UNDERSTOOD. THIS PROPOSAL WILL ASSEMBLE THE COMPONENTS OF THE SIGNALING PATHWAYS THAT LINK EGG ACTIVATION TO THE INITIATING SIGNAL, WHETHER IT IS A SOLUBLE MOLECULE FROM THE SPERM OR EGG CYTOPLASM OR CELL SURFACE RECEPTOR IN THE EGG (OR SPERM) PLASMA MEMBRANE. MOLECULAR TOOLS BASED UPON SIGNALING MOLECULES PREVIOUSLY CLONED FROM A SEA STAR CDNA LIBRARY WILL BE USED FOR THE IN-DEPTH STUDY OF THE SIGNALING PATHWAYS. THE SEA STAR HAS BEEN CHOSEN AS THE MODEL SYSTEM FOR SEVERAL REASONS, INCLUDING THE AVAILABILITY OF HIGH QUALITY MOLECULAR REAGENTS, THE ABILITY TO OBTAIN LARGE QUANTITIES OF GAMETES, THE EASE WITH WHICH CELLS CAN BE MICROINJECTED AND ASSAYED FOR SIGNALING EVENTS, AND THE OPTICAL CLARITY OF THE EGG FOR MICROSCOPY. SPECIFIC DOMAINS FROM KNOWN SIGNALING MOLECULES (SRC1, SRC3, AND PLC ARE IN HAND) WILL BE EXPRESSED AS FUSION PROTEINS THAT WILL BE USED TO IDENTIFY INTERACTING PROTEINS FOLLOWING SECONDARY SELECTION USING ANTI-PHOSPHOTYROSINE ANTIBODIES. THE IDENTITY OF THE PROTEINS THAT INTERACT WITH SRC1, SRC3, OR PLC WILL BE DETERMINED BY TANDEM MASS SPECTROMETRY AMINO ACID SEQUENCING FOLLOWED BY DATABASE IDENTIFICATION USING OUR NEWLY PUBLISHED SEA STAR EGG TRANSCRIPTOME (PRJNA398668). WE HAVE DEVELOPED METHODS FOR IDENTIFICATION OF TYROSINE-PHOSPHORYLATED PROTEINS FROM ZYGOTE SAMPLES, PARTICULARLY THOSE THAT INTERACT WITH THE SH2 DOMAINS OF SRC AND PLC. THE IDENTIFIED CDNA FOR EACH SIGNALING MOLECULE WILL BE CLONED BY RT-PCR TO PRODUCE A LIBRARY OF MOLECULES FOR FURTHER STUDY. THIS PROPOSAL EXPLORES THE FUNCTIONAL ASPECTS OF EACH IDENTIFIED MOLECULE AT USING A COMBINATION OF RNA DEPLETION STRATEGIES AND DIRECT PROTEIN INTERFERENCE WITH FUNCTION-BLOCKING ANTIBODIES AND/OR FUSION PROTEIN CONSTRUCTS. REAL-TIME INTERACTION BETWEEN DESIGNED PROTEIN CONSTRUCTS WITH FERTILIZED EGGS LYSATES WILL BE MONITORED USING BIO-LAYER INTERFEROMETRY. THE RESULT WILL BE THE ELUCIDATION OF A NETWORK OF PROTEINS THAT INTERACT IN THE ECHINODERM EGG TO FACILITATE EGG ACTIVATION DURING FERTILIZATION. THIS PROJECT WILL ENGAGE BIOMEDICAL SCIENCE GRADUATE STUDENTS ALONG WITH MEDICAL AND VETERINARY STUDENTS IN THE LABORATORY. ALL STUDENTS WILL BE TRAINED TO WORK WITH GAMETES, AND IN BIOINFORMATICS AND SELECTED MOLECULAR BIOLOGY METHODS BY THE PI AND BY PEER-PEER TEACHING. STUDENTS WILL EARN CO- AUTHORSHIP ON MANUSCRIPTS AND PROJECT FUNDS WILL ALSO SUPPORT ATTENDANCE AT REGIONAL AND NATIONAL RESEARCH CONFERENCES TO ALLOW THE STUDENTS TO PRESENT THEIR WORK.

ELUCIDATION OF AN INFORMED DRUG DOSING SCHEME TO MINIMIZE KIDNEY INJURY

**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** CRYPTOSPORIDIOSIS POSES A GLOBAL PUBLIC HEALTH THREAT CHARACTERIZED BY LIFE-THREATENING DIARRHEA IN NEONATES, BUT SEVERE CLINICALDISEASE IN ADULT CATTLE AND PEOPLE IS UNCOMMON. DESPITE SUBSTANTIAL IMPACTS ON THE HEALTH AND ECONOMY OF THE CATTLE INDUSTRY AND THE PUBLIC, EFFECTIVE PREVENTATIVE AND THERAPEUTIC INTERVENTIONS ARE LACKING. THIS IS, IN PART, DUE TO GAPS IN OUR UNDERSTANDING OF HOW CRYPTOSPORIDIOSIS CAUSES DISEASE DIFFERENTLY IN NEONATES COMPARED TO ADULTS, AND A LACK OF ROBUST MODELS TO STUDY THIS DISEASE. INTERACTIONS BETWEEN INTESTINAL CELLS, IMMUNE CELLS, AND FACTORS IN THE TISSUES SERVE AS THE FIRST LINE OF DEFENSE AGAINST CRYPTOSPORIDIOSIS AND ULTIMATELY DETERMINE THE SEVERITY OF THE DISEASE. THE OBJECTIVE OF THIS WORK IS TO: 1) IDENTIFY NEW TARGETS FOR TREATING CRYPTOSPORIDIOSIS BY UNRAVELING THE IMPACT OF AGE (CALVES VS. ADULTS) ON THE DEVELOPMENT OF PROTECTIVE IMMUNITY TO CRYPTOSPORIDIOSIS AND 2) TO VALIDATE AN AGE-SPECIFIC MODEL TO STUDY CRYPTOSPORIDIOSIS. THIS PROJECT HYPOTHESIZES THAT THESE IMMUNE INTERACTIONS (CELLS AND TISSUE FACTORS) WILL DIFFER IN MAGNITUDE AND TYPE IN CALVES COMPARED TO ADULT CATTLE IN AN AGE-DEPENDENT MANNER. THIS WORK WILL ADVANCE OUR KNOWLEDGE OF HOW THE IMMUNE SYSTEM DEVELOPS IN CALVES' OVERTIME AND WILL DETERMINE HOW IMMUNE SYSTEM DEVELOPMENT CONTRIBUTES TO AGE-RELATED SUSCEPTIBILITY TO INFECTION. IN DOING SO, THIS STUDY WILL IDENTIFY PREVENTATIVE AND THERAPEUTIC TARGETS THAT WILL LATER BE EVALUATED FOR EFFICACY. FURTHER, THE ROBUST MODEL AND APPROACH USED HERE WILL SUPPORT AN INVESTIGATION INTO HOW OTHER INFECTIOUS AGENTS CAUSE DISEASE AND PROMOTE THERAPEUTIC DISCOVERY FOR COUNTLESS OTHER INFECTIONS IN CATTLE.

MOLECULAR BASIS OF THE SELECTIVE ASSEMBLY OF FUNCTIONALLY DISTINCT PRC1S - PROJECT SUMMARY/ABSTRACT PROBLEM: POLYCOMB REPRESSIVE COMPLEX 1 (PRC1) IS A MULTI-PROTEIN ASSEMBLY THAT EPIGENETICALLY REGULATES CHROMATIN, WHICH WHEN MISREGULATED, RESULTS IN CANCER. ORIGINALLY IDENTIFIED IN DROSOPHILA AS A FOUR-COMPONENT COMPLEX, PRC1 HAS EXPANDED ITS MEMBERSHIP AND FUNCTIONAL REPERTOIRE OVER EVOLUTION. AN IMPORTANT UNANSWERED QUESTION CONCERNING HUMAN PRC1 IS HOW CERTAIN COMBINATIONS OF PRC1 PROTEINS ASSEMBLE WHILE OTHERS DO NOT, AND HOW THE TYPES OF PRC1S FORMED CHANGE DURING CELLULAR DIFFERENTIATION. PRC1 ASSEMBLY IS CURRENTLY UNDERSTOOD TO OCCUR THROUGH A SERIES OF 1:1 PROTEIN-PROTEIN INTERACTIONS. THIS VIEW, UNFORTUNATELY, DOES NOT EXPLAIN HOW THE PROTEIN-PROTEIN INTERACTION OF ONE PRC1 DOMAIN CAN SOMEHOW INFLUENCE THE BINDING SELECTIVITY OF ANOTHER, SEEMINGLY UNRELATED PROTEIN-PROTEIN INTERACTION. WE HAVE IDENTIFIED NOVEL INTERACTIONS SECONDARY TO THE KNOWN 1:1 DIRECT INTERACTIONS THAT PROVIDE SELECTIVE CHECKPOINTS FOR INCLUDING SPECIFIC PROTEIN COMBINATIONS THEREBY ALLOWING SELECTIVE PRC1 ASSEMBLIES. OBJECTIVE: WE WILL SYSTEMATICALLY CHARACTERIZE THESE SECONDARY PROTEIN-PROTEIN INTERACTIONS THEN INVESTIGATE ITS ROLE IN THE ASSEMBLY AND FUNCTION OF THE DISTINCT PRC1S. METHODS: WE WILL USE BIOPHYSICAL METHODS (X-RAY CRYSTALLOGRAPHY, ANALYTICAL ULTRACENTRIFUGATION, BIOLAYER INTERFEROMETRY) TO DISSECT THE MOLECULAR BASIS OF THESE SELECTIVE ASSEMBLIES. THE FUNCTIONAL CONSEQUENCES OF THE SECONDARY INTERACTIONS THAT FORM THESE ASSEMBLIES WILL BE ASSESSED USING A NOVEL FRET- BASED HISTONE MODIFICATION ASSAY. SIGNIFICANCE: GENE REGULATION IS PERFORMED BY MANY DIFFERENT PROTEINS, ALL OF WHICH WORK WITHIN MULTI-COMPONENT SYSTEMS. CURRENT GENOMIC APPROACHES TO INVESTIGATING GENE REGULATION, WHILE INFORMATIVE, LACK A MOLECULAR PERSPECTIVE OF PROTEIN-PROTEIN INTERACTIONS NECESSARY FOR A COMPLETE UNDERSTANDING OF THESE SYSTEMS. WE PROPOSE TO FILL THIS GAP BY DETERMINING HOW SPECIFIC PRC1S ASSEMBLE AND FUNCTION. BY DEFINING THE MOLECULAR CHOREOGRAPHY UNDERLYING PRC1 ASSEMBLY, WE WILL PROVIDE A NEW PERSPECTIVE ON THE REGULATION AND FUNCTION OF THESE COMPLEXES IN GENOME REGULATION. OUR RESULTS MAY ALSO BE BROADLY APPLICABLE FOR UNDERSTANDING OTHER GENE REGULATORY SYSTEMS, MANY OF WHICH UTILIZE MULTI- COMPONENT SYSTEMS WITH DIFFERENT HOMOLOG COMBINATIONS.

THE ROLE OF SWI/SNF CHROMATIN REMODELERS IN HOMOLOGOUS RECOMBINATION AND GENOME STABILITY - MULTIPLE SUBUNITS OF THE SWI/SNF CHROMATIN REMODELING COMPLEXES HAVE BEEN IDENTIFIED AS A NOVEL CLASS OF TUMOR SUPPRESSORS MUTATED IN UP TO 20% OF HUMAN CANCERS, BUT THEIR MECHANISM OF TUMOR SUPPRESSION IS STILL POORLY UNDERSTOOD. THESE COMPLEXES ARE COMPOSED OF A MUTUALLY EXCLUSIVE ATPASE SUBUNIT (EITHER BRG1 OR BRM), A SET OF CORE FACTORS, AND A GROUP OF ACCESSORY SUBUNITS. SWI/SNF COMPLEXES WERE FIRST IDENTIFIED AS TRANSCRIPTIONAL ACTIVATORS AND THEREFORE MOST OF THE RESEARCH EFFORTS HAVE BEEN FOCUSED ON THE ROLE OF THESE ATPASES IN THE TRANSCRIPTIONAL REGULATION OF A VARIETY OF CELLULAR PATHWAYS INVOLVED IN CARCINOGENESIS. MORE RECENT WORK HAS LINKED BRG1 TO DNA REPAIR. WE IDENTIFIED A COMPLEX CONTAINING TOPBP1-E2F1-RB RESPONSIBLE FOR THE RECRUITMENT OF BRG1 TO DNA DOUBLE STRAND BREAKS (DSBS). MOREOVER, WE ALSO IDENTIFIED A FUNCTION FOR BRG1 STIMULATING DNA END RESECTION AND HOMOLOGOUS RECOMBINATION (HR) BY REDUCING NUCLEOSOME DENSITY AT DSBS AND PROMOTING THE RECRUITMENT OF THE CTIP NUCLEASE. HOWEVER, THE ROLE THAT THE OTHER ATPASE (BRM) AND OTHER NON-CATALYTIC SUBUNITS OF THE SWI/SNF COMPLEX MAY PLAY IN THIS FUNCTION IS STILL UNKNOWN. THE GOAL OF THIS PROPOSAL IS TO FURTHER DEFINE THE MECHANISM BY WHICH BRG1 AND BRM STIMULATE DNA END RESECTION AND HR, TO DETERMINE TO WHAT EXTENT SWI/SNF SUBUNITS ARID1A AND BRD7 ARE REQUIRED FOR THIS FUNCTION, AND TO TEST WHETHER WE CAN SENSITIZE BREAST CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS BY INACTIVATING THESE SWI/SNF SUBUNITS. OUR HYPOTHESIS IS THAT BRG1 REDUCES NUCLEOSOME DENSITY AT DSBS, THUS ALLOWING THE RECRUITMENT OF THE DNA END RESECTION NUCLEASE CTIP AND STIMULATING DNA END RESECTION AND HR, AND THAT ARID1A AND BRD7 ARE IMPORTANT FOR ANCHORING THESE COMPLEXES AT DSBS. THE UNCOVERING OF A FUNCTION IN DSB REPAIR FOR SWI/SNF ACCESSORY SUBUNITS COULD HELP EXPLAIN THEIR TUMOR SUPPRESSOR ACTIVITIES. MOREOVER, IDENTIFYING MULTIPLE SWI/SNF SUBUNITS REQUIRED FOR HR, WOULD ALSO IDENTIFY A DNA REPAIR VULNERABILITY THAT COULD BE EXPLOITED THERAPEUTICALLY AGAINST SWI/SNF-MUTATED CANCERS. IN ORDER TO TEST THIS HYPOTHESIS, WE WILL, FIRST, DETERMINE WHETHER A BRG1- OR BRM- ATPASE-DEAD MUTANT WOULD BE ABLE TO STIMULATE DNA END RESECTION AND PROMOTE THE RECRUITMENT OF THE CTIP NUCLEASE. SECOND, WE WILL DEFINE THE ROLE NON-CATALYTIC SWI/SNF SUBUNITS ARID1A AND BRD7 PLAY IN THE RECRUITMENT OF BRG1, CHROMATIN REMODELING AT DSBS, DNA END RESECTION, AND HR, BY ANALYZING THE GENERATION OF SINGLE-STRANDED DNA AND ATR SIGNALING AFTER DNA DAMAGE. THIRD, WE WILL DETERMINE WHETHER WE CAN SENSITIZE BREAST CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, INCLUDING POLY (ADP-RIBOSE) POLYMERASE (PARP) INHIBITORS, BY INACTIVATING BRG1, BRM, ARID1A, AND BRD7 SUBUNITS. THIS SYSTEMATIC STUDY OF THE FUNCTION OF THE SWI/SNF SUBUNITS IN DNA END RESECTION AND HR WILL FURTHER OUR UNDERSTANDING OF THE BIOLOGY OF THESE COMPLEXES, THEIR FUNCTIONS, AND THE REQUIRED COMPOSITION OF THESE COMPLEXES IN ORDER TO PERFORM THIS FUNCTION IN HR. MOREOVER, WE COULD POTENTIALLY IDENTIFY DNA REPAIR VULNERABILITIES IN SWI/SNF-MUTATED CANCERS THAT COULD BE EXPLOITED THROUGH SPECIFIC CHEMOTHERAPEUTIC REGIMENS DESIGNED FOR HR-DEFICIENT MALIGNANCIES.

CHOLINERGIC MODULATION OF XII MOTONEURONS AND XII PREMOTONEURONS

PRDM16 AND MECOM IN MOUSE EMBRYONIC MANDIBLE AND PALATE DEVELOPMENT.

MECHANISMS OF CADMIUM-INDUCED DYSGLYCEMIA

THE ROLE OF THE GUT MYCOBIOTA IN REGULATING HOST LIPID ABSORPTION AND OBESITY - PROJECT SUMMARY A LEADING CAUSE OF OBESITY AND DIABETES IS CONSUMPTION OF A WESTERN-STYLE DIET RICH IN SATURATED FAT AND SIMPLE SUGARS. RECENT RESEARCH SHOWS THAT HIGH FAT (HF)-HIGH SUGAR DIETS ALTER THE MICROBIAL COMPOSITION OF THE GUT. INTERESTINGLY, WE PREVIOUSLY SHOWED THAT HF DIETS HAVE A STRONG IMPACT ON THE SMALL BOWEL MICROBIOTA SPECIFICALLY IN THE JEJUNUM, THE MAJOR SITE OF NUTRIENT DIGESTION AND ABSORPTION. MOREOVER, JEJUNAL HF MICROBES INCREASED LIPID ABSORPTION IN ADULT GERM-FREE MICE COMPARED TO LOW FAT (LF) DIET MICROBES COLLECTED FROM THE JEJUNUM. HOWEVER, IN THIS STUDY, WE FOCUSED ON THE BACTERIAL TAXA AS OPPOSED TO FUNGAL TAXA. A CRITICAL GAP EXISTS IN THE LITERATURE REGARDING THE ROLE OF FUNGI IN REGULATING THE ABSORPTIVE CAPACITY OF THE GUT IN RESPONSE TO HF DIETS. OUR LONG-TERM GOAL IS TO ELUCIDATE THE MECHANISMS BY WHICH CANDIDATE FUNGI SUCH AS CANDIDA REGULATE LIPID ABSORPTION, FAT TRANSPORT AND ADIPOSITY. THE OBJECTIVE OF THIS APPLICATION IS TO DETERMINE THE IMPACT OF CANDIDA, IN YEAST OR HYPHAL FORM, ON LIPID DIGESTIVE AND ABSORPTIVE CAPACITY AND OBESITY DEVELOPMENT. IN ADDITION, WE WILL EXAMINE THE LOCALIZATION OF CANDIDA ALONG THE LENGTH OF THE GUT. OUR PRELIMINARY DATA DEMONSTRATE THAT C. ALBICANS IN YEAST AND HYPHAL FORM TRIGGERS THE UPREGULATION OF GENES INVOLVED IN FAT ABSORPTION. WEEKLY SUPPLEMENTATION OF HEAT- KILLED C. ALBICANS ALSO INCREASED BODY WEIGHT GAIN IN MICE FED A HF DIET AND INDUCED FATTY ACID TRANSLOCASE (CD36) EXPRESSION IN THE JEJUNUM. AS EMERGING EVIDENCE SUGGESTS THAT DIET-GUT MICROBE INTERACTIONS HAVE THE POTENTIAL TO PROMOTE DISEASE, WE DEVELOPED OUR CENTRAL HYPOTHESIS THAT THE GUT MYCOBIOTA CONTRIBUTES TO LIPID ABSORPTIVE AND DIGESTIVE CAPACITY IN THE SMALL INTESTINE. TWO SPECIFIC AIMS ARE PROPOSED TO TEST THIS HYPOTHESIS: AIM 1) TEST THE LOCALIZATION AND MORPHOLOGY OF C. ALBICANS AND IMPACT ON HOST LIPID UPTAKE AND OBESITY, AIM 2) DETERMINE THE MOLECULAR MECHANISMS INVOLVED IN C. ALBICANS-MEDIATED LIPID ABSORPTION. WE HAVE ONLY REACHED THE PRECIPICE OF UNDERSTANDING HOW BACTERIA REGULATE NUTRIENT DIGESTION AND ABSORPTION AND EVEN LESS IS KNOWN REGARDING THE ROLE OF INTESTINAL FUNGI. THE PROPOSED RESEARCH IS INNOVATIVE AND SIGNIFICANT BECAUSE IT WILL BETTER DEFINE THE SMALL INTESTINAL MYCOBIOTA, REGIONAL LOCALIZATION OF CANDIDA AND BETTER DEFINE THE MECHANISMS OF HOST-MICROBE INTERACTIONS THAT REGULATE ABSORPTION CONTRIBUTING TO THE DEVELOPMENT OF OBESITY.

CYCLOOXYGENASE-2 SIGNALING IN CELL SENESCENCE AND ITS ROLE IN CHEMOTHERAPY-INDUCED LONG-TERM ADVERSE SEQUELAE

ISOLATION OF NOVEL RODENT CHLAMYDIAE

EFFECTS OF CHRONIC INTERMITTENT HYPOXIA ON CHOLINERGIC MODULATION AT HYPOGLOSSAL MOTONEURONS - PROJECT SUMMARY/ABSTRACT EXPOSURE TO CHRONIC INTERMITTENT HYPOXIA (CIH) IS A COMMON CONSEQUENCE OF OBSTRUCTIVE SLEEP APNEA (OSA) WHERE PATIENTS EXPERIENCE REPEATED APNEAS AND HYPOPNEAS THROUGHOUT THE NIGHT. ACCUMULATING EVIDENCE INDICATES THAT CIH CAN LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES IN THE BRAINSTEM NEURONS THAT CONTROL BREATHING. NORMALLY, ACTIVITY OF THE TONGUE, INNERVATED BY HYPOGLOSSAL MOTONEURONS, STIFFENS THE AIRWAY TO KEEP IT OPEN, BUT THIS ACTIVITY DROPS DRAMATICALLY DURING SLEEP AND CONTRIBUTES CAUSALLY TO OSA IN SUSCEPTIBLE INDIVIDUALS. DURING SLEEP, REDUCED HYPOGLOSSAL MOTONEURON ACTIVITY LIKELY RESULTS FROM ACTIVATION OF SLEEP-SPECIFIC MUSCARINIC (I.E. ACTIVATION OF MUSCARINIC ACETYLCHOLINE RECEPTORS) MODULATION AT HYPOGLOSSAL MOTONEURONS. THE SPECIFIC EFFECTS OF MUSCARINIC MODULATION WILL DEPEND ON THE MUSCARINIC ACETYLCHOLINE RECEPTORS PRESENT, WHERE M1, M3, AND M5 MUSCARINIC RECEPTORS HAVE CANONICALLY EXCITATORY EFFECTS WHEREAS THE M2 MUSCARINIC RECEPTOR SUBTYPE HAS A CANONICALLY INHIBITORY EFFECT, AS WELL AS THE COMPLIMENT OF ION CHANNELS THAT ARE MODULATED BY MUSCARINIC RECEPTORS. THIS PROJECT WILL EXPLORE THE HYPOTHESIS THAT CIH LEADS TO SIGNIFICANT CHANGES IN CHOLINERGIC SYNAPTIC INPUTS TO, AND CELLULAR PROPERTIES OF, HYPOGLOSSAL MOTONEURONS RESULTING IN AN INCREASED EXCITATORY EFFECT OF MUSCARINIC MODULATION AT HYPOGLOSSAL MOTONEURONS. THIS PROJECT USES POWERFUL IMMUNOFLUORESCENCE METHODS IN COMBINATION WITH IN VITRO ELECTROPHYSIOLOGY TO EVALUATE NEUROANATOMICAL AS WELL AS FUNCTIONAL CHANGES IN CHOLINERGIC SIGNALING AT HYPOGLOSSAL MOTONEURONS IN TWO SPECIFIC AIMS. IN AIM 1, THE PROJECT WILL DETERMINE THE EXPRESSION PATTERN OF MUSCARINIC ACETYLCHOLINE RECEPTOR SUBTYPES IN NEONATAL AND ADULT MICE EXPOSED TO CHRONIC INTERMITTENT HYPOXIA COMPARED TO MICE NAÏVE TO CHRONIC INTERMITTENT HYPOXIA. THIS AIM WILL ALSO EXPLORE CHANGES IN THE CHOLINERGIC INPUTS TO HYPOGLOSSAL MOTONEURONS IN RESPONSE TO CHRONIC INTERMITTENT HYPOXIA EXPOSURE. IN AIM 2, THE PROJECT WILL USE ELECTROPHYSIOLOGY TECHNIQUES TO TEST IN NEONATAL AND ADULT MICE THE FUNCTIONAL CHANGES OF MUSCARINIC MODULATION AT HYPOGLOSSAL MOTONEURONS IN RESPONSE TO CHRONIC INTERMITTENT HYPOXIA EXPOSURE. THIS AIM WILL EVALUATE THESE EFFECTS BOTH AT THE NETWORK LEVEL USING THE RHYTHMIC SLICE PREPARATION AND ALSO IN INDIVIDUAL HYPOGLOSSAL MOTONEURONS USING WHOLE CELL ELECTROPHYSIOLOGY METHODS. THESE STUDIES WILL CONTRIBUTE EXCELLENT TRAINING OPPORTUNITIES FOR GRADUATE AND PROFESSIONAL STUDENTS, THUS PROVIDING SCIENTIFIC TRAINING TO THE NEXT GENERATION OF CLINICIANS. FURTHERMORE, THE EXPECTED OUTCOMES WILL ADVANCE UNDERSTANDING OF CELLULAR AND SYNAPTIC CHOLINERGIC MECHANISMS THAT CHANGE IN RESPONSE TO EXPOSURE TO CHRONIC INTERMITTENT HYPOXIA. THIS FUNDAMENTAL INFORMATION WILL BE ESSENTIAL TO DEVELOP STRATEGIES TO EXPLORE IN VIVO THE CHOLINERGIC MECHANISMS THAT CONTRIBUTE TO STATE-DEPENDENT REDUCTIONS IN AIRWAY TONE AND HOW THOSE MECHANISMS CHANGE IN RESPONSE TO CHRONIC INTERMITTENT HYPOXIA EXPOSURE. THESE DATA WILL CONTRIBUTE TO THE MISSION OF THE NATIONAL HEART LUNG, AND BLOOD INSTITUTE OF IMPROVING THE HEALTH AND QUALITY OF AMERICANS SUFFERING FROM SLEEP DISORDERED BREATHING.

BLENDING DENTIN TO DENTIN: BIOMETRIC HYDROGELS FOR DENTIN TISSUE ENGINEERING - PROJECT SUMMARY DENTAL CARIES IS A MAJOR HEALTH CONCERN IN MOST INDUSTRIALIZED COUNTRIES, IN WHICH MOST CHILDREN, YOUNG AND OLDER ADULTS HAVE EXPERIENCED THE DISEASE AT LEAST ONCE IN THEIR LIFETIME. IN RECENT STUDY (2019) ON THE IMPACT OF ORAL DISEASES ON GLOBAL PUBLIC HEALTH, UNTREATED CARIES FIGURES AS THE MOST PREVALENT AND CONSEQUENTIAL AMONGST ALL ORAL CONDITIONS, AFFECTING MORE THAN 3 BILLION PEOPLE WORLDWIDE, WITH STRONG DETRIMENTAL EFFECT ON QUALITY OF LIFE AND HIGH COSTS FOR INDIVIDUALS, FAMILIES, AND SOCIETY. MOREOVER, CARIES DISEASE IS UNEQUALLY DISTRIBUTED IN POPULATIONS WITH A SIGNIFICANT SOCIOECONOMIC GRADIENT. ALTHOUGH DENTAL CARIES IS ESSENTIALLY A PREVENTABLE CONDITION, ITS PREVALENCE HAS BARELY DIMINISHED OVER THE LAST 40 YEARS. WHILE A DEFINITIVE APPROACH TO PREVENT AND MANAGE DENTAL CARIES HAS YET TO BE FOUND, RESTORATIVE BIOMATERIALS AND TECHNIQUES REMAIN AS THE ONLY EXISTING RESOURCES FOR REHABILITATION OF THE CARIES-AFFECTED TOOTH. THE PRIMARY GOAL OF RESTORATIVE DENTISTRY IS TO REPAIR TOOTH DAMAGED STRUCTURES BY REPLACING THEM WITH SYNTHETIC MATERIALS AIMING AT THE RE-ESTABLISHMENT OF TOOTH AESTHETICS AND FUNCTION. CURRENT RESTORATIVE PROCEDURES FULLY DEPEND ON EFFECTIVE MICROMECHANICAL INTERACTIONS BETWEEN RESIN METHACRYLATES AND NANOSTRUCTURED ORGANIC MACROMOLECULES OF DENTIN (MAINLY COLLAGEN), THE BULKIEST SUBSTRATE OF TOOTH DEMANDING SUBSTANTIAL REPAIR IN DENTAL REHABILITATION SCHEMES. AS QUOTED BY SEVERAL DENTAL MATERIAL SCIENTISTS, INFILTRATION OF RESIN METHACRYLATES WITHIN PARTIALLY DEMINERALIZED DENTIN IS A TYPE OF ON-DEMAND TISSUE ENGINEERING. NONETHELESS, CREATING DURABLE RESIN-BASED FILLINGS IS STILL A SIGNIFICANT CHALLENGE IN ADHESIVE DENTISTRY. THE NIDCR 2009-2013 STRATEGIC PLAN ON TOOTH-COLORED RESIN RESTORATIONS REPORTED THAT THE AVERAGE REPLACEMENT TIME OF THESE RESTORATIONS IS ONLY 5.7 YEARS. THE MAJOR REASON FOR REPLACEMENT OF SUCH RESTORATIONS HAS BEEN ATTRIBUTED TO ENZYMATIC DEGRADATION OF THE RESIN-DENTIN BONDED INTERFACE, WHICH ULTIMATELY FACILITATES RECURRENT CARIES. ESTIMATED COSTS TO REPLACE DEFECTIVE RESIN FILLINGS ARE IN THE ORDER OF ABOUT FIVE BILLION DOLLARS PER YEAR IN THE US ALONE. THE OVERALL GOAL OF THIS PROPOSAL IS TO USE MODIFIED NATURAL BIOMATERIALS TO ADDRESS THIS MATTER. THIS STUDY WILL DEVELOP HYBRID HYDROGELS BY MEANS THE FUNCTIONALIZATION OF EXTRACELLULAR MATRIX (ECM) OF DEMINERALIZED DENTIN WITH ACRYLAMIDES TO PRODUCE RESIN DENTAL ADHESIVES THAT ARE LESS VULNERABLE TO UNDERGO HYDROLYTIC DEGRADATION. IN ADDITION, THIS PROPOSAL WILL PIONEER A DENTAL ADHESIVE THAT IS TRULY BIOMIMETIC FOR ENDOGENOUS DENTIN AND, AS SUCH, WILL HAVE THE CAPACITY NOT ONLY REPAIR DENTAL CARIES LESIONS, BUT TO REGENERATE DENTIN BETTER THAN CURRENT METHACRYLATE DENTAL ADHESIVES. THIS PROGRAM WILL OFFER EXCELLENT TRAINING OPPORTUNITIES FOR GRADUATE AND PROFESSIONAL STUDENTS, THUS PROVIDING SCIENTIFIC SUPPORT TO THE NEXT GENERATION OF CLINICIANS. FURTHERMORE, WHILE THIS TECHNOLOGY INTENDS PRIMARILY ADVANCE DENTIN BIOENGINEERING AND REHABILITATION, THERE IS A POTENTIAL TO TRANSLATE OUR FINDINGS TO OTHER BIOMEDICAL APPLICATIONS WHERE THE USE OF ECM-DERIVATIVE HYDROGELS IS KEY TO MEDIATE IN-SITU TISSUE REGENERATION.

TARGETING ENDOTHELIAL DYSFUNCTION IN A GENETIC MOUSE MODEL OF AORTIC ANEURYSM: IMPLICATIONS FOR PREVENTION AND THERAPY

THE ROLE OF 12-LIPOXYGENASE IN ALDOSTERONE SECRETION

DEVELOPMENT AND EVALUATION OF CRRT-SPECIFIC PRECISION DOSING MODELS TO OPTIMIZE BETA-LACTAM TREATMENT FOR PATIENTS WITH HOSPITAL-ACQUIRED PNEUMONIA - PROJECT ABSTRACT HOSPITAL-ACQUIRED PNEUMONIA (HAP) CAUSED BY ANTIBIOTIC-RESISTANT PATHOGENS SUCH AS KLEBSIELLA AEROGENES, KLEBSIELLA PNEUMONIAE, AND PSEUDOMONAS AERUGINOSA ARE RESPONSIBLE TREATMENT FAILURE AND MORTALITY RATES UP TO 50% AND 30%, RESPECTIVELY. MEROPENEM IS A MAINSTAY FOR THE TREATMENT OF HAP, BUT ANTIBIOTIC RESISTANCE CONTINUES TO ERODE ITS CLINICAL EFFICACY. IMPORTANTLY, THE EFFICACY OF BETA-LACTAMS DEPENDS ON ACHIEVING ADEQUATE PHARMACOKINETIC-PHARMACODYNAMIC (PK/PD) EXPOSURES; HOWEVER, MANY PATIENTS WITH HAP EXPERIENCE INADEQUATE PK/PD BECAUSE OF CHANGES IN PK CAUSED BY CRITICALLY ILLNESS. PRECISION DOSING STRATEGIES CAN OVERCOME PK VARIABILITY CAUSED BY CRITICAL ILLNESS, BUT PRECISION DOSING REQUIRES ROBUST MODELS; SUCH MODELS FOR CRITICALLY ILL PATIENTS WHO DEVELOP KIDNEY INJURY AND REQUIRE CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) ARE CURRENTLY LACKING FOR HAP PATIENTS. WITHOUT PRECISION DOSING MODELS TO HELP GUIDE ANTIBIOTIC DOSING, THESE VULNERABLE PATIENTS WILL CONTINUE TO EXPERIENCE HIGH RATES OF TREATMENT FAILURE AND DEATH. WHEREAS THE STATUS QUO TREATMENT OF HAP PATIENTS REQUIRING CRRT USES POPULATION-BASED DOSING SCHEMES, OUR PROPOSAL WILL INNOVATE PRECISION DOSING (I.E., INDIVIDUALIZED) STRATEGIES FOR PATIENTS WITH HAP. WE WILL LEVERAGE THE INFRASTRUCTURE OF THE SUCCESSFUL CLINICAL RESPONSE IN PNEUMONIA THERAPY (SCRIPT) SYSTEMS BIOLOGY CENTER TO ROBUSTLY ADDRESS THE UNMET NEEDS OF PATIENTS ON CRRT. OUR LONG-TERM GOAL IS TO DEVELOP PRECISION DOSING STRATEGIES THAT OVERCOME PK VARIABILITY CAUSED BY SEVERE ILLNESS. THE PROJECT OBJECTIVE IS TO UTILIZE THE INFRASTRUCTURE, SAMPLES, AND DATA COLLECTED IN SCRIPT TO DEVELOP PRECISION DOSING MODELS FOR HAP. OUR CENTRAL HYPOTHESIS IS: (1) CRRT LEADS TO VARIABILITY IN BETA-LACTAM PK WITH STANDARD “ONE-SIZE-FITS ALL” HAP DOSING REGIMENS WHICH (2) INCREASES THE RISK OF CLINICAL TREATMENT FAILURE IN HAP, (3) REQUIRING PRECISION DOSING SCHEMES. THE RATIONALE FOR OUR STUDY IS THAT PRECISION DOSING IS NEEDED FOR CRRT PATIENTS WITH HAP AND THAT THESE APPROACHES MUST BE TRANSLATED CLINICALLY. IN AIM 1, WE WILL DEVELOP AND QUALIFY PRECISION DOSING MODELS FOR MEROPENEM IN CRRT. IN AIM 2, WE WILL DESCRIBE MEROPENEM PK/PD TARGET ATTAINMENT IN PLASMA AND IN THE LUNG FOR PATIENTS REQUIRING CRRT. IN AIM 3, WE WILL CREATE A WEB-BASED DOSING CALCULATOR FOR TRANSLATION TO PRACTICE. OUR STUDY WILL HAVE A POSITIVE CLINICAL IMPACT BY PROVIDING CLINICIANS WITH THE TOOLS NECESSARY TO ENSURE THAT EACH PATIENT’S DOSING IS OPTIMIZED. THIS RESEARCH IS SIGNIFICANT BECAUSE IT ADDRESSES A CRITICAL UNMET NEED FOR OPTIMIZED THERAPY. UPON COMPLETION, OUR STUDY WILL HAVE ROBUSTLY CHARACTERIZED ALVEOLAR PK IN CRRT PATIENTS, FILLING A GAP IN THE RIGOR OF PRIOR RESEARCH. WE WILL HAVE TRANSLATED OUR PRECISION DOSING MODEL PREDICTIONS INTO ACTIONABLE DOSING REGIMENS, WHICH IS INNOVATIVE AS NO SUCH CALCULATORS EXIST. OUR PRECISION DOSING CALCULATOR WILL BE EVALUATED IN A FUTURE R01-FUNDED RANDOMIZED CONTROLLED TRIAL.

QUANTIFYING RENAL INJURY AMONG THE MOST COMMONLY USED CLINICAL ANTIBIOTIC COMBINATIONS

THE INFLUENCE OF VOCAL LOADING UPON THE HEALING OF EXPERIMENTAL VOCAL FOLD INJURY - PROJECT SUMMARY THE DEVELOPMENT AND MAINTENANCE OF A SPEAKING AND SINGING FUNDAMENTAL FREQUENCY, WHILE ALSO ACHIEVING VOCAL CLARITY THROUGHOUT LIFE, ARE IMPORTANT PUBLIC HEALTH CONCERNS. SYMPTOMS OF DYSPHONIA ARE AMONG THE MOST COMMON COMMUNICATION DISORDERS. CURRENTLY THERE IS NO TREATMENT TO RESTORE A NATIVE VOCAL FOLD LAMINA PROPRIA COMPOSITION OR LARYNGEAL MOVEMENTS AFTER INJURY. RESEARCH IS LIMITED BECAUSE THERE IS NO IN VIVO MODEL FOR LARYNX INJURIES THAT EXPRESS A VOCAL BEHAVIOR THAT CAN SERVE AS A RELIABLE PHENOTYPIC MARKER. IN GENERAL, AN ANIMAL MODEL CAN BENEFIT RESEARCH IF ITS BEHAVIOR CAN SERVE AS MARKER FOR THE ONSET OR THE TIME-COURSE OF A PATHOLOGY AFFECTING A COMPLEX BEHAVIOR. SPECIFICALLY, THE AVAILABILITY OF AN ANIMAL MODEL THAT COMBINES EXPERIMENTAL AND GENETIC ACCESSIBILITY WITH IMPORTANT SIMILARITIES TO HUMAN VOICE PRODUCTION COULD ALLOW STRONGER INFERENCES. HERE WE PROPOSE (1) TO QUANTIFY KEY ANATOMICAL FEATURES OF THE VOCAL ORGAN DURING POSTNATAL DEVELOPMENTAL IN A NEW MODEL, AND (2) TO DESCRIBE THE TIME-COURSE OF WOUND HEALING AFTER EXPERIMENTAL VOCAL FOLD INJURY IN A VOCAL DOSE- DEPENDENT FASHION. RESULTS WILL BE INTEGRATED IN A COMPUTATIONAL VOCAL FOLD MODEL. COMPLETION OF THIS WORK WILL PROVIDE THE FIELD WITH A NEW MOUSE MODEL FOR THE STUDY OF VOCAL DISEASE MECHANISMS AND THERAPEUTIC DEVELOPMENT. IT WILL ALSO INFORM THE ROLE OF VOCAL OCCUPANCY ON THE HEALING PROCESS OF VOCAL FOLDS.

ELACRIDAR: IDENTIFICATION OF THE MOLECULAR TARGET RELEVANT TO ITS ANTI-PRION EFFECTS AND ITS APPLICATION TO OTHER PROTEIN MISFOLDING NEURODEGENERATIVE DISEASES - PRION DISEASES, WHILE EXCEPTIONALLY RARE, HAVE PROVIDED A ROAD MAP TO LINK MANY PROTEIN MISFOLDING NEURODEGENERATIVE DISEASES IN PROFOUND MECHANISTIC WAYS INCLUDING THE PRION-LIKE SPREAD OF PATHOLOGICAL PROTEIN AGGREGATES FROM CELL-TO-CELL AND THE NEUROTOXICITY INDUCED BY SOLUBLE OLIGOMERS OF THESE ASSEMBLIES. PRION DISEASES ALSO AFFECT OTHER ANIMALS, INCLUDING MODEL ORGANISMS (AND IMMORTALIZED CELL LINES), MAKING THEM THE ONLY NEURODEGENERATIVE DISEASE THAT CAN BE DIRECTLY STUDIED IN LABORATORY EXPERIMENTS. THIS UNPRECEDENTED SCENARIO HAS ALLOWED FOR THE TESTING AND CHARACTERIZATION OF SMALL MOLECULE THERAPEUTICS UNDER REAL LIFE CONDITIONS. WE HAVE RECENTLY DISCOVERED A NOVEL ANTI-PRION COMPOUND, ELACRIDAR, AND PRELIMINARY DATA SUGGESTS THAT IT EXERTS ITS EFFECTS THROUGH ACTIVATING THE LYSOSOME, THE ORGANELLE RESPONSIBLE FOR THE DEGRADATION OF UNWANTED PROTEINS. BECAUSE OF THE CENTRAL ROLE OF LYSOSOMES TO PROTEIN DEGRADATION, WE EXTENDED THESE STUDIES TO DETERMINE THAT ELACRIDAR IS ALSO EFFICACIOUS AGAINST MISFOLDED Α-SYNUCLEIN AND TAU, PROTEINS ASSOCIATED WITH MORE COMMON NEURODEGENERATIVE DISEASES. IN THIS APPLICATION, WE PROPOSE EXPERIMENTS DESIGNED TO DEFINE THE MECHANISM OF ACTION WHEREBY ELACRIDAR EXERTS ITS ANTI-PRION EFFECTS THROUGH IDENTIFICATION OF THE INTRACELLULAR SITE(S) WHERE IT ACCUMULATES, THE ACCOMPANYING PROTEOMIC CHANGES INDUCED BY THIS ACCUMULATION, AND THE IDENTIFICATION OF THE MOLECULAR TARGET RESPONSIBLE FOR THESE EFFECTS. WE ALSO PROPOSE TO FURTHER EXPLORE THE EFFECTS OF ELACRIDAR AGAINST PATHOLOGICALLY MISFOLDED FORMS OF Α-SYNUCLEIN AND TAU USING ASSAYS TO MONITOR THEIR CELL-TO-CELL SPREAD, DEGRADATION, AND NEUROTOXICITY. WE ANTICIPATE THAT THE KNOWLEDGE GAINED BY THESE INVESTIGATIONS WILL PROVIDE NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES.

STRUCTURE-FUNCTION ANALYSIS OF ZEBRAFISH ENCODED 3-OST ENZYME FOR HSV-1 ENTRY

ELUCIDATING THE TEMPORAL MECHANISM OF VANCOMYCIN KIDNEY TOXICITY AS A MEANS TO PREVENT INJURY - PROJECT ABSTRACT: THERE IS A FUNDAMENTAL NEED TO UNDERSTAND THE TEMPORALITY OF THE MECHANISM FOR VANCOMY- CIN ACUTE KIDNEY INJURY (VAN AKI) BECAUSE MECHANISTIC KNOWLEDGE TO DATE HAS NOT LED TO SAFER CARE. HOWEVER, DOING SO REQUIRES SERIAL BIOPSY AND HAS BEEN DEEMED IMPOSSIBLE IN TRADITIONAL RODENT EXPERIMENTS AND UNETHI- CAL IN HUMANS. OUR SWINE MODEL OF INTUBATED, SEDATED, AND PARALYZED PIGS OFFERS PHYSIOLOGIC AND SITUATIONAL SIMILARITY TO HUMAN CRITICAL ILLNESS AND FURTHER ALLOWS SERIAL BIOPSY AND MODERATE VOLUME PHLEBOTOMY. DEFINING THE INCITING MECHANISM WILL PAVE THE WAY FOR AKI PREVENTION STUDIES THAT WILL PRECISELY TARGET: A) AVOIDANCE OF CELLULAR ACCUMULATION SUCH AS THROUGH CELLULAR UPTAKE AT THE PROXIMAL TUBULE CELL FOR VANCOMYCIN AND MANY OTHER NEPHROTOXINS, E.G., MEGALIN MEDIATED UPTAKE OR B) TUBULAR CONDITIONS THAT MINIMIZE THE LIKELIHOOD OF URO- MODULIN COMPLEX FORMATION, E.G., OSMOTIC GRADIENT MANAGEMENT. THE LONG-TERM GOAL OF THIS RESEARCH PROGRAM IS TO IMPROVE THE KIDNEY SAFETY PROFILE FOR CRITICALLY NECESSARY ANTIBIOTIC THERAPIES. VANCOMYCIN (VAN) IS AN EX- EMPLAR STUDY DRUG, AS IT IS THE MOST PRESCRIBED ANTIBIOTIC IN THE HOSPITAL SETTING AND CAUSES KIDNEY DAMAGE THAT LEADS TO EXCESS MORBIDITY AND MORTALITY. THE OBJECTIVES OF THIS APPLICATION ARE TO: 1) DEFINE THE MECHANISTIC TEMPORALITY OF VAN AKI SO THAT PREVENTION STRATEGIES CAN BE FOCUSED LATER AND 2) IDENTIFY THE METABOLOMIC PATH- OGNOMONIC SIGNATURE IN BLOOD THAT PRECEDES VAN AKI. THE CENTRAL HYPOTHESES IN THIS PROPOSAL ARE THAT: 1) TEMPORALITY OF THE PREVIOUSLY DEFINED VAN AKI MECHANISMS IS CRITICALLY IMPORTANT, WITH THE FIRST EVENT INITIATING A CHAIN REACTION LEADING TO TOXICITY. IDENTIFYING THIS IGNITION POINT WILL ALLOW PREVENTION STRATEGIES TO BE PRECISELY TARGETED, AND 2) CHARACTERIZING THE BLOOD METABOLOME WILL IDENTIFY PATHOGNOMONIC SIGNATURES THAT PRECEDE SUS- TAINED INJURY AND WILL REPRESENT SUBSTANTIAL IMPROVEMENTS OVER THE STATUS QUO MONITORING APPROACHES SUCH AS SERUM CREATININE OR URINARY BIOMARKERS THAT ARE SUBJECT TO VARIABILITY FROM DILUTION. THE RIGOR OF PRIOR RESEARCH DEMONSTRATES THAT: 1) VAN CAUSES HISTOPATHOLOGIC KIDNEY DAMAGE AND CHANGES TO GLOMERULAR FILTRATION RATE. 2) OUR VERY SMALL PILOT DATA WITH THREE SWINE DEMONSTRATE PROMISE FOR IDENTIFYING METABOLOMIC SIGNATURES THAT PRE- CEDE AKI. IN THIS PROPOSAL, WE AIM TO 1) DETERMINE THE INCITING MECHANISM AND TEMPORALITY OF VANCOMYCIN AKI IN SWINE AND CLASSIFY THE CORRESPONDING THE CHANGES IN GLOMERULAR FUNCTION AND OTHER GOLD STANDARDS AND 2) CHARACTERIZE THE BLOOD METABOLOME OF SWINE THAT DEVELOP AND DO NOT DEVELOP AKI. THIS PROJECT IS INNOVATIVE AS NO PREVIOUS APPROACHES HAVE BEEN ABLE TO ANSWER MECHANISTIC TEMPORALITY, AND IDENTIFYING BLOOD METABO- LOMIC SIGNATURES IS LIKELY TO ADVANCE THE STATUS QUO FOR TIMELY KIDNEY INJURY DETECTION. IDENTIFICATION OF EARLY IN- JURY IS ESPECIALLY TRANSLATIONAL SINCE IT WILL BE IDENTIFIED FROM A MODEL THAT IS PHYSIOLOGICALLY AND SITUATIONALLY SIM- ILAR TO THE HUMAN CONDITION OF CRITICAL ILLNESS. THESE CONTRIBUTIONS WILL BE SIGNIFICANT BECAUSE VAN KIDNEY INJURY IS COMMON WITH CURRENT APPROACHES, AND PROPOSED METHODOLOGIES ARE RELEVANT TO UNDERSTANDING OTHER DRUGS (E.G., POLYMYXIN B AND CISPLATIN) THAT CAUSE AKI. RESULTS FROM THIS PROPOSAL WILL LEAD TO DIRECTED CLINICAL TRIALS.

TESTING ADAPTIVE HYPOTHESES OF PLIO-PLEISTOCENE HOMININ CRANIOFACIAL EVOLUTION

STRATEGIES TO AVOID DRUG INDUCED KIDNEY INJURY IN THE TREATMENT OF MULTI-DRUG RESISTANT PATHOGENS - PROJECT ABSTRACT: THERE IS A FUNDAMENTAL NEED TO IMPROVE TREATMENT FOR METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS. WE WILL DEFINE HOW DYNAMIC TOXICITY THRESHOLDS CHANGE FOR VANCOMYCIN WITH CO-NEPHROTOXINS AND NEPHROPROTECTANTS FOR ADULTS AND CHILDREN USING RICHLY COLLECTED CLINICAL DATA AND AGE-APPROPRIATE ANIMAL MODELS. DYNAMIC TOXICITY THRESHOLDS WILL ULTIMATELY ENABLE PRECISION DOSING STRATEGIES FOR SAFE AND EFFECTIVE VANCOMYCIN EXPOSURES. THE LONG-TERM GOAL OF THIS RESEARCH IS TO IMPROVE THE KIDNEY SAFETY PROFILE OF CRITICAL ANTIBIOTICS. VANCOMYCIN IS THE MOST USED HOSPITAL ANTIBIOTIC AND CAUSES DRUG INDUCED KIDNEY INJURY (DIKI). THE OBJECTIVES OF THIS PROPOSAL ARE TO: 1) LEVERAGE AGE-SPECIFIC ANIMAL MODELS TO DEFINE THE `DYNAMIC TOXICITY THRESHOLD' IN THE SETTING OF CONCOMITANT THERAPIES FOR ADULTS AND CHILDREN AND 2) LINK DATA FROM THE BENCH TO THE BEDSIDE AND SIMULATE DOSING STRATEGIES THAT ENSURE SAFE AND EFFECTIVE THERAPY IN BOTH ADULTS AND CHILDREN. THE CENTRAL HYPOTHESIS IS THAT CO-NEPHROTOXINS LOWER THE VANCOMYCIN TOXICITY THRESHOLD FOR DIKI. UNDERSTANDING THIS THRESHOLD WILL ALLOW CLINICIANS TO USE PRECISION DOSING AND NEPHROPROTECTANT STRATEGIES TO DECREASE DIKI. PRIOR RESEARCH SHOWS: A) SPECIFIC VANCOMYCIN CONCENTRATIONS CAUSE DIKI. B) KIDNEY INJURY MOLECULE-1 (KIM-1) AND OTHER BIOMARKERS ARE SENSITIVE AND SPECIFIC FOR AKI. C) OUR RAT MODEL FOR VANCOMYCIN AKI LINKS TO HUMAN OUTCOMES, SERVING AS A TRANSLATIONAL PLATFORM. WE AIM TO QUANTIFY DYNAMIC EXPOSURE:TOXICITY THRESHOLD CHANGES FOR VANCOMYCIN DIKI +/- AN EXEMPLAR NEPHROTOXIN, AND +/- AN EXEMPLAR NEPHROPROTECTANT, AND LINK TO RAT MODELS. AIM 1 USES FLUCLOXACILLIN (CO-NEPHROTOXIN) AND PROTAMINE (NEPHROPROTECTANT) TO CREATE DYNAMIC TOXICITY THRESHOLDS. TESTING ALL DRUGS SIMULTANEOUSLY WILL ADDRESS IF A NEPHROPROTECTANT CAN RESTORE THE THERAPEUTIC WINDOW FOR VANCOMYCIN WITH A CO-NEPHROTOXIN. WE WILL BRIDGE TO HUMAN BY LINKING OUR RAT MODEL TO CAMERA2, A LARGE VANCOMYCIN TRIAL. AIM 2 QUANTIFIES DYNAMIC EXPOSURE:TOXICITY THRESHOLD CHANGES FOR VANCOMYCIN +/- VASOPRESSORS IN AN AGE-APPROPRIATE RAT MODEL. IMPORTANTLY, WE WILL ADAPT OUR WELL-CHARACTERIZED ADULT RAT MODEL TO A JUVENILE RAT MODEL (ANALOG OF A 2-YEAR-OLD PATIENT). USING VANCOMYCIN PHARMACOKINETICS AND KIDNEY INJURY BIOMARKERS, WE WILL LINK THE JUVENILE RAT MODEL TO CHILDREN WITH MULTIPLE ORGAN DYSFUNCTION SYNDROME FROM OUR HIGHLY UNIQUE AMPLE STUDY (R01HD103755). THIS PROJECT WILL BE INNOVATIVE BECAUSE 1) DYNAMIC TOXICITY THRESHOLDS ARE NOVEL AND WILL ENABLE PRECISION MEDICINE AND 2) ADAPTING OUR RAT MODEL TO THE PEDIATRIC ENVIRONMENT FACILITATES BRIDGING TO ONE OF THE LARGEST CLINICAL DATASETS OF VANCOMYCIN PHARMACODYNAMICS IN CHILDREN. THESE CONTRIBUTIONS WILL BE SIGNIFICANT BECAUSE “REAL WORLD” PATIENTS OFTEN RECEIVE CO-NEPHROTOXINS; A PLATFORM IS NECESSARY TO DEFINE INJURY RISK OUTSIDE OF CLINICAL TRIAL SCENARIOS THAT ARE NOT RELEVANT FOR MOST PATIENTS. THIS PROPOSAL ADDRESSES THE NIH MISSION TO `INNOVATE RESEARCH STRATEGIES' TO `CURE HUMAN DISEASES' BY CREATING A PLATFORM THAT CAN FUNNEL SUCCESSFUL PRE-CLINICAL APPROACHES TO CLINICAL TRIALS.

COLLABORATIVE RESEARCH: THE EFFECTS OF MUSCULOSKELETAL DESIGN ON BIPEDAL WALKING AND RUNNING PERFORMANCE

** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** FOOD ANIMAL VETERINARIANS ARE CRITICAL IN MAINTAINING THE HEALTH AND WELFARE OF FOOD ANIMALS, ENSURING A SAFE AND AMPLE FOOD SUPPLY, SAFEGUARDING PUBLIC HEALTH, PROTECTING GLOBAL FOOD SECURITY, AND SUPPORTING THE U.S. ECONOMY. FOR NATIVE AMERICANS, FOOD ANIMALS HAVE AN ADDITIONAL CULTURAL AND SPIRITUAL COMPONENT. YET, THERE IS A SEVERE SHORTAGE OF VETERINARIANS THAT SERVE RESERVATIONS, WITH VETERINARIANS WHO PROVIDE SERVICES TO FOOD ANIMALS ESSENTIALLY NON-EXISTENT. FOR EXAMPLE, THE NAVAJO NATION, THE LARGEST LAND AREA HELD BY A NATIVE AMERICAN TRIBE IN THE UNITED STATES COMPRISING 16 MILLION ACRES AND APPROXIMATELY THE SIZE OF THE STATE OF WEST VIRGINIA HAS ONLY ONE VETERINARIAN THAT SERVES THE ENTIRE COMMUNITY AND PRIMARY DOMESTIC ANIMALS. MULTIPLE FACTORS, INCLUDING THE LOW ENROLLMENT OF NATIVE AMERICAN STUDENTS IN VETERINARY SCHOOLS, EXPLAIN THE LACK OF VETERINARIANS ON RESERVATIONS. THE LACK OF EXPOSURE OF RESERVATION YOUTH TO CAREER OPPORTUNITIES IN THE VETERINARY MEDICINE FIELDPARTLY EXPLAINS THE LIMITED ENROLLMENT OF NATIVE AMERICAN STUDENTS IN THE PROFESSION. WHILE THE SHORTAGE OF FOOD ANIMAL VETERINARIANS IS A MULTIFACTORIAL PROBLEM, THERE IS AN ATTAINABLE OPPORTUNITY TO HELP RESOLVE THIS PROBLEM BY TARGETING CHILDREN FROM UNDERSERVED AREAS SUCH AS RESERVATIONS AND EXPOSING THEM TO VETERINARY PRACTICE IN A BID TO HAVE MORE STUDENTS CHOOSING VETERINARY MEDICINE AS A CAREER. IN ADDITION, A CURRICULUM-BASED APPROACH WILL ALSO HELP STUDENTS WHO ARE ALREADY ENROLLED IN VETERINARY SCHOOL.TO HELP SOLVE THE PROBLEM OF SHORTAGE OF FOOD ANIMAL PRACTICE VETERINARIANS IN UNDERSERVED AREAS, THE FARM ANIMAL MEDICINE DEPARTMENT AT MIDWESTERN UNIVERSITY, COLLEGE OF VETERINARY MEDICINE, IS STARTING AN EXTERNSHIP THAT INVOLVES TRAINING OF VETERINARY STUDENTS ON RURAL FOOD ANIMAL PRACTICE WHILE INVOLVING NATIVE AMERICAN YOUTHS ON RESERVATIONS. THIS SPECIALIZED PROGRAM IS SPECIFICALLY DESIGNED TO MEET THE DEFICIENCIES IDENTIFIED IN VETERINARY CURRICULA AND TRAINING AS WELL AS TO EXPOSE THE NATIVE AMERICAN YOUTHS TO CAREER OPPORTUNITIES VETERINARY MEDICINE. BY PROVIDING A FOCUS ON PRACTICE IN RURAL OR UNDERSERVED AREAS, THE PROGRAM ADDRESSES WORK ENVIRONMENTS THAT FREQUENTLY LACK SUPPORT AND GUIDANCE FOR A NEW GRADUATE. THE PROGRAM INVOLVES MIDWESTERN UNIVERSITY VETERINARY FACULTY AND STUDENTS, VETERINARY STUDENTS FROM OTHER VETERINARY COLLEGES IN UNITED STATES, AND NATIVE AMERICAN YOUTHS IN SCHOOLS. THE DEPARTMENT WILL OFFER VETERINARY SERVICES WHICH INCLUDE DIRECT PATIENT CARE AS WELL AS HERD HEALTH/PRODUCTION MEDICINE SERVICES FOR TWO WEEKS, THREE TIMES A YEAR ON NAVAJO NATION. THE PROGRAM IS EXPECTED TO HELP PRODUCE CONFIDENT FOOD ANIMAL VETERINARIANS WHO WILL PRACTICE FOR A LONG TIME. WE ALSO EXPECT THE PROGRAM TO STIMULATE MORE NATIVE AMERICAN YOUTH ON NAVAJO NATION TO BE INTERESTED IN VETERINARY MEDICINE AND ENROLL IN VETERINARY SCHOOLS.

COLLABORATIVE RESEARCH: AFTER THE BRIDGERIAN CRASH: AN INTEGRATED ANALYSIS OF MAMMALIAN PALEOCOMMUNITIES AND PALEOECOLOGIES DURING THE MIDDLE EOCENE.

FUNCTIONS OF EPSTEIN-BARR VIRUS LMP2A IN LATENCY

MANZAMINE A AS AN ANTI-INFLAMMATORY TREATMENT FOR RHEUMATOID ARTHRITIS

ROLE OF THE ABG LOCUS OF E COLI IN FOLATE CATABOLISM

FEASIBILITY OF A NEW METHODOLOGY FOR DENTAL EDUCATION IN TEMPOROMANDIBULAR DISORDERS THROUGH VIRTUAL PATIENT-BASED LEARNING - PROJECT SUMMARY/ABSTRACT TEMPOROMANDIBULAR DISORDERS (TMD) INVOLVE PAIN AND DYSFUNCTION IN THE MASTICATORY MUSCLES, TEMPOROMANDIBULAR JOINT, AND ASSOCIATED STRUCTURES, AFFECTING ABOUT 30% OF THE POPULATION. DESPITE ITS PREVALENCE, EFFECTIVE TMD MANAGEMENT FACES CHALLENGES DUE TO A LIMITED UNDERSTANDING AMONG DENTAL PROFESSIONALS WHICH DERIVES FROM INADEQUATE EDUCATION DURING THEIR TRAINING. THE ESTABLISHMENT OF OROFACIAL PAIN AS A NEW DENTAL SPECIALTY IN 2020 PROMPTED THE INCLUSION OF TMD EDUCATION IN PREDOCTORAL DENTAL PROGRAMS ACROSS US DENTAL SCHOOLS FROM JULY 2022. HOWEVER, THE EXTENT OF TMD EDUCATION VARIES SIGNIFICANTLY IN TERMS OF CONTENT AND EXPERTISE OF FACULTY DELIVERING THE TEACHING. MOREOVER, DUE TO THE LIMITED NUMBER OF OROFACIAL PAIN SPECIALISTS WITHIN PREDOCTORAL DENTAL SCHOOLS, MANY TMD PATIENTS ARE REFERRED ELSEWHERE FOR TREATMENT OR CONSIDERED OUTSIDE THE SCOPE OF THE UNIVERSITY, LEAVING DENTAL STUDENTS WITH INSUFFICIENT CLINICAL EXPOSURE TO TMD CASES DURING THEIR TRAINING. GIVEN THESE GAPS IN KNOWLEDGE WITH THE PRESENT MODALITIES OF EDUCATION AND THE LIMITED CLINICAL EXPOSURE TO TMD CASES OFFERED BY MOST PREDOCTORAL DENTAL INSTITUTIONS TO THEIR STUDENTS, THERE IS A CRITICAL NEED TO EXPLORE NEW EDUCATIONAL METHODOLOGIES TO OVERCOME THESE ISSUES. THE PROPOSED PROJECT AIMS TO ADDRESS THESE CRITICAL GAPS BY DEVELOPING AND TESTING A VIRTUAL PATIENT-BASED LEARNING (VPBL) METHODOLOGY, INCORPORATING REAL PATIENT DATA INTO INTERACTIVE CLINICAL SCENARIOS AND INTEGRATING IT IN THE TMD CURRICULUM OF A PREDOCTORAL DENTAL SCHOOL LACKING AN OROFACIAL PAIN PROGRAM. THE APPROPRIATENESS AND COMPREHENSIVENESS OF THE VIRTUAL PATIENT CLINICAL SCENARIOS WILL BE REVIEWED AND TESTED BY EXPERTS IN THE FIELD (AIM 1). SUBSEQUENTLY, THE FEASIBILITY AND UTILITY OF THIS NEW TECHNOLOGICAL AND EDUCATIONAL METHODOLOGY WILL BE ASSESSED AMONG THIRD- AND FOURTH-YEAR DENTAL STUDENTS AT A PREDOCTORAL DENTAL SCHOOL WITH A REDCAP QUESTIONNAIRE (AIM 2). THE CENTRAL HYPOTHESIS IS THAT DIGITAL LEARNING INTEGRATED INTO THE PREDOCTORAL TMD CURRICULUM WILL DEMONSTRATE HIGH LEVELS OF FEASIBILITY, ACCEPTABILITY, USEFULNESS, AND APPLICABILITY FOR CLINICAL REASONING. THE OVERARCHING GOAL OF THIS PROGRAM IS TO IMPROVE QUALITY OF CARE FOR UNDERSERVED TMD PATIENTS BY EQUIPPING FUTURE DENTAL PROVIDERS WITH THE NECESSARY SKILLS TO DIAGNOSE AND MANAGE TMD CONDITIONS EFFECTIVELY. IMPLEMENTING VPBL OFFERS A PROMISING SOLUTION TO BRIDGE THE GAPS IN DENTAL EDUCATION AND THE LIMITED CLINICAL EXPOSURE TO TMD CASES DURING PREDOCTORAL TRAINING. THE FINDINGS OF THE PROPOSED PROJECT WILL INFORM ABOUT THE FEASIBILITY AND UTILITY OF INTEGRATING THIS INNOVATIVE TECHNOLOGY INTO DENTAL EDUCATION. FOLLOWING A SUCCESSFUL RANDOMIZED CLINICAL TRIAL, A FUTURE R01 GRANT WILL EXPLORE THE FULL POTENTIAL OF THIS PROGRAM THROUGH DISSEMINATION AND IMPLEMENTATION (D&I) STRATEGIES. BY DISSEMINATING THE VPBL PLATFORM TO DENTAL INSTITUTIONS ACROSS THE NATION AND INTEGRATING IT INTO CURRICULA, THE PROPOSED PROJECT AIMS TO FILL IMPORTANT GAPS IN KNOWLEDGE OF FUTURE DENTAL PROFESSIONALS AND IMPROVE TREATMENT TO AN UNDERSERVED POPULATION. BY DOING SO, IT AIMS TO ADVANCE DENTAL EDUCATION WHILE PROMOTING INNOVATIVE APPROACHES.

PRECLINICAL TRIALS OF NFKAPPAB INHIBITION IN THE TREATMENT OF MUSCULAR DYSTROPHY

COLLABORATIVE RESEARCH: EVOLUTION OF LONG-DISTANCE COMMUNICATION IN VOCAL RODENTS

MUCIN EXPRESSION IN RHEUMATOID ARTHRITIS

PNR: UNDERSTANDING THE IMPACT OF SELECTIVE BREEDING ON CHRONIC WASTING DISEASE MANAGEMENT IN WHITE-TAILED DEER

COLLABORATIVE RESEARCH: PALEONTOLOGICAL AND GEOLOGICAL CONTEXTS OF HUMAN ORIGINS -THIS PROJECT STUDIES 6-MILLION-YEAR-OLD PALEONTOLOGICAL SITES TO RETRIEVE FOSSIL, PALEOENVIRONMENTAL, AND GEOLOGICAL DATA RELEVANT FOR UNDERSTANDING HUMAN ORIGINS. THE AGE OF THE FOSSIL SITES COINCIDES WITH THE EMERGENCE OF THE HUMAN LINEAGE, AND THE PALEONTOLOGICAL ASSEMBLAGES PROVIDE NOVEL INFORMATION REGARDING THE ECOLOGICAL CONTEXTS AND EVOLUTIONARY HISTORIES OF RELATED FAUNA. THE PROJECT SUPPORTS FIELD WORK, ANALYTICAL ANALYSES, GRADUATE AND UNDERGRADUATE STUDENT TRAINING OPPORTUNITIES, AND PUBLIC SCIENCE OUTREACH. PALEONTOLOGICAL SITES SAMPLING THE CRITICAL PERIOD WHEN HUMAN ANCESTORS FIRST EVOLVED (6 MILLION YEARS AGO) ARE EXCEPTIONALLY RARE. THE INVESTIGATORS CONDUCT INTENSIVE (I) PALEONTOLOGICAL RECOVERY, (II) PALEOENVIRONMENTAL RECONSTRUCTION THROUGH MULTIPLE PROXIES, AND (III) REFINEMENT AND EXPANSION OF THE REGIONAL GEOLOGICAL FRAMEWORK IN A KEY REGION FOR UNDERSTANDING HOMININ ORIGINS. LOCAL PALEOCLIMATE, VEGETATION STRUCTURE, AND HERBIVORE COMMUNITY ECOLOGY ARE INVESTIGATED USING PHYTOLITH ANALYSES AND STABLE ISOTOPE ANALYSES OF PALEOSOL CARBONATES, LEAF WAXES, AND FOSSIL MAMMALIAN TOOTH ENAMEL. GEOLOGIC WORK INCLUDES TEPHRA ANALYSIS, STRATIGRAPHIC MEASUREMENTS, AND HIGH-RESOLUTION MAPPING TO CONSTRAIN THE AGE AND ENVIRONMENTAL CONTEXT AND ENABLE LOCAL CORRELATIONS AND LINKAGES TO OTHER PALEONTOLOGICAL SITES. THE MULTI-PROXY APPROACH USED IN THIS PROJECT PROVIDES ROBUST DIETARY NICHE AND ENVIRONMENTAL RECONSTRUCTIONS TO BETTER CONTEXTUALIZE THE FOSSIL ASSEMBLAGES DURING THE EMERGENCE OF THE HUMAN LINEAGE. 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.

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

HPSL - DENTISTRY - CLOSEOUT DOCUMENT NUMBER

GENETIC REGULATION OF THE TWIN ARGININE TRANSLOCATION SYSTEM IN SALMONELLA ENTERICA SEROVAR TYPHIMURIUM

COLLABORATIVE RESEARCH: DEVELOPING KINETIC 3D COMPUTATIONAL MODELS OF BIPEDAL WALKING -HUMAN BIPEDAL WALKING UNDERLIES NUMEROUS ASPECTS OF OUR ECOLOGY AND BEHAVIOR. KNOWLEDGE OF FOOT ANATOMY AND FUNCTION IS ESSENTIAL BECAUSE THE FOOT INTERFACES DIRECTLY WITH THE GROUND DURING WALKING OR RUNNING, AND IT IS IMPORTANT TO UNDERSTAND HOW VARIATION IN FOOT ANATOMY MAY IMPACT BIOMECHANICS. THIS RESEARCH ADVANCES CURRENT UNDERSTANDINGS OF HOMININ BIPEDALISM BY INTEGRATING ANATOMIC AND KINEMATIC DATA AND DEVELOPING AI-DRIVEN 3D COMPUTATIONAL FOOT MODELS FOR APES AND HUMANS. THE STUDY PROVIDES FUNDING AND TRAINING FOR STUDENTS AND INCLUDES OUTREACH ACTIVITIES DIRECTED TO THE PUBLIC. RESULTS FROM THIS STUDY AID IN THE DEVELOPMENT OF NEW TRANSLATIONAL METHODS FOR INVESTIGATING ANATOMICAL VARIATION ASSOCIATED WITH FOOT PATHOLOGY (E.G., FLAT FEET) AND INFORM ABOUT THE EFFECTS OF FOOTWEAR ON FOOT MUSCLE USE AND SOFT TISSUE DISORDERS (E.G., PLANTAR FASCIITIS). THIS STUDY APPLIES AN INTEGRATIVE EXPERIMENTAL MODELING-SIMULATION APPROACH. THE STUDY CONDUCTS DIRECT COMPARISONS REGARDING THE INTRINSIC FOOT BIOMECHANICS OF HUMAN AND APE, INFORMING AND COMPARING THEIR MUSCULOSKELETAL DESIGN. THE STUDY: (1) CONDUCTS LOADING EXPERIMENTS ON HUMAN AND APE FEET; (2) BUILDS MUSCULOSKELETAL MODELS OF HUMAN AND APE FEET; (3) INTEGRATES EXPERIMENTAL DATA WITH THESE MODELS TO CALCULATE INTRINSIC FOOT DYNAMICS, AND; (4) PERFORMS DYNAMIC SIMULATIONS TO LINK INTRINSIC FOOT MUSCULOSKELETAL STRUCTURE TO WALKING KINEMATICS, KINETICS, MUSCLE ACTIVATION, AND METABOLIC COST. ADVANCED AI-SUPPORTED COMPUTATIONAL MODELING TECHNIQUES ARE APPLIED TO TEST LONG-HELD IDEAS REGARDING THE FORM-FUNCTION RELATIONSHIPS IN HOMININ FEET. THE STUDY INFORMS INTERPRETATIONS OF THE HOMININ FOSSIL RECORD, YIELDS SOFT TISSUE AND MECHANICAL PROPERTY DATA, AND GENERATES DETAILED MUSCULOSKELETAL MODELS THAT INFORM TRANSLATIONAL RESEARCH. 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.

NSL - GRADUATE NURSING - OTHER ADMIN CHANGES

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

HPSL - PODIATRY - CLOSEOUT DOCUMENT NUMBER

SL - OPTOMETRY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

CLOSEOUT DOCUMENT NUMBER

DIRECTED GRANTS

NOVEL EFFECTS OF GENISTEIN ON TENDON REMODELING IN A MODEL OF ESTROGEN-DEFICIENCY

COLLABORATIVE RESEARCH: HUMAN AND NON-HUMAN INFLUENCES ON SPECIES BIODIVERSITY IN AN ISLAND ECOSYSTEM

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

NURSE ANESTHETIST TRAINEESHIPS

USDA ANIMAL HEALTH AND DISEASE RESEARCH GRANT

NURSE ANESTHETIST TRAINEESHIPS

ADVANCED EDUCATION NURSING TRAINEESHIP

ANIMAL HEALTH AND DISEASE RESEARCH

PROJECT ABSTRACT WITHIN THE PURVIEW OF ONE HEALTH, THIS PROJECT AIMS TO FOSTER INTERDISCIPLINARY RESEARCH AND COLLABORATIVE EFFORTS AT MIDWESTERN UNIVERSITY'S COLLEGE OF VETERINARY MEDICINE THAT ENHANCE THE WELL-BEING OF ANIMALS, HUMANS, AND THE ECOSYSTEM. THERE IS A SHARED COMMITMENT AMONG DEDICATED FACULTY ACROSS BOTH BASIC AND CLINICAL DISCIPLINES TO EXPLORE ANIMAL AND HUMAN DISEASES TO PROMOTE THE CORE TENANTS OF ONE HEALTH. TO REACH THESE OBJECTIVES, WE WILL ADDRESS THE FOLLOWING AIMS: 1) EXPLORE THE EPIDEMIOLOGY AND PATHOGENESIS OF INFECTIOUS DISEASES AFFLICTING BOTH ANIMALS AND PEOPLE. THIS WILL ENCOMPASS PREVALENT CONDITIONS WITHIN OUR COUNTY, STATE, AND NATION, PARTICULARLY RELATED TO VECTOR-BORNE DISEASES; 2) FACILITATE RESEARCH CONCERNING IMMUNOLOGY AND PATHOLOGY OF ANIMAL AND HUMAN INFECTIONS USING VARIOUS ASSAYS TO EXPLORE THE IMPACT OF THESE INFECTIONS ON HOST IMMUNE RESPONSES AND DISEASE PROGRESSION; AND 3) PIONEER INTERVENTION STRATEGIES THAT ADDRESS TREATMENT OF THESE INFECTIONS. LEVERAGING INNOVATIVE FACILITIES AND ANIMAL MODELS WITH AN EMPHASIS ON LIVESTOCK/FARM ANIMALS, OUR RESEARCH SEEKS TO DEVELOP GROUNDBREAKING SOLUTIONS FOR SAFEGUARDING HEALTH ACROSS SPECIES. WITHIN THIS FRAMEWORK, WE WILL ENSURE THAT OUR APPROACH ALIGNS WITH THE USDA'S MISSION TO SECURE THE HEALTH AND WELL-BEING OF BOTH AGRICULTURAL AND NATURAL ECOSYSTEMS.

COLLABORATIVE RESEARCH: COMPARATIVE MORPHOLOGICAL ANALYSIS OF THE HAND AND WRIST IN ARDIPITHECUS RAMIDUS AND MIOCENE HOMINOIDS

WITHIN THE PURVIEW OF ONE HEALTH, THIS PROJECT AIMS TO FOSTER INTERDISCIPLINARY RESEARCH AND COLLABORATIVE EFFORTS AT MIDWESTERN UNI VERSITY'S COLLEGE OF VETERINARY MEDICINE THAT ENHANCE THE WELL-BEING OF ANIMALS, HUMANS, AND THE ECOSYSTEM. THERE IS A SHARED COMMITMENT AMONG DEDICATED FACULTY ACROSS BOTH BASIC AND CLINICAL DISCIPLINES TO EXPLORE ANIMAL AND HUMAN DISEASES TO PROMOTE THE CORE TEN ANTS OF ONE HEALTH. TO REACH THESE OBJECTIVES, WE WILL ADDRESS THE FOLLOWING AIMS: 1) EXPLORE THE EPIDEMIOLOGY AND PATHOGENESIS OF INFECTIOUS DISEASES AFFLICTING BOTH ANIMALS AND PEOPLE. THIS WILL ENCOMPASS PREVALENT CONDITIONS WITHIN OUR COUNTY, STATE, AND NATION, PARTICULARLY RELATED TO VECTOR-BORNE DISEASES; 2) FACILITATE RESEARCH CONCERNING IMMUNOLOGY AND PATHOLOGY OF ANIMAL AND HUMAN INFECTIONS USING VARIOUS ASSAYS TO EXPLORE THE IMPACT OF THESE INFECTIONS ON HOST IMMUNE RESPONSES AND DISEASE PROGRESSION; AND 3) PIONEER INTERVENTION STRATEGIES THAT ADDRESS TREATMENT OF THESE INFECTIONS. LEVERAGING INNOVATIVE FACILITIES AND ANIMAL MODELS WITH AN EMPHASIS ON LIVESTOCK/FARM ANIMALS, OUR RESEARCH SEEKS TO DEVELOP GROUNDBREAKING SOLUTIONS FOR SAFEGUARDING HEALTH ACROSS SPECIES. WITHIN THIS FRAMEWORK, WE WILL ENSURE THAT OUR APPROACH ALIGNS WITH THE USDA'S MISSION TO SECURE THE HEALTH AND WELL-BEING OF BOTH AGRICULTURAL AND NATURAL ECOSYSTEMS.

ANIMAL HEALTH AND DISEASE RESEARCH

THE PROPOSED PROJECT IS A HIGHLY INTEGRATED MULTIDISCIPLINED COLLABORATIVE EFFORT BY FACULTY WHO ARE COMMITTED TO ADVANCING BASIC AND CLINICAL RESEARCH IN ANIMAL HEALTH AND DISEASE THAT WILL FURTHER THE PRINCIPLE OF ONE HEALTH. THE OBJECTIVE OF THIS PROJECT IS TO INCREASE ANIMAL HEALTH AND DISEASE RESEARCH ACTIVITIES AT THE MIDWESTERN UNIVERSITY COLLEGE OF VETERINARY MEDICINE IN LINE WITH THE PRINCIPLES OF ONE HEALTH. ONE HEALTH ISSUES INCLUDE ZOONOTIC DISEASES, ANTIMICROBIAL RESISTANCE, VECTOR-BORNE DISEASES, AND OTHER HEATH THREATS. TO MEET THESE GOALS, WE WILL ADDRESS THE FOLLOWING AIMS. 1). INVESTIGATE THE EPIDEMIOLOGY AND PATHOGENESIS OF ANIMAL AND HUMAN INFECTIOUS DISEASES PREVALENT IN THE STATE AND NATION, INCLUDING CRYPTOSPORIDIOSIS, RIFT VALLEY FEVER, CANINE DISTEMPER, AND FOOT AND MOUTH DISEASE. 2). TO FACILITATE STUDIES ON THE IMMUNOBIOLOGY AND PATHOLOGY OF ANIMAL AND HUMAN INFECTIONS, IN VITRO, EX VIVO AND IN VIVO ASSAYS WILL BE DEVELOPED TO EXAMINE THE EFFECT OF THESE INFECTIONS IN HOST IMMUNE RESPONSE AND DISEASE. 3). DEVELOP INTERVENTION APPROACHES TO TREAT AND/OR PREVENT ANIMAL AND HUMAN DISEASES, EMPLOYING ANIMAL MODELS OF INFECTION AND DISEASE AND STATE-OF-ART FACILITIES. SUCCESSFUL COMPLETION OF THIS PROJECT WILL FACILITATE OUR UNDERSTANDING OF THE REQUIREMENTS FOR ATTAINING THE LONG-TERM GOAL OF OPTIMAL HEALTH FOR ANIMALS, PEOPLE, AND THE ENVIRONMENT.

NURSE ANESTHETIST TRAINEESHIPS

WITHIN THE PURVIEW OF ONE HEALTH, THIS PROJECT AIMS TO FOSTER INTERDISCIPLINARY RESEARCH AND COLLABORATIVE EFFORTS AT MIDWESTERN UNI VERSITY'S COLLEGE OF VETERINARY MEDICINE THAT ENHANCE THE WELL BEING OF ANIMALS, HUMANS, AND THE ECOSYSTEM. THERE IS A SHARED COMMITMENT AMONG DEDICATED FACULTY ACROSS BOTH BASIC AND CLINICAL DISCIPLINES TO EXPLORE ANIMAL AND HUMAN DISEASES TO PROMOTE THE CORE TEN ANTS OF ONE HEALTH. TO REACH THESE OBJECTIVES, WE WILL ADDRESS THE FOLLOWING AIMS: 1. EXPLORE THE EPIDEMIOLOGY AND PATHOGENESIS OF INFECTIOUS DISEASES AFFLICTING BOTH ANIMALS AND PEOPLE. THIS WILL ENCOMPASS PREVALENT CONDITIONS WITHIN OUR COUNTY, STATE, AND NATION, PARTICULARLY RELATED TO VECTOR BORNE DISEASES; 2. FACILITATE RESEARCH CONCERNING IMMUNOLOGY AND PATHOLOGY OF ANIMAL AND HUMAN INFECTIONS USING VARIOUS ASSAYS TO EXPLORE THE IMPACT OF THESE INFECTIONS ON HOST IMMUNE RESPONSES AND DISEASE PROGRESSION; AND 3. PIONEER INTERVENTION STRATEGIES THAT ADDRESS TREATMENT OF THESE INFECTIONS. LEVERAGING INNOVATIVE FACILITIES AND ANIMAL MODELS WITH AN EMPHASIS ON LIVESTOCK/FARM ANIMALS, OUR RESEARCH SEEKS TO DEVELOP GROUNDBREAKING SOLUTIONS FOR SAFEGUARDING HEALTH ACROSS SPECIES. WITHIN THIS FRAMEWORK, WE WILL ENSURE THAT OUR APPROACH ALIGNS WITH THE USDA'S MISSION TO SECURE THE HEALTH AND WELL BEING OF BOTH AGRICULTURAL AND NATURAL ECOSYSTEMS.

ANIMAL HEALTH AND DISEASE RESEARCH

SL - PODIATRY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

ANIMAL HEALTH AND DISEASE RESEARCH

COLLABORATIVE RESEARCH: INTEGRATIVE ANALYSIS OF THE SCALING OF PRIMATE FEEDING SYSTEMS

PCL - OSTEOPATHIC MEDICINE - PD CHANGES

HPSL - DENTISTRY - PD CHANGES

LDS - OSTEOPATHIC MEDICINE - CORRECTIONS IN BUDGET PERIOD/PROJECT PERIOD

HPSL - PHARMACY - CLOSEOUT DOCUMENT NUMBER

COLLABORATIVE RESEARCH: THE EVOLUTION OF HAIR AND FUR: PROXIMATE AND ULTIMATE MECHANISMS SHAPING PRIMATE PELAGE VARIATION

CLOSEOUT DOCUMENT NUMBER