Loyola University Of Chicago

LOYOLA_CARES_INSTITUTIONAL

LOYOLA CARES

TCR GENE MODIFIED T CELLS FOR ADOPTIVE IMMUNOTHERAPY

STRUCTURAL DETERMINANTS OF CALCIUM PUMP REGULATION

COLLABORATIVE INTEGRATION OF HCV MOLECULAR VIROLOGY AND MATHEMATICAL MODELING

MECHANISMS OF VIRAL PROTEASES IN CORONAVIRUS REPLICATION AND PATHOGENESIS

PARADOXICAL EFFECTS OF NF-KB IN ISCHEMIA; NOVEL POLYMERIC GENE SILENCING IN VIVO

IDO1 AND IMMUNOTOLERANCE IN GLIOBLASTOMA

GSK-3? LOCALIZES TO THE MYOFILAMENT AND MODIFIES ITS FUNCTION IN ISCHEMIC CARDIOMYOPATHY

PLUS LOYOLA CLINICAL CENTER

INVESTIGATING INTERFERON ANTAGONISTS IN DELAYING INNATE IMMUNE RESPONSES TO SARS-COV-2 - TITLE: INVESTIGATING INTERFERON ANTAGONISTS IN DELAYING INNATE IMMUNE RESPONSES TO SARS-COV-2 PI: SUSAN C. BAKER, PHD, LOYOLA UNIVERSITY CHICAGO STRITCH SCHOOL OF MEDICINE THE GOAL OF THIS PROPOSAL IS TO DETERMINE HOW VIRAL INTERFERON ANTAGONISTS FUNCTION IN THE REPLICATION AND PATHOGENESIS OF CORONAVIRUSES, PARTICULARLY DURING REPLICATION OF SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2). CORONAVIRUSES (COVS) ARE A DIVERSE FAMILY OF POSITIVE-SENSE RNA VIRUSES THAT INCLUDE PATHOGENIC STRAINS INFECTING HUMAN AND ANIMAL HOSTS. COVS HAVE REPEATEDLY JUMPED FROM ANIMAL RESERVOIRS INTO HUMAN CIRCULATION, CAUSING SEVERE DISEASE AND PANDEMICS, AS WE ARE CURRENTLY EXPERIENCING WITH SARS-COV-2. DEVELOPING APPROPRIATE PROTECTIVE MEASURES AGAINST EMERGING COVS, INCLUDING SARS-COV- 2, WILL DEPEND UPON GAINING AN UNDERSTANDING OF CORONAVIRUS-HOST INTERACTIONS. WE DISCOVERED THAT THE ENDORIBONUCLEASE (ENDOU), A HIGHLY CONSERVED COMPONENT OF THE COV REPLICASE COMPLEX, REDUCES DSRNA SPECIES RECOGNIZED BY HOST PATTERN RECOGNITION RECEPTOR MDA5, DELAYING THE INDUCTION OF INTERFERON. WE REPORTED THAT VIRUSES EXPRESSING AN INACTIVE FORM OF ENDOU REPLICATE AS EFFICIENTLY AS WILD TYPE VIRUS IN IFN NON- RESPONSIVE CELLS. IMPORTANTLY, REPLICATION OF ENDOU MUTANT COVS IN INTERFERON-RESPONSIVE CELLS ACTIVATE ROBUST IMMUNE RESPONSES, WHICH EXTINGUISHES VIRUS REPLICATION AND REDUCES PATHOGENESIS IN ANIMALS. RECENTLY, WE IDENTIFIED THE TARGET OF ENDOU ACTIVITY TO BE POLY-URIDINE CONTAINING NEGATIVE SENSE RNA, WHICH WE TERM PUN RNA. THIS REMOVAL OF THE PUN RNA DELAYS THE GENERATION OF DSRNA SPECIES THAT ARE RECOGNIZED BY HOST PATTERN RECOGNITION RECEPTOR MDA5. WE HYPOTHESIZE THAT ENDOU ACTIVITY CONTRIBUTES TO THE DELAY IN THE INNATE IMMUNE RESPONSE TO SARS-COV-2 REPLICATION. HERE, WE PROPOSE TO INVESTIGATE THE MECHANISM OF HOW ENDOU ACTS IN SARS-COV-2, HOW ENDOU ASSOCIATES WITH THE REPLICASE COMPLEX, AND HOW PUN RNA CONTRIBUTES TO ACTIVATING MDA5. IN AIM 1, WE WILL EVALUATE ENDOU AND OTHER IFN ANTAGONISTS FOR THEIR ROLE AS MODULATORS OF TYPE I AND TYPE III IFN RESPONSES TO SARS-COV-2 INFECTION IN PRIMARY HUMAN AIRWAY CELLS AND IN ENTEROCYTES. WE WILL USE REVERSE GENETICS TO GENERATE VIRUSES WITH INACTIVE IFN ANTAGONISTS AND EVALUATE THE EFFECTS OF COMBINING INACTIVATION OF ENDOU WITH INACTIVATING MUTATIONS OF OTHER VIRAL PROTEIN IFN ANTAGONISTS. IN AIM 2 WE WILL DELINEATE AND DISRUPT ENDOU INTERACTIONS WITHIN THE CORONAVIRUS REPLICASE COMPLEX. THE RESULTS OF THESE STUDIES WILL GUIDE STRATEGIES FOR DISRUPTION OF ENDOU FROM THE COV REPLICASE COMPLEX, WHICH WOULD ACTIVATE PROTECTIVE IMMUNE RESPONSES TO COV INFECTIONS. IN AIM 3, WE WILL IDENTIFY REGIONS OF POLY-URIDINE NEGATIVE-SENSE RNA, TERMED PUN RNA, REQUIRED FOR RECOGNITION BY ENDOU AND MDA5. THESE STUDIES WILL PROVIDE NEW INFORMATION ON HOW PUN RNAS ARE RECOGNIZED BY ENDOU AND MDA5. OVERALL, THESE STUDIES WILL DEFINE A NEW MECHANISM FOR HOW AN ENDORIBONUCLEASE ACTS AS A VIRULENCE FACTOR. THIS NEW INFORMATION CAN BE USED TO DEVELOP ANTIVIRAL THERAPIES AND VACCINES AGAINST EXISTING AND EMERGING CORONAVIRUSES.

GENETICS OF HYPERTENSION IN BLACKS

LIGAND-INDEPENDENT SIGNALING OF ESTROGEN RECEPTOR BETA AND THE AGING BRAIN

MOLECULAR MECHANISMS OF FOCAL ADHESION KINASE IN PROMOTING HEPATOCARCINOGENESIS

NEUROMOLECULAR CONSEQUENCES OF ADOLESCENT BINGE DRINKING

METS-SLEEP: SLEEP TIMING, GUT MICROBIOTA AND CARDIOMETABOLIC RISK ACROSS THE EPIDEMIOLOGIC TRANSITION

COMPUTATIONAL MODELING FOR HCV VACCINE TRIAL DESIGN AND OPTIMAL VACCINE-BASED COMBINATION INTERVENTIONS - PROJECT SUMMARY/ABSTRACT DESPITE REMARKABLE PROGRESS WITH DIRECT-ACTING ANTIVIRALS (DAAS), HEPATITIS C VIRUS (HCV) INFECTION REMAINS A SERIOUS GLOBAL PUBLIC HEALTH PROBLEM WITH OVER 1% OF THE WORLD’S POPULATION AND ABOUT 3 MILLION IN THE UNITED STATES (U.S.) INFECTED. THE U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES RECENTLY RENEWED THE ACTION PLAN TO PREVENT, CARE AND TREAT VIRAL HEPATITIS TO ELIMINATE VIRAL HEPATITIS INFECTION AS A PUBLIC HEALTH THREAT AND THE WHO INTRODUCED GLOBAL TARGETS FOR THE CARE AND MANAGEMENT OF HCV. WHILE THE HIGHEST UPTAKE OF HCV TREATMENT OCCURRED IN 2017 AND 1.5 MILLION PEOPLE WERE CURED, 1.6 MILLION NEW INFECTIONS OCCURRED. DUE TO MANY TREATMENT BARRIERS, ONLY AN ESTIMATED 21% OF INFECTED PATIENTS ARE DIAGNOSED AND ONLY 2% OF TOTAL INFECTED PATIENTS ARE BEING TREATED FOR THE DISEASE ANNUALLY. DAAS ALONE ARE UNLIKELY TO ACHIEVE HCV ELIMINATION; AS SUCH, THE DEVELOPMENT OF A VACCINE TO PREVENT HCV INFECTION IS AN IMPORTANT FOCUS OF ONGOING RESEARCH. VACCINE CLINICAL TRIALS FOR HCV INFECTION WILL NEED TO RECRUIT FROM HIGH-RISK POPULATIONS, SUCH AS PERSONS WHO INJECT DRUGS (PWID), WHO CONTRIBUTE AN ESTIMATED 60% OF ALL NEW HCV INFECTIONS IN THE U.S. AND HAVE AN INCREASING INCIDENCE OF HCV, ESPECIALLY AMONG YOUNG PWID. ADDITIONALLY, LIMITED ACCESS TO DAA TREATMENT, SYRINGE SERVICE PROGRAMS (SSP), AND CONTINUED INJECTION DRUG USE POSES CHALLENGES AMONG PWID EVEN AS TREATMENT WITH MEDICATION FOR OPIOID USE DISORDER (MOUD) IS EXPANDING. FACTORS CONTRIBUTING TO TRANSMISSION AND SUCCESSFUL INTERVENTION (DAAS, MOUD, SSP) AMONG PWID ARE DYNAMIC AND COMPLEX AND OCCUR AT THE INDIVIDUAL (E.G., PATHOGEN-HOST INTERPLAY, RISK BEHAVIORS), SOCIAL (E.G., INJECTION NETWORK, SOCIAL NORMS), STRUCTURAL (E.G., ACCESS TO SSP AND MOUD), AND GEOGRAPHIC (E.G., INTERACTION LOCATIONS) LEVELS. AS SUCH, PERFORMING HCV VACCINE RANDOMIZED CLINICAL TRIALS (RCT) IN THE PWID POPULATION PRESENTS MAJOR CHALLENGES. WE PROPOSE TO DEVELOP AN INTEGRATED COMPREHENSIVE COMPUTATIONAL MODELING APPROACH TO EXAMINE THESE CHALLENGES SYSTEMATICALLY AND ASSESS THE IMPACT OF SPECIFIC RCT MODIFICATIONS ON CLINICAL TRIAL SUCCESS. TO EXPLORE VACCINE TRIAL DESIGN AND OUTCOMES, OUR INTERDISCIPLINARY TEAM WILL: (1) DESIGN AND EVALUATE CLINICAL TRIALS IN LOW INCIDENCE PWID SITES, USING METROPOLITAN CHICAGO AS THE MODEL, WHICH REDUCES THE CHANCE OF SOMEONE BECOMING EXPOSED BEFORE BEING FULLY PROTECTED; (2) DESIGN AND EVALUATE CLINICAL TRIALS IN HIGH INCIDENCE PWID SITES, USING SAN FRANCISCO AS THE MODEL, WHICH INCREASES THE CHANCE OF SOMEONE BECOMING EXPOSED BEFORE BEING FULLY PROTECTED; AND (3) DISCOVER EFFECTIVE HCV VACCINE-BASED INTERVENTION STRATEGIES TO ACHIEVE WHO ELIMINATION GOALS IN THE CONTEXT OF A LICENSED VACCINE. THE LITERATURE SUPPORTS THAT NON-STERILIZING VACCINES ARE EXPECTED TO BE THE FOCUS OF FUTURE TRIALS, REMINISCENT OF RECENT COVID-19 VACCINES, THEREFORE WE WILL SIMULATE THEIR EFFECT ON TRANSMISSION TO REACH ELIMINATION. WE WILL ACCOUNT FOR SSP AND MOUD AND THEIR EFFECT ON OUTCOMES IN TWO CITIES WITH DISPARATE HCV EPIDEMIC PROFILE AMONG PWID—CHICAGO AND SAN FRANCISCO.

DATA-DRIVEN MATHEMATICAL AND COMPUTATIONAL MODELING OF HEPATITIS D INFECTION AND TREATMENT RESPONSE

ALCOHOL INTOXICATION AND POSTBURN INTESTINAL IMMUNITY

HOST-ASSOCIATED BIOFILM FORMATION AND DISPERSAL MECHANISMS

NOVEL PARACRINE MECHANISMS FOR CELL-BASED THERAPY OF INJURED LUNGS

A NOVEL ANTI-SPORE NASAL VACCINE FOR PROTECTION FROM ANTHRAX

TRAINING IN NEUROIMMUNOENDOCRINE EFFECTS OF ALCOHOL

THE FEMALE URINARY MICROBIOME AND URINARY INCONTINENCE

MAINTAINING B CELL IMMUNITY WITH AGED B LYMPHOCYTES

DETERMINANTS AND CONSEQUENCES OF LOW VITAMIN D IN POPULATIONS OF AFRICAN DESCENT

GUT MICROBIOTA, SHORT CHAIN FATTY ACIDS, AND ADIPOSITY ACROSS THE EPIDEMIOLOGIC TRANSITION

SOMATIC DIVERSIFICATION OF IMMUNOGLOBULIN GENES IN GALT

NEW MECHANISMS OF SERCA REGULATION: DIMERIZATION AND MICROPEPTIDES

DEFINING THE NUCLEAR IMPORT PATHWAYS OF HIV-1 - ABSTRACT HUMAN IMMUNODEFICIENCY VIRUS (HIV-1), LIKE ALL PRIMATE LENTIVIRUSES POSSESSES THE ABILITY TO INFECT NON-DIVIDING CELLS BY ENGAGING WITH COMPONENTS OF THE NUCLEAR PORE COMPLEX AND MEDIATING THE NUCLEAR TRANSLOCATION OF THE VIRAL RIBONUCLEOPROTEIN COMPLEX (RNP) FOR SUBSEQUENTLY INTEGRATION INTO THE HOST CELL GENOME. THE VIRAL CAPSID PROTEIN (CA) INTERACTS WITH NUMEROUS HOST FACTORS INVOLVING CONSTITUENTS OF THE NUCLEAR PORE COMPLEX (NPC) TO ACCOMPLISH THE PROCESS OF NUCLEAR IMPORT. UNFORTUNATELY, THE EXACT MECHANISM BY WHICH HIV-1 TRANSLOCATES THROUGH THE NUCLEAR PORE COMPLEX REMAINS ONE OF THE LEAST UNDERSTOOD STEPS OF THE VIRAL LIFE CYCLE. IN ADDITION, RECENT EVIDENCES SUPPORTING THE NOTION OF NPCS BEING MORE HETEROGENEOUS THAN PREVIOUSLY THOUGHT FURTHER CONFOUNDS THIS SITUATION. WE HAVE DEVELOPED AN INDUCIBLE NUCLEAR PORE BLOCKADE THAT ALLOWS THE RATE OF NUCLEAR IMPORT OF FUNCTIONAL, INFECTIOUS VIRAL GENOMES TO BE MONITORED IN ANY RELEVANT CELLS TYPES. USING THIS TECHNIQUE, WE OBSERVE THAT CERTAIN CA MUTANTS ARE INSENSITIVE TO A NUP62 MEDIATED NUCLEAR PORE BLOCKADE IN CELLS WHICH POTENTLY BLOCK INFECTION BY WILD TYPE CA, DEMONSTRATING THAT HIV-1 CAN UTILIZE DISTINCT NUCLEAR IMPORT PATHWAYS DURING INFECTION. IN THIS APPLICATION, WE WILL DETERMINE THE DEGREE TO WHICH NPC ARE HETEROGENEOUS AND MAP THE SPECIFIC NUCLEAR PORE CONSTITUENTS THAT MAKEUP THE NPCS UTILIZED BY HIV-1 DURING NUCLEAR ENTRY. WITH OUR NUCLEAR PORE BLOCKADE, WE NOW HAVE THE CAPABILITY TO BLOCK NPCS USING DIFFERENT NUCLEAR PORE CONSTITUENTS. AS SUCH, THIS APPLICATION AIMS TO DEFINE AND VISUALIZE THE SPECIFIC NUCLEAR PORE CONSTITUENTS THAT INTERACT AND MEDIATE THE NUCLEAR IMPORT OF HIV-1 AND HOW SPECIFIC NPC USAGE AFFECTS VIRAL INTEGRATION IN TARGET CELLS. COLLECTIVELY THIS APPLICATION WOULD CLOSE CRITICAL GAPS TO OUR UNDERSTANDING IN TO THE NUCLEAR IMPORT OF HIV-1.

COMPREHENSIVE PREPARATION OF SCHOOL PSYCHOLOGISTS TO SUPPORT THE MENTAL HEALTH OF STUDENTS THAT ARE CULTURALLY AND LINGUISTICALLY DIVERSE IN THE CICERO COMMUNITY

MOLECULAR GENETICS OF MLL-ASSOCIATED LEUKEMIA

ADVANCED NURSING EDUCATION WORKFORCE

WEIGHTING LONGITUDINAL DATA TO ACCESS OPIOID ANALGESIA TAPERING OUTCOMES AMONG PATIENTS WITH CO-OCCURRING CHRONIC PAIN AND SUBSTANCE USE DISORDER - PROJECT SUMMARY/ABSTRACT IN 2016, THE CENTERS FOR DISEASE CONTROL (CDC) RELEASED GUIDELINES RECOMMENDING NON-PHARMACOLOGIC TREATMENT FOR CHRONIC PAIN OVER USE OF OPIOID ANALGESIA IN RESPONSE TO RISING OVERDOSE DEATHS AND BASED ON STUDIES SHOWING NONOPIOID AND MULTIDISCIPLINARY APPROACHES TO PAIN CONTRIBUTE TO FUNCTIONAL AND PAIN SEVERITY IMPROVEMENTS. CDC GUIDELINES ALSO RECOMMENDED OPIOID TAPERING FOR CHRONIC PAIN PATIENTS WITH SUBSTANCE USE DISORDER (SUD) AND TRANSITION TO MEDICATIONS FOR OPIOID USE DISORDER (MOUD) FOR PATIENTS WITH CO-OCCURRING OPIOID USE DISORDER (OUD). WHILE OPIOID TAPERING HAS BEEN WIDELY IMPLEMENTED, FEW STUDIES ASSESS TRANSITIONS TO MOUD OR MULTIDISCIPLINARY MEDICINE USE SPECIFICALLY AMONG PATIENTS WITH CHRONIC PAIN AND CO-OCCURRING SUD. A PRIMARY REASON FOR THIS LIMITED KNOWLEDGE IS THE POPULATION WITH CHRONIC PAIN AND CO-OCCURRING SUD IS OFTEN RELATIVELY SMALL IN ANY GIVEN HEALTHCARE FACILITY OR SYSTEM, AND OUTCOMES OF INTEREST MAY OCCUR IN LOW TOTAL NUMBERS. THUS, A LARGE DATABASE IS REQUIRED TO CONDUCT MULTIFACTORIAL RESEARCH ON OUTCOMES ASSOCIATED WITH DIFFERENT APPROACHES TO OPIOID TAPERING, ESPECIALLY WHEN EVALUATING WHETHER TRENDS HOLD AMONG SMALLER DEMOGRAPHIC GROUPS. TO ADDRESS THIS CRITICAL GAP, OUR GOAL IS TO CREATE WEIGHTS FOR THE CERNER REAL-WORLD© DATABASE, WHICH INCLUDES ELECTRONIC HEALTH RECORDS (EHR) DATA FROM OVER 100 MILLION UNIQUE U.S. PATIENTS AT 600 PARTICIPATING HOSPITALS AND CLINICS. OUR HYPOTHESIS IS THAT WEIGHTING THE DATABASE WILL SIGNIFICANTLY ENHANCE ITS REPRESENTATIVENESS IN ORDER TO LONGITUDINALLY ASSESS THE RELATIONSHIP BETWEEN OPIOID TAPERING, MULTIDISCIPLINARY MEDICINE, MOUD, AND OUTCOMES FOR CHRONIC PAIN PATIENTS WITH CO-OCCURRING SUD. OUR AIMS ARE TO USE AMERICAN HOSPITAL ASSOCIATION AND U.S. CENSUS DATA TO CREATE WEIGHTS, STRATIFIED BY HOSPITAL CHARACTERISTICS AND ADJUSTED BY DEMOGRAPHIC VARIABLES, FOR ANALYZING THE CERNER DATABASE (AIM 1); VALIDATE THE WEIGHTING SCHEME IN AIM 1 BY COMPARING WEIGHTED ESTIMATES FROM THE CERNER DATABASE TO ESTIMATES FROM A WELL-ESTABLISHED POPULATION (THE NATIONWIDE INPATIENT SAMPLE) FOR CHRONIC PAIN, SUD, AND OVERDOSE DIAGNOSES AND RELEVANT MULTIDISCIPLINARY PAIN INTERVENTIONS FOR THE YEARS 2000-2025 (AIM 2); AMONG PATIENTS WITH CHRONIC PAIN AND CO-OCCURRING OUD, EXAMINE HOW TAPERING OPIOID ANALGESICS AND TRANSITIONING TO MOUD AFFECTS RISK FOR OVERDOSE, SUICIDE, AND OTHER HOSPITALIZATIONS, AND ASSESS HOW SEX AND RACE/ETHNICITY OPERATE AS EFFECT MODIFIERS IN THESE RELATIONSHIPS (AIM 3); AND AMONG PATIENTS WITH CHRONIC PAIN AND CO-OCCURRING SUD, EXAMINE HOW TAPERING OPIOID ANALGESICS WHILE USING MULTIDISCIPLINARY PAIN TREATMENT AFFECTS RISK FOR OVERDOSE, SUICIDE, AND OTHER HOSPITALIZATIONS, AND ASSESS HOW SEX AND RACE/ETHNICITY OPERATE AS EFFECT MODIFIERS IN THESE RELATIONSHIPS (AIM 4). THIS PROJECT WILL CREATE A NATIONAL DATABASE WITH VALIDATED WEIGHTING THAT WILL ENABLE RIGOROUS EXAMINATION OF OPIOID TAPERING APPROACHES AMONG PATIENTS WITH CHRONIC PAIN AND CO-OCCURRING SUD, WHICH WILL SUBSEQUENTLY IMPROVE KNOWLEDGE OF HOW MULTIDISCIPLINARY PAIN TREATMENT AND MOUD AFFECT RISKS, WHILE CONSIDERING TAPERING-RELATED INEQUITIES AMONG DEMOGRAPHIC SUBPOPULATIONS.

THE NKA INTERACTOME IN HEALTH AND DISEASE - PROJECT SUMMARY/ABSTRACT: THE NA/K-ATPASE (NKA), OR “SODIUM PUMP”, IS AN ENZYME THAT TRANSPORTS IONS ACROSS CELL MEMBRANES. BETWEEN 30-70% OF THE CELL’S ATP BUDGET IS SPENT BY THE NKA TO CREATE STRONG CHEMICAL GRADIENTS FOR SODIUM AND POTASSIUM. THESE GRADIENTS CONTROL CELL VOLUME, SUPPORT ELECTRICAL SIGNALING (ACTION POTENTIALS) AND ENERGIZE MANY OTHER TRANSPORT PROCESSES. DISRUPTION OF SODIUM HANDLING IS ASSOCIATED WITH DISEASES INCLUDING CARDIAC HYPERTROPHY/FAILURE, PARKINSON’S DISEASE, SCHIZOPHRENIA, AND ALZHEIMER’S DISEASE. VARIOUS CELL TYPES IN DIVERSE TISSUES OF THE BODY HAVE VERY DIFFERENT REQUIREMENTS FOR NA/K TRANSPORT, AND TRANSPORT RATES MUST RESPOND TO PHYSIOLOGICAL CHALLENGES (E.G. EXERCISE). TO ADAPT NKA TO THESE DIFFERENT CONDITIONS, THE PUMP IS REGULATED BY TISSUE-SPECIFIC TRANSMEMBRANE PEPTIDES THAT INCREASE OR DECREASE THE PUMP’S ENZYMATIC ACTIVITY. IN AIM 1 OF THE PROJECT WE WILL FOCUS ON THE NORMAL PHYSIOLOGICAL REGULATION OF NKA BY FXYDS, TESTING HOW FXYD PROTEINS BIND AND STABILIZE SPECIFIC NKA CONFORMATIONS TO ALTER NKA TRANSPORT KINETICS. WE WILL USE NOVEL SPECTROSCOPIC ASSAYS TO INVESTIGATE THE STRUCTURE AND STABILITY OF DIFFERENT NKA-FXYD REGULATORY COMPLEXES. WE WILL INVESTIGATE HOW PHYSICAL COUPLING OF TWO PUMPS INTO A SINGLE FUNCTIONAL UNIT CAN ALLOW FASTER OVERALL CYCLING. AIM 2 IS THE TRANSLATIONAL ARM OF THE RESEARCH PROJECT. THE RESEARCH TEAM WILL INVESTIGATE HOW NKA REGULATION BY FXYDS BECOMES DISORDERED IN DISEASE, USING PROTEOMIC ANALYSIS TO COMPARE THE NKA-FXYD INTERACTOME IN HEALTHY AND FAILING HUMAN HEART TISSUE. WE WILL DETERMINE WHETHER FRAGMENTS OF DIGESTED MEMBRANE PROTEINS MAY DISRUPT NKA FUNCTION IN DISEASE. WE WILL ALSO TEST THE FEASIBILITY OF USING GENE DELIVERY OF AN INHIBITORY SPECIES (FXYD1) AS A THERAPY TO IMPROVE THE CONTRACTION STRENGTH OF A FAILING HEART. FINALLY, WE WILL COMPARE FXYDS THAT ACTIVATE NKA AND FXYDS THAT INHIBIT NKA. THE PROJECT BRINGS TOGETHER 6 DIFFERENT INVESTIGATORS THAT SPECIALIZE IN DIFFERENT COMPLEMENTARY APPROACHES. THE LABORATORY OF THE PROJECT PI, PROF. SETH ROBIA, USES FLUORESCENCE SPECTROSCOPY AND CELL PHYSIOLOGY TO INVESTIGATE THE STRUCTURE, AFFINITY, AND FUNCTION OF NKA-FXYD COMPLEXES IN CARDIAC MYOCYTES AND HETEROLOGOUS CELLS. HE WORKS CLOSELY WITH TWO LOYOLA UNIVERSITY CHICAGO COLLEAGUES: JONATHAN KIRK (CO-I) AND PETE KEKENES-HUSKEY (CO-I). PROF. KIRK WILL USE PROTEOMICS APPROACHES SUCH AS MASS SPECTROMETRY TO DISCOVER POST- TRANSLATIONAL MODIFICATIONS AND NOVEL NKA REGULATORS. PROF. KEKENES-HUSKEY WILL ASSIST WITH COMPUTATIONAL MODELING OF THE PROTEIN COMPLEXES. PROF. JULIE BOSSUYT (MPI) WILL INVESTIGATE A-A COUPLING, CONDUCTING MICROSCOPY AND BIOCHEMISTRY EXPERIMENTS TO IDENTIFY THE INTERACTION INTERFACE. PROF. ARTIGAS (CO-I) AT TEXAS TECH WILL PERFORM DETAILED ELECTROPHYSIOLOGICAL ANALYSES OF FXYD PROTEINS AND MEMBRANE PROTEIN FRAGMENTS. PROF. RAZVAN CORNEA (CONSULTANT) IS AN EXPERT IN MEMBRANE PROTEIN BIOPHYSICS. HE WILL ADVISE THE TEAM ON ALL ASPECTS OF THE PROJECT. TOGETHER, THE COLLABORATORS WILL UNCOVER IMPORTANT NEW INFORMATION ABOUT NKA-FXYD STRUCTURE/FUNCTION RELATIONSHIPS, AND LEARN HOW THESE MECHANISMS BECOME DISORDERED IN DISEASE.

LOYOLA RESEARCH COMPUTING CORE

PATHOLOGICAL RESPONSES TO MITOCHONDRIAL ROS IN SEPSIS-INDUCED CARDIAC DYSFUNCTION

BINGE ALCOHOL-INDUCED NEURODEGENERATION AND OMEGA-3 DHA PROTECTION

EXPERIMENTAL IMMUNOLOGY TRAINING GRANT

UNCOVERING AND HARNESSING CONNECTED METABOLIC PATHWAYS ESSENTIAL TO VIRUS INFECTION.

MINDFULNESS BASED STRESS REDUCTION FOR PSYCHO-IMMUNE DYSREGULATION IN CANCER

IMMUNE DYSREGULATION BY PSYCHOSOCIAL DISTRESS

THE IMPACT OF A RACE-BASED STRESS REDUCTION INTERVENTION ON WELL-BEING, INFLAMMATION, AND DNA METHYLATION IN OLDER AFRICAN AMERICAN WOMEN AT RISK FOR CARDIOMETABOLIC DISEASE - PROJECT SUMMARY THIS RANDOMIZED CONTROLLED TRIAL WILL EVALUATE THE IMPACT OF A NOVEL RACE-BASED STRESS REDUCTION PROGRAM ON WELL-BEING, INFLAMMATORY BURDEN, AND DNA METHYLATION (DNAM) IN OLDER AFRICAN AMERICAN (AA) WOMEN AT RISK FOR CARDIOMETABOLIC DISEASE (CMD). ALTHOUGH THE NUMBER OF DEATHS RELATED TO CMD CONTINUES TO DECLINE, THAT DECLINE HAS SLOWED RECENTLY WITH AAS BEARING A DISPROPORTIONATE BURDEN. FURTHERMORE, WOMEN FACE MORE SEX- SPECIFIC RISK FACTORS FOR INCREASED ADIPOSITY AND AA WOMEN HAVE THE HIGHEST PREVALENCE OF OBESITY, HYPERTENSION, AND PREDIABETES COMPARED TO ALL OTHER RACIAL AND ETHNIC GROUPS. CHRONIC STRESS IS ASSOCIATED WITH LOW-GRADE INFLAMMATION AND INCREASED CMD RISK. GROWING EVIDENCE DEMONSTRATES THAT STRESSORS SUCH AS RACISM AND DISCRIMINATION ARE SIGNIFICANT CONTRIBUTING FACTORS TO PSYCHOLOGICAL DISTRESS, LOW-GRADE CHRONIC INFLAMMATION, AND CMD HEALTH DISPARITIES AMONG MINORITIES, PARTICULARLY AMONG OLDER AA WOMEN WHO ENDURE THE INTERSECTION OF BOTH RACISM AND SEXISM ACROSS THEIR LIFESPAN. RESILIENCE, STRESS, AND ETHNICITY (RISE) IS A GROUP-BASED, 8-WEEK INTERVENTION THAT INTEGRATES COGNITIVE-BEHAVIORAL STRATEGIES FOCUSED ON THE BIOPSYCHOSOCIAL IMPACT OF RACISM, RACIAL IDENTITY DEVELOPMENT, AND EMPOWERMENT. BASED ON OUR PRELIMINARY WORK, WE ANTICIPATE THAT PARTICIPATION IN RISE WILL REDUCE PSYCHOLOGICAL DISTRESS AND INFLAMMATION. FURTHER, OUR PREVIOUS WORK DEMONSTRATED THAT WOMEN WITH HIGH LEVELS OF PERCEIVED DISCRIMINATION HAVE A GREATER PROINFLAMMATORY CYTOKINE RESPONSE TO ACUTE STRESS AND DECREASED DNAM OF GENES RELATED TO INFLAMMATION AND HYPERTENSION. DNAM IS ONE TYPE OF EPIGENETIC PROCESS THAT MODULATES GENE EXPRESSION BY ADDING OR REMOVING METHYL GROUPS TO DNA IN RESPONSE TO THE ENVIRONMENT. STUDIES DEMONSTRATE THAT HYPER OR HYPO METHYLATION OF GENES DUE CHRONIC STRESSORS, INCLUDING RACISM AND DISCRIMINATION ARE SIGNIFICANTLY ASSOCIATED WITH CMD RISK. EMERGING EVIDENCE DEMONSTRATES THAT PSYCHOBEHAVIORAL INTERVENTIONS MAY MODIFY METHYLATION OF STRESS RESPONSE-RELATED GENES POTENTIALLY BUFFERING THE IMPACT OF PSYCHOLOGICAL STRESS AT THE MOLECULAR LEVEL. HOWEVER, FEW STUDIES HAVE EXAMINED THE IMPACT OF A PSYCHOBEHAVIORAL INTERVENTION ON CHANGES IN DNAM AND NONE HAVE ADDRESSED CHRONIC STRESS IN OLDER AA WOMEN.THEREFORE, THE SPECIFIC AIMS ARE: (1) DETERMINE THE EXTENT TO WHICH PARTICIPATION IN RISE DECREASES STRESS-RELATED SYMPTOMS AND INFLAMMATORY BURDEN IN OLDER AA WOMEN AT RISK FOR CMD; (2) EVALUATE THE EXTENT TO WHICH RISE INCREASES THE USE OF ADAPTIVE COPING VERSUS MALADAPTIVE COPING STRATEGIES IN OLDER AA WOMEN AT RISK FOR CMD; AND (3) DETERMINE THE EXTENT TO WHICH PARTICIPATION IN RISE MODIFIES DNAM OF STRESS RESPONSE- RELATED CANDIDATE GENES IN OLDER AA WOMEN AT RISK FOR CMD FROM BASELINE TO POST RISE INTERVENTION. AA WOMEN 50 TO 70 YEARS OF AGE WHO ARE AT RISK FOR CMD WILL BE RANDOMIZED INTO EITHER AN 8-WEEK RISE PROGRAM OR A HEALTH EDUCATION PROGRAM. RISE IS AN INNOVATIVE INTERVENTION THAT ADDRESSES PERCEIVED RACISM AND DISCRIMINATION AT THE INDIVIDUAL LEVEL. FURTHER, RISE HAS THE POTENTIAL TO IMPROVE THE HEALTH OF MINORITY WOMEN IMPACTED BY RACISM AND DISCRIMINATION.

SEX-SPECIFIC REGULATION OF MICRORNAS IN ALZHEIMER DISEASE - PROJECT SUMMARY ALZHEIMER’S DISEASE IS MORE PREVALENT IN WOMEN THAN MEN, YET A BIOLOGICAL BASIS FOR THIS SEX DIFFERENCE IS NOT UNDERSTOOD. THE PRIMARY OBJECTIVE OF THIS PROPOSAL IS TO UNDERSTAND HOW 17SS-ESTRADIOL (E2) REGULATES MICRORNA (MIR) BIOGENESIS AND STABILITY ACROSS THE LIFESPAN AND IN ALZHEIMER’S DISEASE (AD). WE HYPOTHESIZE THAT DYSREGULATION OF E2-MEDIATED MIR EXPRESSION IN THE AGED BRAIN LEADS TO GREATER ALZHEIMER DISEASE RISK IN WOMEN. THE STUDIES PROPOSED ARE FOCUSED ON UNDERSTANDING HOW ESTROGENS REGULATE THESE MIRS TO GET A BETTER UNDERSTANDING OF THEIR DYSREGULATION IN AD - SPECIFICALLY IN WOMEN. THIS WILL ADDRESS A MAJOR GAP IN OUR UNDERSTANDING BECAUSE HOW E2 INFLUENCES THE COMPONENTS OF THE MIR BIOGENESIS PATHWAY TO REGULATE MATURE MIR EXPRESSION LEVELS IN A CELL- AND/OR AGE-SPECIFIC MANNER IS UNKNOWN, DESPITE SEVERAL STUDIES DEMONSTRATING TEMPORAL AND CELL-SPECIFIC EFFECTS OF E2 ON MIR EXPRESSION IN A VARIETY OF ORGAN SYSTEMS. OUR PRIOR STUDIES DEMONSTRATED THAT E2 TREATMENT ALTERED THE EXPRESSION LEVELS OF A SUBSET OF MIRS IN THE FEMALE BRAIN, AND THE ABILITY TO REGULATE THESE MIRS DEPENDED ON AGE, BRAIN REGION, AND LENGTH OF E2 DEPRIVATION (I.E., TIME POST- MENOPAUSE). COLLECTIVELY THE EXPERIMENTS IN AIM 1 WILL TEST THE HYPOTHESIS THAT E2 DIFFERENTIALLY MEDIATES MATURE MIR STABILITY DEPENDING ON AGE AND IN ALZHEIMER’S DISEASE. WE WILL USE MIR DEGRADATION ASSAYS TO DETERMINE WHETHER AGE AND/OR E2 AFFECT THE RATE OF MIR DEGRADATION AND, USING A PROTEOMICS APPROACH, IDENTIFY THE CIS- AND TRANS-ACTING FACTORS THAT REGULATE MIR STABILITY. AIM 2 WILL ADDRESSES MECHANISTICALLY HOW A SELECT SUBSET OF MIRS COULD BE SPECIFICALLY REGULATED BY E2 POST-TRANSCRIPTION. WE WILL TEST THE HYPOTHESIS THAT HNRNP H BINDING TO ERSS REDUCES ITS ASSOCIATION WITH PRI-MIR TRANSCRIPTS, ERSS INTERACTS WITH BRCA1 TO DIFFERENTIALLY FACILITATE DROSHA COMPLEX ASSEMBLY, AND THAT THESE INTERACTIONS ARE DEPENDENT ON AGE AND E2 TREATMENT. AIM 3 WILL DETERMINE THE EFFECTS OF AGE AND E2 ON MIR SUBCELLULAR LOCALIZATION AND ASSESS DISRUPTION OF E2- MEDIATED MIR SUBCELLULAR LOCALIZATION IN ALZHEIMER’S DISEASE. THIS AIM WILL TEST THE HYPOTHESIS THAT E2 FACILITATES SUBCELLULAR TRAFFICKING OF MIRS, THEREBY IMPACTING MIR FUNCTION. MOREOVER, WE WILL TEST THE HYPOTHESIS THAT MIR SUBCELLULAR LOCALIZATION CHANGES ACROSS THE LIFESPAN AND THAT NORMAL AGE-RELATED SUBCELLULAR LOCALIZATION IS DISRUPTED IN ALZHEIMER’S DISEASE. IMPACT: UNDERSTANDING THE BASIC MOLECULAR SIGNALING PATHWAYS OF E2 IN THE AGING BRAIN WILL HELP DRIVE THERAPEUTIC ADVANCES AND INFORM TREATMENT STRATEGIES FOR WOMEN WITH ALZHEIMER’S DISEASE.

INTESTINAL BACTERIA AND EPITHELIAL BARRIER DISRUPTION AFTER ALCOHOL AND BURN INJURY

NATIONAL INSTITUTE FOR MENTORING EARLY MINORITY FACULTY IN NEUROSCIENCE

USING THE FITBIT FOR EARLY DETECTION OF INFECTION AND REDUCTION OF HEALTHCARE UTILIZATION AFTER DISCHARGE IN PEDIATRIC SURGICAL PATIENTS - PROJECT SUMMARY PEDIATRIC APPENDECTOMY, THE MOST PREVALENT INPATIENT PROCEDURE IN CHILDREN, IS ASSOCIATED WITH SIGNIFICANT BURDEN TO THE PATIENT, THEIR PARENTS, HEALTHCARE SYSTEMS AND THIRD PARTY PAYORS. AFTER DISCHARGE, MONITORING BY PARENTS CONSISTS ONLY OF SUCH “PROXY” SUBJECTIVE ASSESSMENTS, WHICH HAVE BEEN REPORTED AS INACCURATE, AND RESULTED IN BOTH INCREASED COMPLICATIONS (E.G., READMISSIONS), AND WASTED HEALTHCARE RESOURCES (E.G., POTENTIALLY AVOIDABLE EMERGENCY DEPARTMENT (ED) VISITS AFTER SURGERY). ADVANCES IN CONSUMER WEARABLE DEVICES (“CWDS”) THAT PASSIVELY AND NON-INVASIVELY MONITOR PHYSICAL ACTIVITY (PA), HEART RATE (HR), AND SLEEP ARE USHERING IN A NEW ERA OF SYMPTOMS SCIENCE, PARTICULARLY AFTER SURGERY. THEIR EXPANDING CAPABILITY TO GENERATE CONTINUOUS, VALID, OBJECTIVE, AND ACTIONABLE MEASURES IN NEAR-REAL TIME IN CHILDREN, PROVIDE OPPORTUNITIES TO DETECT ALTERED POST-OPERATIVE RECOVERY PATTERNS EARLY, AND THEREFORE IMPROVE THE PRECISION AND TIMELINESS OF ANY NECESSARY CLINICAL INTERVENTIONS. THE PROPOSED STUDY WILL USE A CWD, THE FITBIT INSPIRE 2, AND WILL APPLY MACHINE LEARNING METHODS TO THE FITBIT DATA (PHYSICAL ACTIVITY, HR, AND SLEEP) TO CREATE CLINICALLY MEANINGFUL ALERTS FOR EARLY DETECTION OF POSTOPERATIVE INFECTION. DURING HOSPITALIZATION AND CONTINUING AFTER DISCHARGE, A FITBIT INSPIRE 2, A WIDELY-USED, COMMERCIALLY WEARABLE DEVICE WELL-TOLERATED BY YOUNG CHILDREN (3- 18 YEARS OLD) WILL BE USED TO MEASURE STEP COUNTS, SLEEP, AND HR. THE PROPOSAL HAS 2 AIMS. AIM 1 DEVELOPS AND VALIDATES MACHINE LEARNING ALGORITHM FOR INFECTION USING THE FITBIT. AIM 2 PROSPECTIVELY FEEDS NEAR-REAL TIME FITBIT DATA ON POSTOPERATIVE APPENDECTOMY PATIENTS TO CLINICIANS, AND EXAMINES THEIR EFFECT ON CLINICAL DECISION MAKING, TIME TO FIRST CONTACT WITH THE HEALTHCARE SYSTEM, AND ON OVERALL HEALTHCARE USE PATTERNS. THE PROPOSAL IS ALIGNED WITH NINR’S RESEARCH PRIORITIES. METHODS DEVELOPED FROM THIS WORK WILL PAVE THE WAY TO DEVELOP SIMILAR ALGORITHMS FOR OTHER PATIENT POPULATIONS NEEDING A PROXY, AS WELL AS TO CHARACTERIZE OTHER SURGERIES AND, SHOULD IMPROVE OVERALL POSTOPERATIVE MANAGEMENT FOR ALL SURGICAL PATIENTS.

MODELING THE EPIDEMIOLOGIC TRANSITION: ENERGY EXPENDITURE, OBESITY AND DIABETES

MECHANISMS OF CONTRACTILE NETWORK ASSEMBLY

CYBERCORPS SCHOLARSHIP FOR SERVICE: CYBERRAMBLERS BOLSTER NATIONAL SECURITY -CYBERSECURITY IS CRITICAL TO ALL ASPECTS OF MODERN LIFE, FROM ENERGY, COMMERCE, FINANCE, EDUCATION, AND HEALTHCARE TO MANUFACTURING AND AGRICULTURE. WELL-TRAINED CYBERSECURITY PROFESSIONALS SERVING IN THE GOVERNMENT WORKFORCE ARE CRITICAL TO NATIONAL SECURITY. THIS PROJECT WILL ESTABLISH THE CYBERRAMBLERS ? LOYOLA UNIVERSITY CHICAGO CYBERCORPS? SCHOLARSHIP FOR SERVICE PROGRAM TO IMPROVE THE UNITED STATES' NATIONAL SECURITY. SCHOLARS WILL BE TRAINED IN TECHNICAL KNOWLEDGE FROM COMPUTER SCIENCE AND CYBERSECURITY, AND SOCIAL AND BEHAVIORAL KNOWLEDGE OF CYBERCRIME FROM PSYCHOLOGY, AND CRIMINAL JUSTICE AND CRIMINOLOGY. THIS LEADS TO SCHOLARS RECEIVING A WELL-ROUNDED CYBERSECURITY EDUCATION AND TRAINING. FOUR COHORTS OF UNDERGRADUATE STUDENTS MAJORING IN THE B.S. FOR CYBERSECURITY PROGRAM WILL BE RECRUITED FOR A TOTAL OF 20 STUDENTS OVER FIVE YEARS. THE STUDENT RECRUITMENT PROCESS EMPHASIZES RECRUITING AND RETAINING MEMBERS OF UNDERREPRESENTED AND UNDERSERVED GROUPS. THE OUTCOME OF THIS PROJECT WILL BE A WELL-PREPARED COHORT OF CYBERSECURITY PROFESSIONALS AND LEADERS READY TO MEET THE NATION?S CYBERSECURITY WORKFORCE NEEDS. THE PROJECT WILL BUILD ON THE EXISTING INTERDISCIPLINARY CYBERSECURITY PROGRAM TO RECRUIT STUDENTS FROM COMPUTER SCIENCE, CYBERSECURITY, PSYCHOLOGY, AND CRIMINAL JUSTICE AND CRIMINOLOGY. EACH CYBERRAMBLER SCHOLAR WILL RECEIVE TWO YEARS OF SCHOLARSHIP SUPPORT AND ADVISING AND MENTORING SUPPORT TO ENSURE ADEQUATE PROGRESS TOWARD GRADUATION AND SUCCESSFUL JOB PLACEMENT. SCHOLARS WILL BE INVOLVED IN INTERDISCIPLINARY RESEARCH AND EDUCATION AND RECEIVE TRAINING TO DEVELOP THE CRITICAL THINKING, INDEPENDENCE, TEAMWORK, AND TECHNICAL KNOWLEDGE REQUIRED IN A CYBERSECURITY CAREER. THESE SCHOLARSHIPS FOR SERVICE WILL PROVIDE THE NECESSARY HANDS-ON TRAINING AND EDUCATION FOR SCHOLARS TO START A SUCCESSFUL CYBERSECURITY CAREER AS PART OF THE GOVERNMENT WORKFORCE. TO ENSURE THE EFFECTIVENESS AND SUSTAINABILITY OF THE PROGRAM, COMPREHENSIVE FORMATIVE AND SUMMATIVE EVALUATION MECHANISMS WILL BE USED TO ASSESS THE PROGRESS AND ACHIEVEMENTS OF THE STUDENT SCHOLARS. THESE WILL SPECIFICALLY FOCUS ON SCHOLARS? SKILL DEVELOPMENT, KNOWLEDGE ACQUISITION, AND READINESS TO MEET THE NATION'S CYBERSECURITY WORKFORCE NEEDS. THIS PROJECT AIMS TO CREATE CYBERSECURITY PROFESSIONALS WHO WILL POSITIVELY IMPACT NATIONAL SECURITY AND MEET THE EVOLVING CHALLENGES OF THE CYBER LANDSCAPE THROUGH STRATEGIC RECRUITMENT, INTERDISCIPLINARY CYBERSECURITY-FOCUSED CURRICULUM, RIGOROUS EVALUATION, AND GOVERNMENT PARTNERSHIPS. THIS PROJECT IS SUPPORTED BY THE CYBERCORPS? SCHOLARSHIP FOR SERVICE (SFS) PROGRAM, WHICH FUNDS PROPOSALS ESTABLISHING OR CONTINUING SCHOLARSHIP PROGRAMS IN CYBERSECURITY AND ALIGNS WITH THE U.S. NATIONAL CYBER STRATEGY TO DEVELOP A SUPERIOR CYBERSECURITY WORKFORCE. FOLLOWING GRADUATION, SCHOLARSHIP RECIPIENTS ARE REQUIRED TO WORK IN CYBERSECURITY FOR A FEDERAL, STATE, LOCAL, OR TRIBAL GOVERNMENT ORGANIZATION FOR THE SAME DURATION AS THEIR SCHOLARSHIP SUPPORT. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

MICROBE-DRIVEN DEVELOPMENT OF GALT

SELENOF IS A NOVEL TUMOR SUPPRESSOR AND A NEW TARGET TO OVERCOME RACIAL DISPARITY IN BREAST CANCER. - PROJECT SUMMARY / ABSTRACT THIS PROPOSAL ADDRESSES THE CHALLENGE OF CLOSING THE RACIAL DISPARITY GAP IN BREAST CANCER MORTALITY BY IDENTIFYING A CONTRIBUTING BIOLOGICAL FACTOR AND DEVELOPING THERAPEUTIC STRATEGIES TO OVERCOME ITS IMPACT. THE SELENOPROTEIN, SELENOF, WAS RECENTLY IDENTIFIED AS A NEW TUMOR SUPPRESSOR IN BREAST CANCER. THE BROAD HYPOTHESIS IS THAT LOWER SELENOF LEVELS IN AFRICAN AMERICAN PATIENTS CONTRIBUTE TO THE RACIAL DISPARITY IN BREAST CANCER MORTALITY BY DRIVING TUMOR PROGRESSION AND POOR PATIENT OUTCOME. THEREFORE, THERAPEUTIC STRATEGIES TO MITIGATE ITS LOSS ARE NEEDED TO HELP CLOSE THE DISPARITY GAP. THE SCIENTIFIC PREMISE FOR THE HYPOTHESIS IS BASED ON THE FOLLOWING: 1) THE GENOMES OF BREAST TUMORS FROM AFRICAN AMERICANS HAVE A 5-10 FOLD HIGHER FREQUENCY OF SELENOF SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS), WHICH ACCOUNT FOR LOWER SELENOF PROTEIN LEVELS, 2) SELENOF MRNA EXPRESSION IS SIGNIFICANTLY LOWER IN BREAST TUMORS FROM AFRICAN AMERICAN PATIENTS COMPARED TO CAUCASIANS, AND LOWER SELENOF LEVELS PREDICT SHORTER SURVIVAL IN THESE PATIENTS, 3) LOSS OF SELENOF IN NORMAL BREAST EPITHELIAL CELLS RESULTED IN INCREASED PROLIFERATION AND ABROGATED CELL DEATH, FEATURES OF CELLULAR TRANSFORMATION, AND 4) OVEREXPRESSION OF SELENOF IN BREAST CANCER CELLS INDUCED CELL DEATH, BLOCKED PROLIFERATION AND SURVIVAL, ENHANCED RESPONSE TO THERAPIES, AND INHIBITED TUMOR GROWTH IN VIVO. THE EUKARYOTIC INITIATION FACTOR 4A3 (EIF4A3) WAS IDENTIFIED AS A TRANSLATIONAL REPRESSOR OF SELENOF. THE SELENOF LOCUS SNPS ARE PREDICTED TO ENHANCE EIF4A3’S BINDING AFFINITY RESULTING IN STRONGER REPRESSION OF SELENOF TRANSLATION. PRELIMINARY DATA SHOWED THAT PHARMACOLOGIC INHIBITION OF EIF4A3 RESULTS IN INCREASED SELENOF PROTEIN LEVELS AND REDUCED BREAST CANCER CELL VIABILITY IN A SELENOF-DEPENDENT MANNER. LOSS OF SELENOF ALSO RESULTED IN HYPERACTIVATION OF THE KINASE/RNASE INOSITOL-REQUIRING ENZYME 1 (IRE1), A MASTER REGULATOR OF THE UNFOLDED PROTEIN RESPONSE. THIS RENDERED CELLS HIGHLY SUSCEPTIBLE TO IRE1 INHIBITION, THUS IDENTIFYING A NEW VULNERABILITY IN THESE CELLS. FOUR AIMS ARE PROPOSED: 1) DETERMINE THE MECHANISMS UNDERLYING SELENOF-INDUCED CELL FATE IN BREAST CANCER, 2) DETERMINE WHETHER LOSS OF SELENOF DRIVES TUMORIGENESIS BY USING AFRICAN AMERICAN DERIVED XENOGRAFTS AND A MURINE MODEL OF BREAST CANCER, 3) DETERMINE THE IMPACT OF SNPS ON THE REGULATION OF SELENOF TRANSLATION BY EIF4A3, AND 4) DETERMINE WHETHER EIF4A3 OVEREXPRESSION AND THE SNPS CONTRIBUTE TO REDUCED SELENOF TUMOR LEVELS AND POOR OUTCOME IN AFRICAN AMERICAN BREAST CANCER PATIENTS. OUR WORK WILL ESTABLISH SELENOF AS A NEW TARGET TO REDUCE RACIAL DISPARITY IN BREAST CANCER, AND THUS SUPPORT THE DEVELOPMENT OF SELENOF-BASED THERAPIES. IN THE CLINIC, SELENOF’S SNPS AND LEVELS CAN ALSO SERVE AS CANDIDATE BIOMARKERS TO IDENTIFY AFRICAN AMERICAN PATIENTS AT RISK OF AGGRESSIVE DISEASE. THE DISTINCT THERAPEUTIC STRATEGIES INVESTIGATED HERE ARE LIKELY TO RESULT IN NOVEL AND MORE EFFECTIVE PERSONALIZED MEDICINE AND MAY HELP CLOSE THE DISPARITY GAP.

A REGULATORY CASCADE THAT CONTROLS PNEUMOCOCCAL CAPSULE BIOSYNTHESIS

MONOCYTE REGULATION OF INFANT IMMUNE RESPONSES

NURSING WORKFORCE DIVERSITY

SOUTHWEST ONCOLOGY GROUP

ETHANOL EFFECTS ON RECOVERY AFTER INJURY

MARKERLESS MOTION TRACKING OF LUNG TUMORS USING DUAL ENERGY IMAGING

COLLABORATIVE INTEGRATION OF HEPATITIS B MOLECULAR VIROLOGY AND MATHEMATICAL/COMPUTATIONAL MODELING

NURSE, EDUCATION, PRACTICE, QUALITY AND RETENTION - REGISTERED NURSES IN PRIMARY CARE

A NOVEL ANTI-INFLAMMATORY PROTEIN THERAPEUTIC THAT IMPROVES RESUSCITATION AND REDUCES TRAUMA, SHOCK AND ISCHEMIA INDUCES TISSUE DAMAGE

TRAINING IN TRAUMA AND BURN RESEARCH

CHROMATIN ORGANIZATION AS A PREDICTOR OF STRESS INDUCED IMMUNE DYSREGULATION

COMPUTATIONAL DISCOVERY OF EFFECTIVE HEPATITIS C INTERVENTION STRATEGIES

CUBA CIVIL SOCIETY PROGRAM - CNECT

LINKING NICOTINIC ACTIVATION WITH SKIN INNATE IMMUNITY AND ATOPIC DERMATITIS

ANALYZING THE SPREAD OF ANTHRAX IN FARMS IN PAKISTAN AND JORDAN

FRANK-STARLING'S LAW OF THE HEART: CELLULAR MECHANISMS

PS09-007, EVALUATING LOCALLY DEVELOPED HOMEGROWN HIV PREVENTION INTERVENTIONS

ENGLISH LANGUAGE ACQUISITION: NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM

COMMENSAL EXOPOLYSACCHARIDE PROTECTION FROM INFLAMMATION

INFLAMMASOME-MEDIATED CORNEAL EPITHELIAL CELL DEFENSES INHIBITED BY PATHOGENIC BACTERIA - PROJECT SUMMARY/ABSTRACT THE HEALTHY CORNEAL EPITHELIUM IS AN EFFECTIVE BARRIER TO PATHOGENIC AND ENVIRONMENTAL BACTERIA. BECAUSE OF THIS, CORNEAL INFECTION OR KERATITIS MODELS OFTEN RELY ON BYPASSING THE EPITHELIUM ALTOGETHER BY INTRODUCING MICROBES DIRECTLY INTO THE CORNEAL STROMA, WHERE THEY INITIATE IMMUNE CELL RESPONSES THAT CAN DAMAGE TISSUE AND CAUSE VISION-THREATENING SCARRING. A LIMITATION OF THIS EXPERIMENTAL APPROACH IS THAT EPITHELIAL DEFENSE MECHANISMS ARE UNABLE TO BE IDENTIFIED OR INVESTIGATED. THE BACTERIAL PATHOGEN PSEUDOMONAS AERUGINOSA IS THE MOST COMMON INFECTION ASSOCIATED WITH SOFT CONTACT LENS WEAR, SUGGESTING IT IS UNIQUELY CAPABLE OF CAUSING INFECTION IN THE STROMA EVEN WHEN THE EPITHELIUM REMAINS INTACT. ONE WAY IN WHICH P. AERUGINOSA COLONIZES THE EPITHELIUM IS BY INVADING AND REPLICATING INSIDE EPITHELIAL CELLS, WHICH HAS BEEN INVESTIGATED IN CULTURED CELLS, AND OBSERVED IN MOUSE CORNEAL INFECTION MODELS. PRELIMINARY DATA SHOW THAT THE TOXIN EXOS PRODUCED BY P. AERUGINOSA SUPPRESSES CASPASE-4 MEDIATED PYROPTOSIS OF INVADED CORNEAL EPITHELIAL CELLS, BUYING TIME FOR BACTERIA TO REPLICATE IN A PROTECTED NICHE. ADDITIONAL DATA INDICATE THAT A DIFFERENT INFLAMMASOME PATHWAY IS ALSO ACTIVE IN CORNEAL EPITHELIAL CELLS, AND LEADS TO PRODUCTION OF THE CYTOKINE IL-1SS, WHICH EXOS ALSO SUPPRESSES. THEREFORE, A NOVEL ROLE FOR EXOS IN CORNEAL INFECTION COULD BE TO PROLONG A NICHE FOR BACTERIA TO REPLICATE WITHIN CORNEAL EPITHELIAL CELLS, WHILE LIMITING SECRETION OF CYTOKINES THAT RECRUIT IMMUNE CELLS. USING IMAGING METHODS TO SELECTIVELY MONITOR INVADED CELLS, AND CRISPR-CAS9 TO MANIPULATE CORNEAL EPITHELIAL CELLS GENETICALLY, WE WILL ANSWER THREE OUTSTANDING QUESTIONS REGARDING BOTH CORNEAL EPITHELIAL DEFENSE, AND BACTERIAL SUBVERSION OF IT: 1. HOW DOES EXOS BLOCK CASPASE-4-MEDIATED PYROPTOSIS? 2. HOW DO CORNEAL EPITHELIAL CELLS DETECT AND RESPOND TO P. AERUGINOSA? 3. WHAT IS THE SIGNIFICANCE OF EPITHELIAL CELL INFLAMMASOME ACTIVATION AND PYROPTOSIS IN PROTECTING THE EYE FROM DEVELOPING KERATITIS IN THE STROMA? SUCCESSFUL COMPLETION OF THESE AIMS WILL IDENTIFY A NEW MECHANISM OF HOST DEFENSE AT THE OCULAR SURFACE, FURTHER OUR UNDERSTANDING OF INFLAMMASOMES IN EPITHELIAL CELLS, AND ELUCIDATE HOW A UNIQUELY DEVASTATING CORNEAL PATHOGEN IS ABLE TO OVERCOME HOST DEFENSES.

KCNQ CHANNELS AND VASOCONSTRICTOR SIGNAL TRANSDUCTION

MECHANISMS UNDERLYING SEXUALLY DIFFERENTIATED BRAIN REMODELING DURING ADOLESCENCE

ACETYL PHOSPHATE AS A GLOBAL STRESS SIGNAL

PHOSPHODIESTERASE 1 (PDE1) REGULATION OF MYOCARDIAL CALCIUM AND FUNCTION - PROJECT SUMMARY THE CYCLIC NUCLEOTIDE CAMP SERVES AS A SECOND MESSENGER CRITICAL IN MULTIPLE CELLULAR PROCESSES. TWO PROTEINS HELP TO REGULATE THE LEVEL OF CAMP. G-PROTEIN COUPLED RECEPTORS (GPCRS) ARE TRANSMEMBRANE PROTEINS INVOLVED IN CAMP PRODUCTION. G PROTEINS ARE HETEROTRIMERIC, AND A SUBSET OF GPCRS CONSISTS OF A STIMULATORY, CATALYTIC G⍺ SUBUNIT (G⍺S) THAT UPON RECEPTOR LIGAND BINDING, INCREASE ADENYLYL CYCLASE (AC) PRODUCTION OF CAMP. PHOSPHODIESTERASES (PDES), ON THE OTHER HAND, HYDROLYZE CAMP INTO AMP. IN HEART FAILURE ANIMAL MODELS AND HUMAN PATIENTS, PDE1 INHIBITION HELPS TO IMPROVE CARDIAC FUNCTION BY INCREASING MYOCARDIAL CONTRACTILITY, IMPROVING RELAXATION, AND VASODILATING TO LOWER HEMODYNAMIC STRESS ON THE HEART. THESE EFFECTS ARE SIMILAR TO THOSE UPON PDE3 INHIBITION, BUT WHEREAS THE LATTER IS ASSOCIATED WITH FATAL ARRHYTHMIAS, NO ARRHYTHMIC EVENTS HAVE BEEN ASSOCIATED WITH PDE1 INHIBITOR USE. COMPARTMENTALIZED CAMP SIGNALING THAT IS UNIQUE TO PDE1 VS PDE3 MAY HELP TO EXPLAIN THIS IMPORTANT DIFFERENCE. IT IS KNOWN THAT SPECIFIC PDE-GPCR PAIRINGS WORK TOGETHER TO REGULATE DISTINCT POOLS OF CAMP. THE HEART EXPRESSES MORE THAN 200 GPCRS AND 3 CAMP-HYDROLYZING PDES (1, 3, AND 4). UNIQUE PAIRINGS HELP TO ESTABLISH COMPARTMENTALIZED GRADIENTS OF CAMP SIGNALING THAT ENABLE THE MODULATION OF SPECIFIC CELLULAR PROCESSES IN RESPONSE TO DIFFERENT STIMULI. WHILE MULTIPLE GPCR PAIRINGS WITH PDE3 OR PDE4 HAVE BEEN KNOWN, WHICH GPCR(S) PAIR WITH PDE1 REMAINS UNKNOWN. IN THIS DIVERSITY SUPPLEMENTAL PROJECT, WE WILL IDENTIFY THE GPCR(S) THAT FUNCTIONALLY ENHANCE(S) THE POSITIVE INOTROPIC EFFECTS OF PDE1 INHIBITION. WE WILL DO SO BY EMPLOYING CARDIOMYOCYTE CONTRACTILITY AND CALCIUM, AND FORSTER RESONANCE ENERGY TRANSFER (FRET) IMAGING EXPERIMENTS, AND CARDIAC SLICE PHYSIOLOGIC STUDIES. GUINEA PIG HEARTS, WHICH ARE MUCH MORE LIKE THE HUMAN HEART IN PDE BIOLOGY VERSUS THE COMMONLY USED RAT AND MOUSE MODELS WILL BE USED. OUR HYPOTHESIS IS THAT PDE1 WILL ESTABLISH A G⍺S- ASSOCIATED CAMP GRADIENT THAT IS DISTINCT FROM THAT REGULATED BY PDE3. THIS IS AN IMPORTANT QUESTION BECAUSE OF CLINICAL POTENTIALS OF PDE1 INHIBITION IN PATIENTS WITH PARKINSON’S DISEASE OR HEART FAILURE. THE COMPLETION OF OUR AIM WILL THUS CONTRIBUTE ORIGINAL FINDINGS WITH DIRECT CLINICAL RELEVANCE THAT CAN POTENTIALLY HELP IMPROVE THE HEALTH AND LIFE QUALITY OF PATIENTS.

CONTRIBUTION OF CDIA TO PSEUDOMONAS AERUGINOSA PATHOBIOLOGY - PROJECT SUMMARY/ABSTRACT PSEUDOMONAS AERUGINOSA IS A LEADING CAUSE OF HEALTHCARE-ACQUIRED INFECTIONS WORLDWIDE. MANY GLOBALLY- DISTRIBUTED HIGH-RISK STRAINS ARE EMERGING DUE TO AN INCREASE IN ANTIBIOTIC RESISTANCE AND ACQUISITION OF NOVEL VIRULENCE TRAITS. WITH DIMINISHING TREATMENT OPTIONS FOR MANY OF THESE SEVERE P. AERUGINOSA INFECTIONS, STUDIES AIMED AT UNCOVERING THE VIRULENCE STRATEGIES USED BY THESE AGGRESSIVE CLINICAL STRAINS SHOULD HELP TO IDENTIFY NEW TARGETS FOR THERAPEUTIC INTERVENTION. OUR RESEARCH PROGRAM AIMS TO ELUCIDATE VIRULENCE STRATEGIES THAT ENHANCE THE PATHOGENICITY OF P. AERUGINOSA. WE RECENTLY EMPLOYED A COMPARATIVE GENOMICS APPROACH TO INTERROGATE THE ACCESSORY GENOMES OF 100 CLINICAL ISOLATES FOR POTENTIAL FACTORS THAT AUGMENT THE VIRULENCE OF P. AERUGINOSA. BY COMPARING VIRULENCE IN A MOUSE INFECTION MODEL WITH THE PRESENCE OR ABSENCE OF GENES IN THE ACCESSORY GENOME, WE IDENTIFIED SEVERAL VIRULENCE DETERMINANTS ENRICHED AMONG HIGHLY VIRULENT P. AERUGINOSA STRAINS THAT WERE ABSENT FROM LESS VIRULENT STRAINS. FROM THIS WORK WE IDENTIFIED AN ACCESSORY VIRULENCE FACTOR THAT SPANNED A PORTION OF TWO GENES ENCODING PRODUCTS INVOLVED IN CONTACT-DEPENDENT GROWTH INHIBITION (CDI). CDI IS ONE TYPE OF COMPETITIVE MECHANISM MICROORGANISMS USE TO ANTAGONIZE THEIR IMMEDIATE NEIGHBORS BY DELIVERING PROTEIN TOXINS DIRECTLY INTO TARGETED CELLS. THIS ANTAGONISM IS EXECUTED BY CDIA, A LARGE MULTIDOMAIN EXOPROTEIN THAT SITS AT THE SURFACE OF AN ATTACKING CELL AND DELIVERS A SELF-CONTAINED TOXIN DOMAIN INTO THE TARGETED CELL. THE IMPORTANCE OF THIS PROPOSAL STEMS FROM OUR DISCOVERY THAT: (I) CDIA CONTAINS A TOXIN DOMAIN THAT HAS TRNASE ACTIVITY AGAINST PROKARYOTIC AND EUKARYOTIC SUBSTRATES, (II) MUTATIONS THAT ABROGATE THE IN VITRO TRNASE ACTIVITY ATTENUATE BOTH CDI AND VIRULENCE IN MICE, (III) THE CDIA-TOXIN DOMAIN HAS CYTOPATHIC EFFECTS ON EUKARYOTIC CELLS DEPENDENT UPON ITS TRNASE ACTIVITY. TO OUR KNOWLEDGE THIS DULE ROLE FOR CDIA IN BOTH INTERBACTERIAL COMPLETION AND VIRULENCE WITHIN A MAMMALIAN HOST HAS NOT YET BEEN INVESTIGATED FOR P. AERUGINOSA. FROM THIS PRELIMINARY WORK WE HYPOTHESIZE THAT P. AERUGINOSA CAN UTILIZE CDIA TO INTOXICATE HOST CELLS FOR OVERCOMING BARRIERS TO INFECTION. OUR PROPOSAL SEEKS TO ANSWER A NUMBER OF OUTSTANDING QUESTIONS AT THE MOLECULAR (AIM 1), CELLULAR (AIM 2), AND ORGANISMAL (AIM 3) LEVEL. SUCCESSFUL COMPLETION OF THESE AIMS WILL PROVIDE DETAILED INSIGHT INTO HOW CDIA CONTRIBUTES TO P. AERUGINOSA PATHOBIOLOGY.

THE ROLE OF PTEN PHOSPHORYLATION REMODELING IN HEMATOPOIETIC STEM CELL REGULATION

PROBING CELLULAR INTRACELLULAR CALCIUM SIGNALING AND SENSING THROUGH COMPUTATION

NUCLEAR LIPID-SENSOR IN TYPE II DIABETIC NEUROPATHY

REQUIREMENTS FOR BACTERIAL COLONIZATION OF ANIMAL TISSUE

DEVELOPMENT OF B CELL MEMORY IN ALLERGIC ASTHMA - PROJECT SUMMARY/ABSTRACT ALLERGIC ASTHMA IS A CHRONIC INFLAMMATORY DISEASE OF THE LUNGS WITHOUT CURE. REPETITIVE ALLERGEN EXPOSURE IN THE AIRWAY LEADS TO THE GENERATION OF PATHOGENIC IMMUNE MEMORY AND THE EXCESSIVE PRODUCTION OF ALLERGEN SPECIFIC IGE ANTIBODIES THAT MEDIATE INFLAMMATION, AIRWAY CONSTRICTION AND RESPIRATORY DISTRESS IN PATIENTS WITH ALLERGIC ASTHMA. MEMORY B CELLS ARE A KEY COMPONENT OF IMMUNE MEMORY. THE PHENOTYPIC AND FUNCTIONAL HETEROGENEITY OF MBCS AFFORDS THEIR DIFFERENTIAL ANTIBODY RESPONSES AS WELL AS IMPACT THEIR TRAFFICKING, TISSUE RETENTION AND ABILITY TO DISSEMINATE SYSTEMICALLY. IN A MOUSE MODEL OF ALLERGIC LUNG INFLAMMATION, WE HAVE OBSERVED STABLE LUNG- LOCALIZED MBCS AND EVIDENCE FOR THE GENERATION OF PATHOGENIC ANTIBODY RESPONSES IN SENSITIZED LUNGS. WE HYPOTHESIZE THAT AFTER LOCAL ANTIGEN SENSITIZATION, THE LUNG ACQUIRES IMMUNE FUNCTIONS REMINISCENT OF THOSE IN SECONDARY LYMPHOID TISSUES, CAPABLE OF MAINTAINING LONG-LIVED MEMORY B CELLS AS WELL AS GENERATING NEW MBCS THAT CAN RECIRCULATE AND DISSEMINATE IN OTHER TISSUES TO MEDIATE SYSTEMIC ALLERGIC INFLAMMATION. IN THIS STUDY, WE WILL 1) PROBE THE DEVELOPMENT OF MEMORY B CELLS (MBCS) IN ALLERGIC LUNGS INCLUDING IN-DEPTH CHARACTERIZATION OF THE CRITICAL MBC SUBSET THAT CONTRIBUTES TO ALLERGEN SPECIFIC IGE RESPONSE, AND 2) HOW THESE MBCS DISSEMINATE SYSTEMICALLY. WE WILL ALSO 3) EXPLORE STRATEGIES TO INTERCEPT THE SYSTEMIC DISSEMINATION OF PATHOGENIC MBCS TO HALT THE PROGRESSION OF ALLERGIC INFLAMMATION. THESE STUDIES WILL ADVANCE OUR FUNDAMENTAL UNDERSTANDING OF MEMORY B CELLS AS WELL AS HELP DEVISE NEW THERAPEUTIC STRATEGIES FOR ALLERGIC ASTHMA.

THE CELL BIOLOGY OF TRIM5ALPHA

SELF-MANAGEMENT IN ADOLESCENTS AND YOUNG ADULTS WITH SPINA BIFIDA

EFFECTS OF INFECTION ON HOST RESPONSE TO TRAUMA

A PRECISION MEDICINE APPROACH TO RETT SYNDROME

DEVELOP AN ORAL HIV VACCINE USING PAPILLOMA VIRUS-LIKE PARTICLES AS A VECTOR

NEW MECHANISMS OF SERCA2A REGULATION: ROLE OF LUMINAL CALCIUM - PROJECT SUMMARY/ABSTRACT SERCA2A CA PUMP PLAYS A CENTRAL ROLE IN HEART FUNCTION. THE SPEED AT WHICH SERCA2A REMOVES CA FROM THE CYTOSOL IS THE MAIN DETERMINANT OF THE RATE OF CARDIAC MUSCLE RELAXATION. SERCA2A ALSO SETS THE TOTAL AMOUNT OF CA IN THE SARCOPLASMIC RETICULUM (SR), WHICH DETERMINES THE STRENGTH OF CARDIAC CONTRACTION. IT IS NOT SURPRISING, THAT IMPAIRED SERCA2A FUNCTION HAS BEEN REPORTED IN A NUMBER OF PATHOLOGICAL CONDITIONS, INCLUDING HEART FAILURE (HF). THUS, UNDERSTANDING MECHANISMS OF SERCA REGULATION IS OF GREAT CLINICAL IMPORTANCE. BESIDES ACTIVATION OF MUSCLE CONTRACTION, SR LUMINAL CA ([CA]SR) PLAYS AN IMPORTANT ROLE IN REGULATION OF SR PROTEIN FUNCTION. WHILE SERCA2A ACTIVITY CONTROLS [CA]SR, LESS IS KNOWN ABOUT HOW CHANGES IN [CA]SR AFFECT SERCA2A CA TRANSPORT. OUR PRELIMINARY RESULTS SUGGEST THAT SR LUMINAL CA PLAYS AN IMPORTANT ROLE IN REGULATION OF SERCA2A. IN THIS PROJECT WE WILL USE ADVANCED STRUCTURAL ANALYSES, INNOVATIVE MOLECULAR BIOLOGICAL TECHNIQUES, NEW ORGANELLE-SPECIFIC SENSORS, STATE-OF-THE-ART OPTICAL METHODS AND IN VIVO GENE DELIVERY TO EXPLORE THIS NEW MECHANISM OF SERCA2A REGULATION. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT LUMINAL CA REGULATES SERCA2A BY INCREASING THE PUMP’S CATALYTIC EFFICACY AND BY RELIEVING THE PHOSPHOLAMBAN (PLB) INHIBITORY EFFECT. MOLECULAR DYNAMIC SIMULATIONS WILL BE USED TO SELECT SPECIFIC DOMAINS ON THE SERCA2A LUMINAL SIDE THAT ARE INVOLVED IN CA REGULATION. SITE-DIRECTED MUTAGENESIS WILL BE USED TO IDENTIFY THE SPECIFIC AMINO ACIDS THAT FORM THE LUMINAL CA-BINDING SITES AND TO DEVELOP THE LUMINAL CA-INSENSITIVE SERCA2A MUTANT. WE WILL ASSESS EFFECTS OF THE LUMINAL CA REGULATION ON CA TRANSPORT, THE ATPASE ACTIVITY AND THE PLB INTERACTION. THEN, MYOCYTES EXPRESSING THE LUMINAL CA-INSENSITIVE SERCA2A MUTANT WILL BE STUDIED TO DEFINE THE ROLE OF THIS NOVEL MECHANISM IN CARDIAC CA CYCLING. WE EXPECT THAT THE OUTCOME OF THIS WORK WILL GREATLY ADVANCE OUR UNDERSTANDING OF SERCA2A FUNCTION. WE EXPECT THAT THE OUTCOME OF THESE STUDIES WILL PROVIDE A DETAILED VIEW OF THIS NEW MECHANISM OF SERCA2A REGULATION, ADVANCING OUR UNDERSTANDING OF THE CA PUMP’S FUNCTION. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT LUMINAL REDOX POTENTIAL REGULATES SERCA2A BY STABILIZING ITS LUMINAL CA BINDING SITES, THUS, IMPROVING THE PUMP’S REGULATION BY [CA]SR. MOLECULAR DYNAMIC SIMULATIONS WILL BE USED TO FORECAST THE ROLE OF THE SERCA2A LUMINAL DISULFIDE BOND IN THE PUMP CATALYTIC CYCLE. WE WILL ASSESS WHETHER MUTATION OF LUMINAL CYSTEINES LEADS TO A LOSS-OF-FUNCTION PHENOTYPE BY ABOLISHING SERCA2A REGULATION BY LUMINAL CA. NEWLY DEVELOPED APPROACHES TO MEASURE LUMINAL REDOX POTENTIAL AND [CA]SR WILL BE USED TO DEFINE THE CROSS-TALK BETWEEN LUMINAL REDOX POTENTIAL AND SERCA2A ACTIVITY. WE WILL INVESTIGATE THE CONTRIBUTION OF THIS NEW MECHANISM TO SERCA2A DYSFUNCTION AND CA MISHANDLING IN HF. THE LIKELY OUTCOME OF THESE STUDIES IS A NEW CONCEPT THAT CAN EXPLAIN HOW ALTERATIONS IN SERCA2A STRUCTURE/FUNCTION CAUSE DEFECTS IN CA REGULATION IN HF.

CAN THE SUNSHINE VITAMIN IMPROVE MOOD AND SELF-MANAGEMENT IN WOMEN WITH DIABETES

USE OF NOVEL ANGIOPOIETIN-1 MIMETIC PEPTIDE FOR THE TREATMENT OF BURN SHOCK-ASSOCIATED ENDOTHELIAL DYSFUNCTION IN SEVERE BURN INJURY

RIP1/RIP3-CALPAIN-STAT3 AND NF-KAPPA B PATHWAYS IN AML PATHOGENESIS AND TREATMENT

BRAVE MINORITY YOUTH VIOLENCE PREVENTION PROGRAM

MECHANISMS OF ENTEROPATHOGENIC E. COLI EFFECTS ON POLARITY AND TIGHT JUNCTIONS

TARGETING HSP70 IN AUTOIMMUNE VITILIGO

A NEW PHARMACOLOGICAL TARGET TO REDUCE THE INCIDENCE OF ACUTE RESPIRATORY DISTRESS SYNDROME AFTER ACUTE LUNG INJURY IN TRAUMA PATIENTS

MODULATING TOLERANCE IN A SPONTANEOUS MOUSE MODEL OF AUTOIMMUNE VITILIGO

THE ROLE OF SPARTIN IN AUTOPHAGY OF LIPID DROPLETS: IMPLICATIONS FOR SPG20 DISEAS

LOYOLA-UKRAINIAN CATHOLIC UNIVERSITY INTERNATIONAL BIOETHICS RESEARCH TRAINING PROGRAM

TCR AFFINITY AND THERAPEUTIC EFFICACY OF T CELLS

DEFINING THE MICROTUBULE MOTORS WHICH DRIVE THE UNCOATING AND TRAFFICKING OF HIV

RESCUING ANTI-TUMOR RESPONSES OF TCR-TD T CELLS BY NKG2D-STIMULATION

STRENGTHENING THE CAPACITY OF THE AFRICAN UNION TO PROMOTE GOVERNANCE AND THE RULE OF LAW IN ITS STATES

PROBING MACROPHAGE CELL NUCLEOTIDE SENSING AND CALCIUM SIGNALING THROUGH COMPUTATION - WHILE INAMMATION IS A NATURAL IMMUNE SYSTEM RESPONSE THAT BEGINS THE HEALING PROCESS, CHRONIC INAM- MATION IS TIED TO MANY HUMAN DISEASES INCLUDING CANCER, CARDIAC DYSFUNCTION, AND SEPSIS. A KEY ELEMENT OF INAMMATORY RESPONSES ARE MACROPHAGES, A WHITE BLOOD CELL THAT ELIMINATES PATHOGENS OR DYING TISSUES. AN ENDOGENOUS 'DANGER SIGNAL', ADENOSINE TRIPHOSPHATE (ATP), STIMULATES CA-DEPENDENT INAMMATORY PATHWAYS IN MACROPHAGES. WHILE PREVIOUS RESEARCH HAS MADE GREAT STRIDES IN UNDERSTANDING INAMMATION, MY LAB SEEKS TO UNCOVER ROLES OF ATP IN DRIVING MACROPHAGE INAMMATORY RESPONSES THROUGH MULTI-SCALE COMPUTATIONAL MODELS WE DEVELOP. WITH NEW MODELS OF INAMMATORY RESPONSES IN MACROPHAGES, OUR LAB CAN PREDICT PROTEIN AND CELL BEHAVIOR IN INTEGRATED, PHYSIOLOGICAL SYSTEMS TO BETTER UNDERSTAND THE IMMUNE SYSTEM. THE CURRENT PARADIGM FOR ATP-TRIGGERED INAMMATION IN MACROPHAGES IS THAT UPREGULATION OF NUCLEOTIDE- SENSING P2X CHANNELS SENSITIZES INAMMATORY RESPONSES, INCLUDING CYTOKINE AND REACTIVE OXYGEN SPECIES (ROS) RELEASE. HOWEVER, THIS PARADIGM DOES NOT ACCOUNT FOR SEVERAL OBSERVATIONS. ONE, WHILE P2X EXPRESSION IS INCREASED IN INAMMATORY MACROPHAGES, THESE RECEPTORS ALSO SUPPORT PHAGOCYTOSIS AND MIGRATION IN RESTING MACROPHAGES. HOW THESE PROCESSES ARE SELECTIVELY CONTROLLED BY P2X SUBTYPES LIKE P2X4 AND P2X7 IS UNRESOLVED. TWO, INAMMATORY MACROPHAGES HARBOR POST-TRANSLATIONAL MODICATIONS (PTMS) OF MANY PROTEINS THAT SENSE CA, YET LITTLE IS KNOWN ABOUT HOW PTMS IMPACT IMMUNE PATHWAYS THEY CONTROL. THREE, RELEASE AND DEGRADATION OF ATP BY PANNEXINS AND ECTONUCLEOTIDASES CONTROL ATP THAT ACTIVATES P2X, YET FEW STUDIES HAVE EVALUATED THEIR COUPLING. OUR LAB IS UNIQUELY POSITIONED TO EXTEND THIS PARADIGM BY PROBING MECHANISMS UNDERLYING THESE OBSERVATIONS AND THE LARGELY UNSTUDIED COUPLING OF P2X-, ATP-, AND CA-DRIVEN INAMMATION. OUR LAB AND ASSEMBLED COLLAB- ORATORS WILL INVESTIGATE THE OVERALL HYPOTHESIS VIA COMPUTATIONAL MODELING AND EXPERIMENTAL APPROACHES: P2X CHANNELS IN MACROPHAGES HELP NUCLEATE CHRONIC INAMMATION VIA ATP-INDUCED ATP RELEASE (AUTOCRINIC) MECHANISMS THAT SELECTIVELY PRIME CA-DEPENDENT, PRO-INAMMATORY SIGNALING PATHWAYS. THIS HYPOTHESIS STEMS FROM QUESTIONS THAT EMERGED FROM OUR INVESTIGATIONS DURING THE INITIAL ESI MIRA AWARD: 1. DOES INCREASED P2X4 AND P2X7 EXPRESSION AND THE RESULTING CA SIGNALS THEY INDUCE IN MACROPHAGES PROLONG PRO-INAMMATORY RELEASE OF CYTOKINES AND ROS? 2. DO PTMS LIKE ROS OXIDATION IN THE CA-SENSOR CALMODULIN (CAM) ATTENUATE ITS ACTIVATION OF PRO-INAMMATORY SIGNALING PATHWAYS? 3. DO (AUTOCRINIC) ATP-INDUCED, ATP RELEASE IN MACROPHAGES PROLONG PRO-INAMMATORY INCREASES IN INTRACELLULAR CA? OUR LONG-TERM GOAL TO UNDERSTAND MACROPHAGE PHYSIOLOGY THROUGH COMPUTATION WILL BE ACCELERATED BY THE PROPOSED INVESTIGATIONS. KEY EXPECTED OUTCOMES FROM THIS GRANT PERIOD INCLUDE NEW MECHANISMS AND SIMULATION TOOLS FOR AUTOCRINIC, ATP-DRIVEN INAMMATORY RESPONSES MEDIATED BY P2X RECEPTORS. SINCE ALL EUKARYOTIC CELLS USE CA, INSIGHTS FROM MODELING MACROPHAGES WILL HAVE BROAD IMPACTS BEYOND IMMUNE FUNCTION.

ADVANCED NURSING EDUCATION WORKFORCE

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

EXTRATUMORAL BIOLOGICAL DETERMINANTS THAT DECREASE SURVIVAL IN OLDER ADULTS WITH GLIOBLASTOMA - PROJECT SUMMARY WILD-TYPE ISOCITRATE DEHYDROGENASE 1/2 GLIOBLASTOMA (GBM) IS THE MOST COMMON AND AGGRESSIVE FORM OF MALIGNANT PRIMARY BRAIN TUMOR IN ADULTS WITH A MEDIAN AGE OF ONSET AT 68-70 YEARS OLD. IDHWT GBM PATIENTS REPRESENT >70% OF ALL GBM PATIENT DIAGNOSES, AND AMONG THOSE INDIVIDUALS, OLDER ADULTS =65 YEARS OF AGE HAVE A SIGNIFICANTLY DECREASED MEDIAN OVERALL SURVIVAL (MOS) AS COMPARED TO YOUNGER IDHWT GBM PATIENTS AFTER TREATMENT WITH STANDARD OF CARE RADIATION (RT) AND TEMOZOLOMIDE. WE HAVE ALSO STUDIED OUR ONGOING CLINICAL TRIAL NCT04047706 AND DETERMINED THAT NEWLY-DIAGNOSED OLDER ADULT IDHWT MGMT PROMOTER UNMETHYLATED GBM PATIENTS WHO ARE TREATED WITH RT, NIVOLUMAB (PD-1 MAB), AND BMS-986205 [IDO ENZYME INHIBITOR (IDOI)] HAVE A DECREASED MOS AS COMPARED TO SIMILARLY-TREATED YOUNGER GBM PATIENTS (P<0.0007). STRIKINGLY, >33% OF THE YOUNGEST PATIENTS IN THIS TRIAL ARE STILL ALIVE AT 36 MONTHS POST-TREATMENT INITIATION. THE POOR PROGNOSIS OF OLDER ADULT GBM PATIENTS STARKLY CONTRASTS WITH INDIVIDUALS WHO UNDERGO TREATMENT FOR OTHER FORMS OF AGGRESSIVE CANCER THAT ARISES OUTSIDE OF THE BRAIN. FOR EXAMPLE, FORMER PRESIDENT JIMMY CARTER WAS DIAGNOSED WITH METASTATIC MELANOMA AT 91 YEARS OF AGE AND SUBSEQUENTLY TREATED WITH IMMUNOTHERAPY. STRIKINGLY, PRESIDENT CARTER IS STILL ALIVE TODAY AT 98 YEARS OLD. WE HYPOTHESIZE THAT MAJOR CONTRIBUTING FACTORS TO THE WORSE SURVIVAL OUTCOMES OF OLDER ADULT GBM PATIENTS DEPEND ON: (I) HOW INTRATUMORAL GENE EXPRESSION LEVELS DO NOT CHANGE WITH DIFFERENCES IN GBM PATIENT AGE [SHAH ET AL., 2021, CELL REPORTS. 37(10):110100], BUT RATHER, (II) HOW EXTRATUMORAL LEVELS OF IMMUNOSUPPRESSION INCREASE IN THE OLDER ADULT BRAIN AND POTENTLY SUPPRESS THERAPEUTIC EFFICACY IN OLDER ADULTS WITH GBM [LADOMERSKY…WAINWRIGHT, 2020, CLINICAL CANCER RESEARCH. 26(19):5232-5245], AND (III) HOW EXTRATUMORAL LEVELS OF SENESCENCE INCREASE IN THE OLDER ADULT BRAIN [KIM…WAINWRIGHT, 2021, NEURO-ONCOLOGY ADVANCES. 3(1):VDAB125]. TO UNDERSTAND THE EFFECTS OF ADVANCED AGE-MEDIATED CHANGES IN THE EXTRATUMORAL OLDER ADULT BRAIN, THAT IN-TURN, PROMOTES THE MALADAPTIVE RESPONSE TO GBM AND/OR GBM TREATMENTS, WE WILL: (I) STUDY EXTRATUMORAL IDO-MEDIATED IMMUNOSUPPRESSION OF THERAPEUTIC EFFICACY IN OLDER ADULT MICE WITH GBM; (II) CHARACTERIZE EXTRATUMORAL SENESCENCE LEVELS AND THEIR EFFECTS ON SURVIVAL OUTCOMES OF OLDER ADULT MICE WITH GBM; (III) QUANTIFY AGING PARAMETERS IN THE EXTRATUMORAL HUMAN BRAIN FROM INDIVIDUALS ACROSS THE LIFESPAN THAT DID OR DID NOT HAVE GBM. THIS RESEARCH IS HIGHLY INNOVATIVE AND SIGNIFICANT FOR ITS GOAL TO UNDERSTAND AGING- DEPENDENT MECHANISMS THAT CONTRIBUTE TO WORSE SURVIVAL OUTCOMES IN OLDER ADULTS WITH IDHWT GBM.

RATIONAL DESIGN OF A UNIQUE VACCINE FOR EMERGING PANDEMIC CORONAVIRUSES - ABSTRACT SARS-COV-2 HAS CAUSED THE GLOBAL COVID-19 PANDEMIC. VACCINES AGAINST SARS-COV-2, MOSTLY USING SPIKE (S) PROTEIN AS A TARGET ANTIGEN TO INDUCE NEUTRALIZING ANTIBODIES, HAVE BEEN DEVELOPED AT UNPRECEDENTED SPEED AND SEVERAL HAVE BEEN APPROVED FOR USE IN HUMAN. THE CURRENTLY DEVELOPED VACCINES INDUCE NEUTRALIZING ANTIBODIES AND PROVIDE PROTECTION AGAINST SARS-COV-2 ORIGINAL STRAIN OR EARLIER VARIANTS, BUT THEY HAVE REDUCED NEUTRALIZING ACTIVITY OR PROTECTION AGAINST RECENT VARIANTS. BASED ON THE FACT THAT THREE PANDEMIC CORONAVIRUSES (COVS) HAVE EMERGED WITHIN 20 YEARS, SOME UNKNOWN COVS WITH PANDEMIC POTENTIAL ARE EXPECTED TO EMERGE IN THE FORESEEABLE FUTURE. THEREFORE, A VACCINE IS URGENTLY NEEDED TO PREVENT A FUTURE EMERGING COV. THREE COV OUTBREAKS CAUSED BY THE THREE HIGHLY PATHOGENIC COVS (SARS-COV, SARS-COV-2 AND MERS-COV) ARE ALL FROM BETA-COVS, IN PARTICULAR, FROM SARBECOVIRUS AND MERBECOVIRUS LINEAGES, WE THUS REASON THAT FUTURE EMERGING COVS CAUSING PANDEMICS MAY MOST LIKELY COME FROM THESE TWO LINEAGES AND THAT BOTH LINEAGES SHOULD BE TARGETED TO DEVELOP A VACCINE TO PREVENT AGAINST THE FUTURE EMERGING VIRUS. HOWEVER, WE CANNOT PREDICT THE SEQUENCES OF S PROTEIN OF FUTURE EMERGING COV TO MAKE A VACCINE TARGETING S TO INDUCE NEUTRALIZING ANTIBODIES. OUR PRIOR DATA SHOWED THAT A S PROTEIN-BASED VACCINE BY USING UBIQUITINATION AND GENE REARRANGEMENT STRATEGY TO ENHANCE ITS DEGRADATION IN PROTEASOME INDUCED STRONG T CELL RESPONSES, IN PARTICULAR CTLS. THIS VACCINE SIGNIFICANTLY PROTECTED MICE AGAINST SARS-COV-2-INDUCED SURVIVAL AND WEIGHT LOSS, AND THE PROTECTION REQUIRED CD4+ AND CD8+ T CELLS. THUS, WE WILL DESIGN COV VACCINES THAT TARGET THE PROTEINS WITH GREAT HOMOLOGY (I.E., S2, M, AND N) FROM SARBECOVIRUSES AND MERBECOVIRUSES TO INDUCE PROTECTIVE T CELLS. FURTHERMORE, UPPER RESPIRATORY TRACT TISSUE-RESIDENT MEMORY T CELLS (TRM) PLAY ESSENTIAL ROLES IN PROVIDING IMMEDIATE PROTECTION, AND MUCOSAL IMMUNIZATION IS THE ONLY WAY TO INDUCE UPPER RESPIRATORY TRACT TRM. BECAUSE PAPILLOMAVIRUS-LIKE PARTICLES (PV- VLPS) INDUCE MUCOSAL IMMUNE RESPONSES, WHICH SERVE AS A MUCOSAL DELIVERY VECTOR AND ADJUVANT, WE HYPOTHESIZE THAT PV-VLPS CAN DELIVER COV HOMOLOGOUS ANTIGENS TO NASAL-ASSOCIATED LYMPHOID TISSUE, AND INDUCE RESPIRATORY TRACT TRM FOR EFFECTIVE PROTECTION AGAINST SARBECOVIRUS AND MERBECOVIRUS-CAUSED RESPIRATORY SYNDROME AND PNEUMONIA. USING SARBECOVIRUSES AND MERBECOVIRUSES AS MODEL VIRUSES, THIS PROPOSAL WILL 1) DEVELOP A PV-VLP-BASED, T CELL-INDUCING MUCOSAL COV VACCINE TARGETING CONSERVED COV ANTIGENS (S2, M AND N) AND USING GENE REARRANGEMENT AND UBIQUITINATION STRATEGIES, 2) DETERMINE IF THE VACCINE INDUCES MUCOSAL AND SYSTEMIC IMMUNE RESPONSES TO SARBECOVIRUSES AND MERBECOVIRUSES, IN PARTICULAR, LONG-TERM UPPER RESPIRATORY TRACT TRM, AND 3) EVALUATE VACCINE'S CROSS-PROTECTIVE EFFICACY AGAINST INFECTIONS OF SARBECOVIRUSES AND MERBECOVIRUSES IN MOUSE MODELS. WE HAVE SOLID PRELIMINARY DATA, WELL-ESTABLISHED ANIMAL MODELS AND VACCINE PLATFORMS, AND A STRONG RESEARCH TEAM WITH DECADES OF EXTENSIVE EXPERIENCE IN DEVELOPING SAFE AND EFFECTIVE COV VACCINES, PROVIDING FEASIBILITY AND BASIS FOR THE PROPOSED STUDIES.

CALCIUM RELEASE CHANNEL DYSFUNCTION: MOLECULAR MECHANISMS

REGULATION OF NOTCH SIGNALING BY ERBB-2: NOVEL THERAPEUTIC STRATEGY

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

NOTCH-1 AND IGF-1 CROSSTALK: NEW THERAPEUTIC STRATEGIES FOR NSCLC

AWARDING LOYOLA UNIVERSITY CHICAGO A TWO YEAR COOPERATIVE AGREEMENT FOR $1,500,000 IN SUPPORT OF THEIR PROGRAM ENTITLED, "YES WE CAN!: PARTNERING WIT

SYSTEMATIC IDENTIFICATION OF HEMATOPOIETIC STEM CELL EXPANSION FACTORS

JNK SUPPRESSION OF CONNEXIN43 ENHANCES ATRIAL FIBRILLATION IN AGED ATRIA

STRUCTURE CHANGES OF ION-MOTIVE ATPASES

THE MODERATION EFFECT OF SOCIAL SUPPORT NETWORKS ON THE RELATIONSHIP BETWEEN OPIOID USE AND SUICIDE ATTEMPTS AMONG NATIVE AMERICAN YOUTH IN NEW MEXICO

CHEMOKINE-MEDIATED MODULATON OF OPIOID-INDUCED PAIN

MECHANISMS OF FORK RESTART IN RESPONSE TO GENOTOXIC STRESS

EFFECTS OF INFECTION ON BURN-INDUCES HYPERMETABOLISM AND ORGAN DYSFUNCTION

NURSE EDUCATION PRACTICE AND RETENTION

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING FOR PROFESSIONALS AND PARAPROFESSIONALS

STRUCTURAL-TRANSCRIPTIONAL RELATIONSHIPS THAT IMPROVE Y537S ESTROGEN RECEPTOR ANTAGONISM - SUMMARY THIS PROPOSAL STUDIES HOW DRUG-INDUCED STRUCTURAL CHANGES TO Y537S ESTROGEN RECEPTOR ALPHA (ERA) IMPACT ANTI- TUMORAL ACTIVITIES IN HORMONE-RESISTANT BREAST CANCER CELLS. BREAST CANCER IS THE SECOND LEADING CAUSE OF CANCER DEATH IN THE UNITED STATES. ACQUIRED RESISTANCE TO HORMONE THERAPIES IS A LEADING CONTRIBUTOR TO MORTALITY. IN APPROXIMATELY 40% OF PROGRESSIVE ER+ PATIENTS, PROLONGED SELECTIVE PRESSURE BY ANTIESTROGENIC THERAPIES GIVES RAISE TO TUMORS BEARING ACTIVATING SOMATIC ESR1 (THE GENE FOR ERA) MUTATIONS. THESE MUTATIONS RESIST INHIBITION BY CLINICALLY APPROVED HORMONE THERAPIES AND ENGAGE NEW TRANSCRIPTIONAL PROGRAMS THAT BOOST METASTATIC POTENTIAL. Y537S MISSENSE MUTATION IS AMONG THE MOST COMMON AND ENABLES THE GREATEST HORMONE-FREE TRANSCRIPTIONAL ACTIVITIES AND RESISTANCE TO ANTIESTROGEN. NEXT GENERATION SELECTIVE ESTROGEN RECEPTOR DEGRADERS (SERDS) HAVE BEEN CLINICALLY DEPLOYED TO ADDRESS THIS MECHANISM OF DRUG RESISTANCE. HOWEVER, THEY SHOW VARIABLE ACTIVITIES IN Y537S ESR1 BREAST CANCERS AND POSSESS COMMON SIDE-EFFECTS THAT WILL LIMIT THEIR LONG-TERM USE. WE RECENTLY STUDIED HOW A PANEL OF 17 SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) AND SERDS BIND TO AND AFFECT Y537S ERA ACTIVITIES IN BREAST CANCER CELLS. WE IDENTIFIED STRUCTURALLY DISTINCT SERMS AND SERDS WITH IMPROVED ACTIVITIES IN THIS SETTING. WHILE STRUCTURALLY DISTINCT, OUR X-RAY CO-CRYSTAL STRUCTURES SHOWED THAT THE MOST EFFECTIVE MOLECULES ENGAGED THE SAME S537-E380 HYDROGEN BOND TO REINFORCE THE THERAPEUTIC ANTAGONIST CONFORMATION. THEREFORE, WE HYPOTHESIZE THAT NOVEL LIGAND-DEPENDENT STRUCTURAL INTERACTIONS WILL IMPROVE THERAPEUTIC ANTAGONISTIC ACTIVITIES IN THE Y537S ESR1 SETTING. IN THIS STUDY, WE WILL LEVERAGE OUR LIBRARY OF OVER 100 DIVERSE SERMS AND SERDS TO REVEAL THE STRUCTURAL-TRANSCRIPTIONAL RELATIONSHIPS THAT UNDERLIE IMPROVED ANTI- CANCER ACTIVITIES Y537S ESR1 BREAST CANCER CELLS. WE WILL START BY STUDYING HOW OUR LIBRARY BINDS TO AND AFFECTS Y537S ERA STRUCTURE AND ANTI-CANCER ACTIVITIES (AIM 1). THIS APPROACH WILL REVEAL THE LIGAND BINDING MODES AND STRUCTURAL INTERACTIONS THAT ENABLE POTENCY. NEXT, WE WILL STUDY HOW THE MOST EFFECTIVE MOLECULES IMPACT Y537S ERA GENOMIC ACTIVITIES INCLUDING PROTEIN-PROTEIN INTERACTIONS, GENOME BINDING, AND TRANSCRIPTIONAL PROGRAMING (AIM 2). THIS APPROACH WILL SHOW WHETHER THE EFFICACIES OF SERMS AND SERDS ARISE FROM ALTERATIONS TO Y537S ERA GENOMIC ACTIVITIES. FINALLY, WE WILL REVEAL THE ANTI-TUMOR AND TISSUE-SPECIFIC ACTIVITIES OF THE MOST EFFECTIVE SERMS AND SERDS IN HORMONE-RESISTANT ER+ BREAST CANCER IN VIVO (AIM 3). THIS APPROACH WILL REVEAL WHETHER OUR IN VITRO OBSERVATIONS CORRESPOND TO IMPROVED ANTI-CANCER ACTIVITIES IN PATIENT-RELEVANT TUMOR MODELS. OVERALL, THESE STUDIES WILL PROVIDE DETAILED STRUCTURAL-TRANSCRIPTIONAL RELATIONSHIPS TO IMPROVE THERAPEUTIC TARGETING OF Y537S ERA IN HORMONE-RESISTANT BREAST CANCER.

TRAUMA CENTER BRIEF ALCOHOL TREATMENTS AND COST EFFECTIVENES

"BURN TRAUMA AND INFECTION"

EVALUATION OF GOAL-DIRECTED PSYCHOLOGICAL CAPITAL AND EMPLOYER COACHING IN HEALTH PROFESSION OPPORTUNITY DEVELOPMENT

EVALUATION OF EMPOWERMENT PATHWAYS TO SELF-SUFFICIENCY IN HEALTH PROFESSIONS OPPORTUNITY WORKFORCE DEVELOPMENT FOR LOW-I

CENTER FOR UNDERREPRESENTED RESEARCH IN ADDICTION (CURA)

SEX DIFFERENCES IN COGNITIVE DYSFUNCTION: MITIGATION BY RNA EDITING - SUMMARY: PRENATAL STRESS (PRS) DISRUPTS BRAIN DEVELOPMENT 1-3 RESULTING IN HIGHER RISK OF DEPRESSION AND ANXIETY5, 6 IN FEMALE OFFSPRING AND A HIGHER RISK OF COGNITIVE DISORDERS SUCH AS AUTISM AND SCHIZOPHRENIA IN MALES7. DATA FROM OUR LABORATORY REVEAL SEX DIFFERENCES IN IMPORTANT MOLECULAR PATHWAYS IN THE CORTICOLIMBIC CIRCUIT IN PSYCHIATRIC DISORDERS, PARTICULARLY IN THE GLUTAMATERGIC SYSTEM12-16. GLUTAMATERGIC TRANSMISSION WITHIN THE HIPPOCAMPUS AND AMYGDALA PLAYS AN IMPORTANT ROLE IN COGNITION, AND RESILIENCE TO STRESS19-24. SIMILAR TO HUMANS, RODENTS SHOW SEX-SPECIFIC REDUCTIONS IN SPATIAL LEARNING AND INCREASED ANXIETY-LIKE BEHAVIORS AFTER EXPOSURE TO PRS 2, 32, 33. WE PROPOSE THAT THE PATHOLOGY OF PRS MAY INCLUDE AN EPITRANSCRIPTOMIC PROCESS KNOWN AS `RNA EDITING'35. PRELIMINARY DATA FROM OUR LABORATORY DEMONSTRATE DISRUPTIONS IN THE PATTERNS OF HIGHLY VARIABLE RNA EDITING IN GLUA SUBUNITS OF THE AMPA-TYPE GLUTAMATE RECEPTOR (AMPAR) IN THE HIPPOCAMPUS OF MICE EXPOSED TO PRS, WITH ASSOCIATED DEFICITS OF SOCIAL COGNITION. SIMILAR PATTERNS OF RNA EDITING OCCUR IN THE HIPPOCAMPUS OF PATIENTS WITH IMPAIRED COGNITION38-40. THE GOAL OF THE PROPOSED RESEARCH IS TO DETERMINE IF GLUA2 EDITING MEDIATES THE LONG-TERM IMPACT OF PRS. OUR CENTRAL HYPOTHESIS IS THAT PRS TRIGGERS REDUCED GLUA2 EDITING, LEADING TO LONG- TERM DETRIMENTAL FUNCTION OF THE HIPPOCAMPUS AND AMYGDALA. TO TEST A CAUSAL EFFECT OF GLUA2 EDITING WE HAVE DEVELOPED TWO NOVEL GLUA2 KNOCKIN MICE: GLUA-A MICE THAT MIMIC 0% IMMUTABLE RNA EDITING AND GLUA-G MICE THAT MIMIC 100% IMMUTABLE RNA EDITING. PRELIMINARY DATA SHOW THAT GLUA-G MUTANT MICE HAVE IMPROVED SPATIAL LEARNING. MALE BUT NOT FEMALE GLUA-G MICE HAVE RELATIVE RESILIENCE TO SOCIAL ISOLATION STRESS AND THERE ARE SEX DIFFERENCES IN RESILIENCE TO THE EFFECTS OF PRS. TO ELUCIDATE THE MECHANISMS THAT UNDERLIE THESE EVIDENTIAL CONNECTIONS BETWEEN SEX, RNA EDITING, STRESS, AND BEHAVIOR, WE PROPOSE THE FOLLOWING AIMS: 1: SEX DIFFERENCES IN THE MITIGATION OF STRESS-INDUCED COGNITIVE DEFICITS BY GLUA2 RNA EDITING, AND 2: SEX DIFFERENCES IN THE ENHANCEMENT OF RESILIENCE TO ADULT STRESS BY GLUA2 RNA EDITING. WE WILL EXPOSE GLUA-G, GLUA-A AND WT MICE TO PRS AND TEST FOR DIFFERENCES BETWEEN GENOTYPE, STRESS EXPOSURE AND SEX IN THE FOLLOWING MEASURES: (I) SYNAPTIC PLASTICITY AND MORPHOLOGY IN THE DG, CA1, CA2 AND CA3 REGIONS OF THE VENTRAL AND DORSAL HIPPOCAMPUS AND BASOLATERAL AMYGDALA. (II) AMPAR TRAFFICKING IN THESE REGIONS USING IMMUNOHISTOCHEMISTRY. (III) GENE EXPRESSION IN THESE REGIONS USING MMRNASEQ AND WESTERN BLOTTING. (IV) MEASUREMENT OF SEX AND STEROID HORMONES, (V) SOCIAL BEHAVIOR, AND COGNITIVE BEHAVIOR. THIS RESEARCH WILL INCREASE OUR UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS TRIGGERED BY STRESS THAT DIFFERENTIALLY DAMAGE THE GLUTAMATERGIC CIRCUITRY OF THE HIPPOCAMPUS AND AMYGDALA IN MALES AND FEMALES. WE WILL ALSO ASCERTAIN WHETHER RNA EDITING CAN MITIGATE STRESS-INDUCED DEFICITS. THIS RESEARCH HAS THE POTENTIAL TO IDENTIFY NOVEL TARGETS FOR PSYCHOTROPIC DRUG DEVELOPMENT AND IDENTIFY AN EXCITING NEW GENETIC MECHANISM FOR THE SAFE MANIPULATION OF SYNAPTIC PLASTICITY TO ENHANCE COGNITION AND STRESS RESILIENCE.

MLL IN MAINTENANCE AND REGULATION OF HOX GENE EXPRESSION

STRUCTURAL AND FUNCTIONAL BASIS OF MYOCARDIAL DYSREGULATION IN GENETIC CARDIOMYOPATHY - OVER THE PAST SEVERAL DECADES, AND ACCELERATING IN RECENT YEARS, THE SARCOMERE HAS BEEN APPRECIATED AS BOTH THE HOTSPOT FOR CARDIOMYOPATHY-CAUSING VARIANTS AND AS A PROMISING DRUG TARGET. THESE VARIANTS CAN ALTER THE STRUCTURE AND REGULATION OF THE SARCOMERE, LEADING TO ALTERED FUNCTION. THE FIELD HAS MADE SIGNIFICANT PROGRESS IN UNDERSTANDING THESE EFFECTS USING VARIOUS MODELS AND WHILE EACH OF THESE HAVE STRENGTHS, THEY ALL HAVE CAVEATS THAT LIMIT THEIR UTILITY IN UNDERSTANDING THE IN VIVO IMPACT OF CARDIOMYOPATHY-INDUCING VARIANTS. THE PORCINE HEART, THE MOST ACCURATE ANIMAL MODEL OF HUMAN HEARTS, HAS SIMILAR ISOFORM COMPOSITION, STRUCTURE, HEART RATE, AND RESPONSE TO PHYSIOLOGICAL STIMULI, ALLOWING STUDIES ON LIVE MUSCLE THAT ARE NOT FEASIBLE WITH BIOBANKED HUMAN SAMPLES. OUR RESEARCH TEAM IS UNIQUELY SUITED FOR THE SOPHISTICATED EXPERIMENTS NECESSARY TO PERFORM THESE STUDIES. TO INTERROGATE THE STRUCTURAL IMPACT OF THESE VARIANTS, WE WILL USE SYNCHROTRON X-RAY DIFFRACTION, THE ONLY TECHNIQUE CAPABLE OF OBTAINING MOLECULAR LEVEL SARCOMERE STRUCTURAL DATA FROM LIVE CARDIAC MUSCLE. SARCOMERE FUNCTION WILL BE ASSESSED BOTH AT ARGONNE AND AT NEARBY LOYOLA UNIVERSITY CHICAGO ON CUSTOM BIOPHYSICAL SETUPS. LASTLY, SARCOMERE STRUCTURE AND FUNCTION ARE REGULATED BY PROTEIN POST-TRANSLATIONAL MODIFICATIONS (PTMS) AND ISOFORM SWITCHING, WHICH WILL BE ASSESSED USING OUR TOP-OF-THE-LINE MASS SPECTROMETRY INSTRUMENTATION. WE WILL INVESTIGATE THE STRUCTURAL BASIS OF MYOFILAMENT FUNCTIONAL DYSREGULATION IN HEALTHY, HYPERTROPHIC (HCM: MYH7R403Q, MYBPC330X), DILATED (DCM: TTN16648X, RBM20R636S) CARDIOMYOPATHY TRANSGENIC PIGS ACROSS THE FOLLOWING THREE AIMS. THESE STUDIES WILL REVEAL THE UNDERLYING STRUCTURAL BASIS FOR CARDIOMYOPATHIES RESULTING FROM SARCOMERE PROTEIN VARIANTS, REVEALING TRANSLATIONAL MECHANISTIC UNDERSTANDING NECESSARY TO TREAT THESE DISEASES. IN AIM 1 WE WILL DETERMINE THE IMPACT OF HCM AND DCM MUTATIONS ON NORMAL SARCOMERE STRUCTURE. WE WILL COLLECT X-RAY DIFFRACTION PATTERNS AND FUNCTIONAL DATA FROM LIVE PORCINE CARDIAC MUSCLE TO INVESTIGATE THE STRUCTURAL BASIS OF PROTEIN VARIANTS LEADING TO HCM AND DCM. IN AIM 2 WE WILL DETERMINE THE IMPACT OF PHYSIOLOGICAL INOTROPIC INTERVENTIONS IN HCM AND DCM. A MAJOR PATHOLOGICAL MECHANISM OF THESE DISEASE-CAUSING VARIANTS IS THAT THEY MODIFY THE SARCOMERE’S ABILITY TO RESPOND APPROPRIATELY TO NORMAL PHYSIOLOGICAL CONDITIONS. HERE WE WILL ASSESS THE RESPONSE TO CONDITIONS WHICH TYPICALLY ELICIT AN IONOTROPIC RESPONSE. IN AIM 3 WE WILL DETERMINE HOW HCM AND DCM MUTATIONS AFFECT SARCOMERE FUNCTION REGULATION BY POST-TRANSLATIONAL MODIFICATIONS.

THE ROLE OF THE THROMBOSPONDINS IN INTIMAL HYPERPLASIA

OPIOID WORKFORCE EXPANSION PROGRAM- PROFESSIONAL

PREDICTING GENE REGULATION ACROSS POPULATIONS TO UNDERSTAND MECHANISMS UNDERLYING COMPLEX TRAITS

PRACTICING DEMOCRACY IN COMMUNITIES: DEVELOPING A COMMUNITY-WIDE CIVIC LEARNING SYSTEM; PROVIDING INSTRUCTIONAL SUPPORTS TO SCHOOLS; GENERATING INNOVATIVE CIVIC LEARNING OPPORTUNITIES FOR STUDENTS.

EMSC PARTNERSHIP GRANTS

LEVERAGING CDC OPIOID OVERDOSE SURVEILLANCE FUNDING FROM THE ALBUQUERQUE AREA SOUTHWEST TRIBAL EPIDEMIOLOGY CENTER TO CREATE TRIBAL DATA AND CULTURALLY CENTER MEDICATIONS FOR OPIOID USE DISORDER - PROJECT SUMMARY/ABSTRACT FATAL OPIOID OVERDOSE RATES ARE HIGHER AMONG AMERICAN INDIAN/ALASKA NATIVE POPULATIONS THAN AMONG HISPANICS, AFRICAN AMERICANS, AND ASIAN AMERICANS, AND ARE JUST BELOW NON-HISPANIC WHITES. AI/AN OPIOID OVERDOSE RATES VARY SIGNIFICANTLY BY STATE AND COUNTY; HOWEVER, TRIBE-LEVEL DIFFERENCES ARE DIFFICULT TO ASCERTAIN DUE TO DECENTRALIZED DATA SYSTEMS THAT DIVIDE STATE HEALTH DATA AND INDIAN HEALTH SERVICE DATA. WHILE COUNTY-LEVEL HEALTH DATA IS OFTEN USED AS A PROXY FOR TRIBAL DATA, STATE DATA OFTEN MISCLASSIFY AN/AN PATIENTS, AND IN COUNTIES CONTAINING THE LANDS OF MULTIPLE TRIBES, COUNTY DATA MAY BLUR SIGNIFICANT INTER-TRIBAL VARIATION. IN ADDITION TO LIMITED TRIBE-SPECIFIC DATA, TREATMENT FOR OPIOID USE DISORDERS ALSO OFTEN FAILS TO ACCOUNT FOR THE DIVERSITY OF TRIBAL POPULATIONS. ON AVERAGE, PATIENTS WHO TAKE MEDICATION FOR OPIOID USE DISORDER (MOUD), AND SPECIFICALLY METHADONE OR BUPRENORPHINE, EXHIBIT IMPROVED TREATMENT RETENTION AND REDUCED RISK OF DRUG OVERDOSE COMPARED TO PATIENTS NOT TAKING MOUD. SOME RESEARCH ALSO SHOWS IMPROVED RETENTION FOR NALTREXONE, ANOTHER MOUD. BECAUSE MOUD INTERVENTIONS ARE RARELY TAILORED TO THE SPECIFIC CULTURAL CONTEXTS OF AI/AN PATIENTS, SOCIAL AND CULTURAL BARRIERS TO TREATMENT PERSIST IN AI/AN COMMUNITIES. TO ADDRESS THESE PROBLEMS, WE PROPOSE TO LEVERAGE CENTER FOR DISEASE CONTROL FUNDING AWARDED TO THE ALBUQUERQUE AREA SOUTHWEST TRIBAL EPIDEMIOLOGY CENTER (AASTEC) FOR IMPROVING DATA QUALITY IN OPIOID OVERDOSE SURVEILLANCE IN NEW MEXICO IN A TWO-PHASE RESEARCH PROJECT. THE PROJECT WILL DRAW UPON A COMMUNITY ADVISORY BOARD COMPOSED OF CLINICIANS AND INDIAN HEALTH FACILITY STAFF, AND USE A COLLABORATION OF EPIDEMIOLOGISTS FROM AASTEC AND THE NEW MEXICO DEPARTMENT OF HEALTH, AND ACADEMIC RESEARCHERS AT THE UNIVERSITY OF UTAH, UNIVERSITY OF NEW MEXICO, AND COLUMBIA UNIVERSITY. IN THE FIRST PHASE, WE WILL ENHANCE TRIBAL SPECIFICITY OF AI/AN OPIOID USE DISORDER AND OVERDOSE DATA BY LINKING AND GEOCODING NEW MEXICO VITAL STATISTICS AND SYNDROMIC SURVEILLANCE DATA. WE WILL THEN USE THESE DATA IN PREDICTIVE MODELS TO DETERMINE THE ROLE OF MODIFIABLE RISK AND PROTECTIVE FACTORS FOR SPECIFIC TRIBAL COMMUNITIES. WE WILL DISSEMINATE ANALYSIS REPORTS TO TRIBAL COMMUNITIES AND SEEK PARTNERSHIPS WITH TRIBES AND INDIAN HEALTH FACILITIES FOR THE SECOND PHASE OF OUR RESEARCH, WHICH ENTAILS A COMMUNITY-BASED PARTICIPATORY RESEARCH PROJECT THAT WILL DEVELOP AND TEST A CULTURALLY CENTERED IMPLEMENTATION PROGRAM FOR MOUD FOR USE IN AI/AN COMMUNITIES. WE WILL USE A STEPPED WEDGE RANDOMIZED DESIGN IN FOUR INDIAN HEALTH FACILITIES TO TEST INITIATION, RETENTION, RELAPSE, AND ACCEPTABILITY OF CULTURALLY CENTERED MOUD AMONG PATIENTS AND CLINIC STAFF OVER TIME. THE PROPOSED RESEARCH WILL STRENGTHEN PARTNERSHIPS BETWEEN TRIBAL COMMUNITIES, AASTEC, AND ACADEMIC RESEARCHERS, AND BETTER ALIGN OPIOID RESEARCH WITH TRIBAL VALUES AND PRIORITIES. WE ANTICIPATE OUR RESEARCH WILL NOT ONLY RESULT IN PUBLICATIONS IN ACADEMIC JOURNALS BUT WILL ALSO RESULT IN TOOLKITS FOR CREATING TRIBE-SPECIFIC DATA ESTIMATES FOR OTHER REGIONS, AND PROTOCOLS FOR CULTURALLY CENTERING MOUD FOR THE CONTEXTS OF OTHER AI/AN COMMUNITIES AND INDIAN HEALTH FACILITIES.

ACE: ACHIEVING COLLEGE EXCELLENCE 2020

NEW MECHANISMS OF CARDIAC RYANODINE RECEPTOR DYSFUNCTION DURING OXIDATIVE STRESS: THE ROLE OF INTERSUBUNIT CROSS-LINKING - PROJECT SUMMARY/ABSTRACT CALCIUM (CA) RELEASE THROUGH THE RYANODINE RECEPTOR (RYR) CA CHANNEL IS ESSENTIAL FOR REGULAR HEART CONTRACTION. DEFECTS IN RYR REGULATION CAUSE AN IMBALANCE IN INTRACELLULAR CA HOMEOSTASIS IN A VARIETY OF CARDIAC DISEASES. THE MOST COMMON CARDIAC PATHOLOGY, SUCH AS MYOCARDIAL INFARCTION, IS ASSOCIATED WITH OXIDATIVE STRESS. RYR CONTAINS A LARGE NUMBER OF CYSTEINE RESIDUES THAT LINK OXIDATIVE STRESS AND CA HOMEOSTASIS. HOWEVER, THE PATHOLOGICALLY RELEVANT CYSTEINES WITHIN RYR REMAIN LARGELY UNKNOWN. AS A RESULT, THE MECHANISMS OF RYR DYSFUNCTION DURING OXIDATIVE STRESS AND MYOCARDIAL INFARCTION ARE NOT FULLY UNDERSTOOD. THIS DELAYS OUR PROGRESS IN DESIGNING EFFECTIVE THERAPEUTIC INTERVENTIONS THAT CAN IMPROVE CA HOMEOSTASIS DURING ISCHEMIC HEART DISEASES. THE MAIN GOAL OF THIS PROPOSAL IS TO DEFINE THE MOLECULAR MECHANISMS OF RYR DYSFUNCTION DURING OXIDATIVE STRESS AND MYOCARDIAL INFARCTION. WE HAVE RECENTLY DISCOVERED THAT OXIDATIVE STRESS ACTIVATES RYR BY FORMING DISULFIDE BONDS BETWEEN TWO NEIGHBORING SUBUNITS: THE INTERSUBUNIT CROSS-LINKING. IT APPEARS THAT ONLY TWO CROSS-LINKING CYSTEINES PLAY A CRITICAL ROLE IN THE RYR RESPONSE TO OXIDATIVE STRESS. IN THIS PROPOSAL WE WILL TEST THE HYPOTHESIS: THE INTERSUBUNIT CROSS-LINKING IS THE PRINCIPAL REDOX MODIFICATION OF RYR RESPONSIBLE FOR CA DYSREGULATION DURING OXIDATIVE STRESS AND MYOCARDIAL INFARCTION. TO TEST THIS HYPOTHESIS, WE HAVE DEVELOPED A TRANSGENIC MOUSE MODEL WITH A UNIQUE RYR2 KNOCK-IN MUTATION THAT PROTECTS RYR FROM THE INTERSUBUNIT CROSS-LINKING. IN AIM 1, WE WILL DEFINE MOLECULAR MECHANISMS OF RYR DYSFUNCTION INDUCED BY THE INTERSUBUNIT CROSSLINKING. WE EXPECT TO SHOW THAT THE CROSS-LINKING ACTIVATES RYR2 BY PROMOTING LONGER CHANNEL OPENINGS. SUCH ALTERATION OF RYR FUNCTION INCREASES CA LEAK AND TRIGGERS PRO-ARRHYTHMOGENIC CA WAVES. WE EXPECT TO SHOW THAT RYR MUTATION THAT PROTECTS THE CHANNEL FROM THE CROSS-LINKING WILL NORMALIZE RYR ACTIVITY, REDUCE CA LEAK, AND PREVENT CA WAVES DURING OXIDATIVE STRESS. IN AIM 2, WE WILL DEFINE THE CRITICAL ROLE OF THE RYR INTERSUBUNIT CROSS-LINKING IN CA DYSREGULATION AND CONTRACTILE DYSFUNCTION DURING MYOCARDIAL INFARCTION. WE EXPECT TO SHOW THAT RYR MUTATION THAT PROTECTS THE CHANNEL FROM THE CROSSLINKING WILL NORMALIZE CARDIAC CA REGULATION AND IMPROVE MYOCARDIAL CONTRACTION IN THE INFARCTED HEART. WE WILL ALSO TEST WHETHER SELECTIVE PHARMACOLOGICAL INTERVENTIONS THAT STABILIZE RYR AT THE INTERSUBUNIT CROSS-LINKING REGION CAN REDUCE CA LEAK AND PREVENT CA WAVES DURING OXIDATIVE STRESS AND MYOCARDIAL INFARCTION.

ENGLISH LANGUAGE ACQUISITION: NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM

MOLECULAR AND CELLULAR DETERMINANTS OF TRIM5ALPHA RESTRICTION OF HIV-1

LOYOLA UNIVERSITY CHICAGO NOYCE SCHOLARS: TEACHING, LEARNING & LEADING WITH SCHOOLS AND COMMUNITIES -THIS PROJECT AIMS TO SERVE THE NATIONAL NEED OF RECRUITING, DEVELOPING, AND RETAINING A DIVERSE AND TALENTED GROUP OF HIGH SCHOOL SCIENCE AND MATHEMATICS TEACHERS WITH THE KNOWLEDGE, PRACTICES, AND DISPOSITIONS TO ENACT CULTURALLY RELEVANT STEM EDUCATION. THE PROJECT WILL IDENTIFY AND ATTRACT HIGH-ACHIEVING STEM MAJORS THROUGH SYSTEMATIC OUTREACH EFFORTS AND A TRY TEACHING STIPEND OPPORTUNITY. RECRUITMENT WILL TARGET A DIVERSE AND QUALIFIED POOL OF APPLICANTS THAT INCLUDES PEOPLE OF COLOR, FIRST GENERATION COLLEGE STUDENTS, VETERANS, AND MULTILINGUAL SPEAKERS. SCHOLARS WILL COMPLETE LOYOLA UNIVERSITY CHICAGO?S INITIAL TEACHER EDUCATION PROGRAM, ALIGNED WITH ILLINOIS? CULTURALLY RESPONSIVE TEACHING AND LEADING STANDARDS, AND DESIGNED TO SUPPORT DEVELOPMENT OF TEACHERS? DEEP UNDERSTANDING OF SUBJECT MATTER AND HOW IT CAN BE TRANSFORMATIVE TO STUDENTS? LIVES. COURSEWORK ALSO EMBEDS PREPARATION FOR EDUCATING MULTILINGUAL LEARNERS AND ENSURES ELIGIBILITY FOR THE STATE'S ENGLISH AS A SECOND LANGUAGE (ESL) ENDORSEMENT. INDUCTION SUPPORT WILL INCLUDE PARTICIPATION IN FIELD EXPERIENCES AND COACHING SHADOW DAYS IN PARTNER SCHOOLS, AS WELL AS ONGOING MENTORING AND COLLABORATIVE PROFESSIONAL LEARNING, ALL DESIGNED TO SUPPORT INSTRUCTIONAL EFFECTIVENESS AND RETENTION. IN THIS PROJECT, LOYOLA?S SCHOOL OF EDUCATION, COLLEGE OF ARTS AND SCIENCES, SCHOOL OF SUSTAINABILITY, AND CENTER FOR SCIENCE AND MATH EDUCATION WILL PARTNER WITH ILLINOIS DISTRICT 219 AND CHICAGO PUBLIC SCHOOLS. FIVE PROJECT GOALS GUIDE THE EXECUTION OF THE PROJECT. FIRST IS TO PROVIDE FINANCIAL AND OTHER SUPPORTS TO AT LEAST 19 HIGH-ACHIEVING PROSPECTIVE BIOLOGY, CHEMISTRY, PHYSICS, AND MATHEMATICS TEACHERS WHO COMMIT TO TEACHING IN HIGH-NEED SCHOOLS. SECOND IS TO INCREASE THE NUMBER AND DIVERSITY OF STEM MAJORS AND PROFESSIONALS ENTERING TEACHING. THE THIRD GOAL IS TO PREPARE CANDIDATES TO WORK WITH CULTURALLY AND LINGUISTICALLY DIVERSE STUDENTS, ENSURING THAT 100% OF SCHOLARS FULFILL REQUIREMENTS FOR THE STATE ENGLISH AS A SECOND LANGUAGE (ESL) ENDORSEMENT. FOURTH IS TO RETAIN TEACHERS IN CHICAGO HIGH-NEED SCHOOLS THROUGH RIGOROUS PREPARATION COMBINED WITH HIGH-QUALITY, MULTI-DIMENSIONAL INDUCTION SUPPORT. FINALLY, THE FIFTH GOAL IS TO STUDY PROGRAM DATA TO INFORM UNDERSTANDING OF URBAN STEM TEACHER PREPARATION, MENTORING, AND INDUCTION SUPPORT. SPECIFICALLY, PROGRAM RESEARCH WILL STUDY POTENTIAL CONNECTIONS AMONG CULTURALLY SUSTAINING INSTRUCTIONAL PRACTICES, INDUCTION SUPPORTS, AND TEACHER RETENTION. THIS TRACK 1: SCHOLARSHIPS AND STIPENDS PROJECT IS SUPPORTED THROUGH THE ROBERT NOYCE TEACHER SCHOLARSHIP PROGRAM (NOYCE). THE NOYCE PROGRAM SUPPORTS TALENTED STEM UNDERGRADUATE MAJORS AND PROFESSIONALS TO BECOME EFFECTIVE K-12 STEM TEACHERS AND EXPERIENCED, EXEMPLARY K-12 TEACHERS TO BECOME STEM MASTER TEACHERS IN HIGH-NEED SCHOOL DISTRICTS. IT ALSO SUPPORTS RESEARCH ON THE EFFECTIVENESS AND RETENTION OF K-12 STEM TEACHERS IN HIGH-NEED SCHOOL DISTRICTS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

REDEFINING STEM TEACHER PREPARATION BY TEACHING, LEARNING ,AND LEADING WITH SCHOOLS AND COMMUNITIES

OSTEOPONTIN REGULATES UBIQUITIN-PROTEASOME DEGRADATION OF STAT1

THE U.S. FISH AND WILDLIFE SERVICE (USFWS) SHIAWASSEE NATIONAL WILDLIFE REFUGE (SNWR) PROPOSES TO CONTROL 200 ACRES OF INVASIVE PLANTS, INCREASE WATERBIRD UTILIZATION, AND REDUCE NUTRIENT RUN-OFF TO THE SAGINAW BAY AREA OF CONCERN THROUGH AN INNOVATIVE MULTI-YEAR RESTORATION AND RESEARCH PROJECT. THIS PROJECT ADDRESSES GLRI ACTION PLAN III PRIORITIES (FOCUS AREA 2) WHICH CALLS TO DEVELOP INVASIVE SPECIES CONTROL TECHNOLOGIES AND REFINE MANAGEMENT TECHNIQUES WITH INNOVATIVE EMERGING TECHNOLOGY, IMPLEMENTED AT A LARGE SCALE.WE PROPOSE TO HARVEST INVASIVE HYBRID CATTAIL (TYPHA X GLAUCA) BIOMASS FROM THE 288-ACRE MAANKIKI SOUTH UNIT WITHIN THE SNWR, CONVERT IT TO BIOCHAR ON-SITE, AND RE-APPLY THE BIOCHAR TO A PORTION OF THE UNIT. THE MAANKIKI SOUTH UNIT WAS RESTORED TO WETLAND FROM AGRICULTURAL FIELDS THROUGH A GLRI-FUNDED RESTORATION PROJECT. HOWEVER, DUE TO ITS LEGACY OF AGRICULTURE AND WATERSHED NUTRIENT ENRICHMENT, THE UNIT QUICKLY BECAME DOMINATED BY HYBRID CATTAIL, ALTERING THE WETLAND S ECOLOGICAL FUNCTIONS AND REDUCING HABITAT QUALITY FOR WATERBIRDS. MANAGING THE CATTAIL WITHIN THE UNIT IS THEREFORE A HIGH PRIORITY FOR SNWR.IN THIS PROJECT, WE WILL MANAGE INVASIVE CATTAILS TO THE BENEFIT OF WATERBIRDS ACROSS 200 ACRES OF MAANKIKI SOUTH UNIT, WHILE SIMULTANEOUSLY CONDUCTING A LARGE-SCALE EXPERIMENT TO TEST THE COMBINED EFFICACY OF INVASIVE SPECIES BIOMASS-HARVEST AND BIOCHAR RE-APPLICATION TO ACHIEVE MULTIPLE BENEFITS. WE WILL ESTABLISH A MULTI-YEAR, HIGHLY REPLICATED EXPERIMENT WITH LARGE 2.5-ACRE PLOTS, TWO LEVEL OF BIOCHAR APPLICATION, TWO-LEVELS OF REPEATED HARVEST, AND CONTROLS. WE WILL HARVEST BIOMASS ANNUALLY WITH ALLOW-GROUND-PRESSURE PLANT HARVESTER AND PROCESS IT ON-SITE WITH A MOBILE BIOCHAR PRODUCTION UNIT. THROUGHOUT THE 4-YEAR STUDY, WE WILL MONITOR PLANT RESPONSE, BIRD UTILIZATION, SOIL NUTRIENT LEVELS, PLANT AVAILABLE NUTRIENTS, SOIL CARBON CONTENT, AND NUTRIENT EXPORT FROM THE UNIT.THIS PROJECT BUILDS DIRECTLY ON GLRI SUPPORTED PROJECTS TO RESTORE MAANKIKI SOUTH UNIT AND TO DEVELOP INNOVATIVE INVASIVE PLANT MANAGEMENT TECHNIQUES. WE ANTICIPATE BROAD ECOLOGICAL BENEFITS INCLUDING THE LONG-TERM REDUCTION OF INVASIVE PLANT DOMINANCE, INCREASED WATERBIRD HABITAT, REDUCED DOWNSTREAM NUTRIENT RUNOFF, AND INCREASED CARBON STORAGE. KNOWLEDGE GAINED WILL BE USED TO DEVELOP MANAGEMENT PROTOCOLS FOR INVASIVE PLANT HARVEST, CONVERSION TO BIOCHAR AND WETLAND RE-APPLICATION.

DYNAMICS AND CONTROL OVER HOST-ASSOCIATED BIOFILM FORMATION AND DISPERSAL

PRESERVATION OF SKELETAL MUSCLE FOLLOWING FROSTBITE INJURY

SPANISH-SPEAKING LATINOS' EARLY LANGUAGE ENVIRONMENTS AND DUAL LANGUAGE DEVELOPMENT

STUDENT SUPPORT SERVICES PROGRAM

MOTS: MODELING OBESITY THROUGH SIMULATION

LOYOLA UNIVERSITY OF CHICAGO WILL INCREASE DEVELOPMENT IN CUBA THROUGH A COMPREHENSIVE PROGRAM TO RAISE THE PERFORMANCE OF CIVIL SOCIETY S BUILDING B

INFLAMMATORY RESPONSE AFTER COMBINED INSULT OF RADIATION AND BURN INJURY

ROLE OF SEROTONIN IN SMYPATHETIC FUNCTION

INTERACTIONS BETWEEN P90 RIBOSOMAL S6 KINASE AND PROTEIN KINASE A

MECHANISMS OF IMPAIRED ERYTHROPOIESIS IN POST BURN ANEMIA OF CRITICAL ILLNESS

REGULATION OF THE CHEMOKINE RECEPTOR CXCR4 BY UBIQUITIN

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM

ADVANCED NURSING EDUCATION GRANTS

STUDENT SUPPORT SERVICES PROGRAM

NOVEL APPROACHES TO DESTROYING BIOTHREAT AGENTS

RANDOMIZED CONTROLLED TRIAL OF MULTISENSORY EARLY ORAL ADMINISTRATION OF HUMAN MILK (M-MILK) FOR VERY PRETERM INFANTS: ENHANCING STRESS REGULATION, NEURODEVELOPMENT, AND ORAL FEEDING SKILLS - PROJECT SUMMARY UP TO 60% OF THE 60,000 VERY PRETERM INFANTS (<32 WEEKS GESTATIONAL AGE) BORN ANNUALLY IN THE US EXHIBIT NEURODEVELOPMENTAL IMPAIRMENTS AND 80% EXPERIENCE ORAL FEEDING DIFFICULTIES. THESE CRITICAL COMORBIDITIES LEAD TO ORAL AVERSION, FAILURE TO THRIVE, DEVELOPMENTAL DELAYS, AND EXTENDED NICU STAY. ADMISSION TO THE NICU EXPOSES INFANTS TO SUBSTANTIAL EARLY LIFE STRESS. EARLY LIFE STRESS IS LINKED TO DISRUPTED STRESS REGULATION, EVIDENCED BY ELEVATED SALIVARY CORTISOL AND ALTERED BUCCAL CELL DNA METHYLATION (DNAM) AT SPECIFIC CPG SITES OF GLUCOCORTICOID REGULATING GENES, NR3C1 EXON 1F AND HSD11B2 PROMOTER. THESE STRESS-RELATED BIOMARKERS ARE FURTHER ASSOCIATED WITH LESS OPTIMAL NEURODEVELOPMENT AND ORAL FEEDING SKILLS. WE PROPOSE THE MULTISENSORY EARLY ORAL ADMINISTRATION OF HUMAN MILK (M-MILK), AN INFANT-LED EARLY NICU INTERVENTION BEGINNING ON DAY 3 OF LIFE. M-MILK PROVIDES VERY PRETERM INFANTS WITH THE ORAL ADMINISTRATION OF SMALL DROPLETS OF MILK WHILE ENGAGING THEIR INNATE SENSES. OUR M-MILK PILOT DATA SHOWED A TREND THAT THE M-MILK GROUP DEMONSTRATED LOWER OVERALL MEAN DNAM OF NR3C1 EXON 1F, ALONG WITH HIGHER ORAL FEEDING SKILL COMPETENCY AND SHORTER TRANSITION FROM FIRST TO FULL ORAL FEEDING COMPARED TO THE STANDARD OF CARE GROUP. OTHERS SHOWED THAT EARLY HUMAN MILK ADMINISTRATION PROVIDED IMMUNE PROTECTION, SUPPORTED ORAL FEEDING TRANSITION, AND REDUCED VENTILATOR-ASSOCIATED PNEUMONIA, OXYGEN NEEDS, NICU STAY, AND COST OF CARE. THE PURPOSE OF THIS RANDOMIZED CONTROLLED TRIAL IS TO EVALUATE M- MILK AS AN EFFECTIVE INTERVENTION TO IMPROVE STRESS REGULATION, SUPPORT OPTIMAL NEURODEVELOPMENT, AND PROMOTE COMPETENT ORAL FEEDING SKILLS IN VERY PRETERM INFANTS. WE WILL RANDOMLY ASSIGN INFANTS (N = 125) BORN <32 WEEKS GESTATIONAL AGE TO EITHER THE M-MILK OR CONTROL GROUP (STANDARD OF CARE). M-MILK WILL BEGIN ON DAY 3 OF LIFE AND CONTINUE UNTIL ORAL FEEDING INITIATION. WE WILL ASSESS STRESS REGULATION (SALIVARY CORTISOL AND BUCCAL CELL DNAM OF NR3C1 EXON 1F AND HSD11B2 PROMOTER), NEURODEVELOPMENT (NEONATAL NEUROBEHAVIORAL SCALE, NNNS-II AND AGES AND STAGES QUESTIONAIRE-3, ASQ-3), AND ORAL FEEDING SKILLS (EARLY FEEDING SKILLS ASSESSMENT, EFS AND NEONATAL EATING ASSESSMENT TOOL, NEOEAT). OUTCOMES WILL BE MEASURED AT BASELINE, ORAL FEEDING INITIATION, 36 WEEKS POSTMENSTRUAL AGE, AND 2 MONTHS CORRECTED AGE. THE STUDY AIMS WILL ADVANCE KNOWLEDGE AS TO THE EFFICACY OF M-MILK AS AN EPIGENETICALLY-INFORMED INTERVENTION TO ENHANCE STRESS REGULATION, NEURODEVELOPMENT, AND ORAL FEEDING SKILLS IN VERY PRETERM INFANTS DURING CRITICAL PERIODS OF NEUROPLASTICITY. FURTHER, INSIGHTS INTO THE BENEFITS OF M-MILK IN THE NICU WILL LAY THE GROUNDWORK FOR FUTURE RESEARCH EXPLORING ITS BROADER APPLICATIONS E.G., ACUTE PAIN MANAGEMENT AND PALLIATIVE CARE. EXPANDED APPLICATIONS HAVE POTENTIAL TO ENHANCE THE HEALTHY DEVELOPMENT OF VERY PRETERM INFANTS BEYOND THE NICU STAY, WHILE ACCOUNTING FOR RISK AND PROTECTIVE FACTORS ASSOCIATED WITH THE HOME AND NEIGHBORHOOD ENVIRONMENT. THIS WORK WILL INFORM FUTURE STUDIES OF THE LONG-TERM EFFICACY OF EARLY NICU INTERVENTIONS, LIKE M-MILK, ON MODIFIABLE EPIGENETIC PROCESSES, THAT HAVE POTENTIAL TO REDUCE LIFELONG HEALTH RISKS FOR VERY PRETERM INFANTS.

URINARY KNOWLEDGE STUDY (U-KNOW)

EXPLOIT DIMETHYL FUMARATE TO UNCOVER DRUGGABLE VULNERABILITIES AND PREVENT RECURRENCE OF ER+ BREAST CANCERS

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - LOYOLA UNIVERSITY CHICAGO’S SCHOOL OF SOCIAL WORK (LUC/SSW) IS OPENING A BEHAVIORAL HEALTH SIMULATION LAB AT THE WATER TOWER CAMPUS TO TRAIN SOCIAL WORK STUDENTS AND PROFESSIONALS IN ALLIED FIELDS (E.G., NURSING, MEDICINE) FOR CAREERS IN MENTAL HEALTH SETTINGS, SCHOOLS, HOSPITALS, STATE AND LOCAL SERVICE AGENCIES, ETC. STUDENTS WILL RECEIVE MENTAL HEALTH AND CRISIS INTERVENTION TRAINING IN A SAFE, CONTROLLED, AND SUPERVISED SIMULATED PRACTICE ENVIRONMENT WITH SIMULATED PATIENTS UTILIZING RECORDING SOFTWARE FOR DETAILED FEEDBACK ON SKILL DEVELOPMENT. TELEBEHAVIORAL HEALTH TRAINING CONDUCTED VIA THE SIMULATION LAB WILL ASSIST AT-RISK COMMUNITIES ACROSS CHICAGO HAVING A DIRECT IMPACT UPON THOSE MOST IN NEED OF MENTAL HEALTH CARE. LUC/SSW HAS INTERNALLY WORKED TO BUILD OUT THE NEW BEHAVIORAL HEALTH SIMULATION LAB ON THE 4TH AND 5TH FLOORS OF MAGUIRE HALL AND FUNDING FROM THIS CFP/CDF PROJECT THROUGH HRSA WILL SUPPORT ESSENTIAL ITEMS INCLUDING SOFTWARE, COMPUTERS, FURNITURE, AND OTHER KEY SUPPLIES (E.G., PROPS). ADDITIONAL SUPPORTIVE FUNDING AND COSTS ASSOCIATED WITH CONSTRUCTION ARE OUTLINED IN THIS SUBMISSION AND ARE BEING COVERED SEPARATELY BY LUC.

COMBINED PRIORITY FOR PERSONNEL DEVELOPMENT

CROSS-AGE PEER MENTORING TO ENHANCE RESILIENCE AMONG LOW-INCOME URBAN YOUTH LIVING IN HIGH VIOLENCE CHICAGO COMMUNITIES.

ABSTRACT THE GOAL OF THE LOYOLA STOP SCHOOL VIOLENCE (LSSV) PROJECT IS TO DEVELOP AND IMPLEMENT AGE-APPROPRIATE, SCHOOL-SPECIFIC, CULTURALLY COMPETENT, RISK FACTOR-RELEVANT, TRAUMA-INFORMED, SCHOOL-WIDE, AND EVIDENCE-BASED SCHOOL VIOLENCE PREVENTION TRAINING PROGRAMS FOR STUDENTS, SCHOOL STAFF AND LAW ENFORCEMENT OFFICERS TO PREVENT STUDENTS’ ENGAGEMENT IN VIOLENT ACTIVITIES, TO IMPROVE SCHOOL STAFF’S AWARENESS OF MENTAL HEALTH NEEDS, AND TO ENSURE A SAFE AND POSITIVE SCHOOL CLIMATE. ADOPTING THE RESPONSE TO INTERVENTION (RTI) VIOLENCE PREVENTION STRATEGIES (I.E., PRIMARY PREVENTION, SECONDARY PREVENTION OR INTERVENTION, TERTIARY PREVENTION OR RESPONSE), THE LSSV PROJECT WILL PROVIDE CBITS AND GREAT TO ONE HUNDRED EIGHTY HIGH RISK STUDENTS, WHILE OFFERING TMHFA, SANDY HOOK PROMISE’S SAY SOMETHING PROGRAM, AND 2ND STEP SEL WITH ANTI-BULLYING PROGRAM TO SIX HUNDRED LOWER RISK TARGET STUDENTS AT SIX PUBLIC SCHOOLS (K-12) IN THREE IMPOVERISHED COMMUNITIES IN CHICAGO FOR THREE YEARS. IN ADDITION, THE LSSV PROJECT PROVIDES YOUTH MHFA TRAINING TO TWO HUNDRED FORTY SCHOOL STAFF AND LOCAL LAW ENFORCEMENT OFFICERS TO IMPROVE THEIR AWARENESS AND RESPONSES TO MENTAL HEALTH ISSUES. FINALLY, THE LSSV PROJECT AIMS TO OFFER STUDENT-INITIATED AND SCHOOL-WIDE VIOLENCE PREVENTION PROGRAMS TO ENSURE A SAFE AND POSITIVE SCHOOL CLIMATE.

MOLECULAR AND CELLULAR DISSECTION OF CIRCADIAN OUTPUT PATHWAYS IN DROSOPHILA

PROMOTING ASTHMA SELF-CARE IN URBAN AFRICAN AMERICAN TEENS

ADVANCE ADAPTATION: INSPIRED- INCLUSIVE PRACTICES IN THE RETENTION AND EQUITY OF DIVERSE FACULTY

TAS::89 0222::TAS CHICAGO CLEAN AIR, CLEAN WATER PROJECT: ENVIRONMENTAL MONITORING FOR A HEALTHY, SUSTAINABLE URBAN FUTURE

CAREER: THE DEVELOPMENTAL REGULATION OF AMNIOTE SKULL DIVERSITY

NURSE EDUCATION, PRACTICE, QUALITY AND RETENTION - WORKFORCE EXPANSION PROGRAM - FOUNDED IN 1935 AS THE FIRST BACCALAUREATE NURSING PROGRAM IN ILLINOIS, LOYOLA UNIVERSITY CHICAGO, MARCELLA NIEHOFF SCHOOL OF NURSING (LUC MNSON) HAS PREPARED OVER 10,000 NURSES TO ASSUME LEADERSHIP IN HEALTH CARE AND IN THE PROFESSION OF NURSING. WE PROPOSE TO CONTINUE OUR TRACK RECORD OF EXCELLENCE IN ACUTE AND LONG-TERM HEALTH CARE IN DESIGNATED RURAL AREAS THROUGH THE “NURSING – PROVIDING ACCESS TO RURAL ACUTE AND LONG-TERM HEALTHCARE (N-PARALTH)” PROJECT. THE N-PARALTH PROJECT WILL INCREASE THE NUMBER OF NURSING STUDENTS RETAINED AND GRADUATED FROM (LUC MNSON, INCREASE THE NUMBER OF NURSING STUDENTS RECEIVING ADDITIONAL SPECIALIZED TRAINING IN RURAL ACUTE AND LONG-TERM CARE SETTINGS, INCREASE THE NUMBER OF NEW GRADUATES FROM LUC MNSON EMPLOYED IN RURAL ACUTE AND LONG-TERM CARE SETTINGS AND INCREASE THE NUMBER OF PRECEPTORS AND CLINICAL FACULTY PREPARED TO EDUCATE LUC MNSON STUDENTS IN RURAL SETTINGS. THIS PROJECT WILL BE ACCOMPLISHED THROUGH THE FOLLOWING N-PARALTH OBJECTIVES: OBJECTIVE 1: CREATE A RURAL HEALTH CARE NURSING SCHOLAR (RHCNS) PROGRAM BEGINNING IN THE STUDENT’S FIRST YEAR OF NURSING EDUCATION AND LASTING THROUGHOUT THEIR BSN EDUCATION WHICH FOCUSES ON EVIDENCE-BASED KNOWLEDGE, SKILLS AND ATTITUDES FOR THE CARE OF RURAL RESIDENTS IN ACUTE AND LONG-TERM CARE FACILITIES. THE RHCNS PROGRAM WILL BE OPEN TO FOUR-YEAR NURSING STUDENTS, ACCELERATED NURSING STUDENTS, INCLUDING BOTH HYBRID AND FACE-TO-FACE NURSING STUDENTS. OBJECTIVE 2: ENHANCE AND EXPAND PARTNERSHIPS WITH NURSES IN RURAL LONG-TERM CARE AND ACUTE CARE SETTINGS PROVIDING CARE FOR RURAL, UNDERSERVED POPULATIONS INCLUDING BENNETT COUNTY CRITICAL ACCESS HOSPITAL, MARTIN, SOUTH DAKOTA, INDIAN HEALTH SERVICE HOSPITAL IN PINE RIDGE, SOUTH DAKOTA AND DESIGNATED CRITICAL ACCESS HOSPITALS AND LONG-TERM CARE FACILITIES IN DESIGNATED RURAL COUNTIES OF ILLINOIS, WISCONSIN, INDIANA, AND MICHIGAN THROUGH THE DELIVERY OF CONTINUED PROFESSIONAL DEVELOPMENT FOR PRACTICING RNS. AS STATED IN THE HRSA PUBLICATION “NURSE WORKFORCE PROJECTIONS, 2021-2036” MICHIGAN IS ONE OF THE TEN STATES WITH THE GREATEST SHORTAGES. OBJECTIVE 3: CREATE AND PILOT-TEST A RURAL, ACUTE CARE AND LONG-TERM CARE, ASYNCHRONOUS, MODULE-BASED EDUCATIONAL PROGRAM FOR BACCALAUREATE NURSING EDUCATION THAT CAN BE REPLICATED BY OTHER SCHOOLS OF NURSING INTERESTED IN EXPANDING THEIR EDUCATIONAL PROGRAMMING TO ADDRESS RURAL ACUTE CARE AND LONG-TERM CARE. MODULES DEVELOPED FOR THE N-PARALTH PROJECT WILL ADDRESS CURRENT RURAL HEALTH ISSUES EMPHASIZING SKILL BUILDING IN EVIDENCED–BASED INTERVENTIONS. IN ADDITION, STRATEGIES WILL BE USED TO ENCOURAGE GRADUATES TO SELECT RURAL HEALTH CARE AS A GEOGRAPHICAL LOCATION TO PROVIDE HEALTH CARE UPON GRADUATION WITH A FOCUS IN ACUTE AND LONG-TERM CARE NURSING AS A SPECIALTY. THE FOUR PATHS (PRE-PROFESSIONAL, PRECEPTOR, PATIENT, AND POPULATION) OF LOYOLA’S CURRENT PATH MODEL WILL ORGANIZE THE PROJECT ACTIVITIES. THE PRE-PROFESSIONAL PATH (I.E. STUDENT) WILL INCLUDE CURRICULUM INTEGRATING RURAL HEALTH CARE WITH ONLINE, HYBRID AND SIMULATED CONTENT, REFLECTIVE JOURNALING, SMALL GROUP AND FACE-TO-FACE CLASSROOM/WORKSHOP EDUCATION, AND SERVICE IMMERSION EXPERIENCES IN RURAL SITES. THE PRECEPTOR PATH WILL PROVIDE TRAINING FOR PRECEPTORS AND FACULTY IN RURAL HEALTH CARE, ACUTE AND LONG-TERM CARE ENSURING THAT REGISTERED NURSES HAVE THE KNOWLEDGE, SKILLS, AND ATTITUDES TO CARE FOR RURAL POPULATIONS. THE PATIENT PATH WILL FOCUS ON ASSESSING RURAL PATIENT NEEDS AND THE DEVELOPMENT OF EDUCATIONAL AND CULTURAL INTERVENTIONS TO SUPPORT PATIENTS IN MAINTAINING THEIR HIGHEST LEVEL OF FUNCTION. THE POPULATION PATH WILL INCORPORATE THEORY AND PRACTICE IN RURAL NURSING AND HEALTH CARE WITH PROPOSED INTERVENTIONS. A STATUTORY FUNDING PREFERENCE IS REQUESTED ON THE BASIS OF PROJECTS THAT SUBSTANTIALLY BENEFIT RURAL POPULATIONS AND THE STATE OF MICHIGAN.

MECHANISMS OF EPIGENETIC GENE REGULATION BY THE DROSOPHILA COMPASS-LIKE COMPLEX

MECHANOTRANSDUCTION VIA LIM DOMAIN PROTEIN MECHANOSENSING - PROJECT SUMMARY MECHANICAL INTERACTIONS PLAY A FUNDAMENTAL ROLE IN PHYSIOLOGY, ALLOWING CELLS TO MOVE, GENERATE FORCES, AND ASSEMBLE INTO MULTICELLULAR STRUCTURES. KEY TO THESE PROCESSES IS THE ABILITY OF CELLS TO TURN MECHANICAL SIGNALS INTO BIOCHEMICAL SIGNALS, AN ACTIVITY KNOWN AS MECHANOTRANSDUCTION. THE SEARCH FOR MECHANOSENSITIVE PROTEINS THAT COULD FACILITATE MECHANOTRANSDUCTION HAS PRIMARILY FOCUSED ON PROTEINS THAT UNDERGO CONFORMATIONAL CHANGES IN RESPONSE TO FORCE OR PROTEINS THAT DISPLAY CHANGES IN THE BOND KINETICS UNDER LOAD. THERE EXISTS ANOTHER CLASS OF PROTEINS, HOWEVER, THAT RECOGNIZE STRUCTURES UNDER STRAIN. THE CANONICAL EXAMPLE OF THIS CLASS OF PROTEINS IS THE LIM DOMAIN PROTEIN ZYXIN, WHICH RECOGNIZES STRAINED ACTIN STRESS FIBERS AND RECRUITS ACTIN POLYMERIZATION FACTORS TO REPAIR THEM. RECENT WORK HAS HIGHLIGHTED THAT THE STRAIN SENSING MECHANISM OF THE LIM DOMAINS IS NOT UNIQUE TO ZYXIN AND THAT NUMEROUS OTHER MEMBERS OF THE FAMILY OF LIM DOMAIN PROTEINS DISPLAY A SIMILAR ABILITY. THIS SUGGESTS LIM DOMAIN PROTEINS COULD ACT AS MECHANOTRANSDUCERS, RECOGNIZING STRAIN VIA THEIR LIM DOMAINS AND CONVERTING IT TO OTHER BIOCHEMICAL SIGNALS VIA INTERACTIONS WITH THE OTHER DOMAINS IN THE PROTEIN. TO EXPLORE THIS HYPOTHESIS FURTHER IT IS CRUCIAL THAT WE UNDERSTAND HOW LIM DOMAINS RECOGNIZE STRAINED ACTIN FILAMENTS, AND HOW THOSE INTERACTIONS PROPAGATE SIGNALS DOWNSTREAM OF THE STRAIN SITES. HERE WE PROPOSE TO ESTABLISH RIGOROUS EXPERIMENTAL STRATEGIES TO DECIPHER THE MECHANISMS UNDERLYING LIM DOMAIN PROTEIN MECHANOTRANSDUCTION. WE EMPLOY A COMBINATION OF BIOPHYSICAL TECHNIQUES INCLUDING LASER ABLATIONS, OPTOGENETICS AND CELL STRETCHING TO QUANTITATIVELY AND REPEATEDLY INDUCE STRAIN SITES IN THE ACTIN CYTOSKELETON. IN AIM 1 WE WILL TEST ALTERNATIVE MECHANISMS OF LIM DOMAIN STRAIN SENSING BY COMPARING PROTEINS FROM THE TESTIN FAMILY OF LIM DOMAIN PROTEINS WHICH REQUIRE ONLY A SINGLE LIM DOMAIN TO RECOGNIZE STRAIN SITES, COMPARED TO THE THREE TANDEM LIM DOMAINS THAT ZYXIN REQUIRES. IN AIM 2 WE WILL TEST WHETHER IN ADDITION TO STRETCHED ACTIN FILAMENTS IN STRESS FIBERS, LIM DOMAIN PROTEINS CAN RECOGNIZE OTHER STRAINED ACTIN STRUCTURES, SUCH AS COMPRESSED STRESS FIBERS OR ACTIN MESHWORKS. FINALLY, IN AIM 3 WE WILL INVESTIGATE HOW BINDING OF LIM DOMAIN PROTEINS TO STRAIN SITES LEADS TO A PROPAGATION OF THAT MECHANICAL SIGNAL TO OTHER PARTS OF THE STRESS FIBER AND THE EXTRACELLULAR MATRIX. TOGETHER THESE STUDIES WILL GREATLY EXPAND OUR KNOWLEDGE OF MECHANOTRANSDUCTION AND PROVIDE INSIGHT INTO THIS FUNDAMENTAL SIGNALING MECHANISM.

ALCOHOL AND LUNG TRANSPLANTATION: UNDERSTANDING DONOR AND RECIPIENT CONSEQUENCES

THE ROLE OF TAK1 IN THE PATHOGENESIS OF BONE MARROW FAILURE SYNDROMES

EMSC TARGETED ISSUE GRANTS

TARGETED THERAPY FOR 11Q23 ACUTE LEUKEMIAS.

ADVANCED NURSING EDUCATION GRANTS

NURSE EDUCATION PRACTICE QUALITY AND RETENTION- REGISTERED NURSE TRAINING PROGRAM - ORGANIZATION: LOYOLA UNIVERSITY CHICAGO, MARCELLA NIEHOFF SCHOOL OF NURSING (MNSON) ADDRESS: 2160 S. 1ST AVENUE, MAYWOOD, IL, 60153 PROJECT DIRECTOR: P. ANN SOLARI-TWADELL, PHD, RN, MPA, FAAN PHONE: (773) 508- 3249 EMAIL: PSOLARI@LUC.EDU PROJECT PERIOD: 9/30/2022 THROUGH 9/29/2025 AS THE FIRST BACCALAUREATE NURSING PROGRAM IN ILLINOIS, LOYOLA UNIVERSITY CHICAGO (LUC), MARCELLA NIEHOFF SCHOOL OF NURSING (MNSON) HAS PREPARED OVER 10,000 NURSES TO BE LEADERS IN THE PROFESSION. WE PROPOSE TO CONTINUE OUR TRACK RECORD OF EXCELLENCE THROUGH THE “SOCIAL DETERMINANTS OF HEALTH–NURSING PROVIDING ACCESS TO HEALTHCARE (SDOH-NPATH)” PROJECT. WE WILL CONSULT WITH OGLALA LAKOTA COMMUNITY NURSING PROGRAM IN PINE RIDGE, SOUTH DAKOTA IN THE DEVELOPMENT OF THIS PROJECT. THE SDOH-NPATH PROJECT INCREASES AND STRENGTHENS SDOH EDUCATION FOR NURSING STUDENTS, CLINICAL AND THEORY FACULTY, PRECEPTORS, AND NURSING LEADERS FROM PARTNERING HEALTH CARE INSTITUTIONS WITH THE GOAL OF PROVIDING CULTURALLY ALIGNED QUALITY NURSING SERVICES IN ACUTE CARE SETTINGS IN RURAL AND URBAN UNDERSERVED AREAS IMPROVING RETENTION AND RESILIENCE OF NURSING STAFF IN ACUTE CARE SETTINGS. SDOH-NPATH STRIVES TO INCREASE DIVERSITY IN THE NURSING WORKFORCE WHILE ENHANCING HEALTHCARE EQUITY IN URBAN AND RURAL UNDERSERVED ACUTE CARE SETTINGS THROUGH DEVELOPING PROGRAMMING WITH CULTURALLY DIVERSE HIGH SCHOOLS IN RURAL AND URBAN AREAS. OUTCOMES ARE TO INCREASE THE NUMBERS OF CULTURALLY DIVERSE NURSING STUDENTS AND ULTIMATELY CULTURALLY DIVERSE NURSES WHO INCORPORATE SDOH INTO THEIR ACUTE CARE NURSING PRACTICE. SDOH-NPATH IS BASED ON THESE OBJECTIVES: OBJECTIVE 1: CREATE AN ACUTE CARE NURSE SCHOLARS PROGRAM (ACNSP) AND SUMMER FELLOWSHIP IN ACUTE CARE NURSING PROGRAM (SFACNP). THE ACNSP WILL BEGIN IN THE SPRING OF THE STUDENT’S FIRST YEAR OF NURSING EDUCATION AND CONTINUE THROUGH GRADUATION WHERE THEY WILL EARN THE DESIGNATION OF ACUTE CARE NURSE SCHOLAR (ACNS). THE PROGRAM FOCUSES ON SDOH EVIDENCE-BAS ED KNOWLEDGE, SKILLS, AND ATTITUDES, PARTICULARLY FOR UNDERSERVED POPULATIONS IN URBAN AND RURAL SETTINGS. THE ACNSP WILL BE OPEN TO TRADITIONAL, ACCELERATED, HYBRID ACCELERATED, RN-BSN STUDENTS AND GRADUATE NURSING STUDENTS. THE SFACNP WILL BE OFFERED IN THE SUMMER BETWEEN THE JUNIOR AND SENIOR YEAR FOR TRADITIONAL NURSING STUDENTS. OBJECTIVE 2: ENHANCE AND EXPAND RECRUITMENT OF DIVERSE HIGH SCHOOL STUDENTS INTO NURSING PROGRAMS BY ENGAGING HIGH SCHOOL STUDENTS THAT REPRESENT UNDERSERVED MINORITY GROUPS. THE ACNS WILL PARTICIPATE IN EDUCATIONAL PROGRAMS THROUGHOUT THE YEAR DESIGNED TO ENHANCE THE HIGH SCHOOL STUDENTS UNDERSTANDING OF NURSING. OBJECTIVE 3: CREATE FOUR TRACKS OF FACE-TO-FACE AND ASYNCHRONOUS, E-LEARNING MODULES FOR A) UNDERGRADUATE NURSING STUDENTS, B) CLINICAL FACULTY AND PRECEPTORS, C) THEORY FACULTY, AND D) NURSING LEADERS IN PARTNERING INSTITUTIONS TO ENSURE INTEGRATION. THE FOUR PATHS (PRE-PROFESSIONAL, PRECEPTOR, PATIENT, AND POPULATION) OF LOYOLA’S PATH MODEL ORGANIZES THE PROJECT ACTIVITIES. THE PRE-PROFESSIONAL PATH (I.E., STUDENT) INCLUDES A CURRICULUM WITH ONLINE, HYBRID, INTERACTIVE, EXPERIENTIAL, AND SIMULATED SDOH ACUTE CARE MODULES. THE PRECEPTOR PATH EDUCATES CLINICAL AND THEORY FACULTY AND SITE PRECEPTORS IN SDOH ACUTE CARE CONTENT TO SUPPORT NURSE RESILIENCE AND RETENTION. THE PATIENT PATH INCORPORATES ASSESSMENTS OF PATIENTS AND FAMILIES WITH COMPLEX ACUTE CONDITIONS USING CULTURALLY APPROPRIATE SDOH STRATEGIES. THE POPULATION PATH INCORPORATES CULTURALLY INFORMED STRATEGIES THAT INCLUDES SDOH FOR ACUTE CARE SETTINGS. A STATUTORY FUNDING PREFERENCE IS REQUESTED BASED ON THE PROJECTS ABILITY TO SUBSTANTIALLY BENEFIT RURAL AND/OR UNDERSERVED POPULATIONS IN CHICAGOLAND AND SOUTH DAKOTA AND MILITARY VETERAN POPULATIONS.

CONTINUATION OF THE URINARY INCONTINENCE TREATMENT NETWORK (UITN)

CELLULAR AND MOLECULAR BASIS OF TONOTOPIC MAP FORMATION IN THE MOUSE COCHLEAR NUCLEUS

COLLABORATIVE RESEARCH: MAKING SPACE FOR STORY-BASED TINKERING TO SCAFFOLD EARLY INFORMAL ENGINEERING LEARNING

NOVEL BURN SEPSIS PROGNOSTIC STRATEGIES: DECIPHERING EARLY IMMUNE PROGENITOR SHIFTS IN BURN SEPSIS DEVELOPMENT AND MODULATION OF HOST BURN RESPONSE THROUGH ANGIOPOIETIN-TIE SIGNALING - RECENT ADVANCEMENTS IN THE TREATMENT OF BURN SHOCK HAVE IMPROVED ACUTE SURVIVAL (THE FIRST 48 HOURS) FROM SEVERE BURN INJURY; HOWEVER, PATIENTS STILL EXPERIENCE MORE THAN 60% MORTALITY DUE TO INFECTIOUS COMPLICATIONS AND SEPSIS. BURN INJURY TRIGGERS A UNIQUE AND PROFOUND IMMUNE RESPONSE FROM A COMBINED HYPOVOLEMIC, CARDIOGENIC, AND DISTRIBUTIVE SHOCK THAT CAN LEAD TO MULTISYSTEM ORGAN FAILURE AND DEATH. FULL-THICKNESS BURNED SKIN CAN ONLY BE TREATED WITH SURGICAL INTERVENTION AND MAY REQUIRE MONTHS OF SURGERY TO ADDRESS. DURING THAT TIME, PATIENTS ARE HIGHLY SUSCEPTIBLE TO INFECTIOUS COMPLICATIONS, INCLUDING SEPSIS. THERE IS A PRESSING NEED FOR NEW STRATEGIES TO REDUCE INFECTION-RELATED MORBIDITY AND IMPROVE OVERALL SURVIVAL AFTER SEVERE BURN INJURY. PRELIMINARY WORK HAS IDENTIFIED 2 UNIQUE FEATURES SEEN EARLY AFTER BURN INJURY THAT CORRELATE WITH THE LATER DEVELOPMENT OF SEPSIS: 1) A MYELOID PROGENITOR LINEAGE SELECTION; AND 2) ELEVATED ANGIOPOIETIN-2 (ANGPT-2). TO IMPROVE THE SURVIVAL OF ALL PATIENTS WITH SEPSIS, THIS PROPOSED RESEARCH PROGRAM AIMS TO ADDRESS THE FOLLOWING 2 CRITICAL CHALLENGES: CHALLENGE 1 IS THE NEED TO IDENTIFY DISTINCT PHENOTYPES OF IMMUNE RESPONSES TO BURN SHOCK AND THEIR RELATION TO THE DEVELOPMENT OF SEPSIS SO THAT NOVEL APPROACHES TO MITIGATE SEPSIS RISK CAN BE DEVELOPED; AND CHALLENGE 2 IS THE NEED TO IDENTIFY THE MECHANISM THROUGH WHICH ELEVATED ANGPT-2 LEADS TO AN INCREASED RATE OF SEPSIS DEVELOPMENT. THIS PROPOSED RESEARCH PROGRAM WILL PROSPECTIVELY FOLLOW PATIENTS WITH SEVERE BURN AND WILL COMBINE THE IDENTIFICATION OF IMMUNE SYSTEM PHENOTYPES WITH MECHANISTIC DRIVERS OF ENDOTHELIAL DYSFUNCTION IN ORDER TO IDENTIFY SEPSIS EARLIER, BETTER PREDICT OUTCOMES, AND IDENTIFY NEW MECHANISMS TO HELP MODULATE THE HOST RESPONSE. THE FIRST PROJECT WILL ADDRESS CHALLENGE 1 BY ANSWERING THE TRANSLATIONAL QUESTION OF WHETHER EARLY CHANGES IN IMMUNE PROGENITOR LINES CAN PREDICT PATIENTS AT RISK FOR THE DEVELOPMENT OF SEPSIS. NOT ALL PATIENTS RESPONSE TO SEVERE BURN IS THE SAME, WHICH MAY BE PARTLY DUE TO DIFFERENCES IN THEIR IMMUNE RESPONSES AT THE LEVEL OF HEMATOPOIETIC PROGENITOR CELLS. THE HYPOTHESIS IS THAT AN IMMUNE PHENOTYPE WITH INCREASED MYELOID PROGENITOR CELLS WILL CORRELATE WITH DEVELOPMENT OF SEPSIS. A MULTIOMICS FRAMEWORK WILL BE USED TO IDENTIFY IMMUNE PHENOTYPES IN THE PERIPHERAL BLOOD AND BONE MARROW FOR PATIENTS WHO DO AND DO NOT DEVELOP SEPSIS. THE SECOND PROJECT WILL ADDRESS CHALLENGE 2 BY DETERMINING WHETHER THE SOURCE OF ANGPT-2 IS THE BURN INJURY ITSELF OR IF THE ELEVATION IN ANGPT-2 IS PART OF THE SYSTEMIC RESPONSE TO THE BURN. THE HYPOTHESIS IS THAT BURNED TISSUE IS THE PRIMARY DRIVER OF ANGPT-2 RELEASE. THIS RESEARCH PROGRAM WILL INTEGRATE IN VITRO MODELS, SPATIAL TRANSCRIPTOMICS, AND A MULTIOMICS FRAMEWORK TO DEFINE HOW ANGPT-2 INCREASES RISK OF SEPSIS DEVELOPMENT. TOGETHER, THESE PROPOSED STUDIES WILL TEST NOVEL METHODS FOR DIAGNOSING AND PREDICTING SEPSIS, WHICH ARE CRITICAL TO IMPROVING OUTCOMES IN BURN SURVIVORS. THE FINDINGS FROM THESE STUDIES ARE ANTICIPATED TO HAVE BROADER SCIENTIFIC AND CLINICAL IMPLICATIONS FOR THE TREATMENT OF SEPSIS IN CRITICAL ILLNESS BY TESTING IMMUNE PHENOTYPE PROGNOSTICATION AND BY MODULATION OF ANGPT-2.

RONALD E. MCNAIR POSTBACCALAUREATE ACHIEVEMENT

LOYOLA ALCOHOL RESEARCH CENTER (LARC)

CAREER: CIRCADIAN CONTROL AND INTEGRATION OF FEEDING AND METABOLIC RHYTHMS IN DROSOPHILA

COLLABORATIVE RESEARCH: DECIPHERING THE GENETIC DIVERSITY OF VIRUSES THROUGH GENE NETWORKS

NEURONAL PLASTICITY AND RECOVERY OF FUNCTION AFTER STROKE

COLLABORATIVE RESEARCH: LATINX FAMILIES' TALK ABOUT SCIENCE IN STORIES WITH YOUNG CHILDREN

MYOFILAMENT PROTEINS IN CARDIOMYOPATHY AND ARRHYTHMIAS

PURPOSE: ECONOMIC DEVELOPMENT INITIATIVE, COMMUNITY PROJECT FUNDING/CONGRESSIONAL DIRECTED SPENDING AWARDS ARE AUTHORIZED UNDER THE CONSOLIDATED APPROPRIATIONS ACT, 2022 PUBLIC LAW 117-328 AND THE EXPLANATORY STATEMENT FOR DIVISION L OF THAT ACT. PROJECTS SELECTED FOR COMMUNITY PROJECT FUNDING/CONGRESSIONAL DIRECTED SPENDING ARE LISTED IN THE JOINT EXPLANATORY STATEMENT (JES) THAT ACCOMPANIES A SPECIFIC FISCAL YEAR’S APPROPRIATIONS ACT OR CONGRESSIONAL RECORD. THE JES LISTS PROJECT, RECIPIENT, STATE, AMOUNT AND CONGRESSIONAL SPONSOR.; ACTIVITIES TO BE PERFORMED: ECONOMIC DEVELOPMENT INITIATIVE, COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING AWARD PROJECTS INCLUDE A WIDE VARIETY OF ACTIVITIES THAT RESULT IN ECONOMIC DEVELOPMENT OR COMMUNITY DEVELOPMENT OUTCOMES. HUD WILL NOT KNOW THE FULL SCOPE OF THE PROJECT UNTIL THE RECIPIENT SUBMITS THE REQUIRED PROJECT NARRATIVE AND CONFIRMS ALIGNMENT WITH THE LANGUAGE AS PROVIDED IN THE CONGRESSIONAL RECORD. TO FIND THE DETAILS OF THE GRANT AWARD AS WRITTEN WITHIN THE CONGRESSIONAL RECORD USE THE FOLLOWING LINK AND PATH SELECTIONS TO GET TO THE DESCRIPTION OF THE ECONOMIC DEVELOPMENT INITIATIVE, COMMUNITY PROJECT FUNDING GRANTS HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/COMM_PLANNING/EDI-GRANTS, SELECT THE FISCAL YEAR OF INTEREST, SCROLL DOWN TO PROGRAM LAWS AND REGULATIONS, UNDER FISCAL YEAR 20XX CONSOLIDATED APPROPRIATIONS ACT, 20XX: CONGRESSIONAL RECORD (JOINT EXPLANATORY STATEMENT).; EXPECTED OUTCOMES: COMPLETION OF THE PROJECT AS DESCRIBED IN THE JOINT EXPLANATORY STATEMENT (JES) PROJECT DESCRIPTION AND SUBSEQUENT APPROVED PROJECT NARRATIVE.; INTENDED BENEFICIARIES: THE PROJECT BENEFICIARIES ARE THE INDIVIDUALS AND/OR ORGANIZATIONS THAT ARE AWARDED GRANT FUNDS OR SERVED BY THE ENTITIES THAT ARE AWARDED GRANT FUNDS AS IDENTIFIED IN THE JES RECIPIENT OR PROJECT DESCRIPTION SECTIONS.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD.

DEVELOPING IMMUNOTHERAPEUTIC OPTIONS FOR TSC

ADVANCED NURSING EDUCATION GRANTS

MECHANISM-BASED DESIGN OF IRON-MEDIATED CARBONYL-OLEFIN METATHESIS PROTOCOLS

CAREER: IMPACT OF ELEMENTAL LIMITATION ON THE EVOLUTION AND COMPOSITION OF BACTERIA -ALL ORGANISMS CONSIST OF A MIXTURE OF ELEMENTS IN DIFFERING RATIOS. ELEMENTS SUCH AS CARBON, NITROGEN, AND PHOSPHORUS ARE NEEDED TO MAKE THE NUCLEIC ACIDS, PROTEINS AND OTHER MOLECULES THAT ARE THE BUILDING BLOCKS OF CELLS. HOWEVER, THE AVAILABILITY OF THESE ELEMENTS IN ORGANISMS? ENVIRONMENTS OFTEN DIFFERS FROM THE PROPORTIONS NEEDED BY ORGANISMS. AS A RESULT, THE AVAILABILITY OF THE SCARCEST ELEMENT CAN LIMIT GROWTH. THIS PROJECT WILL EXPLORE HOW BACTERIA EVOLVE IN RESPONSE TO THE SCARCITY OF DIFFERENT ELEMENTS. BACTERIA WILL EVOLVE UNDER CONTROLLED LABORATORY CONDITIONS WITH VARYING RATIOS OF CARBON, NITROGEN, AND PHOSPHORUS. THE RESEARCHERS WILL MEASURE ELEMENTAL COMPOSITION, GENETIC CHANGES, AND FITNESS OF THE EVOLVED BACTERIA. HUMAN ACTIVITY HAS ALTERED ELEMENTAL AVAILABILITY ACROSS A VARIETY OF HABITATS, INCLUDING ADDITION OF NITROGEN AND PHOSPHORUS AS FERTILIZER. THE RESEARCH IN THIS PROJECT WILL HELP LAY THE FOUNDATION FOR UNDERSTANDING HOW ORGANISMS MAY EVOLVE IN RESPONSE TO CHANGES IN ELEMENTAL AVAILABILITY. THIS PROJECT WILL ALSO PROVIDE RESEARCH EXPERIENCES FOR COMMUNITY COLLEGE STUDENTS WHO WILL CONDUCT AN EVOLUTION EXPERIMENT AS PART OF THEIR INTRODUCTORY BIOLOGY LABORATORY COURSE AND THEN HAVE THE OPPORTUNITY TO CONTRIBUTE TO THE PROJECT AS UNDERGRADUATE RESEARCHERS. THIS PROJECT WILL ADDRESS HOW THE ELEMENTAL COMPOSITION OF BACTERIA EVOLVES IN RESPONSE TO ELEMENTAL LIMITATION. THE RESEARCHERS WILL TEST WHETHER SELECTION UNDER ELEMENTAL LIMITATION FAVORS A NUTRIENT SPARING RESPONSE IN WHICH BACTERIA EVOLVE TO INCORPORATE LESS OF THE LIMITING ELEMENT IN THEIR CELLS. THE EVOLUTIONARY RESPONSE TO ELEMENTAL LIMITATION MAY ALSO DEPEND ON OTHER ASPECTS OF THE ENVIRONMENT. THIS RESEARCH WILL TEST THE ROLE OF DIFFERING SELECTION PRESSURES BY COMPARING THE OUTCOME OF EVOLUTION UNDER SELECTION FOR FASTER GROWTH RATE AND EVOLUTION UNDER SELECTION FOR INCREASED YIELD. RESPONSE TO LIMITATION MAY ALSO DEPEND ON THE STARTING CHARACTERISTICS OF THE ORGANISMS. TO EXPLORE THIS, THE RESEARCHERS WILL ALSO TEST THE ROLE OF GENETIC BACKGROUND ON THE EVOLUTIONARY RESPONSE TO LIMITATION. 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.

PRECLINICAL DEVELOPMENT OF NOVEL SITE BLOCKING ASOS FOR THE TREATMENT OF RETT SYNDROME - SUMMARY AN EMERGING THEME IN NEURODEVELOPMENTAL RESEARCH IS THAT BOTH LOSS OF FUNCTION AND OVEREXPRESSION OF THE SAME GENE CAN RESULT IN AUTISM-ASSOCIATED PHENOTYPES. THIS REALITY IS EPITOMIZED BY THE DISORDER RETT SYNDROME (RTT), WHERE LOSS OF FUNCTION MUTATIONS IN THE METHYL-CPG BINDING PROTEIN 2 (MECP2) GENE ARE PATHOGENIC, BUT EVEN A 1-FOLD INCREASE OVER NEUROTYPICAL LEVELS EVOKES ADVERSE EFFECTS. FROM A THERAPEUTIC STANDPOINT, THE PROBLEM CREATED BY THESE NARROW DOSAGE REQUIREMENTS IS THAT NOT ONLY DOES VIRAL MECP2 DELIVERY NEED TO BE EFFICIENT ACROSS THE ENTIRE HUMAN BRAIN, BUT EACH CELL MUST RECEIVE ROUGHLY THE SAME, RELATIVELY SMALL AMOUNT. TO ADDRESS THIS CHALLENGE, OUR LAB HAS DEVELOPED AN ANTISENSE OLIGONUCLEOTIDE APPROACH (ASO) TO FINE- TUNE MECP2 EXPRESSION BY OUTCOMPETING REPRESSIVE MIRNA FOR BINDING TO THE MECP2 3’UNTRANSLATED REGION (UTR). AS THE CONTRIBUTION OF EACH MIRNA TO GENE EXPRESSION IS MODEST BY NATURE, THE RESULT IS AN INCREMENTAL INCREASE IN MUTANT MECP2 PROTEIN THAT SATURATES AT A CEILING LEVEL PREDICTED TO BE SUBTOXIC. IN CONTRAST TO ANTAGOMIRS, OUR SITE-BLOCKING ASOS (SBASOS) ARE SPECIFIC TO THE MECP2 LOCUS, AND ALLOW THE TARGET MIRNA TO MAINTAIN ALL OTHER BINDING PARTNERS. THE SBASO PROOF OF CONCEPT STUDIES WERE RECENTLY PUBLISHED IN “RNA”, AND SHOW THAT SBASOS DESIGNED TO OUTCOMPETE MIR22, MIR132, AND MIR483 INCREASE MECP2 PROTEIN TO LEVELS THAT PLATEAU AT A 0.4 TO 2-FOLD INCREASE, DEPENDING ON THE MIRNA SITE BEING BLOCKED. SBASO EFFICACY WAS ESTABLISHED IN SH-SY5Y CELLS, WILD-TYPE MICE, FIVE RTT PATIENT FIBROBLAST LINES, AND RTT NEURONAL STEM CELLS, WHERE A DOWNSTREAM MECP2-SIGNALING WAS ALSO RESTORED. ALTHOUGH EXCITING, WE ENCOUNTERED THE UNEXPECTED PROBLEM THAT SBASO EFFICACY AND POTENCY WERE COMPROMISED BY SEVERAL HIGHLY PREVALENT MECP2 MUTATIONS, NARROWING THE APPROACH’S UTILITY. WE HAVE NOW RESOLVED THIS CHALLENGE BY ESTABLISHING THAT CERTAIN CLASSES OF MIRNA ARE SUBJECT TO MUTATION-SPECIFIC REGULATORY FEEDBACK LOOPS WITH MECP2, WHILE OTHER CLASSES ARE NOT. BY BLOCKING THE BINDING OF ONE MECP2-INSENSITIVE MIRNA, MIR181 (SB181), WE OBSERVED ROBUST EFFICACY AND CONSISTENT POTENCY ACROSS FIVE COMMON MECP2 MUTATIONS, SUGGESTING THAT THE SBASO STRATEGY CAN HAVE A BROAD THERAPEUTIC UTILITY. HERE WE PROPOSE A TWO-PHASE DEVELOPMENT STRATEGY OF OUR LEAD SBASO: SB181. IN THE R61 PHASE, WE WILL ESTABLISH SB181 EFFICACY IN IPSC-DERIVED NEURONS FROM COMMON MISSENSE MUTATIONS AT THE LEVEL OF MECP2 EXPRESSION, DOWNSTREAM SIGNALING, AND CELLULAR PHYSIOLOGY. WE WILL THEN DEFINE KEY DMPK AND SAFETY PARAMETERS IN A MECP2T158M/+ MOUSE MODEL, WHICH WILL CORRELATE SB181 EXPOSURE WITH MECP2 LEVELS AS A FUNCTION OF DISTRIBUTION, TIME, AND RTT-LIKE PHENOTYPES. IN THE R33 PHASE, WE WILL DEFINE THE PATIENT SUBPOPULATIONS WHERE SB181 WOULD BE PREDICTED TO BE EFFECTIVE USING ADDITIONAL MISSENSE (MECP2R306C/+) AND TRUNCATING (MECP2R255X/+) MODELS OF RTT. TOGETHER THE R61 AND R33 PHASES WILL ESTABLISH THE CELL TYPES AND MECP2 MUTATIONS IMPACTED BY SB181, WHILE ALSO DEFINING THE DMPK AND SAFETY PROFILE OF THE POTENTIAL THERAPEUTIC, THEREBY FACILITATING THE TRANSITION TO CLINICAL DEVELOPMENT BOTH WITH INDUSTRY PARTNERS AND THE BLUEPRINT NEUROTHERAPEUTICS NETWORK.

ADVANCING INTEGRATED TREATMENT FOR CO-OCCURRING OPIOID AND ALCOHOL USE DISORDERS: A COMPREHENSIVE ANALYSIS OF GLP-1 RECEPTOR AGONISTS AND TRADITIONAL PHARMACOTHERAPIES IN REAL-WORLD SETTINGS - PROJECT SUMMARY/ABSTRACT THE INTERSECTION OF OPIOID USE DISORDER (OUD) AND ALCOHOL USE DISORDER (AUD) PRESENTS A SIGNIFICANT PUBLIC HEALTH CHALLENGE, PARTICULARLY IN CLINICAL SETTINGS WHERE THEIR CO-OCCURRENCE COMPLICATES TREATMENT OUTCOMES AND EXACERBATES THE SEVERITY OF EACH DISORDER. DESPITE ADVANCEMENTS IN PHARMACOTHERAPY FOR OUD AND AUD INDEPENDENTLY, THE TREATMENT OF THESE CO-OCCURRING DISORDERS REMAINS UNDEREXPLORED, ESPECIALLY IN LARGE-SCALE, REAL-WORLD CONTEXTS. OUR RESEARCH AIMS TO ADDRESS THIS GAP BY LEVERAGING THE ORACLE CERNER EHR REAL-WORLD DATA (CRWD), A COMPREHENSIVE NATIONAL DATABASE ENCOMPASSING OVER 100 MILLION PATIENTS, TO CONDUCT AN EXTENSIVE ANALYSIS OF TREATMENT PATTERNS, OUTCOMES, AND PREDICTIVE FACTORS IN PATIENTS WITH CO-OCCURRING OUD AND AUD. OUR STUDY IS STRUCTURED AROUND THREE SPECIFIC AIMS. THE FIRST AIM IS TO ASSESS THE EFFECTIVENESS OF INTEGRATED TREATMENT APPROACHES, INCLUDING FIRST-LINE AUD AND OUD MEDICATIONS ALONG WITH GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP-1 RA), FOR PATIENTS WITH CO-OCCURRING OUD AND AUD. WE WILL FOCUS ON EVALUATING THE REDUCTION IN SUBSTANCE USE, IMPROVEMENTS IN PHYSICAL HEALTH INDICATORS, MENTAL HEALTH IMPROVEMENTS, AND THE UTILIZATION OF DETOXIFICATION SERVICES AND DRUG TESTS. WE HYPOTHESIZE THAT PATIENTS RECEIVING INTEGRATED TREATMENT REGIMENS WILL EXHIBIT BETTER OUTCOMES, SUCH AS LOWER RATES OF ALCOHOL INTOXICATION AND OPIOID OVERDOSE, IMPROVED LIVER FUNCTION, REDUCED HOSPITALIZATION, AND ALLEVIATED MENTAL HEALTH SYMPTOMS. THE SECOND AIM IS TO IDENTIFY DEMOGRAPHIC, RACIAL, AND CLINICAL FACTORS THAT PREDICT ADHERENCE TO TREATMENT REGIMENS IN PATIENTS WITH CO-OCCURRING OUD AND AUD. WE WILL EXAMINE THE CONSISTENCY OF MEDICATION ORDERS, THE DURATION AND DOSAGE CONSISTENCY OF PRESCRIBED TREATMENTS, AND THE ALIGNMENT OF MEDICATION ORDERS WITH CLINICAL APPOINTMENTS. OUR HYPOTHESIS IS THAT SPECIFIC DEMOGRAPHIC AND CLINICAL CHARACTERISTICS WILL SIGNIFICANTLY INFLUENCE TREATMENT ADHERENCE, WITH VARIATIONS OBSERVED ACROSS DIFFERENT PATIENT GROUPS. THE THIRD AIM IS TO INVESTIGATE THE IMPACT OF STABLE AND CONSISTENT COMPREHENSIVE TREATMENT ENGAGEMENT ON LONG-TERM RECOVERY OUTCOMES IN INDIVIDUALS WITH CO-OCCURRING OUD AND AUD. WE WILL MEASURE RELAPSE RATES AND DURATIONS OF ABSTINENCE, HYPOTHESIZING THAT PATIENTS WHO DEMONSTRATE STABLE AND CONSISTENT ENGAGEMENT IN THEIR TREATMENT PROCESS WILL EXHIBIT LOWER RELAPSE RATES AND LONGER DURATIONS OF ABSTINENCE. THIS RESEARCH IS INNOVATIVE IN ITS APPROACH TO LEVERAGING A NATIONAL DATABASE TO ADDRESS THE COMPLEXITIES OF CO-OCCURRING OUD AND AUD. IT IS PARTICULARLY INNOVATIVE IN EXPLORING GLP-1 RA AS A POTENTIAL THERAPEUTIC AGENT IN THE TREATMENT OF THESE CO-OCCURRING DISORDERS. BY INTEGRATING THIS NOVEL APPROACH WITH TRADITIONAL PHARMACOTHERAPIES AND EVALUATING ITS EFFECTIVENESS USING A LARGE-SCALE NATIONAL DATABASE, THIS STUDY AIMS TO CONTRIBUTE SIGNIFICANTLY TO ADDICTION MEDICINE. THE FINDINGS HAVE THE POTENTIAL TO INFORM CLINICAL PRACTICE AND PUBLIC HEALTH POLICY, LEADING TO MORE EFFECTIVE AND PERSONALIZED TREATMENT STRATEGIES FOR INDIVIDUALS AFFECTED BY THESE DISORDERS. ULTIMATELY, THIS RESEARCH WILL PROVIDE EMPIRICAL EVIDENCE TO GUIDE THE DEVELOPMENT OF NEW CLINICAL GUIDELINES OR UPDATES TO EXISTING PROCEDURES AND POLICIES IN TREATING CO-OCCURRING OUD AND AUD.