Commonspirit Health

NEUROBIOLOGY OF MILD COGNITIVE IMPAIRMENT IN THE ELDERLY

CIRI ONCOLOGY RESEARCH ALLIANCE (CORA)

PATHOGENESIS OF VASCULAR MALFORMATIONS IN HEREDITARY HEMORRHAGIC TELANGIECTASIA: FROM DISEASE MECHANISM TO NEW THERAPIES

IMAGING BIOMARKERS OF NEUROTOXICITY IN WELDERS

MICROGLIA CONTRIBUTION TO DISEASE PATHOGENESIS IN C9ORF72 ALS/FTD - PROJECT ABSTRACT THE ROLE OF MICROGLIA IN THE C9ORF72 (C9) AMYOTROPHIC LATERAL SCLEROSIS (ALS)/ FRONTOTEMPORAL DEMENTIA (FTD) DISEASE SPECTRUM REMAINS POORLY UNDERSTOOD. EARLY INVESTIGATIONS FOUND THAT MICROGLIA ACTIVATION WAS SIGNIFICANTLY HIGHER IN ALS WITH DEMENTIA AND IMPAIRED EXECUTIVE FUNCTION, SUGGESTING THAT MICROGLIA ACTIVATION CORRELATES WITH FTD-LIKE SYMPTOMS IN ALS. MORE RECENT NEUROPATHOLOGIC EXAMINATIONS OF MICROGLIA IN FTLD PATIENT AUTOPSY BRAINS WITH MUTATIONS IN PROGRANULIN VERSUS C9ORF72 CONCLUDED THAT THE OBSERVED MICROGLIA DYSFUNCTION WAS DIFFERENT BETWEEN THE TWO GENETICALLY DIFFERENT PATIENT SUBGROUPS SUGGESTING SPECIFICITY OF MICROGLIA DYSFUNCTION DEPENDING ON THE ETIOLOGY OF THE PATIENT POPULATION. ONE INTERESTING ASPECT OF MICROGLIA- NEURON COMMUNICATION IS THE ROLE OF MICROGLIA IN THE MAINTENANCE AND REFINEMENT OF SYNAPTIC NETWORKS THROUGH THE SELECTIVE PRUNING OF SYNAPSES, WHICH OCCURS PREDOMINANTLY DURING DEVELOPMENT BUT HAS BEEN SHOWN TO ALSO BE TRIGGERED IN ALZHEIMER'S DISEASE (AD) AND RELATED DEMENTIAS, INCLUDING FTD. THE DEGREE OF SYNAPSE LOSS IN AD STRONGLY CORRELATES WITH COGNITIVE DECLINE, EVEN MORE THAN THE AMOUNT OF PLAQUE, TANGLES OR NEURONAL LOSS, AND A RECENT STUDY OF ALS POSTMORTEM TISSUE CONFIRMED INCREASED SYNAPSE LOSS IN THE PREFRONTAL CORTEX OF PATIENTS WITH REPORTED COGNITIVE IMPAIRMENTS. OUR LABORATORY HAS PRELIMINARY DATA SUPPORTING THE HYPOTHESIS THAT THERE IS AN ALTERED NEURAL-IMMUNE INTERACTION IN THE CORTICAL FOREBRAIN REGIONS OF C9ORF72 PATIENTS WITH CONFIRMED FTD IN WHICH MICROGLIA AND NEURONS MODIFY EACH OTHER'S FUNCTION. USING PATIENT-DERIVED HIPSC MICROGLIA AND CORTICAL NEURONS, WE ARE ABLE TO SHOW THAT C9 PATIENT-DERIVED HIPSC MICROGLIA MONO-CULTURES DO HAVE INTRINSIC PHENOTYPES, INCLUDING ALTERED GENE PROFILES, PHAGOCYTIC ACTIVITIES AND LYSOSOMAL FUNCTION. MOST INTERESTINGLY, PRELIMINARY DATA SUGGESTS THAT C9 MICROGLIA DO REGULATE NEURONAL EXCITABILITY AND SURVIVAL OF C9 IPSC NEURONS. TO FURTHER INVESTIGATE THE ROLE AND CONTRIBUTION OF MICROGLIA IN C9 CORTICAL DEGENERATION, WE PROPOSE TO THOROUGHLY INVESTIGATE THE INTRINSIC PROPERTIES OF C9 HIPSC-MICROGLIA (FROM ALL PATIENT SUBGROUPS: FTD, FTD/ALS, ALS; AIM1). FOR THE FIRST TIME, WE WILL THEN CO-CULTURE THESE MICROGLIA WITH C9 AND HEALTHY CONTROL HIPSC CORTICAL NEURONS TO BETTER UNDERSTAND THE CO-REGULATION BETWEEN THESE TWO CELL TYPES (AIM 2). FINALLY, IN THE THIRD AIM, WE WILL STUDY MICROGLIA ACTIVATION AND PATHOLOGY IN C9 PATIENT POSTMORTEM AUTOPSY TISSUE. THIS WILL INCLUDE CELL-TYPE SPECIFIC GENETIC PROFILING FROM EXISTING SNRNA SEQ DATA SETS, IMMUNOHISTOCHEMISTRY OF MICROGLIOSIS AND MULTI-LABEL IMMUNOSTAINING FOR MICROGLIAL-SPECIFIC CANDIDATE GENES/PROTEINS IN CONJUNCTION WITH C9 NEURONAL DISEASE PATHOLOGY MARKERS (TDP-43 AND C9 DPRS) TO GAIN NOVEL KNOWLEDGE ON WHETHER MICROGLIA ARE PREFERENTIALLY ALTERED IN CLOSE VICINITY TO NEURONAL PATHOLOGIES.

ACCOUNTABLE HEALTH COMMUNITIES, TRACK 3DIGNITY SJHMC 2MATCH PROJECT

RURAL MATERNITY AND OBSTETRICS MANAGEMENT STRATEGIES PROGRAM - CHI ST. VINCENT HOSPITAL HOT SPRINGS, 300 WERNER ST., HOT SPRINGS, AR 71913-6406; HOSPITAL: HTTPS://WWW.CHISTVINCENT.COM; PROJECT DIRECTOR: KATHY TAYLOR, DEVELOPMENT DIRECTOR, 501-680-5334, KATHY.TAYLOR503@COMMONSPIRIT.ORG; PROJECT TITLE: AR MOMS GOAL: ALL WOMEN OF CHILDBEARING AGE IN THE TARGET COUNTIES WILL HAVE ACCESS TO A COORDINATED CONTINUUM OF PREGNANCY SERVICES FROM PRE-CONCEPTION THROUGH POST-PARTUM CARE. REQUEST: YEAR 1: $999,356; YEAR 2: $999,204; YEAR 3: $996,490; YEAR 4: $999,702. NETWORK: AR MOMS IS A BROAD COLLABORATIVE OF ENTITIES WHO HAVE WORKED TOGETHER BUT NOT AS A FORMAL NETWORK. CHI ST. VINCENT HOSPITAL-HOT SPRINGS (STV HS) SERVES AS THE LEAD AGENCY AND APPLICANT. NETWORK MEMBERS INCLUDE 2 CAHS, 2 COMMUNITY HOSPITALS, 11 COUNTY HEALTH UNITS (PUBLIC HEALTH), A FQHC, A MEDICAID RURAL HEALTH CLINIC, THE STATE RURAL HEALTH PROGRAMS OFFICE, THE STATE MEDICAID OFFICE, AND ARKANSAS CHILDREN’S HOSPITAL. TARGET SERVICE AREA: ENTIRELY RURAL AR COUNTIES: CALHOUN, CLARK, COLUMBIA, DALLAS, HOT SPRING, HOWARD, MONTGOMERY, OUACHITA, PIKE, POLK AND SEVIER. TARGET POPULATION: THE 11 COUNTIES ARE HOME TO APPROXIMATELY 31,000 WOMEN OF CHILDBEARING AGE WITH AN ESTIMATED 5,500 BIRTHS OVER THE PAST THREE YEARS. TARGETED WOMEN HAVE MEDICAID OR NO INSURANCE AND HAVE HOUSEHOLD INCOMES BELOW $48,000. SEVEN COUNTIES ARE CLASSIFIED AS MATERNITY CARE DESERTS WITH NO MATERNITY CARE EXCEPT ON AN EMERGENCY BASIS. THIS RESULTS IN ONE-THIRD OF WOMEN RECEIVING NO PRENATAL CARE IN THE FIRST TRIMESTER AND MATERNAL MORTALITY NEAR THE WORST NATIONALLY. OPIOID AND NON-ALCOHOL USE DISORDER PLAGUE 30%-40% OF THE LOW-INCOME MOTHERS. CAPACITY TO SERVE RURAL UNDERSERVED POPULATIONS: STV HS HAS SERVED 18 SOUTHWESTERN ARKANSAS COUNTIES FOR MORE THAN 130 YEARS; PROJECT COUNTIES ARE A SUBSET OF THE SERVICE REGION. ALL OTHER HEALTHCARE PARTNERS EXCEPT THE CHILDREN’S HOSPITAL ARE LOCATED IN THE TARGETED RURAL COUNTIES AND SERVE THEIR RURAL CONSTITUENTS’ PRIMARY AND PREVENTI ON CARE NEEDS. PROJECT ACTIVITIES FOCUS ON IN-FILLING THE MATERNAL CARE CONTINUUM, OFFERING LOCAL ACCESS AND KEEPING MOTHERS CLOSE TO HOME. THIS LOWERS FAMILY CHILDCARE, TRANSPORTATION AND ECONOMIC BARRIERS. REGIONALLY, PROVIDING LOCAL CARE DECREASES THE PERCENTAGE OF WOMEN DEEMED HIGH-RISK AND AUTOMATICALLY REFERRED AND TRANSPORTED TO URBAN HOSPITALS FOR PRENATAL AND LABOR/DELIVERY SERVICES. TELEHEALTH ACCESS IS SPOTTY WITH ONLY 66% OF RESIDENTS ABLE TO ACCESS THE INTERNET. MOBILE THRIVE TEAMS WILL PROVIDE THE LOCAL MATERNAL CARE AS THE REGION WORKS TOWARDS INCREASED TELEHEALTH CAPACITY. COMMON REFERRAL, INFORMATION SHARING, AND CONFIDENTIALITY PROTOCOLS WILL BE ESTABLISHED BY THE NETWORK PARTNERSHIP. DATA LIAISONS AT EACH RURAL SITE PLUS THE PROJECT’S DATA COORDINATOR WILL ENSURE COMPREHENSIVE DATA CAPTURE. EXPECTED OUTCOMES: 1) AT LEAST 550 WOMEN WILL EXPERIENCE INCREASED ACCESS TO PREGNANCY, POSTPARTUM SUPPORTS AND RISK APPROPRIATE CARE IN THEIR COUNTY OF RESIDENCE. 3) AT LEAST 30 WOMEN, WHO WOULD HAVE PREVIOUSLY BEEN REFERRED OUT OF THEIR COMMUNITY FOR HIGH RISK OBSTETRIC CARE (?28 WEEKS GESTATION), ARE ABLE TO ACCESS LOCAL RISK APPROPRIATE OBSTETRIC CARE UNTIL AT LEAST 32 WEEKS GESTATION. 4) THE REGION WILL EXPERIENCE INCREASED ACCESS TO OBSTETRIC CARE THROUGH SERVICE COORDINATION AND IMPROVED TELEMEDICINE LINKS. 5) DECREASED HIGH-RISK PREGNANCY RATES WILL YIELD COST SAVINGS THAT, COMBINED WITH REGIONAL STRATEGIES, CAN BE REINVESTED IN THE CARE CONTINUUM TO SUSTAIN ACCESSIBLE RURAL SERVICES. FUNDING PREFERENCE: CHI ST. VINCENT HOSPITAL HOT SPRINGS REQUESTS A FUNDING PREFERENCE BASED ON QUALIFICATION 1 – HPSA WITH ALL 11 TARGETED COUNTIES DESIGNATED HPSA. SPECIAL CONSIDERATION: CHI ST. VINCENT HOSPITAL HOT SPRINGS IS REQUESTING SPECIAL CONSIDERATION BASED ON THE INCLUSION OF A SIGNED MOU WITH THE ARKANSAS STATE MEDICAID AGENCY INCLUDED IN ATTACHMENT 14.

MRI ASSESSMENT OF TUMOR PERFUSION, PERMEABILITY AND CELLULARITY

CELLULAR AND MOLECULAR MEDIAL TEMPORAL LOBE PATHOLOGY IN ELDERLY PREMCI SUBJECTS

ALLOANTIBODIES TO MHC INDUCES AUTOIMMUNITY AND OBLITERATIVE AIRWAY DISEASE (OAD)

NOVEL PET MARKERS OF COGNITIVE IMPAIRMENT IN MANGANESE NEUROTOXICITY

A TRANSLATIONAL EVALUATION OF SUR1-TRPM4 IMAGING ENDOPHENOTYPES AND GENETICS TO DIRECT PRECISION MEDICINE FOR CEREBRAL EDEMA AFTER TRAUMATIC BRAIN INJURY - FOR DECADES, THERE HAS BEEN A CRITICAL GAP IN TRANSLATING PRECLINICAL WORK ON MECHANISMS OF CEREBRAL EDEMA IN TRAUMATIC BRAIN INJURY (TBI) TO CLINICALLY AVAILABLE TARGETED THERAPIES THAT IMPROVE OUTCOME. THIS IS IMPORTANT BECAUSE CEREBRAL EDEMA MANAGEMENT COMMANDS SUBSTANTIAL CLINICAL AND FINANCIAL RESOURCES IN SEVERE TBI, YET IT REMAINS A COMMON CAUSE OF DEATH AND DISABILITY. CURRENT TREATMENTS ARE INDISCRIMINATE, REACTIONARY AND MORBID - NONE IMPROVE OUTCOME. GUIDELINE-BASED PROTOCOLS USE A TEMPLATED APPROACH TO THIS IMMENSELY COMPLEX PROCESS WITHOUT ADDRESSING INDIVIDUAL DIFFERENCES IN CONTRIBUTORY PATHWAYS OR EDEMA ENDOPHENOTYPES. THE LONG -TERM GOAL IS TO HARNESS RELEVANT INDIVIDUAL DATA (GENETIC, MOLECULAR, IMAGING, PHYSIOLOGIC) TO DIRECT A PRECISION MEDICINE APPROACH TO TREAT TBI EDEMA AND RELATED CONTUSION EXPANSION. THIS R01 FOCUSES ON LOGICAL NEXT STEPS TO ADDRESS EXISTING KNOWLEDGE GAPS IN A UNIQUE, KEY EDEMA PATHWAY INVOLVING SULFONYLUREA RECEPTOR-1 (SUR1) AND ITS REGULATED CATION CHANNEL TRPM4. PROMISING RESULTS FROM SUR-1 INHIBITION (GLYBURIDE, GLY) IN PRECLINICAL AND EARLY CLINICAL BRAIN INJURY TRIALS HAVE GENERATED EXCITING MOMENTUM IN THIS PATHWAY. THE OBJECTIVE OF THIS TRANSLATIONAL R01 IS TO DEFINE THE IMPACT OF SUR1-TRPM4 RELATED GENETIC AND PROTEIN VARIABILITY ON DIFFERENT EDEMA ENDOPHENOTYPES, CONTUSION GROWTH AND RESPONSE TO INHIBITION IN PRECLINICAL AND HUMAN TBI. THE RATIONALE IS THAT IDENTIFYING THESE INDIVIDUAL DIFFERENCES DIRECTLY INFORMS PATIENT RISK-STRATIFICATION, PROGNOSIS, TRIAL DESIGN, AND TARGETED THERAPY; ULTIMATELY IMPROVING OUTCOME. THE CENTRAL HYPOTHESIS IS THAT SUR1 PROTEIN EXPRESSION AND GENETIC VARIABILITY INFLUENCE THE ENDOPHENOTYPE, EXTENT, AND THERAPEUTIC RESPONSE OF TBI EDEMA. AIM 1 DEFINES CORRELATIONS BETWEEN SUR1-TRPM4 EXPRESSION AND MRI EDEMA ENDOPHENOTYPES IN THREE CLINICALLY RELEVANT COMPLEMENTARY MOUSE MODELS. AIM 2 TESTS EFFECTS OF SUR1 INHIBITION (GLY, INDUCIBLE KNOCKOUT) IN THESE MODELS ON MRI EDEMA ENDOPHENOTYPES, CONTUSION, AND OUTCOME. AIM 3 IDENTIFIES IMPACT OF GENETIC VARIATION IN THE SUR1 PATHWAY ON TBI EDEMA AND CONTUSION GROWTH (ON IMAGING) IN A SINGLE-CENTER HUMAN TEST-COHORT, AND A MULTICENTER VALIDATION-COHORT. THE WORK IS FEASIBLE AS SHOWN BY ROBUST PRELIMINARY RESULTS AND THE TOOLS, EXPERTISE AND TRACK RECORD OF SUCCESSFUL COLLABORATIONS AMONG COINVESTIGATORS. THIS WORK IS INNOVATIVE IN CONCEPT AND METHODOLOGY: IT SHIFTS A GUIDELINE-BASED PARADIGM TOWARD PRECISION MEDICINE, LINKS CLINICALLY MEASURABLE EDEMA ENDOPHENOTYPES (MRI) WITH A MOLECULAR PATHWAY AND TARGETED INHIBITION IN DIFFERENT TBI MODELS, AND USES A NOVEL TRANSGENIC MOUSE TO GENERATE SUR1-TRPM4 EXPRESSION MAPS. THIS RESEARCH IS SIGNIFICANT, WITH HIGH IMPACT IF SUCCESSFUL: LINKING SUR1-TRPM4 EXPRESSION AND INHIBITION TO MRI ENDOPHENOTYPES (AIMS 1-2) DIRECTLY TRANSLATE TO IDENTIFYING APPROPRIATE PATIENTS FOR TARGETED THERAPY AND TRIALS. DISTINGUISHING HIGH VS LOW RISK GENETIC PROFILES (AIM-3) WILL IDENTIFY PATIENTS IN WHOM SUR1-TRPM4 IS A MAJOR CONTRIBUTOR TO TBI EDEMA AND CONTUSION GROWTH, AND CHANNEL INHIBITION MAY BE HIGHLY BENEFICIAL- DIRECTING CLINICAL CARE AND TRIALS. ULTIMATELY, SUCH KNOWLEDGE HAS THE POTENTIAL TO TRANSFORM PRECISION-MEDICINE CARE OF THIS DEVASTATING SECONDARY INJURY AND IMPROVE TBI OUTCOME.

MANGANESE-INDUCED NEUROTOXIC EFFECTS RESEARCH IN SOUTH AFRICA (MINERS)

DIGNITY HEALTH ST JOSEPH'S BEHAVIORAL HEALTH CENTER MAT PDOA PROGRAM - COMMONSPIRIT HEALTH'S ST. JOSEPH'S BEHAVIORAL HEALTH CENTER (SJBHC) WILL EXPAND MEDICATION-ASSISTED TREATMENT (MAT) FOR RESIDENTS OF STOCKTON IN CALIFORNIA'S CENTRAL VALLEY IN SAN JOAQUIN COUNTY. 5,000 COMMUNITY MEMBERS WILL BE REACHED AND 475 ADULTS WITH OPIOID USE DISORDER (OUD), INCLUDING PROBATIONERS AND PAROLEES, WILL RECEIVE MAT TREAMENT AND RECOVERY SERVICES OVER THE 5-YEAR GRANT PERIOD; 50% WILL REDUCE ILLICIT AND PRESCRIPTION OPIOID USAGE. COMMONSPIRIT HEALTH (CSH) IS ONE OF THE NATION'S LARGEST NONPROFIT HEALTH SYSTEMS. FORMED WITH THE MERGER OF CATHOLIC HEALTH INITIATIVES (CHI) AND DIGNITY HEALTH IN 2019, IT IS COMPRISED OF 137 HOSPITALS AND MORE THAN 1,000 CARE CENTERS IN 21 STATES, SERVING 20 MILLION PATIENTS ANNUALLY. OUR PATIENT POPULATION REFLECTS THE GEOGRAPHIC, ETHNIC AND SOCIO-ECONOMIC DIVERSITY OF THE AMERICAN "MELTING POT". A VISIONARY LEADER IN HEALTHCARE, CSH IS SHIFTING ITS CARE PARADIGM FROM AN EMPHASIS ON CARING FOR THE SICK CARE TO A MISSION OF PREVENTING ILLNESS, ACHIEVING HEALTH EQUITY, AND ADVOCATING FOR SOCIAL JUSTICE. IN 2018, 11 EMERGENCY DEPARTMENTS (EDS) IN THE CSH SYSTEM BECAME ACCESS POINTS FOR MAT, AN INNOVATIVE COMBINATION OF FDA-APPROVED OPIOID AGONIST MEDICATIONS - METHADONE, BUPRENORPHINE , NALTREXONE - AND BEHAVIORAL HEALTH SERVICES AND COUNSELING. AS A RESULT OF THE PROGRAM'S SUCCESS, CSH HAS SINCE EXPANDED MAT TO 25 OUT OF THE SYSTEM'S 30 CALIFORNIA EDS IN 2021. WITH SAMHSA FUNDING, THE ACCESS MAT PROJECT WILL PROVIDE MAT AND RECOVERY SERVICES TO ADULTS, 18 AND OVER: 50 IN YEAR 1, 100 IN YEAR 2, 125 IN YEAR 3, AND 150 IN YEARS 4 AND 5. 10-20% OF CLIENTS WILL BE FORMERLY INCARCERATED. ACCESS MAT WILL STRENGTHEN THE LINK BETWEEN MAT, COUNSELING, AND RECOVERY SERVICES AT SJBHC AND ST. JOSEPH'S MEDICAL CENTER EMERGENCY DEPARTMENT'S EMBEDDED MAT PROGRAM. IMPORTANTLY, ACCESS MAT WILL INITIATIVE OUTREACH AND ENGAGEMENT IN THE COMMUNITY, AND WORK WITH SAN JOAQUIN COUNTY CORRECTIONAL HEALTH CARE AND OTHER CORRECTIONAL FACILITIES TO SUPPORT TREATMENT FOR INMATES WITHIN 4 MONTHS OF RELEASE. CSH ST. JOSEPH'S BEHAVIORAL HEALTH CENTER WILL IMPLEMENT ALL REQUIRED ACTIVITIES IN ORDER TO: 1. INCREASE THE NUMBER OF INDIVIDUALS WITH OUD RECEIVING MAT AT SJBHC 2. TRIPLE THE NUMBER OF X-WAIVERED CLINICIANS AT ST. JOSEPH'S MEDICAL CENTER 3. DECREASE ILLICIT OPIOID DRUG USE AND PRESCRIPTION OPIOID MISUSE AMONG PARTICIPANTS 4. CREATE A MAT PIPELINE FOR INCARCERATED ADULTS WITH OUD WHO ARE WITHIN FOUR MONTHS OF RELEASE AND OTHER HARD TO REACH, DIVERSE POPULATIONS IN THE CENTRAL VALLEY 5. SUSTAIN NEW SYSTEM INNOVATIONS AND ROLL THEM OUT TO OTHER SITES AFTER THE GRANT PERIOD BASED ON SJBHC'S 40 YEAR HISTORY OF TREATMENT FOR INDIVIDUALS WITH SUBSTANCE USE DISORDERS, WE ANTICIPATE THAT 50% OF INDIVIDUALS ENROLLED IN THE PROGRAM WILL ACHIEVE SOBRIETY FROM OPIOIDS AND COMPLETE THE COURSE OF TREATMENT AND THAT 50% OF THESE WILL SUCCESSFULLY TAPER OFF THEIR MEDICATION WITHIN 3-6 MONTHS.

ROLES OF AGING AND CELLULAR SENESCENCE IN THE DEVELOPMENT OF INTRACRANIAL ANEURYSM RUPTURE - PROJECT SUMMARY CLINICAL STUDIES HAVE CONSISTENTLY SHOWN A STRONG ASSOCIATION BETWEEN AGING AND INCREASED RISK FOR INTRACRANIAL ANEURYSM RUPTURE. AGING HAS TRADITIONALLY BEEN CONSIDERED A NON-MODIFIABLE RISK FACTOR. HOWEVER, IT IS BECOMING EVIDENT THAT SOME OF THE BIOLOGICAL CHANGES ASSOCIATED WITH AGING CAN BE MODIFIABLE OR PARTIALLY REVERSIBLE. THUS, PHARMACOLOGICAL THERAPIES TARGETING AGE-RELATED BIOLOGICAL EVENTS MAY BE UTILIZED TO PREVENT ANEURYSMAL RUPTURE. AGING INDUCES DIVERSE CHANGES IN CELLULAR HOMEOSTASIS. ONE OF THE HALLMARKS OF AGING IS CELLULAR SENESCENCE, A STATE OF PERMANENT PROLIFERATIVE ARREST. SENESCENT CELLS SECRETE PRO-INFLAMMATORY AND TISSUE REMODELING CYTOKINES COLLECTIVELY CALLED THE "SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE" (SASP). IN ADDITION TO AGING, CELLULAR STRESSES INDUCED BY INFLAMMATION, REACTIVE OXYGEN SPECIES, MITOCHONDRIAL DYSFUNCTION, AND HEMODYNAMIC STRESSES CAUSE "PREMATURE, PATHOLOGICAL SENESCENCE" IN BOTH YOUNG AND AGED INDIVIDUALS. THUS, WE HYPOTHESIZE THAT EXCESSIVE SENESCENT CELL BURDEN COLLECTIVELY CAUSED BY AGE-RELATED AND PREMATURE SENESCENCE MAY PROMOTE ANEURYSMAL RUPTURE THROUGH SASP-INDUCED INFLAMMATION, TISSUE REMODELING, AND TISSUE DAMAGE. WE WILL TEST WHETHER THE ELIMINATION OF SENESCENT CELLS PREVENTS ANEURYSMAL RUPTURE. IN ADDITION, WE WILL IDENTIFY A RUPTURE-PROMOTING SASP PROFILE USING A PROTEOMIC APPROACH. AIM 1 IS TO TEST WHETHER AGING PROMOTES ANEURYSM RUPTURE WHILE INCREASING THE TOTAL SENESCENT CELL BURDEN. USING A MOUSE OF ANEURYSM, WE WILL ESTABLISH THE LINK BETWEEN AGING AND THE PROMOTION OF ANEURYSM RUPTURE IN BOTH SEXES. WE WILL ALSO ASSESS POTENTIAL SEX DIFFERENCES IN SENESCENCE AND THEIR CONTRIBUTIONS TO ANEURYSM RUPTURE. AIM 2 IS TO TEST WHETHER CELLULAR SENESCENCE PROMOTES ANEURYSM RUPTURE. WE UTILIZE PHARMACOLOGICAL AND TRANSGENE-MEDIATED “SENOLYTIC” APPROACHES TO ESTABLISH THE CAUSAL LINK BETWEEN CELLULAR SENESCENCE AND ANEURYSM RUPTURE. WE WILL EMPLOY (2A) A PROTOTYPICAL SENOLYTIC DRUG, ABT263 AND (2B) TRANSGENE-MEDIATED SENOLYSIS OF P16-3MR MICE. IN ADDITION, WE WILL ASSESS THE RELATIVE CONTRIBUTION BETWEEN AGE-RELATED SENESCENCE AND STRESS-INDUCED PREMATURE SENESCENCE. AIM 3 IS TO IDENTIFY RUPTURE-PROMOTING SASP PROFILE AND ESTABLISH A SCREENING PLATFORM FOR FUTURE STUDIES. 3A. BY APPLYING PROTEOMICS TO THE CEREBRAL ARTERIES FROM AIMS 1 AND 2, WE WILL IDENTIFY A RUPTURE-PROMOTING SASP PROFILE. 3B. WE WILL IDENTIFY THE CELL TYPE THAT PRODUCES RUPTURE-PROMOTING SASPS. USING THE DATA FROM 3A AND 3B, WE WILL ESTABLISH AN "IN VITRO TO IN VIVO" SCREENING PLATFORM FOR TESTING EXISTING SENOLYTICS AND SENOMORPHS. 3C. WE WILL VALIDATE THE SCREENING PLATFORM AND KEY RUPTURE-PROMOTING SASPS. THIS PROPOSAL SEEKS TO ESTABLISH THE CAUSAL LINKS BETWEEN AGING, SENESCENCE, AND ANEURYSMAL RUPTURE. THE SCREENING PLATFORM DEVELOPED IN THIS PROPOSAL WILL BE USED TO TEST EXISTING SENOLYTICS AND SENOMORPHS FOR PREVENTING ANEURYSMAL RUPTURE IN FUTURE STUDIES.

AN INTEGRATIVE COMPUTATIONAL MULTIMODAL APPROACH TO DISENTANGLE PATHOPHYSIOLOGIC HETEROGENEITY OF AGE-RELATED WHITE MATTER HYPERINTENSITIES - ABSTRACT WHITE MATTER HYPERINTENSITIES (WMH) ARE AN IMPORTANT FACTOR IN THE OCCURRENCE AND PROGRESSION OF STROKE, COGNITIVE DECLINE, AND DEMENTIA IN THE AGING POPULATION, BUT POSE A PUZZLING CHALLENGE IN EVALUATIONS OF BRAIN HEALTH AND DISEASE DUE TO ITS UNDERLYING PATHOLOGIC HETEROGENEITY. WHILE WMH ARE FREQUENTLY CONSIDERED AS A CONSEQUENCE OF CEREBRAL SMALL-VESSEL DISEASE (CSVD), EMERGING EVIDENCE SUGGEST WMH MAY ALSO ARISE FROM NON-VASCULAR PROCESSES INCLUDING ALZHEIMER’S DISEASE (AD)-RELATED NEURODEGENERATION OR NEUROINFLAMMATION. UNDERSTANDING THE MULTIFACTORIAL ETIOLOGIES OF WMH IS CRITICAL FOR DEVELOPMENT OF MUCH NEEDED THERAPIES AND PREVENTATIVE STRATEGIES, ESPECIALLY GIVEN ITS HIGH PREVALENCE IN OLDER COMMUNITY PERSONS. HOWEVER, COMMONLY USED ASSESSMENT METHODS BASED ON GLOBAL SEVERITY BURDEN FAIL TO ADDRESS SUCH HETEROGENEITY. WMH SPATIAL PATTERNS IS A NOVEL PHENOTYPE THAT CAN BE EXTRACTED FROM STRUCTURAL MRI DATA USING ADVANCED PATTERN ANALYSIS METHODS THAT CAPITALIZES ON VARIABILITY IN WMH TOPOGRAPHY ACROSS DIFFERENT DISEASES. WE PREVIOUSLY SHOW THAT MACHINE LEARNING (ML)-DERIVED SPATIAL PATTERNS OF WMH MORE PRECISELY CAPTURE THE UNDERLYING HETEROGENEITY IN WMH PATHOLOGY COMPARED TO STANDARD REGION OR LOBAR- BASED CLASSIFICATIONS. DISTINCT ML-DERIVED WMH SPATIAL PATTERNS HAVE UNIQUE ASSOCIATIONS WITH DIFFERENT WMH ETIOLOGIES, DISTINGUISHING BETWEEN WMH ARISING FROM CSVD SUBTYPES (CEREBRAL AMYLOID ANGIOPATHY VS. HYPERTENSIVE), AD, AND NORMAL AGING. WE HYPOTHESIZE THAT FOCUSING ON ML-DERIVED WMH SPATIAL PATTERNS WILL GREATLY EXPAND THE DISCOVERY OF GENETIC CONTRIBUTIONS TO WMH, LEADING TO BETTER UNDERSTANDING OF THE MOLECULAR BASIS OF WMH AND DEVELOPMENT OF MECHANISM-BASED TREATMENTS. TO THIS END, WE WILL LEVERAGE EXISTING NEUROIMAGING AND GENETIC DATA RESOURCES FROM 7 COHORTS ENRICHED FOR DIVERSE CONDITIONS WITH HIGH WMH PREVALENCE (N=4,872) AS THE DISCOVERY COHORT, AND THE UK BIOBANK (UKB, N>60,000) REPRESENTING THE GENERAL POPULATION. THIS WILL ALLOW US TO DERIVE DISTINCT, DISEASE-SPECIFIC WMH SPATIAL PATTERNS FROM NEUROIMAGING DATA USING MACHINE LEARNING, EXAMINE THEIR BIOLOGICAL CORRELATION WITH VASCULAR AND AMYLOID- RELATED TRAITS, AND EVALUATE RELEVANCE OF ML-DERIVED WMH SPATIAL PATTERNS FOR PREDICTING LONG-TERM DEVELOPMENT OF STROKE OR DEMENTIA (AIM 1). WE WILL INTEGRATE MOLECULAR QUANTITATIVE TRAIT LOCI (QTL) DATA INTO GENOME-WIDE ASSOCIATION ANALYSIS (GWAS) OF ML-DERIVED WMH SPATIAL PATTERNS TO PRIORITIZE IDENTIFICATION OF CAUSAL, FUNCTIONALLY ACTIVE GENES (AIM 2). WE WILL PERFORM GENOMICS-DRIVEN DRUG DISCOVERY USING MENDELIAN RANDOMIZATION (MR) TO IDENTIFY THERAPEUTIC TARGETS RELEVANT TO WMH (AIM 3). THIS PROJECT LEVERAGES THE COMBINED EXPERTISE OF THE PI AND ASSEMBLED TEAM IN NEUROIMAGING, GENOMICS, AND INFORMATICS. COMPLETION OF PROJECT AIMS WILL GREATLY ADVANCE OUR UNDERSTANDING OF GENETIC CONTRIBUTIONS TO WMH, PROVIDING NOVEL MECHANISTIC INSIGHTS INTO THE ROLE OF WHITE MATTER LESIONS IN BRAIN HEALTH, ACCELERATE THERAPEUTIC DISCOVERY BY IDENTIFICATION OF DRUG REPOSITIONING OPPORTUNITIES, AND LAY THE GROUNDWORK FOR PERSONALIZED DIAGNOSIS AND CARE BY DISENTANGLING THE HETEROGENOUS NATURE OF WMH AT THE INDIVIDUAL LEVEL.

ASSESSMENT OF LENALIDOMIDE TO TREAT ALZHEIMER'S DISEASE

EGF-ADAM17 AXIS IN THE PATHOPHYSIOLOGY OF INTRACRANIAL ANEURYSM

ALPHA-SYNUCLEIN AGGREGATION DISRUPTS MOTILITY, SYNAPTIC TRANSMISSION, AND CALCIUM SIGNALING IN THE MYENTERIC PLEXUS OF THE RAT COLON

REPURPOSING SIPONIMOD FOR ALZHEIMER'S DISEASE - SUMMARY/ABSTRACT REPURPOSING SIPONIMOD FOR ALZHEIMER’S DISEASE ALZHEIMER’S DISEASE (AD) IS A NEURODEGENERATIVE DISORDER WITH SEVERAL COMPLEX NEUROPATHOLOGIES SUSPECTED TO DEVELOP SEQUENTIALLY BUT THAT OVERLAP OVER TIME AS SYMPTOMS PROGRESS TO DEMENTIA. THUS, TO BE EFFECTIVE, FUTURE INTERVENTION STRATEGIES WILL LIKELY REQUIRE COMBINATION THERAPIES OR PLEIOTROPIC AGENTS TO TACKLE SEVERAL AD MOLECULAR PATHOGENIC PATHWAYS SIMULTANEOUSLY. FOR MORE THAN A DECADE, OUR GROUP HAS BEEN EXPLORING THE REPURPOSING OF IMMUNOMODULATORS FOR AD. RECENT DISCUSSIONS WITH COLLABORATORS SPECIALIZED IN MULTIPLE SCLEROSIS SUGGEST THAT SPHINGOSINE-1-PHOSPHATE RECEPTOR (S1PR) MODULATORS ARE STRONG CANDIDATES FOR REPURPOSING IN AD. INDEED, S1PR MODULATORS ARE BLOOD BRAIN BARRIER (BBB) PENETRANT AND DISPLAY PLEIOTROPIC ACTIONS, INCLUDING IMMUNOMODULATION AND NEUROPROTECTIVE PROPERTIES. S1P IS A VERSATILE ENDOGENOUS MOLECULE THAT REGULATES SEVERAL SIGNALING PATHWAYS BY BINDING TO FIVE G-PROTEIN-COUPLED RECEPTORS, WHICH ARE EXPRESSED IN HIGH LEVELS IN CARDIAC, VASCULAR, IMMUNE, AND BRAIN CELLS. THIS WIDESPREAD LOCALIZATION OF S1PR WAS THE HISTORICAL BASIS FOR NOVARTIS PHARMACEUTICALS, INC, TO DEVELOP ORAL FORMULATIONS OF S1PR MODULATORS FOR MULTIPLE SCLEROSIS (MS), WHICH PROVED SUCCESSFUL AND RESULTED IN TWO MARKETED COMPOUNDS. IN THE PRESENT PROJECT, WE INTEND TO COLLABORATE WITH NOVARTIS TO USE THE MOST RECENTLY FDA-APPROVED S1PR MODULATOR SIPONIMOD. BASED ON MS AND ANIMAL EXPERIMENTATION LITERATURE, WE HYPOTHESIZE THAT SIPONIMOD COULD LOWER THE RATE OF BRAIN ATROPHY IN AD SUBJECTS. IN THIS PHASE II, PROOF-OF-CONCEPT, RIGOROUS TRANSLATIONAL CLINICAL STUDY, MILD AD SUBJECTS WILL BE RANDOMIZED 2:1 AND RECEIVE A SLOW UP-TITRATION REGIMEN OF SIPONIMOD UP TO 1 MG/DAY (N=70) OR PLACEBO (N=35) FOR 12 MONTHS, FOLLOWED BY A 6-MONTH WASHOUT PERIOD. PRIMARY OBJECTIVES ARE DRUG SAFETY AND TOLERABILITY IN AD SUBJECTS ASSESSED VIA REGULAR CLINICAL TESTS THROUGHOUT THE DOSING PERIOD. CRITICALLY, EVENTUAL TREATMENT-EMERGENT TOXICITIES WILL DRIVE OUR GO/NO-GO DECISION PROCESS TO PURSUE OR STOP DOSING. THE SECONDARY OBJECTIVE IS TO DETERMINE DRUG EFFECT ON RELATIVE ANNUAL BRAIN ATROPHY RATES IN THE TWO GROUPS BY COMPARING PRE- AND POST- EXPOSURE VOLUMETRIC MRI DATA. TERTIARY OBJECTIVES ARE COGNITION AND CSF MARKERS OF AD (AMYLOID, TAU, P-TAU) AND INFLAMMATION. AS AN EXPLORATORY OBJECTIVE, WE WILL ALSO INVESTIGATE WHETHER BLOOD CELL COUNTS AND BLOOD BIOMARKERS CAN BE USED AS DYNAMIC SURROGATE MARKERS OF DRUG EFFICACY. BECAUSE SIPONIMOD HAS DEMONSTRATED POSITIVE IMMUNOMODULATORY AND NEUROPROTECTIVE ACTIONS IN MS, AND BECAUSE ITS TOXICITY PROFILE IS FAVORABLE FOR USE IN OLDER INDIVIDUALS, THIS DRUG HAS A STRONG POTENTIAL TO ALTER MARKERS OF AD PATHOLOGY AND DISEASE TRAJECTORY.

HYPOTHALAMIC NEUROCIRCUIT REMODELING TO TREAT DIABETES

CHRONIC LUNG ALLOGRAFT DYSFUNCTION: ROLE FOR TUMOR SUPPRESSOR LKB1 IN EXOSOMES - PROJECT SUMMARY/ABSTRACT LUNG TRANSPLANTATION (LTX) IS A THERAPEUTIC OPTION FOR PATIENTS WITH ADVANCED LUNG DISEASES. LONG-TERM SURVIVAL AFTER LTX IS, HOWEVER, LIMITED BY CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD). CLAD MOST COMMONLY MANIFESTS ITSELF AS BRONCHIOLITIS OBLITERANS SYNDROME (BOS) AND ABOUT 50% OF RECIPIENTS (LTXRS) WILL DEVELOP BOS WITHIN 5 YEARS POST-LTX. EPITHELIAL-MESENCHYMAL-TRANSITION (EMT) AND FIBROSIS HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF BOS. WE DEMONSTRATED THAT LIVER KINASE 1 (LKB1), A TUMOR SUPPRESSOR GENE, IS DOWNREGULATED IN BOS BUT NOT IN STABLE BIOPSIES USING BOTH WESTERN BLOTTING AND ALDEHYDE BEAD CONJUGATED EXOSOMES BY FLOW CYTOMETRY. WE ALSO DEMONSTRATED THAT LKB1 KNOCKDOWN INDUCES EXOSOME RELEASE FROM AIRWAY EPITHELIAL CELL LINE, BEAS-2B, AND ANOTHER HUMAN AIRWAY EPITHELIAL CELL LINE, HPBEC. EXOSOMES RELEASED FROM LTXRS WITH BOS ALSO INDUCES EMT WHICH WAS REGULATED BY LKB1 IN BEAS-2B AND HPBEC. NANOSTRING ANALYSES IDENTIFIED LKB1 KNOCKDOWN INDUCED PDGFRSS EXPRESSION IN HUMAN AIRWAY EPITHELIAL CELLS. WE ALSO DEMONSTRATED THAT BIOPSIES FROM BOS LTXRS HAD REDUCED LKB1 AND INCREASED PDGFSSR WITH INVERSE CORRELATION. THESE NOVEL FINDINGS INDICATE AN IMPORTANT ROLE FOR THE TUMOR SUPPRESSOR GENE LKB1 IN THE REGULATION OF PDGFSSR AND, THEREFORE, FIBROSIS DEVELOPMENT. STUDIES PROPOSED USING BOTH CLINICAL SAMPLES AND IN VITRO CELL CULTURE MODEL, WE WILL DEFINE THE MECHANISM BY WHICH EXOSOMES WITH DOWNREGULATED LKB1 RELEASED FROM TRANSPLANTED LUNGS MEDIATE EMT LEADING TO CLAD. AIM 1 OF THE PROPOSAL IS TO DETERMINE SERIALLY WHETHER INACTIVATION OF LKB1 IN EXOSOMES ISOLATED FROM PLASMA FROM LTXRS WITH KNOWN RISK FACTORS (PRIMARY GRAFT DYSFUNCTION [PGD]), ACUTE REJECTION [AR] AND RESPIRATORY VIRAL INFECTIONS [RVI]) CAN BE USEFUL AS A NON- INVASIVE BIOMARKER FOR LTXRS AT RISK FOR CLAD. OUR HYPOTHESIS IS THAT PERSISTENT DOWNREGULATION OF LKB1 IN EXOSOMES WILL BE A BIOMARKER FOR LTXRS AT RISK FOR DEVELOPING CLAD. THE SECOND GOAL IS TO DETERMINE AND QUANTITATE EXOSOMES WITH LKB1/AMPK1 USING SERIAL RETROSPECTIVELY STORED PLASMA FROM LTXRS WITH KNOWN CLINICAL DIAGNOSIS WILL BE A MORE SENSITIVE MARKER FOR CLAD AND TO DETERMINE ITS POTENTIAL TO DIFFERENTIATE RESTRICTIVE ALLOGRAFT SYNDROME AND BOS BY DEFINING THEIR IMMUNOLOGICAL AND MOLECULAR PROPERTIES. OUR THIRD GOAL IS TO DEFINE THE MECHANISMS BY WHICH LOSS OF LKB1 RESULTS IN EMT AND UPREGULATION OF PDGFRSS AND PROMOTES THE PATHOGENESIS OF CLAD. TOWARDS THIS; A) WE WILL DEFINE THE REGULATORY MECHANISMS SUPPRESSING LKB1 IN LTXRS WITH PGD, AR AND RVI, RISK FACTORS FOR CLAD, AND B) WE WILL DETERMINE THE MECHANISMS BY WHICH LKB1 DOWNREGULATION LEADS TO UPREGULATION OF PDGFRSS AND ITS SIGNALING PATHWAYS WHICH CONTRIBUTES TOWARDS DEVELOPMENT OF FIBROSIS. RESULTS FROM THESE STUDIES WILL PROVIDE NOVEL INFORMATION FOR THE ROLE OF LKB1, IN EMT AND FIBROSIS RELATED PATHOLOGIES INCLUDING CLAD FOLLOWING LTX.

FUNDS WILL BE USED TO PROVIDE EMERGENCY FINANCIAL AID GRANTS TO STUDENTS FOR EXPENSES RELATED TO THE DISRUPTION OF CAMPUS OPERATIONS DUE TO CORONAVIRUS

MULTI-SCALE FUNCTIONAL CONNECTIVITY IN PRECLINICAL MODELS OF PARKINSON'S DISEASE - PROJECT SUMMARY / ABSTRACT: PARKINSON’S DISEASE IS A PROGRESSIVE NEURODEGENERATIVE DISORDER AND IS ASSOCIATED WITH SIGNIFICANT MOTOR AND NON-MOTOR SYMPTOMS, TRACEABLE TO THE LOSS OF NIGRAL DOPAMINE NEURONS IN ADDITION TO WIDESPREAD CIRCUIT DYSFUNCTION EXTENDING BEYOND THE DYING NIGROSTRIATAL TRACT. IMAGING-BASED BIOMARKERS PLAY A CRITICAL ROLE IN ASSESSING PARKINSON’S-RELATED PATHOLOGICAL CHANGES, BUT CURRENT BIOMARKERS ARE LIMITED IN THEIR DIAGNOSTIC AND PROGNOSTIC ABILITY, PARTICULARLY IN EARLY DISEASE STAGES WHEN INTERVENTION WOULD BE MOST BENEFICIAL. FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI) ENABLES THE STUDY OF BRAIN ACTIVATION AND HAS BEEN WIDELY USED TO STUDY GLOBAL FUNCTIONAL NETWORK CHANGES IN PARKINSON’S DISEASE. HOWEVER, STANDARD FMRI IS LIMITED IN ITS ABILITY TO ROBUSTLY MEASURE SUBTLE CHANGES WITH DISEASE, IN PART DUE TO LOW SENSITIVITY AND SPECIFICITY; FURTHERMORE, INTERPRETATION OF STANDARD FMRI IS CHALLENGING DUE TO THE INDIRECT LINK BETWEEN NEURONAL FUNCTION AND MRI SIGNAL CHANGE. THIS LACK OF ROBUST DIRECT BIOMARKERS IS A CRITICAL GAP THAT ULTIMATELY LIMITS OUR ABILITY TO UNDERSTAND THE UNDERLYING PATHOLOGICAL CHANGES, AS WELL AS EVALUATE EMERGING THERAPIES. TO OVERCOME THESE LIMITATIONS, WE PROPOSE TO LEVERAGE AN ADVANCED MULTI-CONTRAST FMRI METHOD THAT PROVIDES HIGH CONTRAST SENSITIVITY, AS WELL AS DISTINCT MICROVASCULAR SENSITIVITY. BY COUPLING THIS METHOD WITH PHARMACOLOGICAL AND CHEMOGENETIC MANIPULATIONS, A DIRECT LINK BETWEEN FMRI-BASED FUNCTIONAL NETWORKS AND UNDERLYING NEURONAL FUNCTION CAN BE INFERRED. MORE SPECIFICALLY, THIS PROJECT AIMS TO A) CHARACTERIZE MULTI-CONTRAST (TOTAL VASCULAR AND MICROVASCULAR) FUNCTIONAL CONNECTIVITY NETWORKS IN TWO COMPLEMENTARY PRECLINICAL MODELS THAT RECAPITULATE CLASSIC HALLMARKS OF PARKINSON’S DISEASE - THE PROGRESSIVE PFF SYNUCLEINOPATHY MODEL AND THE ACUTE 6-OHDA MODEL; B) ASSESS THE EFFECT OF PHARMACOLOGICAL DOPAMINE MODULATION ON FUNCTIONAL NETWORKS, USING BOTH ACUTE AND CHRONIC TREATMENT PARADIGMS, ANALOGOUS TO THE STANDARD TREATMENT PARADIGM; AND C) INVESTIGATE THE EFFECT OF ENDOGENOUS MODULATION OF THE DORSAL RAPHE SEROTONERGIC CIRCUIT AND THE LOCUS COERULEUS NORADRENERGIC CIRCUIT – BOTH OF WHICH ARE PROPOSED TO BE INVOLVED IN CERTAIN NON-MOTOR SYMPTOMOLOGY – ON FUNCTIONAL NETWORKS USING CHEMOGENETIC METHODS. THESE STUDIES WILL PROVIDE INSIGHT INTO FUNCTIONAL NETWORK CHANGES THAT OCCUR OVER DIFFERENT VASCULAR SCALES AND VIA DIFFERENT NEUROTRANSMITTER POPULATIONS. THE DEVELOPMENT OF ROBUST MRI BIOMARKERS THAT RELATE TO DOPAMINERGIC, SEROTONERGIC, AND NORADRENERGIC CIRCUIT FUNCTION AND DYSFUNCTION MAY ALSO PROVIDE INSIGHT INTO THE MULTIFACETED NATURE OF PARKINSON’S DISEASE THAT CONTRIBUTES TO BOTH MOTOR AND NON-MOTOR SYMPTOMS. AS FUNCTIONAL BRAIN NETWORK DYSFUNCTION IS WIDELY OBSERVED IN PARKINSON’S DISEASE, THIS INTEGRATIVE APPROACH WILL ENABLE THE DEVELOPMENT OF ROBUST BIOMARKERS OF PARKINSON’S DISEASE WITH WELL-CHARACTERIZED PATHOPHYSIOLOGICAL ORIGINS, WHICH IS A CRITICAL SHORTCOMING OF CURRENT TECHNOLOGIES.

MECHANISMS FOR INTRACRANIAL ANEURYSM RUPTURE

DEFAULT MODE NETWORK DYSFUNCTION IN DOWN SYNDROME - DOWN SYNDROME (DS), THE MOST COMMON GENETIC CAUSE OF INTELLECTUAL DISABILITY, FORM THE LARGEST POPULATION WITH A GENETIC PREDISPOSITION IN MIDLIFE TO DEVELOP ALZHEIMER’S DISEASE (AD). VIRTUALLY EVERYONE WITH DS EXHIBIT NEUROFIBRILLARY TANGLES (NFTS) CONTAINING-TAU AND SS-AMYLOID (ASS) PLAQUES SIMILAR TO AD BY THE FOURTH DECADE OF LIFE, WHICH INCREASE WITH AGE. GREATER THAN 70% OF PEOPLE WITH DS ULTIMATELY DEVELOP DEMENTIA, MAKING THIS POPULATION AN EXCELLENT NATURALLY-OCCURRING HUMAN MODEL FOR THE STUDY OF THE PATHOGENESIS OF DEMENTIA WITH TRANSLATION TO AD. ALTHOUGH NFT PATHOLOGY IS TIGHTLY LINKED TO THE DEGREE OF DEMENTIA IN BOTH AD AND DS COMPARED TO ASS PLAQUES, THE CELLULAR MECHANISMS UNDERLYING COGNITIVE DECLINE IN DS REMAIN LARGELY UNEXPLORED. THE GOAL OF THIS PROJECT IS TO ELUCIDATE THE MOLECULAR AND CELLULAR EVENTS UNDERLYING THE SELECTIVE VULNERABILITY OF FRONTAL CORTEX (FC) AND PRECUNEUS (PREC) PYRAMIDAL NEURONS. THESE TWO INTERCONNECTED HUBS OF THE DEFAULT MODE NETWORK (DMN) ARE INVOLVED IN EPISODIC MEMORY AND SELF-AWARENESS AND ARE DYSFUNCTIONAL IN AD AND DS. WE RECENTLY REPORTED THAT PEOPLE WITH DS WITH DEMENTIA DISPLAY A GREATER NUMBER OF NFTS IN FC PYRAMIDAL NEURONS CONTAINING ADVANCED TAU PATHOLOGY COMPARED TO THOSE WITHOUT DEMENTIA. INTERESTINGLY, WE ALSO FOUND THAT FC NFT-POSITIVE NEURONS IN DS WITH DEMENTIA DISPLAY A DIFFERENT TRANSCRIPTOMIC SIGNATURE COMPARED TO NON- DEMENTED DS, DESPITE HAVING SIMILAR FC PLAQUE LOADS BETWEEN THE DS GROUPS. THESE FINDINGS SUGGEST A KEY ROLE FOR TAU PATHOBIOLOGY IN THE ONSET OF DEMENTIA IN DS. INTERESTINGLY, NEURONAL DEGENERATION IS MANIFESTED BY A CONFLUENCE OF INTRACELLULAR EVENTS LEADING TO ALTERATIONS IN TAU MRNA SPLICING BEFORE THE ONSET OF CLINICAL SYMPTOMS. RECENT EVIDENCE DEMONSTRATED THAT MISLOCALIZED SPLICING OF U1 SMALL NUCLEAR RIBONUCLEOPROTEINS (SNRNPS) ARE ASSOCIATED WITH NFTS IN SPORADIC AND FAMILIAL AD AND DS, BUT NOT OTHER TAUOPATHIES. WE NOW REPORT GREATER DEFECTS IN SPLICING PROTEINS, PARTICULARLY THOSE ASSOCIATED WITH ALTERNATIVE SPLICING OF TAU, THAT OCCUR IN THE MORE ADVANCED STAGES OF NFT DEVELOPMENT IN THE FC IN DS WITH DEMENTIA COMPARED TO THOSE WITHOUT DEMENTIA. IN THIS PROJECT, WE WILL INVESTIGATE THE MOLECULAR PATHOBIOLOGY OF SELECTIVELY VULNERABLE DMN NEURONS IN PEOPLE WITH DS WITH AND WITHOUT DEMENTIA USING CONCEPTUALLY AND TECHNICALLY INNOVATIVE APPROACHES: SPLICING ANTIBODIES DURING THE POST-TRANSLATIONAL PROGRESSION OF TAU EVOLUTION, SINGLE POPULATION MICROARRAY AND RNA TRANSCRIPTOMICS, COMBINED WITH FUNCTIONAL GENE PATHWAY ANALYSIS. THIS PROPOSAL EXPECTS TO LAY THE FOUNDATION FOR A WIDE RANGE OF POTENTIAL INTERVENTIONS FOR THE DESIGN OF NOVEL DRUGS AND BIOMARKERS FOR THE PREVENTION OF DEMENTIA IN DS WITH TRANSLATION TO AD.

MOLECULAR MECHANISMS UNDERLYING GLIOMA INVASION OF THE HUMAN SUBVENTRICULAR ZONE

THIS EDA INVESTMENT WILL LEVERAGE PUBLIC AND PRIVATE SECTOR RESOURCES TO RENOVATE THE EIGHTH FLOOR OF THE ST. FRANCIS MEDICAL CENTER IN GRAND ISLAND, NE TO ACCOMMODATE EXPANSION OF VOCATIONAL TRAINING PROGRAMS IN HEALTHCARE. THE RENOVATED FLOOR WILL SUPPORT THE ACADEMY OF MEDICAL SCIENCES, ONE OF SIX ACADEMIES WITHIN GRAND ISLAND SENIOR HIGH THAT PROVIDES STUDENTS HAND-ON TRAINING IN VARIOUS MEDICAL PROGRAMS INCLUDING EMERGENCY SERVICES, HEALTHCARE, SPORTS MEDICINE/THERAPY AND BIOMEDICAL SCIENCES. THE ACADEMY WILL PROVIDE ENTRY INTO A VARIETY OF OCCUPATIONAL PATHWAYS ENSURING A PIPELINE OF HEALTH CARE WORKERS IN A RURAL AREA OF CENTRAL NEBRASKA. THE ACADEMY WILL SUPPORT THE DEVELOPMENT OF THE WORKFORCE NEEDED TO SUPPORT HEALTHCARE IN THE REGION AND WILL HELP DIVERSIFY THE WORKFORCE FROM A PRIMARILY AGRICULTURE-BASED EMPLOYMENT. THIS PROJECT WAS MADE POSSIBLE BY THE REGIONAL PLANNING EFFORTS LED BY THE SOUTH CENTRAL ECONOMIC DEVELOPMENT DISTRICT. EDA FUNDS THE SOUTH CENTRAL ECONOMIC DEVELOPMENT DISTRICT TO BRING TOGETHER THE PUBLIC AND PRIVATE SECTORS TO CREATE AN ECONOMIC DEVELOPMENT ROADMAP TO STRENGTHEN THE REGIONAL ECONOMY, SUPPORT PRIVATE CAPITAL INVESTMENT AND CREATE JOBS.

PLASTICITY AND NEUROCIRCUIT REMODELING IN THE MEDIOBASAL HYPOTHALAMUS TO TREAT DIABETES

QUANTITATIVE ASSESSMENT OF PERIPHERAL NERVE INJURY AND REPAIR VIA MULTI-PARAMETRIC MRI

THE ROLE OF MAST CELLS IN THE PATHOPHYSIOLOGY OF INTRACRANIAL ANEURYSM

PATHWAYS LINKING NEUROPSYCHIATRIC SYMPTOMS WITH ALZHEIMER'S DISEASE NEUROIMAGING BIOMARKERS AND THE OUTCOME OF INCIDENT MILD COGNITIVE IMPAIRMENT/ DEMENTIA

TARGETING OLIG2 CO-REGULATORS FOR MALIGNANT GLIOMA THERAPY

MRI BIOMARKERS OF TRAUMATIC PERIPHERAL NERVE INJURY AND REPAIR: VALIDATION AND MULTISITE APPLICATION

DIFFUSION MRI BIOMARKERS OF PERIPHERAL NERVE TRAUMA - PROJECT SUMMARY PERIPHERAL NERVE DAMAGE FOLLOWING TRAUMA RESULTS IN CATASTROPHIC LOSS OF SENSORIMOTOR FUNCTION IF NOT TREATED IN A TIMELY MANNER. IN SEVERE CASES, SURGICAL REPAIR IS REQUIRED TO REGAIN FUNCTION, BUT OUTCOMES REMAIN SUBOPTI- MAL (WITH A FAILURE RATE REACHING 40%). WHILE ELECTRODIAGNOSTICS ARE VALUABLE INDICATORS OF NERVE FUNCTION AND MUSCLE DENERVATION, THEY ARE OFTEN CHALLENGING TO INTERPRET EARLY POST-INJURY, LIMITING OUR ABILITY TO DETERMINE IF SURGICAL INTERVENTION IS WARRANTED. AFTER SURGERY, IT CAN ALSO TAKE MANY MONTHS FOR ELECTRODIAGNOSTICS TO INDICATE WHETHER AXONS ARE SPROUTING ACROSS THE REPAIR SITE AND REGENERATING TOWARD THEIR MOTOR OR SENSORY TARGET. IN BOTH CASES, THIS OFTEN RESULTS IN A “WAIT AND WATCH” APPROACH THAT RELIES ON THE CLINICAL MANIFESTATIONS OF REIN- NERVATION (E.G., THE RETURN OF SENSORIMOTOR FUNCTION), WHICH ULTIMATELY DELAYS CLINICAL DECISION-MAKING AND IN- CREASES THE LIKELIHOOD OF PERMANENT MUSCLE ATROPHY, SENSORY LOSS, AND THE FORMATION OF PAINFUL NEUROMAS. GIV- EN THESE LIMITATIONS, A BIOMARKER THAT MONITORS NERVE REGENERATION THROUGHOUT THE RECOVERY PROCESS WOULD IM- PROVE SENSORIMOTOR OUTCOMES BY ALLOWING FOR THE EARLIER IDENTIFICATION OF I) NERVES THAT REQUIRE SURGERY AND II) FAILED REPAIRS AFTER SURGERY, EVEN GUIDING RE-OPERATION (WHEN NECESSARY) IN THE LATTER CASE. DIFFUSION TENSOR IM- AGING (DTI) IS AN MRI METHOD THAT YIELDS INDICES (E.G., FRACTIONAL ANISOTROPY, FA) SENSITIVE TO NERVE PATHOLOGIES. WE PREVIOUSLY DEMONSTRATED THAT I) FA VALUES FROM EX VIVO RAT NERVES RELATE TO AXON DENSITY AND BEHAVIORAL OUTCOMES FOLLOWING TRAUMA AND SURGICAL REPAIR AND II) FA VALUES FROM HUMAN NERVES REPORT ON FAILED SURGERIES, SUCCESSFUL REOPERATIONS, AND INJURY SEVERITY. WHILE PROMISING, LARGER-SCALE STUDIES ARE REQUIRED FOR CLINICAL VALI- DATION GIVEN THE HETEROGENEOUS NATURE OF TRAUMATIC NERVE INJURIES. FURTHERMORE, WE KNOW THAT DTI LACKS SPECI- FICITY IN THE PRESENCE OF CONCURRENT EDEMA AND DE/REGENERATION EARLY AFTER TRAUMA. IN LINE WITH THESE CHALLENG- ES, OUR OVERARCHING GOAL IS TO MOVE NERVE DIFFUSION BIOMARKERS TOWARD CLINICAL TRIAL READINESS BY I) DEVELOPING ADVANCED DIFFUSION METHODS WITH INCREASED PATHOLOGICAL SPECIFICITY TO REGENERATION; II) DEMONSTRATING CON- SISTENCY ACROSS MRI VENDORS/SITES; III) AND PROVIDING CLINICAL VALIDATION BY EXPANDING TO A LARGER-SCALE, MULTI-SITE STUDY TO EVALUATE WHETHER PRE- AND POST-SURGICAL DIFFUSION MRI PREDICTS CLINICAL OUTCOMES. THIS MULTI-PI PROJECT REPRESENTS A UNIQUE COLLABORATION BETWEEN SCIENTISTS WITH EXPERTISE IN ADVANCED PERIPHERAL NERVE MRI AND WORLD-CLASS PERIPHERAL NERVE SURGEONS. WE WILL USE THE COMPLEMENTARY TECHNICAL AND CLINICAL EXPERTISE OF THE TEAM TO IDENTIFY NOVEL DIFFUSION-BASED BIOMARKERS BASED ON THE SPHERICAL MEAN TECHNIQUE (SMT) AND OPTI- MIZE/EVALUATE PERFORMANCE. WE HYPOTHESIZE THAT SMT PARAMETERS PREDICT SURGICAL OUTCOMES WITH HIGHER LEVELS OF SENSITIVITY AND SPECIFICITY THAN BOTH DTI AND STANDARD CLINICAL METHODS. IF SUCCESSFUL, THESE SMT-BASED BI- OMARKERS WILL ALLOW PHYSICIANS TO RECOMMEND SURGICAL INTERVENTIONS AND DETECT FAILED REPAIRS EARLIER THAN IS CUR- RENTLY POSSIBLE. ONCE ESTABLISHED, THESE METHODS WILL ALSO LIKELY BE OF CLINICAL UTILITY IN PROXIMAL INJURIES, WHERE THE PROGNOSIS FOR RECOVERY IS CURRENTLY POOR DUE TO THE PROLONGED TIME REQUIRED TO DETECT FAILED REGENERATION.

EARLY HEAD START-CHILD CARE PARTNERSHIPS

SOUTH AFRICAN MANGANESE ENVIRONMENTAL NEUROTOXIC EFFECTS RESEARCH (SMELTER) - ABSTRACT MANGANESE (MN) IS A WELL-ESTABLISHED NEUROTOXICANT THAT LIKELY INDUCES NEURODEGENERATION THROUGH INFLAMMATORY PATHWAYS. MILLIONS OF PEOPLE WORLDWIDE EXPERIENCE HIGH LEVELS OF ENVIRONMENTAL MN FROM POINT SOURCE EMISSIONS OR ASSOCIATED FUGITIVE DUST. IN THE FIRST FIVE YEARS OF THE SMELTER (SOUTH AFRICAN MANGANESE ENVIRONMENTAL NEUROTOXIC EFFECTS RESEARCH) STUDY, WE ASSEMBLED A COHORT OF >800 BLACK AFRICAN RESIDENTS, INCLUDING >700 EXPOSED TO MN EMISSIONS FROM ONE OF THE WORLD’S LARGEST MN SMELTERS IN MEYERTON, SOUTH AFRICA. WE DEVELOPED AND VALIDATED STUDY ASSESSMENT TOOLS IN THE APPROPRIATE SOUTH AFRICAN LANGUAGES, MEASURED ENVIRONMENTAL MN IN MEYERTON AND A COMPARABLE NON-EXPOSED REFERENCE COMMUNITY (ETHEMBALETHU), EXAMINED PARTICIPANTS USING THE UNIFIED PARKINSON DISEASE RATING SCALE MOTOR SUBSECTION PART 3 (UPDRS3), AND EVALUATED PARTICIPANTS USING TARGETED COGNITIVE AND MOOD ASSESSMENTS. WE DEMONSTRATED THAT MEYERTON RESIDENTS HAD MARKEDLY POORER PERFORMANCE IN THESE OUTCOMES AS COMPARED TO ETHEMBALETHU RESIDENTS. THESE NEUROLOGICAL HEALTH EFFECTS WERE ASSOCIATED WITH CONCENTRATIONS ~100-200 NG/M3 OF MN AS PARTICULATE MATTER (PM) <2.5 ΜM IN DIAMETER (PM2.5-MN), A LEVEL CONSISTENT WITH OTHER POINT SOURCES THROUGHOUT THE WORLD. IN THIS PROPOSAL, WE WILL BUILD ON THESE ACCOMPLISHMENTS BY INVESTIGATING WHETHER MN EXPOSURE IS ALSO ASSOCIATED WITH PROGRESSION OF THE OBSERVED MOTOR AND COGNITIVE HEALTH EFFECTS IN THIS SAME COHORT AND TO ESTIMATE LONGITUDINAL, IN ADDITION TO CROSS-SECTIONAL, ASSOCIATIONS. WE SUCCESSFULLY EMPLOYED THIS APPROACH IN OUR STUDIES OF MN-EXPOSED WELDERS IN THE U.S. IN WHOM LONGITUDINAL STUDIES WERE REQUIRED TO SHOW DOSE-RESPONSE EFFECTS. TO BETTER CHARACTERIZE MN EXPOSURE AND MECHANISM OF NEUROTOXICITY, WE WILL INCORPORATE BRAIN MAGNETIC RESONANCE IMAGING (MRI), INCLUDING SEQUENCES DESIGNED TO ASSESS NEUROINFLAMMATION. WE WILL ALSO EXPAND OUR AIR MONITORING TO EXPLORE THE CONTRIBUTION OF PM SIZE ON MOTOR, COGNITIVE, AND NON-MOTOR HEALTH OUTCOMES, AS WELL AS NEUROINFLAMMATION AS ASSESSED BY BRAIN MRI. FINALLY, WE WILL IMPLEMENT A DISSEMINATION PLAN TO INFORM COMMUNITY AND NATIONAL STAKEHOLDERS OF STUDY RESULTS. OUR OVERARCHING HYPOTHESIS IS THAT ENVIRONMENTAL MN EXPOSURE TWO ORDERS OF MAGNITUDE BELOW CONTEMPORARY OCCUPATIONAL EXPOSURE IS ASSOCIATED WITH PROGRESSION OF BOTH PARKINSONISM AND COGNITIVE DYSFUNCTION AND THAT NEUROINFLAMMATION MEDIATES THE RELATIONSHIP BETWEEN ENVIRONMENTAL MN EXPOSURE AND CLINICAL NEUROTOXICITY. WE FURTHER HYPOTHESIZE THAT PARTICLE SIZES <1ΜM (I.E., THE MORE INSPIRABLE PARTICLES WITHIN PM2.5) WILL BE MORE STRONGLY ASSOCIATED WITH CLINICAL OUTCOMES THAN LARGER SIZES. ACCOMPLISHING THESE AIMS WILL INFORM INTERNATIONAL ENVIRONMENTAL MN REGULATIONS AND WILL ADDRESS AN IMPORTANT ENVIRONMENTAL JUSTICE CONCERN IDENTIFIED BY A COMMUNITY OF PARTICIPANTS TYPICALLY UNDERREPRESENTED IN ENVIRONMENTAL HEALTH RESEARCH. THE PROPOSED AIMS ADDRESS THE NIEHS STRATEGIC THEME, “PROMOTING TRANSLATION – DATA TO KNOWLEDGE TO ACTION.”

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

BARROW NEUROLOGICAL INSTITUTE APPLICATION TO BECOME A NEURONEXT SITE.

A NOVEL BIFUNCTIONAL AGENT AS A RADIOSENSITIZER FOR GLIOBLASTOMA AND RADIOPROTECTOR OF NORMAL BRAIN

ROLE OF MACROPHAGES IN HHT PATHOGENESIS AND THERAPY

A MULTICENTER, RANDOMIZED CONTROLLED TRIAL OF CEREBROSPINAL FLUID DRAINAGE IN ACUTE SPINAL CORD INJURY

GENOTYPIC AND PHENOTYPIC EXAMINATION OF DISEASE PATHOGENEIS IN C8ORF72 FTD

AD GENETIC RISK AS A PROGNOSTIC FACTOR FOR COGNITIVE OUTCOMES AFTER TBI

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - NON-CONSTRUCTION - THE BARROW NEUROLOGICAL INSTITUTE (BNI) RECENTLY OPENED A STATE-OF-THE-ART DRY LABORATORY SPACE, THE BARROW NEURO ANALYTICS CENTER (BNAC), LOCATED IN THE PARK CENTRAL BIOSCIENCE HUB ADJACENT TO BOTH BNI AND CREIGHTON UNIVERSITY MEDICAL SCHOOL. THE RESEARCH CONDUCTED AT BNAC IS POWERED BY THE NEW HIGH-PERFORMANCE COMPUTE (HPC) NETWORK SUPPORTED BY THE STATE OF ARIZONA. THE HPC SERVER STACK WAS DESIGNED TO SUPPORT SOPHISTICATED MODELING, SIMULATION, AND DATA ANALYTICS ACROSS A RANGE OF NEUROSCIENCE RESEARCH USE CASES. ALL COMPONENTS INVOLVED ARE HOUSED IN A HIGHLY SECURE, ENTERPRISE DATA CENTER WITH MONITORED POWER AND COOLING. BNAC RESEARCHERS ARE PERFORMING STATE-OF-THE-ART SPATIAL STATISTICAL RESEARCH FROM POPULATION TO CELL AND THE COMPUTE NEEDS OF THESE RESEARCHERS EXCEEDS THE EXISTING CAPABILITIES OF THE CURRENT HPC. THIS RESEARCH REQUIRES A SUBSTANTIAL EXPANSION OF OUR GRAPHICAL PROCESSING UNITS (GPUS). TO MEET THE NEEDS OF OUR RAPIDLY EXPANDING SPATIAL STATISTICAL RESEARCH PROGRAMS, WE REQUIRE ADDITIONAL GPU NODES CONSISTING OF THREE DELL POWEREDGE XE9680 RACK SERVERS AND PARTIAL FTE SUPPORT TO INTEGRATE THESE SERVERS INTO THE HPC ENVIRONMENT.

APPLICATION OF HIGHER EDUCATION STABILIZATION FUNDS TO MITIGATE IMPACT OF COVID-19.

DIGNITY HEALTH HUMAN TRAFFICKING VICTIM RESPONSE HOSPITAL PILOT - BAKERSFIELD

TRANSLATIONAL ASSESSMENT OF SULFONYLUREA RECEPTOR-1 AS A BIOMARKER AND THERAPEUTIC TARGET FOR CEREBRAL EDEMA IN TRAUMATIC BRAIN INJURY

SURVIVOR ADVOCATES IN HEALTHCARE

TARGETING CNS EXPRESSION OF CHITINASES AS A NOVEL THERAPY FOR ALS

HUBBARD COUNTY YOUTH SUBSTANCE USE PREVENTION PROJECT

ENDOTHELIAL COMPLEMENT C3A RECEPTOR MEDIATED CEREBRAL INJURY IN A MURINE STROKE MODEL. - PROJECT SUM MARY: STROKE IS THE LEADING CAUSE OF ADULT DISABILITY WORLDWIDE. THOUGH INTRAVENOUS (IV) TISSUE PLASMINOGEN ACTIVATOR (TPA) IMPROVES OUTCOME AFTER STROKE, IT IS LIMITED BY SECONDARY INJURY INCLUDING HEMORRHAGIC TRANSFORMATION, BLOOD-BRAIN-BARRIER DISRUPTION AND EDEMA. ACTIVATION OF COMPLEMENT C3 PLAYS A KEY ROLE IN STROKE PATHOGENESIS, AS THE C3A ANAPHYLATOXIN BINDS TO ITS RECEPTOR TO EXACERBATE ACUTE POST-ISCHEMIC BRAIN INJURY. HOWEVER, THE MECHANISMS UNDERLYING THIS INJURY REMAIN UNCLEAR. THIS STUDY WILL FOR THE FIRST TIME DEFINE A CRUCIAL LINK BETWEEN COMPLEMENT C3A RECEPTOR ASSOCIATED INFLAMMATION AND MYELOID CELL MEDIATED SYNAPTIC DYSFUNCTION POST-STROKE. OUR LONG-TERM GOAL IS TO TRANSLATE C3AR ANTAGONIST THERAPY TO ENHANCE REPERFUSION THERAPY IN STROKE. TO REALIZE THIS GOAL, A THOROUGH UNDERSTANDING OF COMPLEMENT-DEPENDENT PROCESSES IN ISCHEMIC BRAIN IS ESSENTIAL. OUR CENTRAL HYPOTHESIS IS THAT INCREASED ENDOTHELIAL C3A/C3AR SIGNALING WORSENS POST-ISCHEMIC BBB DYSFUNCTION, INFLAMMATION, SYNAPTIC LOSS, AND FUNCTIONAL IMPAIRMENT. WE PROPOSE THE FOLLOWING AIMS: SPECIFIC AIM 1: TO DEMONSTRATE THAT GENETIC INHIBITION OF ENDOTHELIAL C3AR PROTECTS THE BBB, ABROGATES INFLAMMATORY MYELOID CELL INFILTRATION, AND CONFERS NEUROPROTECTION FOLLOWING STROKE. WT AND C3ARFLOX/FLOX- CDH5CRE+AGED MICE FOLLOWING PT/SHAM SURGERY WILL BE ASSESSED FOR NEUROLOGICAL FUNCTION, BBB INTEGRITY, AND TISSUE BIOCHEMISTRY FOR 3 MONTHS. BRAIN/BLOOD SAMPLES WILL BE COLLECTED FOR FACS-ANALYSIS OF MYELOID CELL SUBSETS TO EVALUATE TISSUE INFILTRATION OF PERIPHERAL IMMUNE CELLS AND TISSUE HISTOLOGY. SPECIFIC AIM 2: TO DEMONSTRATE THAT ENDOTHELIAL C3AR GENETIC DELETION WILL PROTECT AGAINST THE DELETERIOUS EFFECTS OF POST-ISCHEMIC TPA ADMINISTRATION EVEN AT DELAYED TIME-POINTS. WT AND C3ARFLOX/FLOX- CDH5CRE+AGED MICE FOLLOWING PT SURGERY CONCURRENT WITH I.V. TPA ADMINISTRATION (ADMINISTERED AT 4H,8H,12H,24H) WILL BE ASSESSED FOR HEMORRHAGE, BBB INTEGRITY, EDEMA, NEUROLOGICAL FUNCTION, TISSUE BIOCHEMISTRY FOR 3 MONTHS. BRAIN/BLOOD SAMPLES WILL BE COLLECTED FOR FACS-ANALYSIS AS IN AIM 1 SPECIFIC AIM 3: TO DEMONSTRATE THAT C3AR MEDIATES POST-ISCHEMIC SYNAPSE ELIMINATION AND DEMONSTRATE THAT INHIBITION OF THIS PROCESS IMPROVES LONG-TERM FUNCTIONAL OUTCOME. WT AND C3ARFLOX/FLOX-CDH5CRE+AGED MICE FOLLOWING PT SURGERY WILL BE ASSESSED FOR SYNAPTIC FUNCTION USING ELECTROPHYSIOLOGY. BRAIN AND BLOOD SAMPLES WILL BE COLLECTED FOR FACS AND TISSUE HISTOLOGY ANALYSIS OF MICROGLIA, NEURONS, SYNAPTIC PROTEIN AND PUNCTA DENSITY IN THE PERI-INFARCT REGION OVER VARYING TIME INTERVALS. EXPECTED OUTCOMES: WE ANTICIPATE THAT COMPLEMENT INHIBITION WILL ATTENUATE BOTH THE ACUTE NEUROVASCULAR INJURY ASSOCIATED WITH POST-ISCHEMIC TPA ADMINISTRATION AS WELL AS LONG-TERM NEUROLOGICAL DYSFUNCTION ASSOCIATED WITH POST-ISCHEMIC SYNAPSE ELIMINATION IN AGED MICE. IMPACT: THESE STUDIES WILL PROVIDE FOUNDATION FOR FUTURE EFFORTS TO TRANSLATE THERAPIES TARGETING THE DELETERIOUS ASPECTS COMPLEMENT ACTIVATION INTO HUMAN STROKE PATIENTS.

MULTI-PARAMETRIC PERFUSION MRI FOR THERAPY RESPONSE ASSESSMENT IN BRAIN CANCER - THE LONG-TERM GOAL OF THIS PROGRAM IS TO IMPROVE PATIENT CARE BY OPTIMIZING AND VALIDATING QUANTITATIVE MAGNETIC RESONANCE IMAGING METHODS FOR THE EARLY PREDICTION OF BRAIN CANCER RESPONSE TO THERAPY. CURRENTLY, CONTRAST-ENHANCED MRI (CE-MRI) REPRESENTS THE STANDARD FOR GUIDING ALMOST ALL ASPECTS OF BRAIN TUMOR CLINICAL MANAGEMENT, INCLUDING SURGICAL BIOPSY/RESECTION, RADIATION TREATMENT PLANNING, AND POST-TREATMENT SURVEILLANCE FOR RESPONSE ASSESSMENT. UNFORTUNATELY, CE-MRI’S ACCURACY REMAINS LIMITED, WHICH CREATES SIGNIFICANT CLINICAL CHALLENGES. THUS, CLINICAL DECISIONS OFTEN REQUIRE SURGICAL BIOPSY FOR DEFINITIVE DIAGNOSIS, WHICH INCREASES MEDICAL COSTS, PATIENT MORBIDITY/MORTALITY, AND RESOURCE UTILIZATION. TO OVERCOME THE LIMITATIONS OF CE-MRI, DYNAMIC SUSCEPTIBILITY CONTRAST (DSC) MRI AND DYNAMIC CONTRAST ENHANCED (DCE) MRI ARE INCREASINGLY USED TO EVALUATE TUMOR PERFUSION AND PERMEABILITY. STUDIES HAVE SHOWN THAT DSC/DCE PARAMETERS CORRELATE WITH TUMOR GRADE, CAN PREDICT THE LIKELIHOOD OF TUMOR PROGRESSION AFTER THERAPY, AND DIFFERENTIATE TREATMENT RELATED EFFECTS VERSUS TUMOR PROGRESSION. HOWEVER, THE WIDESPREAD CLINICAL ADOPTION AND INCORPORATION OF DSC-MRI INTO MULTI-SITE CLINICAL TRIALS HAS BEEN HINDERED DUE TO VARIABLE ACQUISITION METHODS, CONTRAST AGENT DOSING SCHEMES AND ANALYSIS PROTOCOLS, WHICH TO DATE, HAVE YET TO BE STANDARDIZED AND AUTOMATED FOR CLINICAL USE. THESE ISSUES ARE KNOWN TO AFFECT THE REPEATABILITY AND INTERPRETATION OF DSC-MRI METRICS. SPIN AND GRADIENT ECHO (SAGE) DSC-MRI SEQUENCES ENABLE THE USE OF LOWER DOSES OF GD-BASED CONTRAST AGENTS, REQUIRE LESS SCAN TIME, ARE LESS SENSITIVE TO ACQUISITION PARAMETERS, ARE METHODOLOGICALLY MORE REPRODUCIBLE, YIELD MORE ACCURATE PERFUSION PARAMETERS, PROVIDE SIMULTANEOUS MEASURES OF DCE-MRI, VESSEL SIZE AND VESSEL ARCHITECTURAL IMAGING DATA, OXYGEN DELIVERY AND NOVEL METRICS HIGHLY SENSITIVE TO TUMOR CELLULAR CHARACTERISTICS. ACCORDINGLY, SAGE METHODS ENABLE THE INTERROGATION OF UNIQUE AND COMPLEMENTARY READOUTS ON TUMOR MICROSTRUCTURE AND FUNCTION THAT CORRELATE WITH CLINICAL OUTCOMES AND CAN IDENTIFY PATIENTS RESPONDING TO THERAPY. BEFORE CLINICAL TRIALS CAN BENEFIT FROM SAGE BASED DSC-MRI THE ACQUISITION AND ANALYSIS PROTOCOLS NEED TO BE OPTIMIZED, AUTOMATED AND STANDARDIZED. THUS, WE PROPOSE TO: 1) IMPLEMENT MULTI-VENDOR, SAGE- DSC-MRI PROTOCOLS, 2) ESTABLISH AUTOMATED AND OPEN SOURCE ALGORITHMS FOR QUALITY ASSURANCE AND ANALYSIS, 3) PARTNER WITH IMAGING BIOMETRICS TO DEVELOP A COMMERCIALLY INTEGRATED, VENDOR NEUTRAL IMAGE ANALYSIS PLATFORM FOR ANALYZING SAGE DSC-MRI DATA AND 4) VALIDATE SAGE DSC-MRI TOOLS FOR PREDICTING GLIOMA RESPONSE TO BEVACIZUMAB THERAPY. IMPACT ON HEALTHCARE: WE WILL PROVIDE THE NEURO-ONCOLOGY COMMUNITY WITH VALIDATED, QUANTITATIVE IMAGE ACQUISITION AND ANALYSIS METHODS FOR IDENTIFYING EARLY THERAPEUTIC RESPONSE THAT ARE APPROPRIATE FOR MULTI-SITE CLINICAL TRIALS OF CONVENTIONAL AND TARGETED BRAIN TUMOR THERAPIES, THEREBY ENABLING MORE RAPID DRUG DISCOVERY AND IMPROVED INDIVIDUALIZED CARE FOR PATIENTS.

MEDICAL SAFE HAVEN PROGRAM FOR SURVIVORS OF HUMAN TRAFFICKING

RURAL HEALTH CARE SERVICES OUTREACH GRANT PROGRAM

STROKE INDUCED-NK CELL DEFICIENCY: MECHANISMS AND CLINICAL IMPLICATIONS

RETINOID-ACTIVATING GENE THERAPY FOR THE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS

EMERGENCY FUNDING TO SUPPORT STUDENTS IMPACTED BY COVID-19.

DEFAULT MODE NETWORK DYSFUNCTION IN DOWN SYNDROME - DOWN SYNDROME (DS), THE MOST COMMON GENETIC CAUSE OF INTELLECTUAL DISABILITY, FORM THE LARGEST POPULATION WITH A GENETIC PREDISPOSITION IN MIDLIFE TO DEVELOP ALZHEIMER’S DISEASE (AD). VIRTUALLY EVERYONE WITH DS EXHIBIT NEUROFIBRILLARY TANGLES (NFTS) CONTAINING-TAU AND Β-AMYLOID (AΒ) PLAQUES SIMILAR TO AD BY THE FOURTH DECADE OF LIFE, WHICH INCREASE WITH AGE. GREATER THAN 70% OF PEOPLE WITH DS ULTIMATELY DEVELOP DEMENTIA, MAKING THIS POPULATION AN EXCELLENT NATURALLY-OCCURRING HUMAN MODEL FOR THE STUDY OF THE PATHOGENESIS OF DEMENTIA WITH TRANSLATION TO AD. ALTHOUGH NFT PATHOLOGY IS TIGHTLY LINKED TO THE DEGREE OF DEMENTIA IN BOTH AD AND DS COMPARED TO AΒ PLAQUES, THE CELLULAR MECHANISMS UNDERLYING COGNITIVE DECLINE IN DS REMAIN LARGELY UNEXPLORED. THE GOAL OF THIS PROJECT IS TO ELUCIDATE THE MOLECULAR AND CELLULAR EVENTS UNDERLYING THE SELECTIVE VULNERABILITY OF FRONTAL CORTEX (FC) AND PRECUNEUS (PREC) PYRAMIDAL NEURONS. THESE TWO INTERCONNECTED HUBS OF THE DEFAULT MODE NETWORK (DMN) ARE INVOLVED IN EPISODIC MEMORY AND SELF-AWARENESS AND ARE DYSFUNCTIONAL IN AD AND DS. WE RECENTLY REPORTED THAT PEOPLE WITH DS WITH DEMENTIA DISPLAY A GREATER NUMBER OF NFTS IN FC PYRAMIDAL NEURONS CONTAINING ADVANCED TAU PATHOLOGY COMPARED TO THOSE WITHOUT DEMENTIA. INTERESTINGLY, WE ALSO FOUND THAT FC NFT-POSITIVE NEURONS IN DS WITH DEMENTIA DISPLAY A DIFFERENT TRANSCRIPTOMIC SIGNATURE COMPARED TO NON- DEMENTED DS, DESPITE HAVING SIMILAR FC PLAQUE LOADS BETWEEN THE DS GROUPS. THESE FINDINGS SUGGEST A KEY ROLE FOR TAU PATHOBIOLOGY IN THE ONSET OF DEMENTIA IN DS. INTERESTINGLY, NEURONAL DEGENERATION IS MANIFESTED BY A CONFLUENCE OF INTRACELLULAR EVENTS LEADING TO ALTERATIONS IN TAU MRNA SPLICING BEFORE THE ONSET OF CLINICAL SYMPTOMS. RECENT EVIDENCE DEMONSTRATED THAT MISLOCALIZED SPLICING OF U1 SMALL NUCLEAR RIBONUCLEOPROTEINS (SNRNPS) ARE ASSOCIATED WITH NFTS IN SPORADIC AND FAMILIAL AD AND DS, BUT NOT OTHER TAUOPATHIES. WE NOW REPORT GREATER DEFECTS IN SPLICING PROTEINS, PARTICULARLY THOSE ASSOCIATED WITH ALTERNATIVE SPLICING OF TAU, THAT OCCUR IN THE MORE ADVANCED STAGES OF NFT DEVELOPMENT IN THE FC IN DS WITH DEMENTIA COMPARED TO THOSE WITHOUT DEMENTIA. IN THIS PROJECT, WE WILL INVESTIGATE THE MOLECULAR PATHOBIOLOGY OF SELECTIVELY VULNERABLE DMN NEURONS IN PEOPLE WITH DS WITH AND WITHOUT DEMENTIA USING CONCEPTUALLY AND TECHNICALLY INNOVATIVE APPROACHES: SPLICING ANTIBODIES DURING THE POST-TRANSLATIONAL PROGRESSION OF TAU EVOLUTION, SINGLE POPULATION MICROARRAY AND RNA TRANSCRIPTOMICS, COMBINED WITH FUNCTIONAL GENE PATHWAY ANALYSIS. THIS PROPOSAL EXPECTS TO LAY THE FOUNDATION FOR A WIDE RANGE OF POTENTIAL INTERVENTIONS FOR THE DESIGN OF NOVEL DRUGS AND BIOMARKERS FOR THE PREVENTION OF DEMENTIA IN DS WITH TRANSLATION TO AD.

THE ROLE OF TDP-43 ASSOCIATED CRYPTIC EXON INCLUSION IN KARLN ON C9ORF72-MEDIATED CORTICAL NEURODEGENERATION

MULTI-SITE VALIDATION AND APPLICATION OF A CONSENSUS DSC MRI PROTOCOL

MULTI-PARAMETRIC PERFUSION MRI FOR THERAPY RESPONSE ASSESSMENT IN BRAIN CANCER

HEMODYNAMIC MECHANISMS LINKING AORTIC ARCH STIFFNESS WITH BRAIN INSULT IN OLDER ADULTS

LONGITUDINAL NEUROIMAGING AND MOLECULAR BIOMARKERS OF CEREBROVASCULAR HEALTH IN ALS

ENHANCING ACMSD ACTIVITY AS A NOVEL GENE THERAPY FOR ALS

SOUTHWEST ARKANSAS YOUTH OPIOID INTERVENTION

TARGETING SYNAPSE LOSS IN ALS/FTD USING SPINE-REGENERATING COMPOUNDS

MALADAPTIVE 5-HT RAPHE-CORTICOLIMBIC PLASTICITY UNDERLYING THE DEVELOPMENT OF NONMOTOR SYMPTOMS IN PARKINSON'S DISEASE

MALADAPTIVE 5-HT RAPHE-CORTICOLIMBIC PLASTICITY UNDERLYING THE DEVELOPMENT OF NONMOTOR SYMPTOMS IN PARKINSON'S DISEASE

MINNESOTA PREVENTION ALLIANCE IS A MINNESOTA STATEWIDE COALITION - A COLLABORATION OF COMMUNITIES, AGENCIES, ANDORGANIZATIONS FOR STATEWIDE YOUTH SUBSTANCE USE PREVENTION STRATEGIES.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - 375 DIXMYTH AVE, 7TH FLOOR, CINCINNATI, OH 45220-2475 PATRICK E. MUCK, MD W: (513)862-5196; F: (513)221-5865 HTTPS://WWW.TRIHEALTH.COM/ HRSA-23-117 THIS REQUEST ENABLES GOOD SAMARITAN HOSPITAL TO PURCHASE ONE INTRA-OPERATIVE POSITIONING SYSTEM (IOPS) UNIT, AN FDA-APPROVED SURGICAL NAVIGATION SYSTEM PROVIDING SAFE 3D COLOR ARTERIAL VIEWING IN MINIMALLY INVASIVE CARDIOVASCULAR PROCEDURES. THESE PROCEDURES USE X-RAY FLUOROSCOPY AND CAN LAST SEVERAL HOURS, DURING WHICH EVERYONE IN THE ROOM IS EXPOSED TO DANGEROUS IONIZING RADIATION FROM THOUSANDS OF X-RAYS. IOPS REDUCES THE NEED TO EXPOSE PATIENTS AND CAREGIVERS TO THIS RADIATION AND REDUCES THE NEED TO INJECT PATIENTS WITH TOXIC CONTRAST DYES. REPEATED X-RAY EXPOSURE IS KNOWN TO BURN SKIN AND INCREASE CANCER RISK IN PATIENTS, AND CONTRAST DYE CAN CAUSE KIDNEY DAMAGE. FOR HEALTHCARE WORKERS, OCCUPATIONAL RADIATION EXPOSURE BRINGS SERIOUS RISKS INCLUDING CATARACTS, COGNITIVE DEFICITS, MUSCULOSKELETAL INJURIES, BRAIN TUMORS AND OTHER CANCERS THAT MAY NOT SHOW SIGNS OR SYMPTOMS FOR 10 YEARS OR MORE. IOPS MITIGATES THESE PREVENTABLE HEALTH RISKS WHILE GIVING PHYSICIANS SUPERIOR GUIDANCE.

A MINIATURIZED VALVE THAT MIMICS FUNCTIONAL ARACHNOID GRANULATIONS TO TREAT HYDROCEPHALUS

ASTROCYTE REGULATION OF CORTICAL NEURODEGENERATION IN C9ORF72 FTD/ALS - PROJECT ABSTRACT THE GGGGCC (G4C2) HEXANUCLEOTIDE REPEAT EXPANSION (HRE) IN THE FIRST INTRON OF THE GENE C9ORF72, IS THE MOST COMMON GENETIC ABNORMALITY ASSOCIATED WITH FRONTOTEMPORAL DEMENTIA (FTD) AND AMYOTROPHIC LATERAL SCLEROSIS (ALS). THE DISEASE PATHOGENESIS ULTIMATELY LEADS TO THE CONCURRENT DEGENERATION OF CORTICAL FOREBRAIN AND SPINAL MOTOR NEURONS, AND RESULT IN THE CLINICAL DEFICITS OF MOTOR FUNCTION AND DEMENTIA. WHILE THE C9ORF72- FTD/ALS DISEASE PATHOGENESIS HAS BEEN WELL CHARACTERIZED IN SPINAL MOTOR NEURONS AND A CONTRIBUTION OF THE OBSERVED NEURODEGENERATION HAS BEEN ATTRIBUTED TO SPINAL CORD ASTROCYTES, THERE IS LITTLE KNOWN ABOUT THE PATHOBIOLOGY IN CORTICAL ASTROCYTES AND THEIR ROLE IN CORTICAL NEURODEGENERATION, WHICH IS PROPOSED TO CONTRIBUTE TO THE DEMENTIA SYMPTOMS IN THIS PATIENT POPULATION. IN THE PARENT GRANT OF THIS SUPPLEMENT, WE HYPOTHESIZED THAT CORTICAL ASTROCYTES PLAY AN INTEGRAL ROLE IN THE NON-CELL AUTONOMOUS DISEASE PATHOLOGY CONTRIBUTING TO THE DEGENERATION OF CORTICAL NEURONS IN C9ORF72-FTD/ALS. TO TEST THIS HYPOTHESIS, WE PROPOSED CELLULAR AND MOLECULAR ANALYSES OF POSTMORTEM FOREBRAIN AUTOPSY TISSUES AND PATIENT-DERIVED IPSC CORTICAL NEURONS AND CORTICAL ASTROCYTES CO-CULTURE SYSTEMS. WITH THIS SUPPLEMENT, WE EXPAND ON THESE STUDIES AND PROPOSE TO EXAMINE THE CONTRIBUTION OF ASTROCYTE-NEURON CONTACT-DEPENDENT MECHANISMS (AIM 1) AND ASTROCYTE-SECRETED FACTORS (AIM 2) IN CORTICAL NEURODEGENERATION. THESE CONTRIBUTIONS WILL BE TESTED USING IPSC CORTICAL ASTROCYTE- CORTICAL NEURON CO-CULTURE MODELS. THE GRADUATE STUDENT ASSIGNED TO THIS PROJECT, MS. LYNETTE BUSTOS, WILL FOCUS ON KNOWN ASTROCYTE PROTEINS (E.G., NEUROLIGINS AND EPHRINS) THAT MAKE DIRECT CONTACT WITH NEURONAL SYNAPTIC PROTEINS, AS WELL AS ASTROCYTE SECRETED PROTEINS IMPLICATED IN SYNAPSE STRUCTURE AND FUNCTION (E.G. HEVIN, SPARC, THROMBOSPONDINS, GLYPICANS). LYNETTE WILL THOROUGHLY EXAMINE THE ROLE OF THESE PROTEINS IN THE DEGENERATION OF CORTICAL NEURONS. TOGETHER WITH THE STUDIES PERFORMED UNDER THE PARENT GRANT, THESE ANALYSES WILL FOR THE FIRST TIME ELUCIDATE THE CONTRIBUTING ROLE OF CORTICAL ASTROCYTES IN THE NEURODEGENERATION OF CORTICAL NEURONS IN C9ORF72- FTD/ALS, ADDRESSING THE DISEASE MECHANISMS OF DEMENTIA IN THIS SPECTRUM DISORDER. ADDITIONALLY, THIS WORK WILL PROVIDE NOVEL OPPORTUNITIES FOR DRUG TARGET IDENTIFICATION WITH THE HOPE OF IDENTIFYING NOVEL THERAPEUTICS FOR THE AFFECTED PATIENT POPULATIONS.

A SINGLE CELL AND PROTEOMIC PRECISION MEDICINE APPROACH TO GLYBURIDE RESPONSIVE CONTUSION EXPANSION IN SEVERE TRAUMATIC BRAIN INJURY - FOR DECADES, THERE HAS BEEN A CRITICAL GAP IN TRANSLATING PRECLINICAL WORK ON MECHANISMS OF CONTUSION EXPANSION IN TRAUMATIC BRAIN INJURY (TBI) TO CLINICAL THERAPIES THAT IMPROVE OUTCOME. THIS IS IMPORTANT BECAUSE CONTUSION EXPANSION IS A MAJOR DRIVER OF UNFAVORABLE OUTCOME IN TBI WITH UP TO 5X INCREASE IN MORBIDITY AND MORTALITY, YET THERE ARE NO TREATMENTS OR BIOMARKERS TO IDENTIFY PATIENTS AT RISK. THERE IS IMMENSE POTENTIAL TO ADDRESS THIS ISSUE BECAUSE UNLIKE PRIMARY INJURY, CONTUSION EXPANSION RESULTS FROM HOST RESPONSE TO THE INITIAL TBI AND THUS IS A MODIFIABLE SECONDARY INJURY. GUIDELINE-BASED CARE USES A REACTIVE TEMPLATED APPROACH TO THIS HUGELY COMPLEX PROCESS WITHOUT ADDRESSING INDIVIDUAL DIFFERENCES IN CONTRIBUTORY PATHWAYS; IT DOES NOT PREVENT OR LIMIT CONTUSION EXPANSION AND STRUGGLES TO MITIGATE THE LIFE-THREATENING CONSEQUENCES. SUCH HOMOGENEOUS STRATEGIES FOR A HETEROGENEOUS DISEASE HAVE UNSURPRISINGLY LED TO MANY FAILED CLINICAL TRIALS. OUR LONG-TERM GOAL IS TO HARNESS RELEVANT INDIVIDUAL DATA (MOLECULAR, SINGLE-CELL [SC], GENETIC, IMAGING) TO DIRECT PRECISION MEDICINE FOR TBI CONTUSION EXPANSION. THIS R21 ADDRESSES EXISTING KNOWLEDGE GAPS IN A PROMISING THERAPY FOR CONTUSION EXPANSION BEING PRIMED FOR TRANSLATION: GLYBURIDE (GLY). EXISTING RESEARCH GENERATED EXCITING MOMENTUM BUT ALSO REVEALED MAJOR INDIVIDUAL DIFFERENCES IN GLY TARGETS THAT COULD AFFECT DRUG-RESPONSE/SUCCESSFUL TRANSLATION. OUR OBJECTIVE IS TO USE SC AND PROTEOMIC STRATEGIES TO MOLECULARLY ENDOTYPE GLY-TARGETED PATHWAYS OF CONTUSION EXPANSION IN HUMAN TBI. THE RATIONALE IS THAT IT ALLOWS US TO BETTER UNDERSTAND HETEROGENEOUS BENEFITS AND OPPORTUNITIES OF GLY AND OPTIMIZE TRANSLATION: IT INFORMS CELLULAR ORIGINS OF KEY TARGETABLE AND MEASURABLE CONTUSION EXPANSION PATHWAYS. THE CENTRAL HYPOTHESIS IS THAT A SUBSET OF QUANTIFIABLE CELL-TYPE SPECIFIC DIFFERENTIALLY EXPRESSED GENES, PATHWAYS AND PROTEINS TARGETED BY GLY IDENTIFY RISK FOR TBI CONTUSION EXPANSION. AIM 1 DEMONSTRATES THAT CEREBROSPINAL FLUID (CSF) SC TRANSCRIPTOMIC SIGNATURES ENDOTYPE GLY-TARGETED CONTUSION EXPANSION IN HUMANS. AIM 2 DEMONSTRATES THAT CONTUSION EXPANSION IS PRECEDED BY GLY-TARGETABLE PROTEIN BIOMARKERS CHANGES. THE AIMS ARE SYNERGISTIC: CELL-TYPE DIFFERENTIAL GENE EXPRESSION (AIM 1) INFORMS LIKELY SOURCES OF MEASURABLE CSF BIOMARKERS (AIM 2) OF CONTUSION EXPANSION. THE WORK IS FEASIBLE GIVEN EXCITING PILOT DATA, AN EXISTING TBI BIOBANK, AN ESTABLISHED MULTIDISCIPLINARY TEAM AND BIOINFORMATIC PIPELINES. IT IS INNOVATIVE AS IT SHIFTS A GUIDELINE-BASED APPROACH TO PRECISION MEDICINE, CREATES A FIRST-IN-HUMAN ATLAS OF CSF SC RESPONSE IN TBI, AND IDENTIFIES CONTUSION EXPANSION BIOMARKERS IN PATHWAYS TARGETED BY A DRUG BEING TESTED IN HUMAN TBI. THE EXPECTED IMPACT INCLUDES MOLECULAR ENDOTYPE-BASED RISK-STRATIFICATION AND ENRICHED PATIENT- SELECTION FOR GLY TRIALS (HIGH RISK, PHARMACODYNAMIC RESPONSE). UNIQUE CELLULAR COMPONENTS THAT DRIVE CONTUSION EXPANSION COMBINED WITH EARLY CLINICALLY MEASURABLE CSF BIOMARKERS CAN GUIDE UNPRECEDENTED CELL- AND TARGET- PRECISE THERAPY INCLUDING NOVEL (PREVENTIVE) DRUGGABLE TARGETS. THIS LAYS THE FOUNDATION FOR A PARADIGM SHIFTING SC-BASED PRECISION MEDICINE APPROACH TO UNDERSTAND, MONITOR, AND TREAT A DEVASTATING SECONDARY INJURY IN TBI.

DEVELOPMENT OF NOVEL VIRAL VECTORS TO STUDY AND TREAT NEUROINFLAMMATION

CENTRAL IOWA COLLEGES' COORDINATED RESPONSE - A CONSORTIA PROPOSAL OF FOUR CENTRAL IOWA COLLEGES AND UNIVERSITIES

ALPHA-SYNUCLEIN IS CRUCIAL FOR NEURONAL FUNCTION AND SURVIVAL-CHARACTERIZATION OF A NOVEL CONDITIONAL ALPHA-SYNUCLEIN KNOCKOUT MOUSE MODEL

TRANSCRIPTOMIC ASSESSMENT OF PATHOLOGY IN PD WITH DEMENTIA AND DEMENTIA WITH LEWY BODIES USING IPSC NEURONS AND BRAIN TISSUE OF THE SAME INDIVIDUALS - PROJECT ABSTRACT LEWY BODY DEMENTIA (LBD) IS A SPECTRUM DISEASE THAT INCLUDES DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON’S DISEASE DEMENTIA (PDD). THE TWO DEMENTIAS SHARE NEUROPATHOLOGICAL CHARACTERISTICS OF ALPHA- SYNUCLEIN (A-SYN) INCLUSION IN SO CALLED LEWY BODIES, IN ADDITION TO VARIABLE PATHOLOGIES RELATED TO ALZHEIMER’S DISEASE – AMYLOID-BETA (AB) PLAQUES AND/OR NEUROFIBRILLARY TANGLES (NFT) OF HYPERPOSPHORYLATED TAU. ONE OF THE MOST DISTINCT DIFFERENCES BETWEEN PDD AND DLB IS THE TEMPORAL OCCURRENCE OF MOTOR IMPAIRMENTS RELATIVE TO COGNITIVE IMPAIRMENTS. THIS OFTEN CHALLENGES AN ACCURATE DIAGNOSIS AND CONSEQUENTLY APPROPRIATE PATIENT ENROLLMENT IN CLINICAL TRIALS, PATIENT CARE AND EXISTING SYMPTOMATIC TREATMENT. TO BETTER UNDERSTAND THE DISTINCT TEMPORAL PROGRESSION OF THESE TWO DEMENTIAS WE PROPOSE TO UTILIZE PATIENT-DERIVED INDUCED PLURIPOTENT STEM CELL (IPSC) CULTURE MODELS – A DISEASE MODEL SYSTEM THAT OFFERS PERSONALIZED PATIENT ANALYSES AND DRUG SCREENING. TO ENSURE THAT THIS MODEL SYSTEM ACCURATELY REFLECTS THE INDIVIDUAL PATIENT’S DISEASE PATHOGENESIS, WE PROPOSE TO GENERATE IPSCS DIFFERENTIATED INTO NEURONS FROM INDIVIDUALS FROM WHICH WE ALSO HAVE POSTMORTEM AUTOPSY TISSUE AVAILABLE. THIS PROVIDES US WITH THE UNIQUE OPPORTUNITY TO DIRECTLY COMPARE TRANSCRIPTOMICS AND DISEASE PATHOLOGY FROM BRAIN TISSUE AND DIFFERENTIATED IPSC-NEURONS FROM THE SAME INDIVIDUAL. IN ADDITION, WE ARE ABLE TO MONITOR AND CHARACTERIZE DISEASE PROGRESSION IN PDD COMPARED TO DLB IN A TEMPORAL MANNER. WE HYPOTHESIZE THAT IPSC-NEURONS FROM PDD PATIENTS WILL SHOW PHENOTYPIC DIFFERENCES IN THEIR TEMPORAL DISEASE PROGRESSION COMPARED TO DLB PATIENT IPSC-NEURONS. WE FURTHER HYPOTHESIZE THAT THERE ARE SIMILARITIES OF GENE EXPRESSION PROFILES AND DISEASE PATHOLOGIES BETWEEN DIFFERENTIATED IPSC-NEURONS AND PRIMARY AUTOPSY TISSUE OBTAINED FROM THE SAME INDIVIDUALS. TO TEST THIS HYPOTHESIS WE WILL PERFORM SINGLE NUCLEI MULTI-OMICS SEQUENCING (SNRNA- AND ATAC SEQ) FROM PDD, DLB AND HEALTHY CONTROL AUTOPSY BRAIN TISSUES (AIM 1). IN AIM 2, WE WILL DIFFERENTIATE PDD AND DLB IPSCS (FROM THE SAME INDIVIDUALS AS AIM 1) INTO CORTICAL FOREBRAIN NEURONS TO GENERATE A DISEASE-SPECIFIC NEURONAL TRANSCRIPTOME PROFILE AND TO EXAMINE PD AND DEMENTIA-RELATED DISEASE PHENOTYPES. THESE STUDIES WILL FOR THE FIRST TIME STUDY THE TRANSCRIPTOME PROFILE OF PDD AND DLB, EXAMINE CELLULAR DISEASE PHENOTYPES IN A TEMPORAL MANNER AND ADDRESS THE DISEASE MECHANISMS OF LBD IN THIS SPECTRUM DISORDER. ADDITIONALLY, THIS WORK WILL PROVIDE NOVEL OPPORTUNITIES FOR DRUG TARGET IDENTIFICATION WITH THE HOPE OF IDENTIFYING NOVEL THERAPEUTICS AND BIOMARKERS SPECIFIC FOR EACH OF THE TWO DISORDERS. THIS IN RETURN WILL FACILITATE THE MUCH- NEEDED IMPROVEMENT OF DISEASE DIAGNOSIS AND MANAGEMENT OF PDD AND DLB PATIENTS.

NOVEL KNOCK-IN MOUSE MODELS OF ALS AND MYOPATHY-LINKED MATRIN 3 MUTATIONS

INVESTIGATING THE ROLE OF CEREBRAL PERFUSION IN DEMYELINATION AND REPAIR IN MULTIPLE SCLEROSIS WITH MRI - PROJECT SUMMARY / ABSTRACT: MULTIPLE SCLEROSIS IS A CHRONIC, DEBILITATING DISEASE OF THE CENTRAL NERVOUS SYSTEM CHARACTERIZED BY NEUROINFLAMMATION, FOCAL DEMYELINATION, GLIOSIS, AXONAL DEGENERATION, AND NEURONAL LOSS. AS REMYELINATION IS BOTH HIGHLY VARIABLE AND ASSOCIATED WITH IMPROVEMENT OF SYMPTOMS, THERAPIES THAT FOSTER REMYELINATION REPRESENT AN OPPORTUNITY FOR REPAIR PRIOR TO IRREVERSIBLE DAMAGE AND DECLINE. GIVEN THE IMPORTANCE OF MYELINATION, MAGNETIC RESONANCE IMAGING (MRI) BIOMARKERS OF MYELIN INTEGRITY HAVE BEEN DEVELOPED FOR USE IN CLINICAL TRIALS. UNFORTUNATELY, THESE BIOMARKERS REFLECT STATIC LEVELS OF MYELIN AND CANNOT PREDICT DEMYELINATION OR REMYELINATION PROCESSES. RECENT STUDIES HAVE SUGGESTED THAT REMYELINATION RELIES ON ADEQUATE TISSUE PERFUSION. WHILE ALTERED PERFUSION HAS BEEN REPORTED IN MS, THE RELATIONSHIP BETWEEN PERFUSION AND MYELIN HAS NOT BEEN FULLY CHARACTERIZED IN VIVO. FURTHERMORE, WHETHER PERFUSION MRI BIOMARKERS CAN PREDICT DOWNSTREAM MYELIN REPAIR REMAINS AN OUTSTANDING QUESTION. THIS PROPOSAL AIMS TO OVERCOME THIS CHALLENGE BY INVESTIGATING THE ROLE OF PERFUSION IN DEMYELINATION AND REMYELINATION USING MRI BIOMARKERS. THE DEVELOPMENT OF BIOMARKER ASSAYS TO QUANTITATIVELY PROBE BOTH PERFUSION AND MYELIN CONTENT MAY PREDICT REGENERATIVE POTENTIAL AND EVALUATE EMERGING THERAPIES THAT PROMOTE NEUROPROTECTION AND REMYELINATION. TO ASSAY PERFUSION CHANGES, A MULTI-CONTRAST SPIN- AND GRADIENT-ECHO (SAGE) MRI METHOD ENABLES EVALUATION OF HEMODYNAMIC MEASURES AT DISTINCT VASCULAR SCALES (I.E., TOTAL VASCULAR AND MICROVASCULAR REGIMES). GIVEN THE KNOWN MICROVASCULAR COMPONENT OF MS, THE ABILITY TO SPECIFICALLY QUANTIFY MICROVASCULAR FUNCTION MAY PROVIDE A MORE SPECIFIC INDICATOR OF UNDERLYING PATHOLOGY. MYELIN CONTENT CAN BE ASSAYED USING A SELECTIVE INVERSION RECOVERY (SIR) METHOD THAT PROVIDES QUANTITATIVE AND RELIABLE MEASURES OF MYELIN. THE OBJECTIVE OF THIS STUDY IS TO DETERMINE WHETHER VASCULAR FUNCTION IS INDICATIVE OF LESION DEMYELINATION AND REMYELINATION. MORE SPECIFICALLY, THIS PROJECT AIMS TO A) ESTABLISH THE RELATIONSHIP BETWEEN PERFUSION AND MYELIN IN PERSONS WITH RELAPSING-REMITTING MS (PWMS) AND IN HEALTHY CONTROLS; B) ESTABLISH NORMATIVE VALUES IN HEALTHY CONTROLS AND TEST-RETEST REPEATABILITY IN BOTH HEALTHY CONTROLS AND PWMS WITH STABLE DISEASE; AND C) ASSESS WHETHER LESION PERFUSION PREDICTS DEMYELINATION AND REMYELINATION IN PWMS WITH ACTIVE LESIONS. IF SUCCESSFUL, THIS APPROACH WILL ESTABLISH THE ROLE OF MICROVASCULAR CHANGES AS A PRECURSOR OF DISEASE AND PROGNOSTICATOR OF OUTCOMES, AS WELL AS PROVIDE POTENTIAL TREATMENT TARGETS RELATED TO PREVENTING MICROVASCULAR DYSFUNCTION AND ITS DOWNSTREAM EFFECTS. THE DEVELOPMENT OF ROBUST MRI BIOMARKER ASSAYS THAT QUANTITATIVELY PROBE BOTH PERFUSION AND MYELIN CONTENT COULD MORE RELIABLY, AND WITH GREATER BIOSPECIFICITY, ASSESS REGENERATIVE POTENTIAL AND THERAPEUTIC RESPONSE, THUS FILLING A CRITICAL GAP IN BOTH PATIENT CARE AND CLINICAL TRIALS DESIGNED TO EVALUATE EMERGING NEUROPROTECTIVE AND REMYELINATING THERAPIES. MOREOVER, THIS APPROACH MAY PROVIDE INSIGHT INTO THE COMPLEX FACTORS THAT CONTRIBUTE TO BOTH LESION FORMATION AND RESOLUTION.

RIC THERAPY-MEDIATED NEUROPROTECTION IN EYE TRAUMA

TELEHEALTH NETWORK GRANT PROGRAM

CARES ACT, UNMET NEEDS RELATED TO EXPENSES ASSOCIATED WITH CORONAVIRUS

MECHANISMS OF A-I RNA EDITING-MEDIATED NUCLEAR EXPORT OF TDP-43 - TAR DNA BINDING PROTEIN – 43 (TDP-43) IS A CRITICAL RNA BINDING PROTEIN THAT IS INTIMATELY INVOLVED IN MANY ASPECTS OF RNA METABOLISM. WHILE PRIMARILY LOCALIZED TO THE NUCLEUS, TDP-43 SHUTTLES BETWEEN THE NUCLEUS AND THE CYTOPLASM PERFORMING ITS PHYSIOLOGICAL FUNCTIONS. AS AN AGGREGATION PRONE PROTEIN, TDP-43 IS KNOWN TO ACCUMULATE AND FROM PRION-LIKE SOLID AGGREGATES IN THE CYTOPLASM OF CELLS LEADING TO THE SEQUESTRATION OF NUCLEAR TDP-43. THIS BEHAVIOR OF TDP-43 HAS BEEN WELL ESTABLISHED AS A PATHOLOGICAL HALLMARK OF A NEURODEGENERATIVE DISEASE SPECTRUM ENCOMPASSING AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEMENTIA (ALS/FTD) AND HAS BEEN DESCRIBED IN ALZHEIMER’S DISEASE AND RELATED DEMENTIAS. PATHOLOGICAL CYTOPLASMIC TDP-43 INCLUSIONS HAVE BEEN HYPOTHESIZED TO CONTRIBUTE TO DISEASE PATHOGENESIS THROUGH BOTH A NUCLEAR DEPLETION AND THE CYTOPLASMIC AGGREGATION. DESPITE EXTENSIVE RESEARCH, MECHANISMS THAT INITIATE THIS PATHOLOGY UNDER DISEASE CONDITIONS REMAIN ELUSIVE. RECENT STUDIES IN OUR LABORATORY SHOWED THAT ABERRANT RNA A-I EDITING IS PRESENT IN MULTIPLE BRAIN REGIONS OF C9ORF72 ALS/FTD, WHERE WE DETECTED BIDIRECTIONAL CHANGES IN A-I EDITING. SINCE THEN, WE HAVE GENERATED PRELIMINARY DATA SUGGESTING THAT TDP-43 NUCLEAR EXPORT CAN BE REGULATED VIA ADENOSINE DEAMINASE ACTING ON DOUBLE STRANDED RNA (ADAR)-MEDIATED A-I RNA EDITING. WE SHOW THAT ENHANCING RNA A-I EDITING THROUGH ADAR2 OVEREXPRESSION IN MAMMALIAN CELL LINES INDUCES TDP-43 TRANSLOCATION TO THE CYTOPLASM REQUIRING FUNCTIONAL RNA BINDING DOMAINS OF TDP-43. IN CONTRAST, THE OVEREXPRESSION OF CATALYTICALLY INACTIVE ADAR2 DOES NOT ALTER THE NUCLEAR LOCALIZATION OF TDP-43. THESE FINDINGS LED US TO HYPOTHESIZE THAT ABERRANT INCREASES IN A-I EDITING INDUCES TDP-43 CYTOPLASMIC MISLOCALIZATION THROUGH AN RNA DEPENDENT MECHANISM. TO DETERMINE IF THIS EDITING INDUCED TDP-43 NUCLEAR EXPORT ALSO OCCURS IN A NEURONAL ENVIRONMENT, WE WILL EXPAND ON OUR PRELIMINARY DATA AND EXAMINE HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC) DIFFERENTIATED INTO MOTOR NEURONS FOR A-I EDITING-MEDIATED TDP-43 NUCLEAR EXPORT. WE WILL VALIDATE A-I RNA EDITING MEDIATED CYTOPLASMIC ACCUMULATION OF TDP-43 IN IPSC-MNS EXPRESSING DOXYCYCLINE INDUCIBLE TET-ON ADAR2 CONSTRUCTS: WILDTYPE ADAR2, A CATALYTICALLY INACTIVE ADAR2 (ADAR2E396A) AND A CATALYTICALLY HYPERACTIVE ADAR2 (ADAR2E488Q). TO ADDRESS THE EFFECTS OF RNA-EDITING INDUCED TDP-43 MISLOCALIZATION ON TDP-43 FUNCTION, WE WILL EXAMINE TDP-43 INCLUSIONS FOR DISEASE-RELEVANT CHARACTERISTICS (AIM1). TO DETERMINE THE IDENTITY OF MRNAS BOUND TO TDP-43 AND POTENTIALLY BEING NECESSARY FOR A-I RNA EDITING-MEDIATED MISLOCALIZATION, WE WILL PERFORM ECLIP-SEQ ON IPSC-MNS GENETICALLY ALTERED FOR HYPO AND HYPER-EDITING AS DESCRIBED IN AIM1. IN ADDITION, WE WILL PERFORM ECLIP IN C9ORF72 IPSC-MNS TO COMPARE RNA-EDITING INDUCED TDP-43 BOUND TRANSCRIPTS TO THOSE ASSOCIATED WITH ENDOGENOUS DISEASE (AIM 2). FINALLY, IN AIM 3, WE WILL PERFORM EXPLORATORY STUDIES TOWARDS THE IDENTIFICATION OF MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THIS NEW PATHWAY OF TDP-43 NUCLEAR EXPORT USING STABLY TRANSDUCED SH-SY5Y CELLS EXPRESSING THE DOXYCYCLINE-INDUCED TET-ON ADAR2 CONSTRUCTS DESCRIBED ABOVE.

RURAL HEALTH CLINIC VACCINE CONFIDENCE PROGRAM

MINNESOTA PREVENTION ALLIANCE IS A MINNESOTA STATEWIDE COALITION - A COLLABORATION OF COMMUNITIES, AGENCIES, AND ORGANIZATIONS FOR STATEWIDE YOUTH SUBSTANCE USE PREVENTION STRATEGIES.

SINGLE-CELL RNA-SEQ AND CLONAL ANALYSIS OF B CELLS IN MS

FUNDS TO BE USED TO HELP THE INSTITUTIONS AND TITLE-IV-ELIGIBLE STUDENTS WITH COSTS RELATED TO CORONA VIRUS,

HUBBARD COUNTY YOUTH SUBSTANCE USE PREVENTION PROJECT

RYAN WHITE HIV/AIDS PROGRAM PART C EIS COVID-19 RESPONSE

CIRCADIAN REGULATION OF THE DORSOMEDIAL HYPOTHALAMIC NUCLEUS AND ITS IMPACT ON ENERGY HOMEOSTASIS - PROJECT SUMMARY SYSTEMS REGULATING CIRCADIAN TIMING AND ENERGY HOMEOSTASIS ARE TIGHTLY INTEGRATED, AND INCREASING EVIDENCE SUGGESTS THAT CIRCADIAN DISRUPTION (E.G., INDUCED BY SLEEP RESTRICTION, OR EATING DURING THE NORMAL RESTING PERIOD) PREDISPOSES TO OBESITY AND METABOLIC SYNDROME IN HUMANS. THUS, AN IMPROVED UNDERSTANDING OF THE NEUROBIOLOGICAL DETERMINANTS OF FEEDING TIME HAS DIRECT TRANSLATION TO HUMAN HEALTH AND MAY INFORM NOVEL THERAPEUTIC AND DIETARY STRATEGIES TO COMBAT METABOLIC DYSFUNCTION. IN MAMMALS, CIRCADIAN RHYTHMS OF METABOLISM AND BEHAVIOR ARE ORGANIZED BY THE LIGHT-CONTROLLED “MASTER CLOCK” LOCATED IN THE HYPOTHALAMIC SUPRACHIASMATIC NUCLEUS (SCN). IN HARMONY WITH ENVIRONMENTAL LIGHT-DARK CYCLES, THIS BIOLOGICAL PACEMAKER EXPRESSES RHYTHMIC NEURONAL AND MOLECULAR ACTIVITY THAT ENCODES AND TRANSMITS TIME CUES TO DOWNSTREAM BRAIN AREAS AND SUBORDINATE CLOCKS TO ALIGN THEIR ACTIVITY. HOWEVER, HOW RHYTHMIC OUTFLOW FROM THE SCN IS DECODED TO ALIGN DIVERSE PHYSIOLOGICAL AND BEHAVIORAL PROCESSES, INCLUDING FEEDING, IS POORLY UNDERSTOOD. AMONG DOWNSTREAM TARGETS OF THE SCN IMPLICATED IN FEEDING IS THE DORSOMEDIAL HYPOTHALAMIC NUCLEUS (DMH). OUR RECENT FINDINGS SUGGEST THAT THE ACTIVITY OF DMH NEURONS EXPRESSING THE LEPTIN RECEPTOR (DMHLEPR) IS CRITICAL FOR THE CONSOLIDATION OF FEEDING TO THE APPROPRIATE PHOTOPERIOD IN MICE, SUCH THAT INACTIVATION OF DMHLEPR NEURONS PROMOTES OBESITY AND INCREASED LIGHT-CYCLE INTAKE IN BOTH MALE AND FEMALE MICE. OUR PRELIMINARY DATA FURTHER SHOW THAT DMHLEPR NEURONS RECEIVE INPUT FROM THE SUBPARAVENTRICULAR ZONE (SPZ), A CRITICAL RELAY OF CIRCADIAN TIMING FROM THE SCN, AND EXHIBIT DIURNAL VARIATION IN BASAL AND FOOD-EVOKED ACTIVITY. BASED ON THESE OBSERVATIONS, WE HYPOTHESIZE THAT DMHLEPR NEURONS INTEGRATE CLOCK TIME AND SENSORY INPUTS REGARDING FOOD AVAILABILITY TO REGULATE DAILY FEEDING TIME IN MICE. AS A FIRST STEP TO UNDERSTANDING HOW DMHLEPR NEURONS ARE REGULATED, WE PROPOSE TO FIRST IDENTIFY AND CHARACTERIZE NEURAL AFFERENTS BY BOTH HISTOLOGY AND CHANNELRHODOPSIN-ASSISTED CIRCUIT MAPPING (CRACM). WE WILL NEXT EVALUATE WHETHER AFFERENT INPUT FROM THE SPZ, WHICH PUTATIVELY CONVEYS CLOCK TIME FROM THE SCN, IS REQUIRED FOR NORMAL CIRCADIAN FEEDING AND METABOLISM IN MICE. TO BETTER UNDERSTAND HOW DMHLEPR ACTIVITY MAY REGULATE FEEDING BEHAVIORS, WE WILL CHARACTERIZE THE TEMPORAL ACTIVITY DYNAMICS OF THIS POPULATION VIA BOTH IN VITRO AND IN VIVO MULTI-UNIT ELECTROPHYSIOLOGY APPROACHES. FINALLY, WE WILL EXAMINE HOW DMHLEPR ACTIVITY IS INFLUENCED BY ALTERED FEEDING AND LIGHTING SCHEDULES, AND THE REQUIREMENT OF SPZ INPUT FOR THESE EFFECTS. THIS WORK IS EXPECTED TO IMPROVE OUR UNDERSTANDING OF THE NEURAL NETWORKS UNDERLYING ENDOGENOUS RHYTHMS IN BEHAVIOR, FEEDING, AND METABOLISM, AND THEREBY INFORM THE DEVELOPMENT OF NEW THERAPEUTIC AND DIETARY STRATEGIES FOR THE TREATMENT OF HUMANS WITH METABOLIC DYSFUNCTION.

FINANCIAL AID GRANTS TO STUDENTS FOR EXPENSES RELATED TO DISRUPTION OF CAMPUS OPERATIONS DUE TO CORONAVIRUS

RURAL HEALTH CLINIC VACCINE CONFIDENCE PROGRAM

RURAL HEALTH CLINIC VACCINE CONFIDENCE PROGRAM

CHI HEALTH SCHOOL OF RADIOLOGIC TECHNOLOGY - INSTITUTION CARE ACT FUNDING: CARE ACT FUNDING TO BE ALLOCATED FOR COSTS INCURRED FOR MOODLE PLATFOOM AND PERSONNAL PROTECTIVE EQUIPMENT FOR STUDENTS.

MICROGLIA- ASTROCYTE CROSSTALK IN CORTICAL NEURODEGENERATION OF C9ORF72 ALS/FTD - PROJECT ABSTRACT AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE CHARACTERIZED BY LOSS OF SPINAL CORD AND CORTICAL MOTOR NEURONS, AND FRONTOTEMPORAL DEMENTIA (FTD) IS AN EARLY-ONSET DEMENTIA SYNDROME CAUSED BY THE DEGENERATION OF THE FRONTAL AND TEMPORAL LOBES. THE MOST COMMON GENETIC CAUSE OF BOTH THESE DISEASES IS THE GGGGCC(G4C2) HEXANUCLEOTIDE REPEAT EXPANSION (HRE) IN THE FIRST INTRON OF THE C9ORF72. MUCH OF THE KNOWLEDGE IN C9ORF72-ALS/FTD DISEASE PATHOGENESIS THUS FAR HAS COME THROUGH INVESTIGATIONS OF NEURONAL DISEASE MECHANISMS. DESPITE THE LARGE EVIDENCE OF THE ACTIVE INVOLVEMENT OF GLIAL CELLS IN NEURODEGENERATION, LITTLE IS KNOWN ABOUT THE SPECIFIC MECHANISMS. ONE QUESTION THAT REMAINS UNANSWERED IS WHETHER A GLIA-GLIA INTERACTION IS REQUIRED TO INITIATE NEURODEGENERATION, OR DO ASTROCYTES AND MICROGLIA INDEPENDENTLY CONTRIBUTE TO THIS PROCESS? WE HAVE SHOWN AN ALTERED EXPRESSION PROFILE OF MICROGLIA AND ASTROCYTES IN THE FRONTAL CORTEX OF C9ORF72 ALS/FTD PATIENTS. ADDITIONALLY, IN OUR IPSC MODELING SYSTEM WE HAVE SEEN ABERRANT EXPRESSION OF THE NLRP3 INFLAMMASOME IN MICROGLIA AND ASTROCYTES. THESE FINDINGS LEAD TO THE FOLLOWING HYPOTHESIS: MICROGLIA- ASTROCYTE CROSSTALK UNDERLIES A CHRONIC PRO-INFLAMMATORY STATE IN C9ORF72 ALS/FTD. TO INVESTIGATE THIS KNOWLEDGE GAP, WE WILL UTILIZE STATE OF THE ART HUMAN IN VITRO CULTURE SYSTEMS, WHICH OFFER OPPORTUNITIES FOR EASY CELL-TYPE SPECIFIC MANIPULATIONS AND ANALYSES WHILE WORKING WITH HUMAN PATIENT-DERIVED CELLS. WE WILL UTILIZE MONO-CULTURE SYSTEMS TO ASSESS MORPHOLOGICAL, FUNCTIONAL, RNA, AND PROTEIN CHANGES. WE WILL VALIDATE OUR IN VITRO FINDINGS USING ALS/FTD PATIENT BRAIN TISSUES ON BOTH THE RNA AND PROTEIN LEVELS WITH THE INTENT OF UNDERSTANDING THE CELL-TO-CELL REGULATORY MECHANISMS OF GLIA AND THEIR CONTRIBUTION TO DISEASE PATHOLOGY. THESE STUDIES WILL PROVIDE NOVEL MOLECULAR TARGETS AND BIOMARKERS OF DISEASE.

CHI HEALTH SCHOOL OF RADIOLOGIC TECHNOLOGY - STUDENT CARE ACT FUNDING. EACH STUDENT WILL RECEIVE EQUAL FUNDING FROM THE CARE ACT FUNDING.

DLT OPIOID GRANTS

RURAL HEALTH CLINIC VACCINE CONFIDENCE PROGRAM

RURAL COMMUNITIES OPIOID RESPONSE-IMPLEMENTATION

SMALL HEALTH CARE PROVIDER QUALITY IMPROVEMENT

RURAL HEALTH CARE SERVICES OUTREACH GRANT PROGRAM

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