Seattle Institute For Biomedical And Clinical Research

DEMENTIA WITH LEWY BODIES CONSORTIUM

POST-DDP FOLLOW-UP STUDY

OPTIMIZING RECOVERY AND PRESERVATION OF ENDOGENOUS INSULIN SECRETION

LOOK AHEAD: ACTION FOR HEALTH IN DIABETES

PREVENTION OF ALZHEIMER DEMENTIA AND COGNITIVE DECLINE

DEVELOPING NEUROPROTECTIVE STRATEGIES FOR PROTEINOPATHY: A COMPARATIVE MODELING

PRAZOSIN FOR PROPHYLAXIS OF CHRONIC POST-TRAUMATIC HEADACHES IN OEF/OIF/OND SERVICE MEMBERS AND VETERANS WITH MILD TBI

DEFINING THE ROLE OF POST-TBI SLEEP DISRUPTION IN THE DEVELOPMENT OF CTE AND ALZHEIMER'S DISEASE-RELATED NEUROPATHOLOGY - ABSTRACT MILD TRAUMATIC BRAIN INJURY (MTBI, CONCUSSION) HAS EMERGED AS A RISK FACTOR FOR THE DEVELOPMENT OF NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER’S DISEASE (AD) AND CHRONIC TRAUMATIC ENCEPHALOPATHY, WHICH ARE CHARACTERIZED BY THE ABERRANT AGGREGATION OF TAU WITHIN NEURAL CELLS. HOWEVER, THE MECHANISMS LINKING MTBI TO AD-RELATED PATHOLOGY LATER IN LIFE REMAIN UNKNOWN. DISRUPTION OF THE SLEEP-WAKE CYCLE (SWD) IS A FREQUENT CHRONIC COMPLAINT AFTER MTBI AND ALSO ACCOMPANIES THE DEVELOPMENT OF AD. MORE RECENT CLINICAL AND TRANSLATIONAL RESEARCH SUGGESTS THAT SWD MAY ACTUALLY PROMOTE THE DEVELOPMENT OF ALZHEIMER’S-RELATED PATHOLOGY. OUR PRELIMINARY DATA SHOW THAT SLEEP DISTURBANCE IS SIGNIFICANTLY ASSOCIATED WITH LOWER CSF ASS42 LEVELS (AN AD-ASSOCIATED PROFILE) IN VETERANS WITH MTBI >45 YEARS OF AGE. BASED ON THESE FINDINGS, WE PROPOSE THAT POST-TBI SLEEP DISRUPTION PROMOTES THE DEVELOPMENT OF AD-RELATED PATHOLOGY FOLLOWING MTBI. THIS WILL BE DIRECTLY TESTED IN AIM 1. THE GLYMPHATIC SYSTEM IS A RECENTLY CHARACTERIZED BRAIN-WIDE NETWORK OF PERIVASCULAR SPACES THAT SUPPORTS THE CLEARANCE OF BOTH ASS AND TAU. GLYMPHATIC FUNCTION IS GREATEST DURING SLEEP AND IS IMPAIRED BY TBI. OUR PUBLISHED AND PRELIMINARY DATA SHOW THAT MRI-VISIBLE PERIVASCULAR SPACE BURDEN (MV-PVS), A PUTATIVE MARKER OF GLYMPHATIC IMPAIRMENT, IS INCREASED AMONG VETERANS WITH BLAST MTBI AND THAT THESE CHANGES ARE ASSOCIATED WITH AD-RELATED CSF BIOMARKER PROFILES. IN AIM 2, WE WILL USE NOVEL MRI-BASED APPROACHES TO TEST WHETHER GLYMPHATIC IMPAIRMENT PREDICTS THE DEVELOPMENT OF AD-RELATED PATHOLOGY AFTER BLAST MTBI. SLEEP-WAKE BEHAVIOR IS REGULATED THROUGH CENTRAL NORADRENERGIC (NA) NEUROTRANSMISSION, WITH LOCUS COERULEUS (LC)-DERIVED NOREPINEPHRINE (NE) PROMOTING AROUSAL DURING WAKING. IN OUR BLAST MTBI VETERANS, CSF NE WAS ELEVATED COMPARED TO CONTROLS AND ASSOCIATED WITH POOR SLEEP. HOWEVER, THE ROLE THAT CHANGES IN CENTRAL NA SIGNALING PLAY IN PROMOTING AD-RELATED PATHOLOGY FOLLOWING TBI IS UNKNOWN. IN AIM 3 WE WILL TEST WHETHER CHANGES IN MEASURES OF CENTRAL NA TONE PREDICT THE DEVELOPMENT OF AD-RELATED PATHOLOGY AFTER BLAST MTBI. DR. PESKIND’S 10-YEAR LONGITUDINAL VA COHORT WILL CONTRIBUTE 70 PREVIOUSLY- AND NEWLY-ENROLLED VETERANS >45 YEARS OF AGE WITH A HISTORY OF REPETITIVE BLAST MTBIS WHO WILL UNDERGO ASSESSMENT OF: SUBJECTIVE AND OBJECTIVE SLEEP; MULTI-DOMAIN CLINICAL BEHAVIORAL, NEUROLOGICAL, AND NEUROCOGNITIVE ASSESSMENT; GLYMPHATIC FUNCTION MEASURED BY MRI, AND MEASUREMENT OF CSF/PLASMA AD/CTE-RELATED BIOMARKERS AND NE. AIM 1. DEFINE THE ROLE OF SLEEP DISRUPTION IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY. AIM 2. DEFINE THE ROLE OF GLYMPHATIC DYSFUNCTION IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY. AIM 3. DEFINE THE ROLE OF ALTERATIONS IN CENTRAL NA TONE IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY AFTER TBI.

ROLE OF ASTROCYTE EAAT2/GLT1 FAILURE IN ALZHEIMER'S DISEASE PATHOGENESIS - ASTROCYTES ARE IDEALLY POSITIONED TO SUPPORT NEURONAL/SYNAPTIC NEEDS FOR TROPHIC FACTORS, METABOLIC HOMEOSTASIS, AND PROTECTION FROM TOXICITY. WHILE REACTIVE ASTROGLIOSIS IS A PROMINENT FEATURE OF AD, THIS OFFERS VERY LIMITED INSIGHT ABOUT HOW ASTROCYTES INFLUENCE THE DISEASE PROCESS OR HOW THEY MAY BE HARMED. ONE OF THE MOST IMPORTANT FUNCTIONS OF ASTROCYTES IS TO CLEAR EXTRACELLULAR GLUTAMATE TO PREVENT EXCITOTOXICITY. GLUTAMATE TAKEN UP BY ASTROCYTES IS ALSO USED AS A METABOLIC SUBSTRATE FOR BIOSYNTHESIS OF OTHER NEURO- TRANSMITTERS LIKE GABA. THUS, THERE ARE AT LEAST TWO MAJOR WAYS ASTROCYTIC GLUTAMATE CLEARANCE PROTECTS THE BRAIN. IN CORTEX AND HIPPOCAMPUS, THE GLUTAMATE TRANSPORTER SLC1A2 (ALSO CALLED GLT1 OR EAAT2) PLAYS THE MOST IMPORTANT ROLE IN GLUTAMATE CLEARANCE. MOST, BUT NOT ALL SLC1A2 IS IN ASTROCYTES. OUR RESEARCH TEAM HAS SHOWN THAT: (I) SLC1A2 IS DISTURBED IN AD; (II) SLC1A2 LOSS IN AN AD MOUSE MODEL ACCELERATES ONSET OF COGNITIVE IMPAIRMENT; (III) A42 SLOWS SYNAPTICALLY-RELEASED GLUTAMATE UPTAKE IN HIPPO- CAMPAL SLICES; AND (IV) MICE WITH REDUCED ASTROCYTIC SLC1A2 DISPLAY SIGNIFICANT TRANSCRIPTOMIC OVERLAPS WITH AD. THESE DATA COMPLEMENT STRONG WORK FROM OTHER GROUPS AND COLLECTIVELY ARGUE THAT SLC1A2 DYSFUNCTION MAY PLAY AN IMPORTANT ROLE IN AD. HOWEVER, ADDITIONAL CRITICAL QUESTIONS NEED TO BE ANSWERED TO BETTER UNDERSTAND HOW ASTROCYTIC SLC1A2 MAY INTERACT WITH A42 AND TAU PATHOLOGY. SPECIFICALLY, IS THERE PATHOGENIC SYNERGY AMONG THESE PROCESSES? IN AD MORE NEEDS TO BE UNCOVERED ABOUT THE RELATIONSHIP BETWEEN NEURONS AND THE FINE (OFTEN GFAP-NEGATIVE) ASTROCYTIC PROCESSES EXPRESSING NEARLY ALL SLC1A2 IN THE BRAIN—AN ANATOMICAL RELATIONSHIP THAT IS CRUCIAL TO THEIR FUNCTION. IN ADDITION, THERE IS INSUFFICIENT DATA SUPPORTING THE HYPOTHESIS THAT ASTROCYTIC SLC1A2 CAN PLAY A CONTRIBUTING OR CAUSAL ROLE IN EXACERBATING A42 AND TAU PATHOLOGY. THE GOAL OF THIS PROJECT IS TO FILL THESE KNOWLEDGE GAPS. FIRST, WE WILL USE NOVEL MICE WITH REDUCED SLC1A2 SPECIFICALLY IN ASTROCYTES; AND WITH ADENOVIRAL VECTORS (AAVS) EXPRESSING A42 AND TAUP301L, DISSECT THE IN VIVO MOLECULAR INTERACTIONS BETWEEN THESE PATHOGENIC PATHWAYS. WE WILL ADDRESS WHETHER ASTROCYTES ARE LOST IN RESPONSE TO A42 AND/OR TAU. WE WILL USE A NOVEL LENTIVIRUS SYSTEM EXPRESSING SLC1A2, WHICH INFECTS ASTROCYTES, TO TEST WHETHER SPECIFICALLY RESCUING ASTROCYTIC SLC1A2 AMELIORATES NEUROPATHOLOGY, AS WELL AS SLC1A2 FUNCTION. SECOND, USING STATE-OF-THE ART PATCH CLAMP METHODS THAT DIRECTLY MEASURE ASTROCYTE GLUTAMATE CLEARANCE, DISSECT HOW SLC1A2 LOSS, A42, AND TAU EXPRESSION INTERACT TO AFFECT ASTROCYTIC GLUTAMATE CLEARANCE. WE WILL ADDRESS HOW THESE PATHOGENIC PROCESSES INFLUENCE ASTROCYTIC SLC1A2 THAT REGULATE SYNAPTIC NETWORK EXCITABILITY BY SUPPORTING GABAERGIC TRANSMISSION. THIRD, USING WELL-CHARACTERIZED POSTMORTEM BRAINS FROM CONTROL, PRODROMAL, AND AD PATIENTS WE WILL TEST THE POTENTIAL TRANSLATIONAL SIGNIFICANCE OF THE GLUTAMATE TRANSPORTER AND ASTROCYTE NEUROPATHOLOGY WE HAVE REPORTED AND IS SUGGESTED BY OUR NEW PRELIMINARY DATA. TOGETHER, THESE DATA HOLD PROMISE OF ADVANCING OUR KNOWLEDGE OF SLC1A2 AS A POTENTIAL MOLECULAR TARGET FOR INTERVENTION IN AD.

IMPROVING CANCER-RELATED FATIGUE, SEXUAL DYSFUNCTION AND QUALITY OF LIFE IN OLDER MEN WITH CANCER AND ANDROGEN DEFICIENCY

IMPROVING PATIENT-IMPORTANT OUTCOMES WITH TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN WITH A PRIOR HISTORY OF CANCER

MSUT2 MODULATES PATHOLOGICAL TAU IN AD AND MODEL ORGANISMS

IMPROVING THE REACH AND EFFECTIVENESS OF SMOKING CESSATION SERVICES TARGETED TO VETERANS LIVING WITH HIV

ISLET ENDOTHELIAL DYSFUNCTION IN DIABETES

ADVANCING HIGH QUALITY COPD CARE FOR PEOPLE WITH IMMUNE DYSFUNCTION BY IMPLEMENTING EVIDENCE-BASED MANAGEMENT THROUGH PROACTIVE E-CONSULTS (ACHIEVE)

PROSTHETIC KNEE-ANKLE-FOOT SYSTEM WITH BIOMECHATRONIC SENSING, CONTROL, AND POWER GENERATION

PROTECTION FROM PATHOLOGICAL TAU BY ACTIVATION OF THE ER UNFOLDED PROTEIN RESPONSE

TDP-43 IN ALZHEIMER'S DISEASE - ALZHEIMER’S DISEASE, A SEVERE PROGRESSIVE NEURODEGENERATIVE DISEASE OF AGING AND THE MOST COMMON FORM OF DEMENTIA, AFFECTS AN ESTIMATED 30 MILLION PEOPLE WORLDWIDE. PATHOLOGICALLY, ALZHEIMER’S DISEASE IS DEFINED BY THE PRESENCE OF BOTH AMYLOID PLAQUES COMPRISED OF THE PROTEIN AMYLOID-SS (ASS) AND NEUROFIBRILLARY TANGLES CONTAINING THE PROTEIN TAU IN DISEASE AFFECTED BRAIN REGIONS. HOWEVER, 30-57% OF ALZHEIMER’S DISEASE PATIENTS ALSO EXHIBIT TDP-43 AGGREGATES AS AN ADDITIONAL CO-PATHOLOGY. THE PRESENCE OF TDP-43 PATHOLOGY IN ALZHEIMER’S DISEASE CORRELATES WITH HIPPOCAMPAL SCLEROSIS, WORSE BRAIN ATROPHY, MORE SEVERE COGNITIVE IMPAIRMENT, AND MORE RAPID COGNITIVE DECLINE. GIVEN THE RECENT RECOGNITION OF TDP-43 AS A FREQUENT CO- PATHOLOGY IN ALZHEIMER’S DISEASE, UNDERSTANDING ITS CONTRIBUTION TO NEURODEGENERATIVE DISEASE PROCESSES AND POTENTIAL SYNERGIES WITH OTHER PATHOLOGICAL DISEASE-PROMOTING PROTEINS IS A CRITICAL NEED IN THE FIELD. RECENT WORK USING C. ELEGANS FOUND THAT CO-EXPRESSED TAU AND TDP-43 LEADS TO INCREASED NEUROTOXICITY AND PATHOLOGICAL PROTEIN ACCUMULATION. BUILDING ON THIS FOUNDATION, THE PROPOSED AIMS WILL DEVELOP AND UTILIZE NEW TRACTABLE MODELS OF CO-EXPRESSED TAU AND TDP-43 IN ORDER TO UNDERSTAND THE BIOLOGY UNDERLYING THEIR TOXICITY. AIM 1 WILL DEFINE CONSEQUENCES OF LOW OR REGULATABLE LEVELS OF CO-EXPRESSED TAU AND TDP-43 USING BEHAVIORAL AND NEUROIMAGING ASSAYS, AND TEST RELATIONSHIPS BETWEEN TAU AND TDP-43. AIMS 2 AND 3 WILL EMPLOY RNA SEQUENCING TO REVEAL GENE EXPRESSION UNDERLYING COMORBID TAU AND TDP-43 THROUGH AGING IN SIMPLE MODELS, AND IN HUMAN POST-MORTEM BRAIN TISSUE FROM PATIENTS WITH ALZHEIMER’S DISEASE WITH TDP-43 PATHOLOGY. CANDIDATES NOMINATED FROM TRANSCRIPTOMIC APPROACHES WILL BE TESTED FOR FUNCTIONAL ROLES IN TAU AND TDP-43 SYNERGISTIC PROTEINOPATHY USING GENETIC AND TRANSGENIC APPROACHES. THIS WORK WILL CHARACTERIZE MECHANISMS UNDERLYING TAU AND TDP-43 NEUROTOXICITY IN ALZHEIMER’S DISEASE AND IDENTIFY NEW THERAPEUTIC TARGETS AND STRATEGIES. COMPLETION OF THIS PROJECT WILL SIGNIFICANTLY ADVANCE UNDERSTANDING ALZHEIMER’S DISEASE WITH COMORBID TDP-43, AND PROVIDE THE GROUNDWORK FOR FUTURE THERAPEUTIC DEVELOPMENT TARGETING TDP-43 IN ALZHEIMER’S DISEASE.

ON-TRACC: A NOVEL SELF-MANAGEMENT INTERVENTION TO IMPROVE LONG-TERM OUTCOMES IN VETERANS WITH A HISTORY OF MILD TRAUMATIC BRAIN INJURY

EFFECTS OF APOE ISOFORM, SEX AND DIET ON INSULIN REGULATION IN BRAIN

COMPARING ANKLE ARTHRODESIS TO ANKLE ARTHROPLASTY

A PROSTHETIC FOOT EMULATOR TO OPTIMIZE PRESCRIPTION OF PROSTHETIC FEET IN VETERANS AND SERVICE MEMBERS WITH LEG AMPUTATIONS

INTRANASAL INSULIN IN A MOUSE MODEL OF ALZHEIMER'S DISEASE

TARGETING MSUT2 WITH SMALL MOLECULES TO AMELIORATE PATHOLOGICAL TAU - ABSTRACT IN FRONTOTEMPORAL LOBAR DEGENERATION, ALZHEIMER’S DISEASE (AD) AND RELATED TAUOPATHIES, TAU NEUROPATHOLOGY CORRELATES WITH SEVERITY OF DEMENTIA. HOWEVER, INTERVENTIONS FOR AD AND AD RELATED DEMENTIAS (ADRDS) ARE LARGELY LIMITED TO TREATMENT OF SYMPTOMS THAT DO NOT DIRECTLY ALTER TAU PATHOLOGY OR THE RESULTANT NEURODEGENERATION, WITH ONLY ONE ASS-DIRECTED IMMUNOTHERAPEUTIC (ADUHELM) RECENTLY RECEIVING A CONTROVERSIAL ACCELERATED APPROVAL FOR DISEASE MODIFICATION. ALTHOUGH INVESTIGATION INTO ADDITIONAL ASS TARGETED IMMUNOTHERAPIES CONTINUES, THE OBVIOUS NEED REMAINS FOR THE DEVELOPMENT OF TAU-TARGETED DISEASE-MODIFYING THERAPEUTICS. OUR WORK HAS DEMONSTRATED THAT MSUT2 CONTROLS NEURONAL SUSCEPTIBILITY TO TAU TOXICITY IN THE MAMMALIAN BRAIN. THE MECHANISM OF MSUT2 MODULATION OF TAUOPATHY INVOLVES THE MSUT2 CCCH DOMAIN BINDING TO POLY(A) RNA, AS DELETION OF THE CCCH DOMAIN PREVENTS NEURODEGENERATION IN ANIMAL MODELS OF TAUOPATHY. HIGH THROUGHPUT SCREENING OF OVER 100,000 HIGH DIVERSITY COMPOUNDS HAS IDENTIFIED MANY ACTIVE DOSE- RESPONSIVE COMPOUNDS THAT INHIBIT MSUT2 POLY(A) RNA BINDING ACTIVITY, INCLUDING SEVERAL CLASSES OF COMPOUNDS EXHIBITING PROMISING STRUCTURE-ACTIVITY RELATIONSHIPS. THE IDENTIFICATION OF DRUG-LIKE SMALL MOLECULES THAT INHIBIT MSUT2 BINDING TO POLY(A) RNA WILL PROVIDE A PHARMACOLOGICAL MEANS OF INTERVENING AGAINST TAUOPATHY. WE HYPOTHESIZE THAT SMALL-MOLECULE INHIBITORS OF MSUT2/POLY(A) RNA BINDING WILL SLOW OR REVERSE TAU PATHOLOGY AND THE TOXIC CONSEQUENCES OF PATHOLOGICAL TAU. THE SPECIFIC AIMS OF THIS PROPOSAL ARE TO OPTIMIZE POTENT AND SPECIFIC BRAIN-PENETRANT MSUT2 INHIBITORS AND USE THEM TO DEMONSTRATE PROOF-OF-CONCEPT THERAPEUTIC APPROACHES TO TREATING TAUOPATHY. SUCCESSFUL COMPLETION OF THESE AIMS WILL SET THE STAGE FOR FUTURE TRANSLATIONAL STUDIES BY BOTH GENERATING MSUT2 SPECIFIC TOOL COMPOUNDS AND FURTHER VALIDATING A NOVEL THERAPEUTIC TARGET FOR PHARMACOLOGICAL INTERVENTION IN TAUOPATHY DISORDERS.

USE OF WEARABLE SENSORS TO IMPROVE THE EARLY DIAGNOSIS OF DLB - PROJECT SUMMARY/ABSTRACT DEMENTIA WITH LEWY BODIES (DLB) IS DIFFICULT TO DIAGNOSE EARLY IN ITS DISEASE COURSE DUE TO THE OVERLAP IN INITIAL SYMPTOMS WITH ALZHEIMER'S DISEASE (AD). MANY INDIVIDUALS WITH DLB THEREFORE EXPERIENCE LONG DELAYS IN RECEIVING AN ACCURATE DIAGNOSIS. THIS LACK OF SENSITIVITY IN THE CONSENSUS DIAGNOSIS FOR DLB, PARTICULARLY OUTSIDE OF SPECIALTY-CARE CENTERS, MEANS THAT DLB IS ASSOCIATED WITH DELAYED INTERVENTIONS AND INCREASED CAREGIVER BURDEN. WE THUS PROPOSE A TWO-PHASE STUDY THAT INVESTIGATES THE UTILITY OF COMBINING DATA FROM WEARABLE SENSORS, ECOLOGICAL MOMENTARY ASSESSMENTS (EMAS), AND TRADITIONAL MEASURES AS A MULTIDOMAIN APPROACH FOR THE EARLY DIAGNOSIS OF DLB. TO COLLECT AND ANALYZE THESE INTEGRATED OBJECTIVE MEASUREMENTS, WE WILL ESTABLISH A RESEARCH INFRASTRUCTURE THAT INCLUDES AN INTERDISCIPLINARY TEAM OF ENGINEERS, CLINICIANS, RESEARCHERS, AND BIOTECHNOLOGY COMPANIES. IN THE R21, WE WILL ESTIMATE AND COMPARE THE DISTRIBUTIONS OF COGNITIVE, MOTOR, SLEEP, AND BEHAVIORAL MONITORING PROFILES IN SUBJECTS WITH PROBABLE DLB (N=20) AND AD DEMENTIA (N=30). IF THE R21 DEMONSTRATES THE FEASIBILITY OF USING WEARABLE SENSORS AND EMAS IN THIS POPULATION AND THEIR ABILITY TO IMPROVE DISCRIMINATION BETWEEN DLB AND AD, WE WILL PROCEED TO THE NEXT STUDY PHASE. THE R33 AIMS TO CHARACTERIZE AND COMPARE THE TRAJECTORIES OF THESE SAME TRADITIONAL AND NOVEL COGNITIVE, MOTOR, SLEEP, AND BEHAVIORAL MONITORING PROFILES IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT (MCI) AND ONE OR MORE CORE DLB FEATURES (MCI-DLB; N=75) AND IN SUBJECTS WITH AMNESTIC MCI AND NO CORE DLB FEATURES (MCI-AD; N=25). WE HYPOTHESIZE THAT A COMPOSITE MEASURE COMBINING INFORMATION FROM THE BASELINE AND TRAJECTORY MEASURES IN THE LONGITUDINAL R33 WILL IMPROVE DISCRIMINATION BETWEEN INDIVIDUALS WITH MCI-DLB WHO WILL CONVERT TO DLB, AD, OR REMAIN MCI. WE ANTICIPATE THAT THE RESULTS OF THIS STUDY WILL HAVE TANGIBLE BENEFITS TO RESEARCHERS, CLINICIANS, PATIENTS, AND THE CARETAKERS OF PATIENTS. THE IMPROVED ABILITY TO DIFFERENTIATE EARLY DLB FROM EARLY AD WILL ASSIST RESEARCHERS IN SELECTING APPROPRIATE SUBJECTS FOR CLINICAL TRIALS OF AD AND RELATED DISORDERS (ADRD; E.G., DLB). MOREOVER, BECAUSE OF THE LONGITUDINAL NATURE OF THE R33, RESEARCHERS AND CLINICIANS WILL HAVE ACCESSIBLE DATA ON DISEASE PROGRESSION, WHICH CAN BE TREMENDOUSLY HELPFUL IN EVALUATING THE EFFICACY OF TREATMENT. MOST IMPORTANTLY, BY IMPROVING THE DIAGNOSIS OF EARLY DLB, CLINICIANS WILL BE BETTER EQUIPPED TO AVOID PRESCRIBING POTENTIALLY HARMFUL TREATMENTS (E.G., ANTIPSYCHOTICS FOR DLB) AND TO MORE ACCURATELY TAILOR CURRENT OR FUTURE INTERVENTIONS TO PATIENTS EARLIER IN THEIR DISEASE COURSE AT THE TIME THAT SUCH INTERVENTIONS ARE MOST LIKELY TO BE EFFECTIVE.

EFFECT OF DIETARY GLYCEMIC INDEX ON BETA-CELL FUNCTION

A PROSTHETIC FOOT TEST-DRIVE STRATEGY FOR IMPROVING STABILITY AND FALLS-RELATED OUTCOMES IN VETERANS WITH LEG AMPUTATIONS. NEW AWARD.

GENETIC DISSECTION OF CATECHOLAMINERGIC INNERVATION OF THE COGNITIVE CEREBELLUM

INVESTIGATING THE ROLE OF LIPID METABOLISM IN PROTEIN AGGREGATION AND NEURODEGENERATIVE DISEASE PROGRESSION - PROJECT SUMMARY PATHOGENIC PROTEIN AGGREGATES ARE A HALLMARK NEUROPATHOLOGIC FINDING IN MANY NEURODEGENERATIVE DISEASES. MOST RESEARCH HAS THUS FAR FOCUSED ON HOW THESE PATHOGENIC AGGREGATES ARE FORMED. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISM BY WHICH AGGREGATES SPREAD FROM CELL TO CELL, A HALLMARK OF NEURODEGENERATIVE DISEASE PROGRESSION. PARKINSON'S DISEASE (PD) IS THE SECOND MOST COMMON NEURODEGENERATIVE DISEASE. MUTATIONS IN THE GENE GLUCOSIDASE BETA ACID 1 (GBA), WHICH ENCODES A LYSOSOMAL ENZYME PRODUCING CERAMIDE, ARE THE STRONGEST GENETIC RISK FACTOR FOR PD. RECENTLY, GBA MUTATIONS WERE ALSO FOUND TO ASSOCIATE WITH ACCELERATED COGNITIVE AND MOTOR SYMPTOM PROGRESSION, SUGGESTING THAT GBA MUTATIONS INFLUENCE THE SPREAD OF PROTEIN AGGREGATES WITHIN THE BRAIN. RECENT WORK IN PD AND OTHER NEURODEGENERATIVE DISEASES SUGGEST THAT DYSREGULATION OF LIPID METABOLISM, AND IN PARTICULAR CERAMIDE, ALSO HAS AN IMPORTANT ROLE IN PATHOGENESIS. OUR RECENT WORK REVEALED A NOVEL FUNCTION FOR GBA IN REGULATING EXTRACELLULAR VESICLE (EVS) FORMATION AND CARGO. I HYPOTHESIZE THAT GBA DEFICIENCY MEDIATES FASTER PROPAGATION OF PROTEIN AGGREGATES FROM CELL TO CELL THROUGH DYSREGULATION OF EVS. TO INVESTIGATE THE MECHANISMS BY WHICH GBA MUTATIONS INFLUENCE THE PROPAGATION OF PROTEIN AGGREGATES BETWEEN TISSUES AND BETWEEN CELLS, I WILL USE DROSOPHILA, MOUSE AND HUMAN NEURONAL CELL CULTURE MODELS OF GBA DEFICIENCY. I HYPOTHESIZE THAT DECREASED CERAMIDE LEVELS DUE TO GBA DEFICIENCY LEAD TO DYSREGULATION OF EVS, WHICH PROMOTES THE TRANSFER OF PROTEIN AGGREGATES FROM CELL TO CELL AND LEADS TO FASTER PROGRESSION OF NEURODEGENERATION. UNDERSTANDING THE MECHANISMS UNDERLYING THE PRION-LIKE PROPAGATION OF PROTEIN AGGREGATES HAS THE POTENTIAL TO REVEAL NOVEL THERAPEUTIC TARGETS THAT COULD SLOW OR HALT PD AND OTHER NEURODEGENERATIVE DISEASES CHARACTERIZED BY THE SPREAD OF PATHOGENIC PROTEIN AGGREGATION.

FORMATION OF TAU RNA COMPLEXES DISRUPTS TAU FUNCTION AND DRIVES TAU NEUROPATHOLOGY - PATHOLOGICAL TAU PROTEIN ACCUMULATES IN NEURONAL LESIONS AND CONSTITUTES ONE OF THE DEFINING DIAGNOSTIC HALLMARKS OF ALZHEIMER’S DISEASE AND RELATED TAUOPATHY DISORDERS. TAU NEUROPATHOLOGY CORRELATES WITH SEVERITY OF DEMENTIA IN ALZHEIMER’S DISEASE. HOWEVER, TAU RELATED DYSFUNCTION AND AGGREGATION DRIVES NEURODEGENERATIVE CHANGES BY AN INCOMPLETELY UNDERSTOOD MOLECULAR MECHANISM. PREVIOUS WORK HAS DEMONSTRATED THAT RNA BINDING PROTEINS IMPACT TAU FUNCTION AND AGGREGATION IN MODEL SYSTEMS AND DISEASE STATES. IN QUANTITATIVE STUDIES, WE HAVE SHOWN THAT TAU BINDS RNA WITH HIGH AFFINITY BUT LOW SEQUENCE SPECIFICITY. TAU RNA COMPLEXES (TRCS) FORM HIGH MOLECULAR WEIGHT OLIGOMERIC TAU SPECIES THAT MAY BE ON PATHWAY TO FORMATION OF MATURE FIBRILLAR AGGREGATES. WE HAVE PRODUCED A TRC RECOGNIZING MONOCLONAL ANTIBODY (TRC35) THAT DETECTS A DISEASE RELEVANT PATHOLOGICAL TAU CONFORMATION. WE HYPOTHESIZE THAT RNA AND MICROTUBULES (MTS) COMPETE FOR TAU BINDING WITH TRC FORMATION DRIVING NEUROPATHOLOGICAL TAU ACCUMULATION, FIBRIL DEPOSITION, AND NEURODEGENERATION WHILE MT BINDING PROMOTES NEURONAL HOMEOSTASIS. WE PROPOSE 3 SPECIFIC AIMS TO DETERMINE THE IMPACT OF TAU RNA BINDING ACTIVITY ON DISEASE PATHOGENESIS. WE WILL 1) DISSECT THE MOLECULAR FEATURES OF TAU RNA BINDING ACTIVITY AND INTERPLAY WITH TAU MICROTUBULE BINDING ACTIVITY; 2) MAP THE ABUNDANCE, DISTRIBUTION, AND COMPOSITION OF TRC35+ LESIONS IN TAUOPATHY DISORDERS; AND 3) MEASURE THE IMPACT OF TAU RNA COMPLEX FORMATION ON NEURODEGENERATION. COMPLETION OF THE PROPOSED PROJECT WILL IMPACT THE FIELD BY INTEGRATING TAU RNA BINDING FUNCTIONS WITH KNOWN TAU ROLES IN MT STABILIZATION. WE WILL ALSO GAIN SIGNIFICANT UNDERSTANDING OF THE MOLECULAR MECHANISMS INVOLVED IN DISEASE RELEVANT PATHOLOGICAL TAU AGGREGATION AND DEPOSITION IN TAUOPATHY DISORDERS. WE WILL FURTHER MEASURE THE CONTRIBUTION OF TAU/RNA COMPLEXES TO THE NEURODEGENERATION OBSERVED IN TAUOPATHIES.

MICROGLIA AND OPIOID WITHDRAWAL: MECHANISMS OF NEGATIVE REINFORCEMENT - THE CURRENT EPIDEMIC OF OPIOID OVERDOSES HAS BEEN PROPELLED BY BOTH ILLICIT AND PRESCRIBED NARCOTIC PAIN MEDICATIONS. EXTENSIVE OPIOID USE AND REPEATED ABSTINENCE INCREASES THE LIKELIHOOD OF SEVERE WITHDRAWAL AND PERPETUATES THE VULNERABILITY TO RELAPSE VIA MEANS OF NEGATIVE REINFORCEMENT. THE NEGATIVE EMOTIONAL VALENCE OF WITHDRAWAL CAN LAST LONG AFTER THE INITIAL, DRAMATIC PHYSICAL SIGNS, INVOLVING A PROTRACTED NEGATIVE EMOTIONAL STATE, DRUG CRAVING, AND A HIGH LIKELIHOOD OF RELAPSE. THESE COMBINED SYMPTOMS ARE COMMONLY REFERRED TO AS BEING “DOPE SICK”. ADDICTED INDIVIDUALS OFTEN PREFER TO CONTINUE DRUGS RATHER THAN FACE WITHDRAWAL. BEING “DOPE-SICK” HAS MANY ATTRIBUTES OF A SEVERE INFLAMMATORY STATE AND THIS LED US TO INVESTIGATE THE INVOLVEMENT OF MICROGLIA, THE INNATE IMMUNE CELLS THAT RESIDE IN THE BRAIN, IN OPIOID TOLERANCE AND WITHDRAWAL, AND THIS WAS SUPPORTED BY A CEBRA R21 GRANT (R21-DA044757). THAT CEBRA R21 GRANT RESULTED IN OUR FINDINGS OF DRAMATIC CHANGES IN RIBOSOME-BOUND MRNAS—THE “TRANSLATOME”—IN MICROGLIA USING RNA SEQUENCING OF RIBOTAG PURIFIED MICROGLIAL RNAS. THOSE RESULTS PROVIDED US WITH THE LEADS THAT FORM THAT BASIS FOR THIS PROPOSAL. MANY OF THE CHANGES RELATED TO CYCLIC AMP SIGNALING AND ITS DOWNSTREAM TARGETS, AND EXPERIMENTAL CHEMOGENETIC STIMULATION OF GI/O SIGNALING WAS FOUND TO ACTUALLY WORSEN OPIOID WITHDRAWAL. WITH THE UNDERSTANDING THAT GLIA ARE PARTNERS IN PLASTICITY, WE SUSPECT THAT THE RELAPSING/REMITTING NATURE OF OPIOID DEPENDENCE SERVES TO PRIME AND CONDITION MICROGLIA, SHIFTING THE IMPACT FROM TEMPERING WITHDRAWAL DURING INITIAL STAGES TO EXACERBATING WITHDRAWAL AND OPIOID SEEKING AFTER MULTIPLE CYCLES OF TOLERANCE AND WITHDRAWAL. THUS, INVESTIGATIONS INTO THE ROLE OF GLIA IN WITHDRAWAL MAY PROVIDE NEW THERAPEUTIC AVENUES. WE PROPOSE THREE AIMS USING FENTANYL AND A RECENTLY DEVELOPED TRANSGENIC MOUSE THAT ALLOWS CONDITIONAL AND MICROGLIA-SPECIFIC CRE AND TDTOMATO EXPRESSION WITHOUT DISRUPTING MICROGLIA FUNCTION. IN AIM 1 WE WILL ANALYZE THE TRAJECTORY OF THE CHANGING MICROGLIAL TRANSLATOME AFTER ONE VS. FIVE CYCLES OF OPIOID DEPENDENCE AND SPONTANEOUS WITHDRAWAL. IN AIM 2 WE WILL EXAMINE THE PHYSICAL AND BEHAVIORAL CONSEQUENCES OF ONE VS. FIVE CYCLES OF OPIOID DEPENDENCE AND WITHDRAWAL, TO EXPLORE THE IDEA THAT INTERMITTENT CYCLES OF DEPENDENCE AND WITHDRAWAL EXACERBATE THE NEGATIVE CONSEQUENCES OF WITHDRAWAL. WE WILL THEN INVESTIGATE THE HYPOTHESIS THAT THE PURINERGIC RECEPTORS P2Y12 AND P2X7 ARE INVOLVED IN MICROGLIAL RESPONSES DURING INITIAL AND DELAYED PHASES OF OPIOID WITHDRAWAL. IN AIM 3 WE WILL USE AN IN VITRO BRAIN SLICE MODEL WITH 2- PHOTON CONFOCAL IMAGING OF MICROGLIA. WE WILL STUDY THE MICROSTRUCTURE AND MOTILITY OF MICROGLIA USING TIME- LAPSE MICROSCOPY. WE WILL MEASURE REAL-TIME CHANGES IN CYCLIC AMP USING A FRET-BASED BIOSENSOR AND CALCIUM DYNAMICS WITH GCAMP6. THESE THREE AIMS INTEGRATE THE TEMPORAL, BEHAVIORAL, AND MOLECULAR CONSEQUENCES OF MICROGLIAL ENGAGEMENT DURING OPIOID DEPENDENCE AND WITHDRAWAL.

CIRCULATING MIRNAS AND PREDICTION OF BETA-CELL TREATMENT RESPONSE: THE RESTORING INSULIN SECRETION STUDY - ABSTRACT DESPITE TREATMENT, A SIGNIFICANT PROPORTION OF PATIENTS WITH TYPE 2 DIABETES (T2D) DO NOT EXPERIENCE CLINICAL IMPROVEMENT (I.E., LACK TREATMENT RESPONSE). IN ANALYSES OF DATA FROM THE RESTORING INSULIN SECRETION (RISE) STUDY, A RANDOMIZED CONTROLLED TRIAL TESTING THE POTENTIAL OF MEDICAL AND SURGICAL THERAPIES TO IMPROVE AND MAINTAIN SS-CELL FUNCTION, MEMBERS OF OUR TEAM HAVE DEMONSTRATED SUBSTANTIAL HETEROGENEITY IN TREATMENT RESPONSE AT THE LEVEL OF THE SS CELL USING GOLD STANDARD MEASURES FROM HYPERGLYCEMIC CLAMPS. WE KNOW LITTLE, HOWEVER, ABOUT CONTRIBUTING FACTORS TO HETEROGENEITY OF T2D TREATMENT RESPONSE AND LACK TOOLS TO PROSPECTIVELY IDENTIFY TREATMENT RESPONDERS AND NON-RESPONDERS. A MAJOR REASON FOR THIS IS LACK OF CIRCULATING BIOMARKERS THAT PREDICT OR REFLECT TREATMENT RESPONSE AT THE LEVEL OF THE SS CELL. EPIGENETIC REGULATION OF GENES IMPORTANT IN GLUCOSE AND INSULIN METABOLISM BY SHORT NON-CODING RNAS SUCH AS MICRORNAS (MIRNAS) MAY MEDIATE IMPROVEMENT OR PRESERVATION OF SS-CELL FUNCTION WITH TREATMENT, AND CIRCULATING MIRNAS MAY BE PREDICTIVE BIOMARKERS OF TREATMENT RESPONSE. IN THE SS CELL, REGULATION OF GENE EXPRESSION BY MIRNAS IS CRUCIAL TO BOTH INSULIN SECRETION AND CELL TURNOVER. IN ADDITION, MIRNAS SECRETED INTO THE CIRCULATION MAY REFLECT TISSUE-LEVEL DIFFERENCES IN EXPRESSION AND/OR PARTICIPATE ACTIVELY IN INTER-ORGAN CROSSTALK. WHILE MIRNAS IN A VARIETY OF TISSUES AND IN THE CIRCULATION HAVE BEEN SHOWN TO BE ALTERED BY EXPOSURE TO THE RISE INTERVENTIONS IN HUMANS OR IN VITRO MODELS, EFFECTS OF MOST OF THESE MIRNAS IN THE SS CELL ARE NOT YET DESCRIBED. USING DATA AND SAMPLES FROM THE RISE PEDIATRIC MEDICATION STUDY (N=49; R03DK122100; PI WANDER), WE IDENTIFIED 9 PLASMA MIRNAS THAT ARE PROSPECTIVELY RELATED TO TREATMENT RESPONSE IN YOUTH AGED 10–19 YEARS INCLUDING TWO NOVEL MIRNAS, MIR-4468 AND MIR-6727, WHICH ARE PREDICTED TO REGULATE ISLET APOPTOSIS VIA BCL-2 LIKE 1 AND ISLET AMYLOID POLYPEPTIDE. OUR OBJECTIVE IS TO CHARACTERIZE MIRNAS THAT ARE RELATED TO PRESERVATION OR IMPROVEMENT IN SS-CELL FUNCTION AMONG ADULT RISE PARTICIPANTS, DEFINED BY CLAMP-DERIVED MEASURES OF SS-CELL RESPONSE PAIRED WITH INSULIN SENSITIVITY, AFTER TREATMENT WITH MEDICATIONS OR GASTRIC BANDING. TO ACHIEVE THIS GOAL, WE PROPOSE A TWO-PART STUDY. IN AIM 1, WE WILL ASSAY CIRCULATING MIRNAS USING NEXT-GENERATION SEQUENCING AT BASELINE AND AFTER TREATMENT IN A NESTED CASE-CONTROL SAMPLE OF TREATMENT RESPONDERS VS. NON-RESPONDERS IN RISE. IN AIM 2, WE WILL EXAMINE EFFECTS OF MIR-4468, MIR- 6727, AND MIRNAS IDENTIFIED IN AIM 1 ON SS-CELL FUNCTION, SURVIVAL, AND DE-DIFFERENTIATION IN GAIN-OF-FUNCTION IN VITRO EXPERIMENTS USING LOCKED NUCLEIC ACID-BASED MIRNA MIMICS IN HUMAN ISLETS. OUR OVERARCHING HYPOTHESIS IS THAT CIRCULATING MIRNAS CONTRIBUTE TO TREATMENT HETEROGENEITY VIA EFFECTS ON INSULIN SECRETION AND SS-CELL SURVIVAL. TO OUR KNOWLEDGE, THIS PROJECT WILL BE THE FIRST TO DIRECTLY TEST THE ROLE OF TREATMENT-RELATED MIRNAS IN MEDIATING OR REFLECTING TREATMENT RESPONSE. BETTER UNDERSTANDING OF MIRNAS AS BIOMARKERS OF TREATMENT HETEROGENEITY WILL FACILITATE T2D PRECISION MEDICINE BY PROSPECTIVELY IDENTIFYING SUBGROUPS LIKELY TO BENEFIT FROM SPECIFIC TREATMENTS AND PROMOTE DEVELOPMENT OF TARGETED INTERVENTIONS TO PREVENT OR DELAY THE PROGRESSION OF T2D.

GENETICS OF ENDOPHENOTYPES AND SCHIZOPHRENIA

SPOP DRIVES NEURODEGENERATIVE TAUOPATHY - ABSTRACT: AGGREGATED PATHOLOGICAL TAU PROTEIN CONSTITUTES ONE OF THE DIAGNOSTIC HALLMARKS OF ALZHEIMER’S DISEASE (AD) AND RELATED DISORDERS (ADRD). THE MOLECULAR MECHANISMS BY WHICH PATHOLOGICAL TAU CAUSES DYSFUNCTION AND DEGENERATION OF NEURONS REMAINS INCOMPLETELY UNDERSTOOD. HOWEVER, PATHOLOGICAL TAU DRIVEN NEURONAL DYSFUNCTION AND NEURODEGENERATION CLEARLY CAUSE DEMENTIA. TO INVESTIGATE HOW PATHOLOGICAL TAU CONTRIBUTES TO NEURODEGENERATION IN AD AND ADRD, WE ESTABLISHED A TRANSGENIC MODEL IN C. ELEGANS FOR NEURODEGENERATION DRIVEN BY HUMAN TAU AGGREGATION. IN OUR PREVIOUS WORK, WE IDENTIFIED SEVERAL GENES THAT CONTROL TAU TOXICITY IN C. ELEGANS INCLUDING SUT-1, SUT-2, PARN-2, SUT-6, ALY-1, ALY-2, AND ALY-3; ALL OF THESE GENES SHARE THE COMMON PROPERTY OF ENCODING PROTEINS RESIDING WITHIN NUCLEAR SPECKLES. NUCLEAR SPECKLES ARE MEMBRANELESS ORGANELLES WITHIN THE CELL’S NUCLEUS THAT FUNCTION AS HUBS OF RNA PROCESSING. PREVIOUS TRANSLATIONAL WORK FROM OUR LABORATORY AND OTHERS HAVE SHOWN THAT AD/ADRD EXHIBIT DEFECTS IN RNA PROCESSING AND MISLOCALIZATION OF SEVERAL NUCLEAR SPECKLE PROTEINS INCLUDING MSUT2, PABPN1, AND SRRM2. WE HAVE LEVERAGED OUR C. ELEGANS MODEL OF TAUOPATHY TO BEGIN TO DISSECT THE FUNCTIONAL ROLE OF NUCLEAR SPECKLES IN TAU PATHOLOGY. WE FOUND TAU MEDIATED NEURONAL DYSFUNCTION AND NEURODEGENERATION CAN BE RESCUED BY LOSS OF A NUCLEAR SPECKLE RESIDENT E3 UBIQUITIN LIGASE ADAPTOR PROTEIN KNOWN AS SPOP. WE HYPOTHESIZE SPOP-MEDIATED DEGRADATION OF SUBSTRATE PROTEINS IMPACTS THE DYNAMICS AND LIQUID-LIQUID PHASE SEPARATION OF NUCLEAR SPECKLES TO MODULATE THE TOXICITY OF PATHOLOGICAL TAU. GIVEN THE HIGH LEVEL OF CONSERVATION OF THE NUCLEAR SPECKLE PROTEINS AND RNA PROCESSING SYSTEM BETWEEN MAMMALS AND C. ELEGANS, WE PROPOSE TO UTILIZE BOTH C. ELEGANS AND MOUSE TRANSGENIC TAUOPATHY MODELS TO DISSECT THE MOLECULAR MECHANISMS BY WHICH SPOP LOSS OF FUNCTION PROTECTS AGAINST TAU NEUROTOXICITY. THE SPECIFIC AIMS OF THIS PROJECT ARE TO: 1) DEFINE SPOP’S IMPACT ON NEURONAL NUCLEAR SPECKLE COMPOSITION AND DYNAMICS IN TAUOPATHY. 2) IDENTIFY CRITICAL NON-DEGRADATIVE CUL3SPOP E3 LIGASE UBIQUITINATION SUBSTRATE(S) PARTICIPATING IN TAUOPATHY. 3) EXPLORE THE ROLE OF CRITICAL CUL3SPOP SUBSTRATE PROTEINS IN BOTH HUMAN DISEASE AND MOUSE MODELS OF TAUOPATHY. BY COMPLETING THE PROPOSED WORK, WE WILL DEVELOP NEW MOLECULAR UNDERSTANDING OF DISEASE MECHANISMS BY WHICH NUCLEAR SPECKLES AND THE SPOP PROTEIN PARTICIPATE IN TAUOPATHY. THIS WORK WILL ALSO PROVIDE THE FIRST TRANSLATIONAL EFFORT AT UNDERSTANDING WHETHER TARGETED CHANGES IN NUCLEAR SPECKLES CAN PROTECT NEURONS FROM PATHOLOGICAL TAU IN THE MAMMALIAN BRAIN.

DEFINING THE ROLE OF AGE-RELATED GLYMPHATIC PATHWAY IMPAIRMENT IN AMYLOID BETA PLAQUE DEPOSITION

ROLE OF SLEEP DISRUPTION AFTER MTBI AS A DRIVER OF CHRONIC POST-TRAUMATIC HEADACHE - PROJECT SUMMARY/ABSTRACT MIGRAINE-LIKE HEADACHES ARE AMONG THE MOST FREQUENT COMPLAINTS FOLLOWING MILD TRAUMATIC BRAIN INJURY (MTBI), YET THE MECHANISMS UNDERLYING THESE HEADACHES ARE UNKNOWN. A POSSIBLE CLUE IS THAT SLEEP DISRUPTION IS ALSO A COMMON COMPLAINT AFTER MTBI. SLEEP DISRUPTION IS A FREQUENTLY-REPORTED MIGRAINE TRIGGER, WHILE SLEEP IS A WIDELY EFFECTIVE MIGRAINE ABORTIVE. BASED ON THE CLINICAL CONNECTIONS BETWEEN MTBI, HEADACHE AND SLEEP DISRUPTION, WE HYPOTHESIZE THAT SLEEP DISRUPTION CONTRIBUTES TO THE DEVELOPMENT OF POST-TRAUMATIC HEADACHE (PTH) FOLLOWING MTBI. A MECHANISM THAT MAY LINK MTBI, SLEEP AND PTH IS THE IMPAIRMENT OF THE GLYMPHATIC SYSTEM, WHICH IS A RECENTLY CHARACTERIZED BRAIN-WIDE NETWORK OF PERIVASCULAR SPACES THAT SUPPORT THE RAPID EXCHANGE OF CEREBROSPINAL AND INTERSTITIAL FLUID. GLYMPHATIC PATHWAY FUNCTION IS GREATEST DURING SLEEP. IT IS SUPPRESSED DURING WAKING BY CENTRAL NORADRENERGIC TONE AND IS REDUCED BY MTBI. WE PROPOSE THAT THE IMPAIRMENT OF GLYMPHATIC FUNCTION FOLLOWING MTBI MAY CONTRIBUTE TO THE DEVELOPMENT AND PERSISTENCE OF PTH SYMPTOMS. IN SUPPORT OF THIS, OUR PRELIMINARY DATA DEMONSTRATE THAT TREATMENT WITH THE CENTRALLY-ACTIVE A1-ADRENERGIC ANTAGONIST PRAZOSIN IMPROVES BOTH GLYMPHATIC FUNCTION AND AMELIORATES PTH SYMPTOMS IN MICE. THIS PROPOSAL WILL EXTEND THESE FINDINGS BY COMPARING THE EFFECTS OF REPETITIVE IMPACT AND BLAST MTBI ON GLYMPHATIC FUNCTION, TESTING WHETHER TREATMENT WITH PRAZOSIN CAN RESTORE POST-TRAUMATIC GLYMPHATIC FUNCTION. USING WELL ESTABLISHED MOUSE MODELS OF MTBI AND VALIDATED BEHAVIORAL MEASURES OF PTH SYMPTOMS (LIGHT AVERSION AND MECHANICAL FACIAL ALLODYNIA), WE WILL THEN DEFINE THE ROLE OF GLYMPHATIC DYSFUNCTION IN THE DEVELOPMENT OF PTH SYMPTOMS BY TESTING WHETHER THESE SYMPTOMS ARE EXACERBATED IN A TRANSGENIC MOUSE MODEL IN WHICH GLYMPHATIC FUNCTION IS CONSTITUTIVELY IMPAIRED AND WHETHER INCREASING POST-TRAUMATIC GLYMPHATIC FUNCTION PHARMACOLOGICALLY WITH PRAZOSIN IMPROVES PTH SYMPTOMS. IN A SECOND SET OF EXPERIMENTS, WE WILL TEST WHETHER TARGETING SLEEP PROVIDES A PATHWAY FOR IMPROVING POST-TRAUMATIC GLYMPHATIC IMPAIRMENT AND AMELIORATING PTH SYMPTOMS. IN THESE STUDIES WE WILL DEFINE WHETHER THE EFFECT OF SLEEP AUGMENTATION ON PTH BEHAVIORS IS INDEPENDENT OF GLYMPHATIC FUNCTION. IN OUR FINAL STUDIES, WE WILL EVALUATE WHETHER PERIPHERAL OR CENTRAL ALPHA1 OR BETA ADRENERGIC SIGNALING IS A KEY DRIVER OF POST-TRAUMATIC GLYMPHATIC IMPAIRMENT, AND WHETHER TARGETING THESE PROCESSES CAN IMPROVE PTH-ASSOCIATED BEHAVIORS EITHER THROUGH EFFECT ON GLYMPHATIC FUNCTION OR THROUGH MODULATION OF POST-TRAUMATIC SLEEP. THE RESULTS OF THIS STUDY WILL PROVIDE A NOVEL PERSPECTIVE ON THE MECHANISMS UNDERLYING DEVELOPMENT OF PTH THAT WILL POTENTIALLY SUPPORT TARGETING SLEEP DISRUPTION AND GLYMPHATIC FUNCTION AS THERAPEUTIC STRATEGIES FOR MTBI PATIENTS.

A PLACEBO-CONTROLLED AUGMENTATION TRIAL OF PRAZOSIN FOR COMBAT TRAUMA PTSD

OXIDATIVE DYSFUNCTION OF LRP AT THE BLOOD-BRAIN BARRIER IN ALZHEIMER'S DISEASE

GLUCAGON SECRETION AND ISLET NEUROPATHY

MCI, INSULIN AND CHOLESTEROL IN A COMMUNITY SAMPLE

ROLE OF PERIVASCULAR AQUAPORIN-4 POLARIZATION IN POST-TRAUMATIC NEURODEGENERATION

INVESTIGATING HOW SUT-6/NIPP1 REGULATES PATHOLOGICAL TAU - BACKGROUND: ALZHEIMER’S DISEASE AND OTHER NEURODEGENERATIVE DISEASES WITH ACCUMULATION OF PATHOLOGICAL TAU PROTEIN, TERMED TAUOPATHIES, ARE INCREASING IN PREVALENCE AND BURDEN TO THE US POPULATION. HOWEVER, THERE ARE STILL NO THERAPIES TO CURE OR REVERSE TAUOPATHIES. DESPITE STRONG EVIDENCE THAT PATHOLOGICAL TAU CAUSES NEURODEGENERATION AND THE DEVELOPMENT OF NUMEROUS MODELS OF TAU TOXICITY, THE MOLECULAR MECHANISMS UNDERLYING THE TOXICITY INDUCED BY PATHOLOGICAL TAU ARE STILL INCOMPLETELY UNDERSTOOD. TO DISCOVER NOVEL GENETIC SUPPRESSORS OF TAU TOXICITY, FORWARD GENETIC SCREENING WAS PERFORMED IN A CAENORHABDITIS ELEGANS MODEL OF TAUOPATHY. A W292X MUTATION IN SUT-6 (NIPP1 IN MAMMALS) WAS RECENTLY IDENTIFIED AS A NOVEL MODULATOR OF TAUOPATHY. SUT-6/NIPP1 IS A MULTIFUNCTIONAL, MULTIDOMAIN PROTEIN THAT REGULATES PHOSPHATASE ACTIVITY, SPLICING OF MRNAS, AND GENE TRANSCRIPTION. THE W292X MUTANT OF SUT-6 REMOVES THE LAST 11 AMINO ACIDS OFF THE C- TERMINUS OF SUT-6 AND SHOWS STRONG, DOMINANT AND CELL-AUTONOMOUS SUPPRESSION OF TAU-INDUCED TOXICITY WHILE LOSS OF SUT-6 EXPRESSION SHOWS WEAKER SUPPRESSION OF TAU-INDUCED TOXICITY. THIS SUGGESTS THAT ALTERING SUT- 6/NIPP1 INTERACTIONS WITH PROTEIN PARTNERS THAT REGULATE PHOSPHATASE, SPLICING, OR OTHER ACTIVITIES LEADS TO SUPPRESSION OF TAU TOXICITY. HYPOTHESIS: SUT-6/NIPP1 MODULATES TAU TOXICITY BY ALTERING PROTEIN PHOSPHATASE 1 AND/OR SPLICING ACTIVITY IN TRANSLATIONALLY CONSERVED MECHANISMS OF DISEASE. PROPOSAL AIMS: THE SPECIFIC AIMS OF THIS PROJECT ARE: 1) DEFINE THE FUNCTIONS OF SUT-6/NIPP1 IMPORTANT FOR SUPPRESSING TAU TOXICITY BY INTRODUCING MUTATIONS INTO THE SUT-6 GENE AND EVALUATING THE EFFECTS IN A C. ELEGANS MODEL OF TAU PATHOLOGY. 2) DETERMINE DOWNSTREAM MEDIATORS OF SUT-6/NIPP1’S SUPPRESSION OF TAU TOXICITY BY IDENTIFYING NEURONAL INTERACTORS OF SUT-6 AND NIPP1 AND PERFORMING EPISTASIS ANALYSIS OF IDENTIFIED INTERACTORS IN A C. ELEGANS MODEL OF TAU PATHOLOGY. 3) EXAMINE THE TRANSLATIONAL IMPACT OF NIPP1 MODULATION ON TAUOPATHY USING A MOUSE MODEL OF TAU PATHOLOGY. EXPECTED OUTCOMES: THE PROPOSED STUDIES WILL DEEPEN OUR UNDERSTANDING OF A NOVEL, TRANSLATIONALLY RELEVANT MECHANISM FOR REGULATING TAUOPATHY AND OUR OVERALL KNOWLEDGE OF THE MECHANISMS OF TAU-INDUCED TOXICITY, PATHOLOGY AND DISEASE GENERALLY. THIS KNOWLEDGE WILL LEAD TO BETTER THERAPEUTIC STRATEGIES TARGETING TAU IN ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES.

EFFECTS OF CHOLESTEROL IN PANCREATIC ISLETS - PROJECT SUMMARY/ABSTRACT STATINS ARE THE MOST COMMONLY USED CHOLESTEROL-LOWERING MEDICATION; HOWEVER, STATINS INCREASE THE RISK OF NEW-ONSET TYPE 2 DIABETES (T2D). WHILE THIS INCREASED RISK INCLUDES A DIRECT EFFECT OF STATINS TO IMPAIR ISLET SS- CELL FUNCTION, THE UNDERLYING MECHANISMS REMAIN UNCLEAR. WITH STATIN USE TRENDING UP AMONG U.S. ADULTS, THERE IS AN URGENT NEED TO BETTER UNDERSTAND HOW STATINS LEAD TO DEMISE OF THE SS CELL – THIS KNOWLEDGE WILL INFORM STRATEGIES AIMED AT REDUCING PROGRESSION TO T2D IN PATIENTS ON STATIN THERAPY. TO THIS END, WE HAVE GENERATED DATA THAT SHOW A PREVIOUSLY UNRECOGNIZED EFFECT OF STATINS TO PROMOTE MITOCHONDRIAL CHOLESTEROL ACCUMULATION WITHIN ISLETS. SURPRISINGLY, THERE IS ALMOST NO LITERATURE ON MECHANISMS REGULATING MITOCHONDRIAL CHOLESTEROL CONTENT IN SS CELLS. THIS KNOWLEDGE GAP WILL BE ADDRESSED IN THE PROPOSED STUDIES, WHICH FOCUS ON THE ROLE OF CHOLESTEROL TRANSPORT TO MITOCHONDRIA AND ITS SUBSEQUENT METABOLISM IN STATIN-INDUCED SS-CELL TOXICITY. MITOCHONDRIA ARE CHOLESTEROL-POOR ORGANELLES, AND THUS ARE HIGHLY SENSITIVE TO EVEN SMALL INCREASES IN CHOLESTEROL CONTENT. STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR) AND THE CLOSELY RELATED STARD3 PROTEIN MEDIATE CHOLESTEROL TRANSPORT TO MITOCHONDRIA. WE SHOW THAT BOTH STAR AND STARD3 ARE UPREGULATED IN STATIN- TREATED ISLETS. IN SS CELLS, STAR OVEREXPRESSION RESULTS IN MITOCHONDRIAL CHOLESTEROL ACCUMULATION, IMPAIRED INSULIN RELEASE AND REDUCED CELL VIABILITY. ALSO, OUR DATA SUGGEST SS CELLS HAVE LIMITED CAPACITY TO METABOLIZE CHOLESTEROL SINCE THEY EXPRESS ONLY TWO OF THE CYTOCHROME P450 ENZYMES KNOWN TO INITIATE CHOLESTEROL METABOLISM. OF THESE, ONLY CYP27A1 IS DOWNREGULATED IN ISLETS EXPOSED TO STATINS, AND THIS IS ACCOMPANIED BY AN INCREASE IN MIRNA-204, WHICH CAN SUPPRESS CYP27A1 MRNA. WE FIND THAT LACK OF ISLET CYP27A1 PER SE PROMOTES MITOCHONDRIAL CHOLESTEROL ACCUMULATION AND IMPAIRED INSULIN SECRETION. ALSO, WE SHOW STIMULATING MITOPHAGY TO CLEAR CHOLESTEROL-LADEN MITOCHONDRIA IN STATIN-TREATED ISLETS PROTECTS AGAINST SS-CELL DYSFUNCTION. BASED ON OUR DATA, WE HYPOTHESIZE THAT STATIN-INDUCED ABERRATIONS IN CHOLESTEROL TRANSPORT AND METABOLISM LEAD TO MITOCHONDRIAL CHOLESTEROL ACCUMULATION, MITOCHONDRIAL DYSFUNCTION, IMPAIRED INSULIN RELEASE AND SS-CELL DEATH. THE FOLLOWING SPECIFIC AIMS WILL ADDRESS OUR HYPOTHESIS: AIM 1: TO DETERMINE THE CONTRIBUTIONS OF TRANSPORT OF CHOLESTEROL TO MITOCHONDRIA, ITS SUBSEQUENT METABOLISM, OR CLEARANCE OF CHOLESTEROL-LADEN MITOCHONDRIA TO STATIN-INDUCED SS-CELL DYSFUNCTION/DEATH. AIM 2: TO DETERMINE WHETHER REDUCING STAR AND/OR INCREASING CYP27A1 EXPRESSION AMELIORATES THE DETRIMENTAL EFFECTS OF STATINS ON SS-CELL FUNCTION AND MASS IN VIVO. AIM 3: TO IDENTIFY MIRS THAT MITIGATE STATIN-INDUCED DYSREGULATION OF CHOLESTEROL TRANSPORT AND METABOLISM GENES IN HUMAN ISLETS. THIS RESEARCH IS INNOVATIVE AND SIGNIFICANT, AS INVESTIGATING MITOCHONDRIAL CHOLESTEROL ACCUMULATION AND MIRNAS IN STATIN-INDUCED SS-CELL DYSFUNCTION/DEATH WILL INFORM STRATEGIES TO MITIGATE THE RISK OF DEVELOPING T2D.

NORADRENERGIC AGENTS AS POTENTIAL NEW PHARMACOTHERAPIES FOR ALCOHOL DRINKING

ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN GLUCOSE HOMEOSTASIS - PROJECT SUMMARY/ABSTRACT IN TREATING TYPE 2 DIABETES (T2D), THERE IS A PAUCITY OF MEDICATIONS SIMULTANEOUSLY TARGETING DEFICITS IN BOTH SS-CELL FUNCTION AND MASS. ANGIOTENSIN(1-7), A METABOLITE OF THE RENIN-ANGIOTENSIN SYSTEM, MAY FILL THIS GAP; HOWEVER, ITS UNDERLYING MECHANISMS OF ACTION ARE INCOMPLETELY UNDERSTOOD. OUR DATA REVEAL THAT THE INSULINOTROPIC ACTION OF ANGIOTENSIN(1-7) IS DEPENDENT ON ITS HYDROLYSIS TO THE DIPEPTIDE, ANGIOTENSIN(1-2), THE LATTER ALSO CONVEYING PRO-SURVIVAL AND PROLIFERATIVE EFFECTS IN SS CELLS. ANGIOTENSIN(1-2) ACTIVATES G-PROTEIN- COUPLED RECEPTOR FAMILY C GROUP 6 MEMBER A (GPRC6A), WHICH WE SHOW IS EXPRESSED IN ISLET A CELLS. FURTHER, ANGIOTENSIN(1-2) INCREASES A CELL-DERIVED GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RELEASE, SUGGESTING IT ACTS VIA GPRC6A ON THE A CELL TO PROMOTE INSULIN SECRETION IN A PARACRINE FASHION. INDEED, IN GLP-1 RECEPTOR DEFICIENT ISLETS, WE FIND THAT ANGIOTENSIN(1-2) FAILS TO POTENTIATE INSULIN SECRETION; HOWEVER, ITS ABILITY TO ENHANCE SS-CELL SURVIVAL AND PROLIFERATION IS RETAINED. THE LATTER SUGGESTS ANGIOTENSIN(1-2)’S ACTION IS, IN PART, GLP-1 RECEPTOR- INDEPENDENT. BASED ON THESE NOVEL DATA, WE HYPOTHESIZE ANGIOTENSIN(1-2) ENHANCES SS-CELL FUNCTION VIA INTRA- ISLET PARACRINE SIGNALING, AND PROMOTES SS-CELL SURVIVAL/PROLIFERATION VIA A NOVEL GLP-1-INDEPENDENT MECHANISM. THE FOLLOWING SPECIFIC AIMS ADDRESS THIS HYPOTHESIS, WITH THE GOAL OF IMPROVING TREATMENT OPTIONS IN T2D: SPECIFIC AIM 1. TO DETERMINE THE MECHANISM BY WHICH ANGIOTENSIN(1-2) INCREASES ISLET-DERIVED GLP-1 AND INSULIN SECRETION. MICE (IN VIVO) AND ISLETS (IN VITRO) WITH DIPHTHERIA TOXIN-INDUCED A-CELL DESTRUCTION OR A CELL-SPECIFIC GPRC6A KNOCKOUT WILL BE USED TO DETERMINE WHETHER ANGIOTENSIN(1-2)-MEDIATED INCREASES IN INSULIN RELEASE REQUIRE A CELLS OR A-CELL GPRC6A, RESPECTIVELY. WE WILL PROBE MECHANISMS FOR INCREASED GLP-1 RELEASE, AND CONFIRM KEY FINDINGS IN HUMAN ISLETS WITH AND WITHOUT GLP-1 RECEPTOR OR GPRC6A BLOCKADE. SPECIFIC AIM 2. TO IDENTIFY SIGNALING PATHWAYS/PROTEINS MEDIATING THE SS-CELL SURVIVAL AND PROLIFERATIVE EFFECTS OF ANG(1-2) IN HUMAN ISLETS. THE ABILITY OF ANGIOTENSIN(1-2) TO INHIBIT APOPTOSIS, REDUCE DEDIFFERENTIATION AND ENHANCE PROLIFERATION OF SS CELLS WILL BE EXAMINED IN HUMAN ISLETS UNDER NON-DIABETIC AND DIABETIC CONDITIONS. THE CONTRIBUTION OF MECHANISMS INDEPENDENT OF GLP-1 OR GPRC6A WILL BE DETERMINED. EFFECTORS OF ANGIOTENSIN(1-2) ACTION WILL BE IDENTIFIED USING NON-BIASED PHOSPHOPROTEOMICS, THEN LOSS-/GAIN-OF- FUNCTION STUDIES IN ISLETS WILL SERVE AS A PRELIMINARY SCREEN FOR EFFECTORS THAT COULD BE TARGETED THERAPEUTICALLY. SPECIFIC AIM 3. TO DETERMINE WHETHER ANG(1-2) IMPROVES HUMAN ISLET FUNCTION/SURVIVAL IN VIVO, AND WHETHER HYDROLYSIS OF ANG(1-7) IS REQUIRED FOR ITS ANTI-DIABETIC EFFECTS. WE WILL UTILIZE A HUMAN ISLET TRANSPLANT MODEL TO DETERMINE THE ABILITY OF ANGIOTENSIN(1-2) TO IMPROVE SS-CELL FUNCTION/SURVIVAL AND GLYCEMIA IN DIABETIC MICE. FURTHER, WE WILL TEST WHETHER THE INSULINOTROPIC ACTION OF ANGIOTENSIN(1-7) REQUIRES ITS HYDROLYSIS, AS IS THE CASE IN VITRO. THE LATTER IS HIGHLY SIGNIFICANT FOR CLINICAL MANAGEMENT OF T2D BECAUSE IT WILL INFORM ON THE UTILITY OF HYDROLYSIS-RESISTANT ANGIOTENSIN(1-7)-BASED MEDICATIONS CURRENTLY IN DEVELOPMENT.

BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

PRAZOSIN TREATMENT FOR DISRUPTIVE AGITATION IN ALZHEIMER'S DISEASE

IMPACT OF NEPRILYSIN ON ISLET FUNCTION

SARCOPENIA IN MEN WITH PROSTATE CANCER UNDERGOING ADT (SAP-ADT) - PROJECT SUMMARY/ABSTRACT A DECREASE IN MUSCLE MASS AND FUNCTION, KNOWN AS SARCOPENIA, IS HIGHLY PREVALENT IN CANCER PATIENTS AND OFTEN LEADS TO DECREASED ENDURANCE, INCREASED FATIGUE, FALLS, POOR QUALITY OF LIFE (QOL) AND INCREASED MORTALITY. PROSTATE CANCER (PCA) IS THE 2ND MOST COMMON CANCER AND THE 2ND LEADING CAUSE OF CANCER DEATH IN MEN WORLDWIDE, GREATLY IMPACTING SURVIVAL AND QOL IN THESE PATIENTS. ANDROGEN DEPRIVATION THERAPY (ADT) IS THE STANDARD TREATMENT FOR ADVANCED AND METASTATIC PCA. UNFORTUNATELY, ADT EXACERBATES SARCOPENIA CONTRIBUTING TO THE SYMPTOM BURDEN AND POOR OVERALL QOL. DESPITE ITS RELEVANCE, THERE ARE NO APPROVED PHARMACOLOGICAL TREATMENTS FOR SARCOPENIA. SEVERAL GAPS IN OUR KNOWLEDGE IMPEDE THE DEVELOPMENT OF THERAPIES FOR SARCOPENIA: 1) THERE IS NO AGREEMENT ON THE SPECIFIC TOOLS TO ASSESS CLINICALLY RELEVANT OUTCOMES, 2) THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD, 3) THE LIVED EXPERIENCES OF THESE MEN HAVE NOT BEEN ASCERTAINED, AND 4) WE ARE CURRENTLY UNABLE TO PREDICT WHO WILL DEVELOP SARCOPENIA UPON STARTING ADT. THE OVERALL GOALS OF THIS PROPOSAL ARE TO ESTABLISH CLINICAL OUTCOMES AND PREDICTORS OF SARCOPENIA IN PCA PATIENTS UNDERGOING ADT, AND TO CHARACTERIZE PATHWAYS AND MECHANISMS LEADING TO THIS PHENOTYPE, INCLUDING THE ROLE OF MITOCHONDRIA. WE PROPOSE TO PERFORM A CLINICAL TRIAL INCLUDING 70 MEN WITH A DIAGNOSIS OF PCA STARTING ADT. PARTICIPANTS WILL BE FOLLOWED FOR 12 MONTHS. CHANGES IN BODY COMPOSITION, MUSCLE STRENGTH, PHYSICAL PERFORMANCE, AND PATIENT REPORTED OUTCOMES (PROS) INCLUDING FATIGUE AND QOL WILL BE MEASURED, AND THEIR CLINICAL RELEVANCE ASCERTAINED. BLOOD SAMPLES AND MUSCLE BIOPSIES WILL BE OBTAINED AT BASELINE, 6 MONTHS, AND 12 MONTHS TO INVESTIGATE GENES, PROTEINS, AND METABOLITES ALTERED BY ADT AND TO ESTABLISH THE PREDICTIVE VALUE OF THESE BIOMARKERS ON CLINICAL OUTCOMES OF SARCOPENIA USING A COMPREHENSIVE MULTI-OMICS APPROACH. THE SPECIFIC AIMS ARE TO: 1) ESTABLISH THE CLINICAL RELEVANCE OF DIFFERENT OUTCOME MEASURES TO ASSESS SARCOPENIA IN PCA PATIENTS STARTING ADT. WE HYPOTHESIZE THAT ADT WILL CAUSE CLINICALLY MEANINGFUL DECREASES IN APPENDICULAR LEAN BODY MASS (ALBM), MUSCLE STRENGTH, PHYSICAL PERFORMANCE AND QOL, 2) IDENTIFY AND PRIORITIZE THE MOLECULAR PATHWAYS MEDIATING THE EFFECTS OF ADT ON THESE OUTCOMES USING A MULTI-OMICS APPROACH. OUR HYPOTHESIS IS THAT ADT WILL ALTER GENE EXPRESSION, PROTEIN AND METABOLITE LEVELS IN MUSCLE AND PLASMA AS MEASURED BY A COMPREHENSIVE MULTI-OMICS APPROACH, AND THIS WILL BE ASSOCIATED WITH SARCOPENIA, 3) DETERMINE THE ROLE OF BASELINE BIOMARKER LEVELS AS PREDICTORS OF SARCOPENIA; 4) PERFORM MECHANISTIC STUDIES IN MUSCLE TISSUE TO DEFINE THE ROLE OF MITOCHONDRIAL DYSFUNCTION IN ADT-INDUCED SARCOPENIA. WE ANTICIPATE THAT SPECIFIC PATHWAYS PROBED IN PLASMA AND MUSCLE, AND IMPAIRMENTS IN MITOCHONDRIAL FUNCTION AT BASELINE WILL PREDICT THE DEVELOPMENT OF SARCOPENIA UPON STARTING ADT. WE WILL ALSO CHARACTERIZE THE EXPERIENCE OF THESE MEN WITH REGARD TO IMPACT ON QOL. THE DATA GENERATED WILL PROVIDE ESSENTIAL KNOWLEDGE ON INFORMATIVE TOOLS TO MEASURE CLINICALLY RELEVANT OUTCOMES IN ADT-INDUCED SARCOPENIA, AND IDENTIFY NOVEL TARGETS AND CLINICALLY MEANINGFUL PREDICTIVE BIOMARKERS FOR THIS MORBID CONDITION.

CHARACTERIZING AND RESTORING JOINT MOTION IN PATIENTS WITH HALLUX RIGIDUS

ROLE OF BROWN ADIPOSE TISSUE THERMOGENESIS IN OXYTOCIN-ELICITED WEIGHT LOSS

PRAZOSIN AUGEMENTATION OF OUTPATIENT TREATMENT OF ALCOHOL USE DISORDERS IN ACTIVE DUTY SOLDIERS WITH AND WITHOUT PTSD

CLINICAL TRIALS OF THE ADRENERGIC A-1 ANTAGONIST PRAZOSIN FOR ALCOHOL DEPENDENCE

SENSORY FEEDBACK FOR LOWER EXTREMITY PROSTHESES INCORPORATING TARGETED MUSCLE REINNERVATION (TMR)

DEFINING THE ROLE OF POST-TBI SLEEP DISRUPTION IN THE DEVELOPMENT OF CTE AND ALZHEIMER'S DISEASE-RELATED NEUROPATHOLOGY - ABSTRACT MILD TRAUMATIC BRAIN INJURY (MTBI, CONCUSSION) HAS EMERGED AS A RISK FACTOR FOR THE DEVELOPMENT OF NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER’S DISEASE (AD) AND CHRONIC TRAUMATIC ENCEPHALOPATHY, WHICH ARE CHARACTERIZED BY THE ABERRANT AGGREGATION OF TAU WITHIN NEURAL CELLS. HOWEVER, THE MECHANISMS LINKING MTBI TO AD-RELATED PATHOLOGY LATER IN LIFE REMAIN UNKNOWN. DISRUPTION OF THE SLEEP-WAKE CYCLE (SWD) IS A FREQUENT CHRONIC COMPLAINT AFTER MTBI AND ALSO ACCOMPANIES THE DEVELOPMENT OF AD. MORE RECENT CLINICAL AND TRANSLATIONAL RESEARCH SUGGESTS THAT SWD MAY ACTUALLY PROMOTE THE DEVELOPMENT OF ALZHEIMER’S-RELATED PATHOLOGY. OUR PRELIMINARY DATA SHOW THAT SLEEP DISTURBANCE IS SIGNIFICANTLY ASSOCIATED WITH LOWER CSF AΒ42 LEVELS (AN AD-ASSOCIATED PROFILE) IN VETERANS WITH MTBI >45 YEARS OF AGE. BASED ON THESE FINDINGS, WE PROPOSE THAT POST-TBI SLEEP DISRUPTION PROMOTES THE DEVELOPMENT OF AD-RELATED PATHOLOGY FOLLOWING MTBI. THIS WILL BE DIRECTLY TESTED IN AIM 1. THE GLYMPHATIC SYSTEM IS A RECENTLY CHARACTERIZED BRAIN-WIDE NETWORK OF PERIVASCULAR SPACES THAT SUPPORTS THE CLEARANCE OF BOTH AΒ AND TAU. GLYMPHATIC FUNCTION IS GREATEST DURING SLEEP AND IS IMPAIRED BY TBI. OUR PUBLISHED AND PRELIMINARY DATA SHOW THAT MRI-VISIBLE PERIVASCULAR SPACE BURDEN (MV-PVS), A PUTATIVE MARKER OF GLYMPHATIC IMPAIRMENT, IS INCREASED AMONG VETERANS WITH BLAST MTBI AND THAT THESE CHANGES ARE ASSOCIATED WITH AD-RELATED CSF BIOMARKER PROFILES. IN AIM 2, WE WILL USE NOVEL MRI-BASED APPROACHES TO TEST WHETHER GLYMPHATIC IMPAIRMENT PREDICTS THE DEVELOPMENT OF AD-RELATED PATHOLOGY AFTER BLAST MTBI. SLEEP-WAKE BEHAVIOR IS REGULATED THROUGH CENTRAL NORADRENERGIC (NA) NEUROTRANSMISSION, WITH LOCUS COERULEUS (LC)-DERIVED NOREPINEPHRINE (NE) PROMOTING AROUSAL DURING WAKING. IN OUR BLAST MTBI VETERANS, CSF NE WAS ELEVATED COMPARED TO CONTROLS AND ASSOCIATED WITH POOR SLEEP. HOWEVER, THE ROLE THAT CHANGES IN CENTRAL NA SIGNALING PLAY IN PROMOTING AD-RELATED PATHOLOGY FOLLOWING TBI IS UNKNOWN. IN AIM 3 WE WILL TEST WHETHER CHANGES IN MEASURES OF CENTRAL NA TONE PREDICT THE DEVELOPMENT OF AD-RELATED PATHOLOGY AFTER BLAST MTBI. DR. PESKIND’S 10-YEAR LONGITUDINAL VA COHORT WILL CONTRIBUTE 70 PREVIOUSLY- AND NEWLY-ENROLLED VETERANS >45 YEARS OF AGE WITH A HISTORY OF REPETITIVE BLAST MTBIS WHO WILL UNDERGO ASSESSMENT OF: SUBJECTIVE AND OBJECTIVE SLEEP; MULTI-DOMAIN CLINICAL BEHAVIORAL, NEUROLOGICAL, AND NEUROCOGNITIVE ASSESSMENT; GLYMPHATIC FUNCTION MEASURED BY MRI, AND MEASUREMENT OF CSF/PLASMA AD/CTE-RELATED BIOMARKERS AND NE. AIM 1. DEFINE THE ROLE OF SLEEP DISRUPTION IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY. AIM 2. DEFINE THE ROLE OF GLYMPHATIC DYSFUNCTION IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY. AIM 3. DEFINE THE ROLE OF ALTERATIONS IN CENTRAL NA TONE IN THE DEVELOPMENT OF POST-TBI AD-RELATED PATHOLOGY AFTER TBI.

MECHANISMS OF ISLET AMYLOIDOGENESIS

HEALTH THROUGH OBESITY CARE FOR PATIENTS WITH COPD (HOPE)

ANCILLARY STUDY PROPOSAL FOR THE RESTORING INSULIN SECRETION (RISE) STUDY: AUTOIMMUNE MECHANISMS FOR THE PROGRESSIVE DECLINE OF BETA CELL FUNCTION IN

MICRORNA BIOMARKERS OF CUMULATIVE BLAST-MILD TRAUMATIC BRAIN INJURY (MICRO BCB)

THE ROLE OF MITOCHONDRIA IN ADT-INDUCED SARCOPENIA IN PROSTATE CANCER PATIENTS

STRESS AND PTSD MECHANISMS AS TARGETS FOR PHARMACOTHERAPY OF ALCOHOL ABUSE, ADDICTION AND RELAPSE

NOVEL LOWER-LIMB PROSTHESES: COMPARING ADHERENCE, PERSPIRATION, AND RESIDUAL LIMB SKIN HEALTH IN A HOT, HUMID ENVIRONMENT AND DURING ACTIVITIES OF DA

CENTER FOR NEUROREGULATION IN ALCOHOL DEPENDENCE (CENIAD)

DOES SCREENING FOR HCC IN CIRRHOTIC PATIENTS REDUCE HCC-RELATED MORTALITY

TAI CHI PRACTICE AND SLEEP-ACTIVE GLYMPHATIC FUNCTION - PROJECT SUMMARY/ABSTRACT AMYLOID PLAQUE DEPOSITION, A KEY PATHOLOGICAL HALLMARK OF ALZHEIMER’S DISEASE (AD), BEGINS 1-2 DECADES BEFORE MANIFESTATION OF CLINICAL SYMPTOMS OF DEMENTIA. AMONG COGNITIVELY INTACT INDIVIDUALS AND IN AD’S MOST PREVALENT SPORADIC FORM, THE PRODUCTION OF AMYLOID-SS (ASS) DOES NOT CHANGE, WHILE CLEARANCE OF ASS IS SLOWED, INDICATING THAT THE FAILURE OF ASS CLEARANCE MAY UNDERLIE THE DEVELOPMENT OF AD PATHOLOGY AND THAT INTERVENTIONS THAT IMPROVE ITS CLEARANCE MAY PROVIDE AN OPPORTUNITY FOR PRIMARY PREVENTION OF AD. OVER THE PAST 10 YEARS, OUR GROUP HAS HELPED TO DEFINE THE ‘GLYMPHATIC SYSTEM’, A BRAIN-WIDE NETWORK OF PERIVASCULAR PATHWAYS ALONG WHICH CEREBROSPINAL FLUID (CSF) SURROUNDING THE BRAIN EXCHANGES WITH BRAIN INTERSTITIAL FLUID, SUPPORTING THE CLEARANCE OF INTERSTITIAL WASTES, INCLUDING ASS AND TAU. IMPAIRMENT OF GLYMPHATIC CLEARANCE IS OBSERVED IN THE AGING BRAIN AND IN MOUSE MODELS OF AD. THUS, IMPROVING GLYMPHATIC CLEARANCE OF BRAIN INTERSTITIAL PROTEINS MAY BE ONE APPROACH TO PREVENTING THE DEVELOPMENT OF AD. GLYMPHATIC FUNCTION IS REGULATED BY SLEEP-WAKE BEHAVIOR, WITH FASTER CLEARANCE OCCURRING DURING SLEEP. TAI CHI IS A CHINESE MARTIAL ART FOCUSING ON MINDFUL BODY MOVEMENT, POSTURE, AND BREATHING AS AN AVENUE TO ACHIEVE A STATE OF INTERNAL BALANCE, CALM, AND CLARITY. IN CLINICAL STUDIES, PRACTICE OF TAI CHI IS ASSOCIATED WITH IMPROVED SLEEP QUALITY, COGNITION, MOOD, CARDIOVASCULAR AND RESPIRATORY FUNCTION, AND BALANCE/PHYSICAL ACTIVITY. HOWEVER, THE PHYSIOLOGICAL PROCESSES UNDERLYING THE COGNITIVE AND AFFECTIVE EFFECTS OF TAI CHI REMAIN UNDEFINED. WE HYPOTHESIZE THAT TAI CHI PRACTICE IMPROVES GLYMPHATIC FUNCTION. TO TEST THIS HYPOTHESIS, WE WILL ENROLL 75 MIDDLE-AGED (50-70 YEARS) PARTICIPANTS WITH DIFFERENT LEVELS OF TAI CHI PRACTICE EXPERIENCE: TAI CHI PROFICIENTS (10+ YEAR OF PRACTICE, N=25), TAI CHI BEGINNERS (12 MONTHS PRACTICE, N=25) AND TAI CHI NAÏVE PARTICIPANTS (N=25). WE WILL 1) EXAMINE THE ASSOCIATION BETWEEN TAI CHI PRACTICE AND GLYMPHATIC FUNCTION USING MULTI-MODAL MAGNETIC RESONANCE IMAGING (MRI) USING CONTRAST-ENHANCED MRI, T1/FLAIR ASSESSMENT OF MRI-VISIBLE PERIVASCULAR SPACES, INTRAVOXEL INCOHERENT MOTION, AND FAST BOLD-FMRI; 2) EXAMINE RELATIONSHIPS BETWEEN TAI CHI PRACTICE AND SLEEP, INCLUDING SLEEP FRAGMENTATION, EFFICIENCY, AND DURATION, ASSESSED BY SELF-REPORTED QUESTIONNAIRES AND OBJECTIVE MEASUREMENTS OF SLEEP DURATION, FRAGMENTATION AND EFFICIENCY USING A BED PRESSURE MAT. WE WILL EXAMINE THE RELATIONSHIP BETWEEN SLEEP MEASURES AND MRI-ASSESSED GLYMPHATIC FUNCTION. THE ULTIMATE GOAL OF THIS STUDY IS TO ELUCIDATE MECHANISMS OF TAI CHI PRACTICE IN PREVENTION OF AD AND RELATED DEMENTIAS. THIS PILOT STUDY WILL DETERMINE WHETHER LONG-TERM TAI CHI PRACTICE IS ASSOCIATED WITH PHYSIOLOGICAL CHANGES IN GLYMPHATIC FUNCTION AND SLEEP. IF WE FIND CROSS-SECTIONAL ASSOCIATION AMONG TAI CHI PRACTICE, GLYMPHATIC FUNCTION, AND SLEEP, IN THE FUTURE WE WILL INVESTIGATE WHETHER THESE CHANGES ARE ASSOCIATED WITH DURATION OF TAI CHI PRACTICE AND WHETHER THESE CHANGES ARE ASSOCIATED WITH CHANGES IN AD BIOMARKERS IN A LONGITUDINAL STUDY OR IN A PROSPECTIVE RANDOMIZED CLINICAL TRIAL.

THE EFFECTS OF ROSIGLITAZONE IN PATIENTS WITH MCI

OPTIMIZING MEDICATIONS AND LUNG HEALTH IN PEOPLE WITH HIV THROUGH PHARMACIST-LED PROACTIVE E-CONSULTS (OPTIMIZE LUNG-HIV) - PROJECT SUMMARY/ABSTRACT DESPITE EFFECTIVE ANTIRETROVIRAL THERAPY (ART) FOR PEOPLE WITH HIV (PWH), COMMUNITY ACQUIRED PNEUMONIA REMAINS A COMMON CAUSE OF HOSPITALIZATION, RESPIRATORY FAILURE, EXTRAPULMONARY COMPLICATIONS, AND MORTALITY. PNEUMONIA CONTINUES TO BE SUBSTANTIALLY MORE COMMON AMONG PWH COMPARED TO PEOPLE WITHOUT HIV, AND RISK INCREASES WITH AGE AND COMORBIDITY. MODIFIABLE RISK FACTORS FOR PNEUMONIA IN PWH INCLUDE ACTIVE SMOKING, INADEQUATE VACCINATIONS, AND COMMONLY USED POTENTIALLY INAPPROPRIATE MEDICATIONS SUCH AS INHALED CORTICOSTEROIDS (ICS) AND PROTON-PUMP INHIBITORS (PPIS). OUR OVERARCHING OBJECTIVE IS TO IMPROVE GUIDELINE- CONCORDANT CARE AND DECREASE POPULATION RISK OF PNEUMONIA IN PWH. WE WILL TEST WHETHER A PROACTIVE PHARMACIST-DRIVEN E-CONSULT INTERVENTION INCREASES UPTAKE OF APPROPRIATE SMOKING CESSATION PHARMACOTHERAPY, VACCINATIONS AND DEPRESCRIBING OF INAPPROPRIATE ICS AND PPIS FOR PWH COMPARED TO USUAL CARE. WE LEVERAGE A SUCCESSFUL PULMONOLOGIST-DRIVEN PROACTIVE E-CONSULT INTERVENTION THAT IMPROVED QUALITY OF CARE FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN PWH IN THE VETERANS HEALTH ADMINISTRATION (VHA), AND ADAPT OUR INTERVENTION BY PARTNERING WITH PHARMACISTS. AS PHARMACISTS ARE INTEGRATED INTO PRIMARY AND SPECIALTY CARE IN VHA, THIS MODEL CAN EXTEND THE NATIONAL REACH OF OUR INTERVENTION AND MAY BE MORE REALISTIC, COST-EFFECTIVE, AND SCALABLE THAN PULMONOLOGIST DELIVERED E-CONSULTS. WE WILL CONDUCT A MULTICENTER, PATIENT-LEVEL RANDOMIZED CONTROLLED, HYBRID TYPE 1 EFFECTIVENESS-IMPLEMENTATION TRIAL AND ACHIEVE THE FOLLOWING SPECIFIC AIMS (SA): 1. TEST WHETHER A PHARMACIST-LED PROACTIVE E-CONSULT INTERVENTION FOR HIV PROVIDERS IMPROVES EVIDENCE-BASED PULMONARY PHARMACOTHERAPY IN PWH; 2. IDENTIFY KEY FACTORS INFLUENCING THE PROCESS OF ADOPTION, IMPLEMENTATION, MAINTENANCE AND SCALABILITY OF PHARMACIST-LED PROACTIVE E-CONSULTS. WE WILL DETERMINE CLINICAL EFFECTIVENESS BY THE PROPORTION OF MEDICATION RECOMMENDATIONS ENACTED WITHIN 3 MONTHS (PRIMARY OUTCOME) AND AT 12 MONTHS FOR MAINTENANCE (SECONDARY OUTCOME) COMPARING RESULTS BETWEEN E-CONSULT AND USUAL CARE. WE WILL CONDUCT MIXED METHODS ASSESSMENTS TO EVALUATE BARRIERS AND FACILITATORS TO IMPLEMENTATION AND FOR EFFECTIVE ADOPTION AND MAINTENANCE OF A PROACTIVE E-CONSULT PROGRAM, GUIDED BY THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH (CFIR). WE WILL USE THE RE-AIM (REACH, EFFECTIVENESS, ADOPTION, IMPLEMENTATION AND MAINTENANCE) FRAMEWORK TO EVALUATE PROGRAM OUTCOMES AND ASSESS ADOPTION, APPROPRIATENESS AND ACCEPTABILITY TO PATIENTS AND PROVIDERS AS WELL AS IMPLEMENTATION COSTS TO INFORM WIDER DISSEMINATION, AND UNDERSTANDING OF WHAT FACTORS MAY BE CRITICAL FOR THE SUCCESS, MAINTENANCE AND SCALABILITY OF THE PROGRAM. THIS PROJECT WILL YIELD CRITICAL FINDINGS ON EFFECTIVENESS AND SUSTAINABILITY OF PHARMACIST-LED PROACTIVE E-CONSULTS TO IMPROVE DELIVERY OF PHARMACOTHERAPY. OUR INITIAL FOCUS IS ON IMPROVING GUIDELINE-CONCORDANT PHARMACOTHERAPY AND DECREASING EXCESS RISK FOR PNEUMONIA IN PWH. IF SUCCESSFUL, OUR APPROACH COULD BE EXPANDED TO INCLUDE PHARMACIST LED INTERVENTIONS FOCUSED ON OTHER MEDICATIONS THAT ARE COMMONLY UNDER OR OVER-PRESCRIBED.

EFFECT OF PRAZOSIN AND NALTREXONE ON SCRIPTS INDUCED ALCOHOL CRAVING IN VETERANS WITH ALCOHOL USE DISORDERS WITH AND WITHOUT CO-OCCURRING PTSD

MEDICAL ADRENALECTOMY TO ABROGATE LIGAND PRODUCTION IN CASTRATION-RESISTANT PROSTATE CANCER

EFFICACY OF VIRTUAL WARRIOR RENEW THERAPY FOR VETERANS WHO EXPERIENCED MILITARY SEXUAL TRAUMA

PATHWAYS OF THERAPY-INDUCED SENESCENCE IN CANCER

GLIMPSE-PD: GLYMPHATICS IMAGING TO PROBE SLEEP IN PARKINSON'S DISEASE

PERSPIRATION THRESHOLDS AND SECURE SUSPENSION FOR LOWER LIMB AMPUTEES IN DEMANDING ENVIRONMENTS

BILIARY OXYSTEROLS AND CHOLANGIOCARCINOMA

IL-15, BODY COMPOSITITION AND INSULIN SENSIVITY IN AGING

REVERSING TAUOPATHY BY INHIBITING MSUT2 RNA-BINDING ACTIVITY

MUTANT TUBULINS CONFER RESISTANCE TO PATHOLOGICAL TAU - PROJECT SUMMARY/ABSTRACT PATHOLOGICAL TAU IS PRESENT IN A NUMBER OF AGE-RELATED DISEASES (TAUOPATHIES) INCLUDING ALZHEIMER'S DISEASE (AD). WITH A RISING AGED POPULATION THE PREVALENCE OF THESE DISEASES WILL BECOME AN ENORMOUS HEALTHCARE, ECONOMIC AND SOCIAL BURDEN. TO-DATE THERE ARE NO CLINICALLY PROVEN DISEASE ALTERING TREATMENTS. RECENTLY, WE HAVE DISCOVERED MUTANT TUBULIN MODIFIES TAUOPATHY-LIKE PHENOTYPES IN TRANSGENIC C. ELEGANS MODELS, REDUCING HUMAN TAU-INDUCED MOTILITY DEFICITS AND NEURODEGENERATION. WE HYPOTHESIZE THAT MUTANT TUBULIN AMELIORATES TAU-INDUCED PHENOTYPES IN C. ELEGANS BY ALTERING TAU-MICROTUBULE INTERACTIONS. TO TEST OUR HYPOTHESIS WE PROPOSE TO 1) USE C. ELEGANS TO DETERMINE IF THE LEVEL OF TUBULIN SUPPRESSION IS BASED IN TUBULIN EXPRESSION LEVEL 2) USE RECONSTITUTED IN VITRO SYSTEMS TO TEST WHETHER TUBULIN MUTATIONS AFFECT TAU- MICROTUBULE INTERACTIONS AND 3) USE MAMMALIAN PRIMARY NEURONS TO TEST WHETHER MUTANT TUBULIN IMPACTS MICROTUBULE PROPERTIES AND FUNCTION. THE PROPOSED PROJECTS WILL ELUCIDATE THE MECHANISMS OF MUTANT TUBULIN SUPPRESSION OF TAU INDUCED-PATHOLOGY AND TAU-MICROTUBULE INTERACTIONS. ADDITIONALLY, THIS WORK WILL CONTRIBUTE GREATER UNDERSTANDING OF THE CYTOSKELETON IN NEURODEGENERATIVE DISEASE. MY GOAL IS TO DEVELOP A CAREER AS A PRINCIPAL INVESTIGATOR DEVOTED TO THE DISCOVERY OF THE MOLECULAR MECHANISMS UNDERPINNING TAUOPATHIES AND THE ROLES THE CYTOSKELETAL NETWORK PLAY IN NEURODEGENERATION. TO ACCOMPLISH THIS, MY TRAINING PLAN FOCUSES ON 1) EXPANDING MY TECHNICAL TOOLKIT TO INCORPORATE BIOPHYSICAL APPROACHES AND LIVE CELL IMAGING 2) GAINING GREATER KNOWLEDGE IN THE BIOLOGY OF AGING 3) IMPROVING SKILLS IN LABORATORY LEADERSHIP AND EXPANDING MY PROFESSIONAL NETWORK. THE UNIVERSITY OF WASHINGTON AND THE VETERANS AFFAIRS PUGET SOUND HEALTH CARE SYSTEM SHARE AN ABUNDANCE OF RESEARCHERS INTERESTED IN ALZHEIMER'S AND OTHER NEURODEGENERATIVE CONDITIONS. THERE ARE SUBSTANTIAL INTELLECTUAL RESOURCES SUCH AS SEMINARS, JOURNAL CLUBS AND MEETINGS THAT CREATE NUMEROUS OPPORTUNITIES BROADEN MY PERSPECTIVE THROUGH INTERACTIONS WITH THE MEDICAL AND SCIENTIFIC COMMUNITY IN AD-RELATED RESEARCH.

LOW TESTOSTERONE AND CARDIOVASCULAR EVENTS AND MORTALITY

HELPING PATIENTS AND PHYSICIANS CHOOSE THE APPROPRIATE SURGERY FOR END STAGE HALLUX RIGIDUS - PROJECT SUMMARY/ABSTRACT THE PRIMARY OBJECTIVE OF THIS PROJECT IS TO OBTAIN OBSERVATIONAL DATA NECESSARY TO DESIGN A FUTURE CLINICAL TRIAL COMPARING ARTHRODESIS TO MOTION SPARING SURGERY IN PATIENTS WITH HALLUX RIGIDUS (HR). HR IS A DEGENERATIVE DISEASE OF THE FIRST METATARSOPHALANGEAL JOINT (MTPJ1). IT IS THE MOST COMMON FORM OF ARTHRITIS IN THE FOOT, AFFECTING 1 IN 40 PEOPLE OVER THE AGE OF 50 WITH A 2:1 RATIO OF FEMALES TO MALES. THE MTPJ1 PLAYS A CRITICAL FUNCTIONAL ROLE IN WALKING AS IT CARRIES APPROXIMATELY 119% OF AN INDIVIDUAL'S BODY WEIGHT WITH EACH STEP; THEREFORE, THE JOINT PAIN AND LOSS OF MOTION LEAD TO A SIGNIFICANT REDUCTION IN ACTIVITY AND QUALITY OF LIFE FOR PATIENTS. HR IS TYPICALLY TREATED BY MODIFICATIONS TO OR WITHIN THE SHOE COMBINED WITH MODIFICATIONS OF ACTIVITY AND NSAIDS. WHEN THESE TREATMENTS ARE NOT EFFECTIVE, SURGERY MAY BE PERFORMED. ARTHRODESIS (FUSION) IS AN EFFECTIVE MEASURE FOR PAIN CONTROL BUT ELIMINATES MOTION AT THE JOINT LEADING TO LIMITED FOOTWEAR OPTIONS WHICH CAN HAVE A MAJOR IMPACT ON WOMEN, IN PARTICULAR, WHO WEAR SHOES OF VARYING LEVELS OF HEEL ELEVATION. THESE LIMITATIONS HAVE DRIVEN PATIENTS TO SEEK ALTERNATIVES THAT SPARE MTPJ1 MOTION. EARLY PROMISING RESULTS HAVE INTENSIFIED THE DEBATE OVER FUSION VERSUS JOINT SPARING, BUT THEIR COMPARATIVE SAFETY AND EFFICACY IS NOT ESTABLISHED. MULTIPLE JOINT SPARING PROCEDURES INCLUDE (1) VARIOUS ARTHROPLASTIES, (2) CHEILECTOMY WITH OR WITHOUT OSTEOTOMY, AND (3) A SYNTHETIC CARTILAGE IMPLANT. THESE MORE MODERN TECHNIQUES HAVE NOT BEEN COMPARED WITH ARTHRODESIS WITH THE EXCEPTION OF ONE NON-INFERIORITY TRIAL COMPARING A SYNTHETIC CARTILAGE IMPLANT TO ARTHRODESIS WHICH REPORTED SIMILAR RESULTS FOR PAIN AND FUNCTION AND IMPLANT FAILURES AFTER 2 YEARS. THERE ARE NO COMPARATIVE TRIALS EVALUATING CHEILECTOMY. ARTHROPLASTIES INCLUDING SYNTHETIC IMPLANTS INCREASE TREATMENT COSTS BUT PRESERVE MOTION. THEREFORE, THERE IS A STRONG DEMAND TO DETERMINE IF MOTION SPARING IS EQUALLY OR MORE EFFECTIVE COMPARED TO ARTHRODESIS IN OUTCOMES IMPORTANT TO PATIENTS. THE PROPOSED OBSERVATIONAL STUDY (AND SUBSEQUENT U01 TRIAL) IS INTENDED TO OVERCOME THE SPECIFIC GAPS IN THE LITERATURE AND OBSTACLES TO DESIGNING A FUTURE TRIAL INCLUDING: (1) USING OBSERVATIONAL DATA FROM SEVERAL CENTERS THAT EMPLOY MULTIPLE MOTION SPARING PROCEDURES AND ARTHRODESIS TO DETERMINE IF THERE ARE APPRECIABLE DIFFERENCES THAT WILL REQUIRE A SINGLE ARM OR MULTIPLE MOTION SPARING TREATMENT ARMS COMPARED TO FUSION IN A FUTURE TRIAL, (2) IDENTIFYING CORRELATES OF HR DISEASE SEVERITY USING AN EXPERT PANEL WITH EXPLORATORY DATA ANALYSIS OF THE OBSERVATIONAL DATA TO BEGIN THE IMPORTANT PROCESS OF DEVELOPING AND VALIDATING A NOVEL HR CLASSIFICATION SYSTEM, (3) PERFORMING QUALITATIVE INTERVIEWS OF EXISTING PILOT STUDY PATIENTS AT VARIOUS TIME POINTS IN THE FOLLOW-UP PROCESS TO ASCERTAIN WHAT OUTCOMES ARE MOST IMPORTANT TO THEM SO THAT WE CAN ENSURE THE OUTCOMES WE INCLUDE IN THE FUTURE TRIAL MATCH THESE PREFERENCES (FOR MALE AND FEMALE SHOULD THEY DIFFER), AND (4) DESIGNING AND PLANNING A RANDOMIZED CONTROLLED TRIAL OR A FUTURE U01 GRANT.

EFFECTIVENESS AND IMPLEMENTATION OF PTSD TREATMENT FOR SUICIDAL AND MULTI-DIAGNOSTIC CLIENTS IN COMMUNITY PRACTICE SETTINGS

TRAUMA, ALCOHOL, AND AGING - WHILE AGING IS THE NUMBER ONE RISK FACTOR FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIA (ADRD), NOT EVERYONE AGES THE SAME; RISK FACTORS SUCH AS STRESS, INJURY, AND ALCOHOL USE CAN SUBSTANTIALLY CONTRIBUTE TO HOW A PERSON AGES. BLAST TRAUMA IS THE LEADING CAUSE OF MORBIDITY/MORTALITY FOR SERVICEMEMBERS AND VETERANS AND IS AN INCREASINGLY SIGNIFICANT THREAT TO CIVILIANS, FIRST RESPONDERS, AND AID WORKERS (E.G., ONGOING CONFLICT IN UKRAINE, ISRAEL-GAZA). HISTORY OF BLAST TRAUMA CAN INCREASE RISKY ALCOHOL USE, BUT CRITICALLY, HOW THESE RISK- FACTORS MIGHT INTERACT AND/OR SYNERGIZE ACROSS THE LIFESPAN TO ADVERSELY IMPACT AGING AND ADRD IS NOT WELL ESTABLISHED AND TREATMENT OPTIONS ARE LIMITED. THE GLYMPHATIC SYSTEM (THE WASTE CLEARANCE OF THE BRAIN) IS INCREASINGLY RECOGNIZED AS A POTENTIAL MECHANISTIC AND THERAPEUTIC TARGET FOR BRAIN TRAUMA AND ADRD, BUT FEW REPORTS DETAIL THE EFFECTS OF CHRONIC ALCOHOL ON GLYMPHATIC FUNCTION. INDEED, THE GLYMPHATIC SYSTEM WAS RECENTLY HIGHLIGHTED AS AN IMPORTANT NEW RESEARCH AREA AT THE 2023 NIDA-NIAAA FRONTIERS IN ADDICTION RESEARCH MINI- CONVENTION. HERE WE PROVIDE PRELIMINARY DATA DEMONSTRATING A SIGNIFICANT NEGATIVE RELATIONSHIP BETWEEN CHRONIC ALCOHOL INTAKE LEVEL AND GLYMPHATIC FUNCTION. FURTHERMORE, WE FIND THAT BLAST-INDUCED BEHAVIORAL AND GLYMPHATIC DEFICITS ARE POTENTIATED FOLLOWING CHRONIC ALCOHOL INTAKE. TOGETHER, THESE PRELIMINARY RESULTS SUPPORT THE OVERARCHING HYPOTHESIS OF THIS PROPOSAL - THAT BRAIN TRAUMA RESULTS IN INCREASED SUSCEPTIBILITY TO THE NEGATIVE EFFECTS OF ALCOHOL ON ADRD-RELATED OUTCOMES, MEDIATED AT LEAST IN PART BY IMPAIRMENT OF GLYMPHATIC FUNCTION. TRANSLATIONALLY RELEVANT, PRECLINICAL RESEARCH EFFORTS USING RODENT MODELS CAN PROVIDE MUCH NEEDED INSIGHT INTO THE PATHOGENESIS AND OUTCOME TRAJECTORIES FOLLOWING INJURY, AS WELL AS AID IN THE IDENTIFICATION OF POTENTIAL BIOMARKERS AND THERAPEUTIC APPROACHES. TO THIS END, WE RECENTLY DEVELOPED THE SOCIALLY INTEGRATED POLYSUBSTANCE (SIP) SYSTEM, WHERE GROUP HOUSED MICE CAN VOLUNTARILY SELF-ADMINISTER MULTIPLE DIFFERENT ETHANOL DOSES WHILE STILL MAINTAINING CONTINUOUS MONITORING OF INDIVIDUAL INTAKE LEVELS. HERE WE PROPOSE TO UTILIZE THESE NOVEL AND WELL-ESTABLISHED METHODS TO STUDY THE ADVERSE INTERACTIONS OF TRAUMA AND CHRONIC ALCOHOL USE ON CLINICALLY TRACKABLE ADRD-RELATED ENDPOINTS IN MALE AND FEMALE MICE. AIM 1: DEFINE THE EFFECT OF BLAST TRAUMA AND CHRONIC ALCOHOL INTAKE ON ADRD-RELATED BEHAVIORAL OUTCOMES. AIM 2: DEFINE THE EFFECT OF BLAST TRAUMA AND CHRONIC ALCOHOL INTAKE ON ADRD-RELATED BIOLOGICAL OUTCOMES. AIM 3: ESTABLISH THE CONTRIBUTION OF GLYMPHATIC DYSFUNCTION TO THE DEVELOPMENT OF ADRD-RELATED OUTCOMES FOLLOWING CHRONIC ALCOHOL INTAKE. TRAUMA, CHRONIC ALCOHOL USE, AND AGING ARE OFTEN STUDIED IN ISOLATION DESPITE THEM MOST OFTEN OCCURRING IN CONCERT IN REAL LIFE; WITH AN AGING POPULATION AND RATES OF TRAUMA EXPOSURE AND AUD RAPIDLY INCREASING, INVESTMENT IN RESEARCH EFFORTS TO STUDY THESE EVENTS IN COMBINATION USING ETHOLOGICALLY RELEVANT ANIMAL MODELS IS DESPERATELY NEEDED. KNOWLEDGE GAINED CAN BE DIRECTLY TRANSLATED AND UTILIZED TOWARDS THE DEVELOPMENT OF MORE EFFECTIVE TREATMENT APPROACHES FOR THOSE WITH A HISTORY OF TRAUMA AND CHRONIC ALCOHOL USE.

UNFOLDED PROTEIN RESPONSE ACTIVATION PROTECTS NEURONS AGAINST PATHOLOGICAL TAU

USE OF WEARABLE SENSORS TO IMPROVE THE EARLY DIAGNOSIS OF DLB

MOLECULAR REGULATION OF ENDOTHELIAL GLYCOCALYX-MEDIATED TRANSCYTOSIS - PROJECT SUMMARY: ENDOTHELIAL CELLS ARE THE PRIMARY REGULATORY INTERFACE FOR THE EXCHANGE OF SUBSTANCES BETWEEN BLOOD AND TISSUES. THE LUMINAL (BLOOD-FACING) SURFACE OF ENDOTHELIAL CELLS CONTAINS A COMPLEX, CARBOHYDRATE RICH STRUCTURE CALLED THE GLYCOCALYX WHICH IS THE FIRST SURFACE OF INTERACTIONS BETWEEN CIRCULATING COMPONENTS AND ENDOTHELIAL CELLS. HOWEVER, THE INVOLVEMENT OF GLYCOCALYX COMPONENTS IN THE BINDING, UPTAKE, AND TRANSPORT OF SUBSTANCES ACROSS ENDOTHELIAL BARRIERS IS INADEQUATELY UNDERSTOOD, PARTICULARLY IN VIVO. OUR RESEARCH OVER THE LAST 5 YEARS HAS ELUCIDATED FUNDAMENTAL REGULATORY ASPECTS OF GLYCOCALYX-MEDIATED TRANSENDOTHELIAL TRANSPORT OF CHEMOKINES AND VIRAL PROTEINS. WE HAVE OBSERVED THAT THERE ARE TISSUE-SPECIFIC DIFFERENCES IN TRANSPORT REGULATION, AND THAT TRANSPORT CAN OCCUR SELECTIVELY IN DIFFERENT VASCULAR ZONES, SUGGESTING THAT THE MOLECULAR MACHINERY OF THE GLYCOCALYX THAT REGULATES TRANSPORT ALSO VARIES BY TISSUE AND VASCULAR ZONE. A PARTICULAR STRENGTH OF OUR APPROACH IS OUR UNIQUE ABILITY TO CONDUCT HIGHLY SENSITIVE AND RIGOROUS RADIOCHEMICAL-BASED ASSAYS WHICH ENABLE US TO CALCULATE BLOOD-TO-TISSUE TRANSPORT RATES OF PROTEINS IN VIVO AND IN SITU, AS WELL AS OTHER PHARMACOLOGICAL PARAMETERS SUCH AS VASCULAR BINDING, BIODISTRIBUTION, AND CLEARANCE. WE HAVE ALSO DEVELOPED CELL-BASED ASSAYS THAT ARE AMENABLE FOR STUDIES OF GLYCOCALYX-DEPENDENT TRANSENDOTHELIAL TRANSPORT, WITH INTACT HS-DEPENDENT CHEMOKINE TRANSPORT PROCESSES RESEMBLING THOSE IN VIVO. IN THE NEXT 5 YEARS, OUR MAIN GOAL IS TO CHARACTERIZE THE MOLECULAR COMPONENTS THAT REGULATE THE BASIC BIOLOGICAL PROCESS OF GLYCOCALYX-MEDIATED TRANSENDOTHELIAL TRANSCYTOSIS, INCLUDING THOSE THAT CONFER TISSUE SPECIFICITY OF TRANSPORT FUNCTIONS. AS HEPARAN SULFATE (HS) IS A MAJOR COMPONENT OF THE GLYCOCALYX WHICH REGULATES THE TRANSENDOTHELIAL TRANSPORT OF CHEMOKINES, WE WILL FOCUS ON THE MOLECULAR COMPONENTS OF HS- MEDIATED CHEMOKINE TRANSPORT AS AN INITIAL EXAMPLE. WE HYPOTHESIZE THAT CHEMOKINES UNDERGO ENDOTHELIAL TRANSCYTOSIS BY BINDING TO HS ON MEMBRANE-ATTACHED HS PROTEOGLYCANS (HSPGS I.E. SYNDECANS OR GLYPICANS), WHICH ARE SUBSEQUENTLY ENDOCYTOSED AND ROUTED THROUGH VESICULAR PATHWAYS TO THE ABLUMINAL SIDE, WHERE THEY ARE RELEASED. OUR RESEARCH PLAN ENTAILS THE IMPLEMENTATION OF SPATIAL TRANSCRIPTOMICS, PROTEOMICS, GLYCOMICS, AND CELL BIOLOGY TO RELATE OUR IN VIVO FUNCTIONAL RESULTS TO THE EXPRESSION AND COMPOSITION OF ENDOTHELIAL HSPGS IN DIFFERENT TISSUES AND VASCULAR ZONES. WE WILL PAIR THESE RESULTS WITH FUNCTIONAL ASSAYS IN VITRO USING PHARMACOLOGIC AND MOLECULAR APPROACHES TO IDENTIFY THE HSPGS AND ATTACHED HS MOIETIES THAT ARE REGULATING TRANSENDOTHELIAL TRANSPORT. WE WILL ADDITIONALLY CHARACTERIZE TRANSCYTOTIC ROUTING MECHANISMS OF HSPGS AND THEIR BOUND LIGANDS IN VITRO USING FLUORESCENT IMAGING, PHARMACOLOGIC, AND MOLECULAR APPROACHES. ACHIEVEMENT OF THESE GOALS WOULD ADVANCE THE GENERAL KNOWLEDGE OF ENDOTHELIAL CELL BIOLOGY AND ENDOCYTIC/TRANSCYTOTIC TRANSPORT MECHANISMS. OUR FINDINGS WOULD ALSO HAVE BROAD APPLICATIONS IN STUDYING BIOLOGICAL PROCESSES THAT INVOLVE HS/LIGAND INTERACTIONS IN HEALTH AND DISEASE, AND FOR DRUG DEVELOPMENT.

CHARACTERIZATION OF A HUMAN IN VITRO BLOOD-BRAIN BARRIER MODEL TO STUDY THE EFFECTS OF SYSTEMIC AGING ON RESPONSES TO ALZHEIMER'S DISEASE EFFECTORS

OZONE-INDUCED DEPRESSION, COGNITIVE IMPAIRMENT, AND SERUM AMYLOID A: A LUNG-LIVER-BRAIN AXIS

INVESTIGATING A NEUROPROTECTIVE ROLE OF GBA IN ASTROCYTES - A KEY FEATURE OF PARKINSON’S DISEASE (PD) IS ABNORMAL PROTEIN AGGREGATION WITHIN NEURONS IN THE BRAIN. THESE NEURONAL PROTEIN AGGREGATES SPREAD THROUGHOUT THE NERVOUS SYSTEM AS PD PROGRESSES, BUT HOW THIS OCCURS REMAINS UNCLEAR. RECENT WORK SUGGESTS THAT ASTROCYTES, WHICH SUPPORT NEURONAL FUNCTION BY PROVIDING ENERGY AND PROTECTION FROM CELLULAR STRESSORS, MAY ALSO HAVE A NEUROPROTECTIVE ROLE IN PD AND OTHER NEURODEGENERATIVE DISEASES. THIS PROPOSAL INVESTIGATES A POTENTIAL NEW ROLE FOR THE GENE GBA, A COMMON GENETIC RISK FACTOR FOR PD THAT IS ALSO ASSOCIATED WITH FASTER DISEASE PROGRESSION. WHILE MOST STUDIES OF GBA FOCUS EXCLUSIVELY ON ITS ROLE IN NEURONS, WE WILL TEST WHETHER GBA IS REQUIRED IN ASTROCYTES TO UPTAKE AND DEGRADE NEURONAL-DERIVED PROTEINS IN THE EXTRACELLULAR MATRIX TO REDUCE PROPAGATION OF PATHOGENIC NEURONAL PROTEIN AGGREGATES. OUR RECENT WORK USING OUR DROSOPHILA GBA DEFICIENT MODEL (GBADEL) OF PD INDICATES THAT EXOSOMES ARE AN IMPORTANT VEHICLE MEDIATING THE SPREAD OF PROTEIN AGGREGATION. GBA DEFICIENCY DYSREGULATES EXOSOME FORMATION, FUSION, AND/OR CONTENT. SURPRISINGLY, WE FOUND THAT GLIAL EXPRESSION OF WILDTYPE GBA CAN REDUCE PROTEIN AGGREGATION PRESENT IN GBADEL FLY BRAINS. TO FURTHER INVESTIGATE A POSSIBLE NEUROPROTECTIVE ROLE FOR GBA IN ASTROCYTES, WE WILL USE CULTURED NEURONS AND ASTROCYTES DIFFERENTIATED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS GENERATED FROM PD PATIENTS CARRYING GBA MUTATIONS. UNRELATED HEALTHY AGE- AND SEX-MATCHED CONTROL AND ISOGENIC CONTROLS GENERATED BY CRISPR/CAS9 REVERSION OF THE GBA MUTATION TO WILDTYPE WILL BE USED AS CONTROLS. WE WILL FIRST DETERMINE WHETHER GBA IS IMPORTANT FOR ASTROCYTE UPTAKE AND PROCESSING OF NEURONAL-DERIVED EVS BY EXAMINING GBA PD VERSUS CONTROL ASTROCYTE UPTAKE AND INTRACELLULAR TRAFFICKING OF NEURONAL EVS CONTAINING SYNUCLEIN-GFP FUSION PROTEIN. WE WILL THEN TEST WHETHER GBA HAS A NEUROPROTECTIVE ROLE IN ASTROCYTES BY CO- CULTURING GBA PD OR CONTROL ASTROCYTES WITH GBA PD OR CONTROL NEURONS AND EXAMINE PROTEIN AGGREGATION, ENDOLYSOSOMAL TRAFFICKING AND CELL SURVIVAL IN BOTH CELL TYPES. THE RESULTS FROM THIS STUDY COULD UNCOVER NEW THERAPEUTIC TARGETS TO ENHANCE THE NEUROPROTECTIVE FUNCTION OF ASTROCYTES, LEADING TO TREATMENTS THAT COULD SLOW OR HALT THE PROGRESSION OF PD AND OTHER NEURODEGENERATIVE DISEASES CHARACTERIZED BY PROTEIN AGGREGATES.

GRABBING SEROTONIN DURING FEAR - SEROTONIN PLAYS A CRITICAL ROLE IN RESPONDING TO POTENTIALLY THREATENING STIMULI AND MODULATING THE SEROTONIN SYSTEM CAN EITHER EXACERBATE OR AMELIORATE FEAR RESPONSES TO SUBSEQUENT ENCOUNTERS WITH FEAR-PRODUCING STIMULI. MEDICATIONS THAT INHIBIT SEROTONIN REUPTAKE ARE OFTEN USED FOR STRESS DISORDERS, BUT THEIR EFFECTIVENESS IS VARIABLE AND MAY DISSIPATE WITH TIME. AS PART OF A P50 CONTE CENTER PROJECT, WE FOUND THAT REPEATED INESCAPABLE STRESS INCREASED THE EXPRESSION OF FKBP5 IN MOUSE SEROTONIN NEURONS USING DEEP SEQUENCING OF THE SEROTONERGIC TRANSLATOME. THIS GENE ENCODES FKBP51, A PROTEIN THAT ACTS AS A CO-CHAPERONE FOR STEROID RECEPTORS; ITS EXPRESSION IS DYNAMICALLY REGULATED BY COMPLEX PHYSIOLOGICAL AND EPIGENETIC MECHANISMS, AND IT IS POISED TO PLAY A CRITICAL ROLE IN MODULATING GLUCOCORTICOID FEEDBACK MECHANISMS THAT IMPAIR STRESS RESILIENCE. WE HYPOTHESIZE THAT ELEVATED FKBP5 EXPRESSION IN SEROTONIN NEURONS INTERFERES WITH HORMONAL FEEDBACK MECHANISMS THAT ARE NECESSARY FOR SUCCESSFUL ADAPTATION OF THE SEROTONIN SYSTEM TO STRESS. THERE HAS BEEN SCANT RESEARCH INVESTIGATING THE INTEGRATION OF STEROID SIGNALING WITH SEROTONERGIC FUNCTION, AND FKBP5 IS POSITIONED TO ACT AS A KEY INTEGRATOR OF SYSTEMIC STRESS HORMONES AND SEROTONERGIC FUNCTION. IN AIM 1 WE WILL INCREASE OR DECREASE FKBP5 EXPRESSION IN SEROTONIN NEURONS USING INTERSECTIONAL STRATEGIES TO INVESTIGATE HOW THIS FKBP51 MODULATES FEAR LEARNING AND EXTINCTION. IN AIM 2 WE WILL USE THE NOVEL 5-HT BIOSENSOR GRAB5-HT3.0 TO MEASURE SEROTONIN RELEASE IN AMYGDALA IN RESPONSE TO OPTOGENETIC STIMULATION OR DURING FEAR CONDITIONING. WE HAVE DEVELOPED TWO NOVEL CRE-DEPENDENT, CONDITIONAL AAV VECTORS, ONE THAT EXPRESSES FKBP51 AND GFP (FOR OVEREXPRESSION), AND THE OTHER THAT CONTAINS FLOXED AND INVERTED SACAS9 AND A FKBP5-SPECIFIC GUIDE STRAND ON SEPARATE TRANSCRIPTIONAL CASSETTES (FOR KNOCKOUT). FOR AIM 1, WE WILL INJECT THESE VECTORS INTO DORSAL RAPHE NUCLEUS OF PET1-CRE MICE FOR SEROTONIN NEURON-SPECIFIC EXPRESSION. WE WILL INVESTIGATE FEAR LEARNING, RECALL, EXTINCTION, AND RETRIEVAL TO INVESTIGATE HOW HIGH OR LOW LEVELS OF FKBP5 IN SEROTONIN NEURONS AFFECTS PASSIVE COPING IN RESPONSE TO FEARFUL STIMULI. IN AIM 2 WILL ALSO INJECT A NOVEL GRAB FLUORESCENT BIOSENSOR TO MEASURE EXTRACELLULAR SEROTONIN, WHICH WILL BE DETECTED IN RESPONSE TO GRADED OPTOGENETIC STIMULATION OF THE SEROTONIN FIBERS BEFORE AND AFTER FEAR CONDITIONING AND IN RESPONSE TO CUES. THIS WILL REVEAL THE EFFECTS OF HIGH OR LOW LEVELS OF FKBP5 IN SEROTONIN NEURONS ON SEROTONIN RELEASE DYNAMICS IN AMYGDALA. THE RESULTS OF THESE INNOVATIVE EXPERIMENTS WILL FRAME A LARGER R01 PROPOSAL TO INVESTIGATE THE IMPACT OF FKBP5 AND STEROID RECEPTOR SIGNALING ON SEROTONIN NEURONS IN A WIDER RANGE OF BEHAVIORS AND BRAIN REGIONS AND THEIR POTENTIAL ROLE IN FUTURE THERAPEUTICS.

THE UNFOLDING ROLE OF MICROGLIA IN ALCOHOL WITHDRAWAL - ABSTRACT ALCOHOL WITHDRAWAL IS A MEDICAL EMERGENCY AND A BEHAVIORAL BARRIER TO REDUCING ALCOHOL ABUSE. UNLIKE WITHDRAWAL TO OTHER DRUGS, THERE IS AMPLE EVIDENCE THAT WITHDRAWAL TO ALCOHOL BECOMES WORSE AFTER MULTIPLE CYCLES OF ALCOHOL CONSUMPTION AND ABSTINENCE, INCREASING THE RISKS FOR SERIOUS ADVERSE COMPLICATIONS INCLUDING SEIZURES, DELIRIUM TREMENS, AND DEATH. FURTHERMORE, THE NEGATIVE REINFORCEMENT INHERENT TO CYCLES OF ALCOHOL ABSTINENCE AND RELAPSE TO ALCOHOL CONSUMPTION COMPLICATES ANY BEHAVIORAL INTERVENTIONS TO REDUCE ALCOHOL ABUSE. MANY CLUES SUGGEST THAT NEUROINFLAMMATION IS INVOLVED IN BOTH ALCOHOL TOLERANCE AS WELL AS WITHDRAWAL, BUT THIS REALIZATION HAS NOT LED TO NEW TREATMENTS FOR ALCOHOL USE DISORDER. THE PURPOSE OF THIS PROPOSAL IS TO DEVELOP OUR HYPOTHESIS THAT CHRONIC, INTERMITTENT ALCOHOL EXPOSURE ALTERS THE WAY MICROGLIA, THE INNATE IMMUNE CELLS THAT RESIDE IN THE BRAIN, MODULATE NEUROIMMUNE AS WELL AS NEURONAL SYNAPTIC SIGNALING. IN PILOT EXPERIMENTS USING RNA SEQUENCING OF RIBOSOME-ASSOCIATED RNA FROM MICROGLIA AFTER MULTIPLE CYCLES OF ALCOHOL EXPOSURE AND ABSTINENCE, WE FOUND THAT ALCOHOL WITHDRAWAL CAUSES OXIDATIVE STRESS IN MICROGLIA AND ACTIVATES THE “UNFOLDED PROTEIN RESPONSE” (UPR), A MECHANISM THAT IS INVOLVED IN CELLULAR STRESS RESPONSES LEADING TO NEUROINFLAMMATORY SIGNALING AND DERANGEMENTS IN MICROGLIA FUNCTION THAT CAN LEAD TO CELL DEATH. WE PROPOSE TO BLOCK THE FULL ACTIVATION OF THE MICROGLIAL UPR BY KNOCKING OUT CHOP, A KEY TRANSCRIPTION FACTOR INVOLVED IN THIS PATHWAY THAT WAS DRAMATICALLY UPREGULATED IN MICROGLIA DURING WITHDRAWAL, USING A RECENTLY DEVELOPED, SELECTIVE CRE-DRIVER MOUSE LINE, TMEM119-2A-CRE-ERT2/TDTOMATO, CROSSED WITH COMMERCIALLY AVAILABLE FLOXED CHOP MICE TO INVESTIGATE THIS BIOLOGY. WE WILL EXAMINE HOW BLUNTING UPR SIGNALING ALTERS THE SIGNS OF ALCOHOL WITHDRAWAL BY TESTING IF CHOP KNOCKOUT ALTERS SEVERAL BEHAVIORAL MANIFESTATIONS AND REDUCES MICROGLIA MORPHOLOGICAL AND GENE EXPRESSION CHANGES ASSOCIATED WITH WITHDRAWAL. USING IN VIVO TWO-PHOTON TIME LAPSE MICROSCOPY, WE WILL EXAMINE IF CHOP KNOCKOUT FROM MICROGLIA CHANGES MORPHOLOGY AND MOTILITY ASSOCIATED DURING ALCOHOL WITHDRAWAL. WE WILL ALSO TEST WHETHER MICROGLIAL CHOP IMPACTS THE MOTIVATION TO DRINK ALCOHOL IN A MODEL OF VOLUNTARY ALCOHOL DRINKING AFTER MULTIPLE CYCLES OF ETHANOL VAPOR EXPOSURE AND WITHDRAWAL. TOGETHER, THESE EXPERIMENTS EXAMINE THE ROLE OF NEUROINFLAMMATION IN THE MECHANISMS OF ALCOHOL DEPENDENCE AND WITHDRAWAL FROM A NEW ANGLE THAT HAS NOT BEEN PREVIOUSLY CONSIDERED AND IS WELL MATCHED TO THE R21 MECHANISM DUE TO ITS HIGH NOVELTY AND POTENTIAL TO DEVELOP NEW TREATMENTS.

BLAST CONCUSSION MTBI, HYPOPITUITARISM, AND PSYCHOLOGICAL HEALTH IN OIF/OEF VETERANS

USER-CENTERED DESIGN AND EVALUATION OF A VIRTUAL HUMAN PATIENT TO IMPROVE SAFETY PLANNING SKILLS - PROJECT SUMMARY DESPITE UNPRECEDENTED SUICIDE PREVENTION EFFORTS UNDERTAKEN IN THE LAST DECADE, SUICIDE RATES AMONG VETERANS AND MILITARY SERVICE MEMBERS REMAIN ELEVATED RELATIVE TO THE PRE-9/11 ERA, HIGHLIGHTING THE NEED FOR IMPROVED DEVELOPMENT AND IMPLEMENTATION OF SCIENTIFICALLY SUPPORTED INTERVENTIONS FOR THIS AT-RISK POPULATION. THIS PROJECT WILL DEVELOP AN ONLINE, INTERACTIVE VIRTUAL STANDARDIZED PATIENT (VSP) TO TRAIN PROVIDERS WITHIN THE DEPARTMENT OF VETERANS AFFAIRS (VA) TO ADMINISTER THE BRIEF SUICIDE SAFETY PLANNING INTERVENTION (SPI). RESEARCH HAS DEMONSTRATED THE SPI TO BE AN ACCEPTABLE, FEASIBLE, AND EFFECTIVE INTERVENTION FOR VETERANS AT ELEVATED RISK OF SUICIDE. HOWEVER, TRAINING TO CONDUCT THE SPI HAS BEEN LIMITED AND NO CURRENTLY AVAILABLE TRAINING PROVIDES THE OPPORTUNITY FOR BEHAVIORAL REHEARSAL AND INTERACTIVE PRACTICE IN AN ONLINE FORMAT AVAILABLE AT THE CONVENIENCE OF THE PROVIDER. THE CURRENT PROPOSAL WILL DEVELOP A VSP USING BEST PRACTICES IN USER-CENTERED DESIGN TO CREATE A STANDARDIZED TRAINING TOOL TO ASSIST PROVIDERS IN DEVELOPING CLINICAL SKILLS TO MORE EFFECTIVELY IMPLEMENT THE SPI. THE PROJECT WILL INCLUDE A TWO-PHASE STUDY. PHASE I WILL INCLUDE A FORMATIVE EVALUATION TO INFORM THE DESIGN OF THE VSP WITH SPI SPECIFIC CONTENT AND WILL INVOLVE ITERATIVE REVISIONS BASED ON USER- CENTERED DESIGN FEEDBACK FROM VA HEALTHCARE PROVIDERS (N = 10). ONCE THE FINAL VERSION OF THE VSP IS COMPLETED, IT WILL BE EVALUATED IN A MIXED METHODS PILOT STUDY WITH 30 VA HEALTHCARE PROVIDERS TO EXAMINE CHANGES IN PROVIDER SPI CLINICAL SKILLS, KNOWLEDGE, CONFIDENCE, AND SELF-EFFICACY (PHASE II). THIS EVALUATION OF THE VSP WILL ENCOURAGE FUTURE RESEARCH AND DISSEMINATION OF THIS NOVEL TRAINING TOOL, IF EFFECTIVE. THE RESULTING VSP WILL BE COST-EFFECTIVE AND HIGHLY SCALABLE, AND WILL REQUIRE ONLY A DESKTOP COMPUTER WITH INTERNET ACCESS TO RUN. THE VSP WILL BE DEVELOPED TO TARGET TRAINING FOR A WIDE RANGE OF PROVIDERS, NOT JUST THOSE IN MENTAL HEALTH. SIMILARLY, THE TECHNOLOGY WILL BE DEVELOPED SUCH THAT IT COULD BE DISSEMINATED TO PROVIDERS WHO WORK WITH VETERAN AND NON-VETERAN PATIENTS OUTSIDE OF THE VA. THIS TRAINING TOOL WILL BE USEFUL FOR PROVIDERS INITIALLY LEARNING THE SPI, AS WELL AS THOSE WHO WISH TO REFRESH THEIR SKILLS. OUR PROPOSAL BRINGS TOGETHER TWO TEAMS (VA PUGET SOUND AND THE USC INSTITUTE FOR CREATIVE TECHNOLOGIES) WITH A HISTORY OF HIGH IMPACT MENTAL HEALTH TECHNOLOGY DEVELOPMENT. THESE TEAMS HAVE UNIQUE, AND COMPLEMENTARY, EXPERTISE IN ORDER TO SUCCESSFULLY EXECUTE THIS PROPOSAL. RESULTS HAVE THE POTENTIAL TO MAKE A SUBSTANTIAL IMPACT ON THE VA HEALTHCARE SYSTEM AND ITS AT-RISK PATIENTS. NEXT STEPS WILL INCLUDE A FULLY POWERED RANDOMIZED CONTROLLED TRIAL TO EXAMINE THE EFFICACY OF THE DEVELOPED VSP ON PROVIDER BEHAVIORS (CLINICAL SKILLS) AND PATIENT OUTCOMES, FOLLOWED BY DISSEMINATION OF THE VSP TO OTHER VA AND NON-VA SITES, IF EFFICACIOUS.

MECHANISMS OF BLOOD-BRAIN BARRIER DISRUPTION IN TYPE II DIABETES

DISPARITIES IN THE DIAGNOSIS OF ALZHEIMER'S DISEASE AMONG AFRICAN AMERICAN AND EUROPEAN AMERICAN VETERANS

OPTIMIZING PROSTHETIC PRESCRIPTION TO MITIGATE THE EFFECTS OF PERSPIRATION

THE EVALUATION AND REDESIGN OF TRANSMETATARSAL PROSTHETICS TO REDUCE PEAK PLANTAR PRESSURES.

ADVERSE EVENTS ASSOCIATED WITH TESTOSTERONE TREATMENT IN HYPOGONADAL MEN

PRAZOSIN FOR NONCOMBAT TRAUMA PTSD

REFUND CHECK IN THE AMOUNT OF $10.60

ORAL GUCY2C LIGAND BLOCKS COLORECTAL TUMOR PROGRESSION IN PATIENT

CHANGES IN THE CHARACTERISTICS OF PLANTAR SOFT TISSUE WITH DIABETES

GLUCAGON SECRETION AND THE MECHANISM OF ISLET NEUROPATHY

DEVELOPMENT OF A BRIEF VERSION OF COMPENSATORY COGNITIVE TRAINING FOR VETERANS WITH MILD TRAUMATIC BRAIN INJURY.

WHOLE-METHYLOME SEQUENCING TO IDENTIFY UNIQUE EPIGENETIC PROFILES IN LEWY BODY DEMENTIAS

MECHANICAL, MORPHOMETRIC, AND MICROSTRUCTURE PROPERTIES OF FOOT LIGAMENTS

TARGETING THE SUBTYPE OF METASTATIC PROSTATE CANCER DEFICIENT IN DNA REPAIR CAPACITY

TREATING ALS BY TARGETING PATHOLOGICAL TDP-43

14TH SYMPOSIUM OF THE INTERNATIONAL DIABETES EPIDEMIOLOGY GROUP (IDEG)

IN-DEPTH ANALYSIS OF CITRULLINE-SPECIFIC CD4 T-CELLS IN RHEUMATOID ARTHRITIS