Dignity Inc

NEUROBIOLOGY OF MILD COGNITIVE IMPAIRMENT IN THE ELDERLY

EARLY HEAD START

EARLY HEAD START

EARLY HEAD START

EARLY HEAD START

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

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

2008 TITLE III

IMAGING BIOMARKERS OF NEUROTOXICITY IN WELDERS

CENTERS FOR INDEPENDENT LIVING - CENTERS FOR INDEPENDENT LIVING

PEDIATRIC TRAUMATIC BRAIN INJURY CONSORTIUM: HYPOTHERMIA

MITIGATING HOMELESS ENCAMPMENTS THROUGH COORDINATED, WRAPAROUND STABILIZATION SERVICES IN HIGH-IMPACT AREAS OF SEATTLE/KING COUNTY, WA - COLEAD MITIGATES IDENTIFIED HOMELESS ENCAMPMENTS BY PROVIDING OUTREACH, NEEDS ASSESSMENT, SHELTER MATCHING INDIVIDUAL NEEDS, WRAPAROUND STABILIZATION SERVICES AND COORDINATED CARE, SHORT-TERM SHELTER, AND TRANSITION TO PERMANENT HOUSING FOR UNHOUSED PEOPLE IN HIGH-IMPACT AREAS OF SEATTLE/KING COUNTY, WA. OPERATING AT THE INTERSECTION OF HEALTH, SAFETY, AND EQUITY, COLEAD REPRESENTS AN EFFECTIVE STRATEGY TO ADDRESS CRIME AND PUBLIC DISORDER ASSOCIATED WITH PEOPLE WHO HAVE COMPLEX BEHAVIORAL HEALTH CONDITIONS, ARE UNHOUSED, AND HAVE DISPROPORTIONATELY HIGH RATES OF CONTACT WITH LAW ENFORCEMENT AND THE CRIMINAL LEGAL SYSTEM. COLEAD SERVES INDIVIDUALS 18 YEARS AND OLDER WHO COMMIT, OR ARE AT HIGH RISK OF COMMITTING, LAW VIOLATIONS RELATED TO UNMET BEHAVIORAL HEALTH NEEDS AND/OR IMPOVERISHMENT. THEY ARE PEOPLE WHOSE BEHAVIORAL HEALTH ISSUES HAVE TYPICALLY BEEN MET WITH ARREST AND PROSECUTION; WHO ARE COMMONLY ESTRANGED FROM SYSTEMS OF CARE; AND WHO REQUIRE FIELD-BASED ENGAGEMENT AND RE-IMAGINATION OF ACCESS POINTS. IN ADDITION TO THEIR DISPROPORTIONATELY HIGH RATES OF CONTACT WITH THE CRIMINAL LEGAL SYSTEM, PARTICIPANTS OFTEN LACK SAFE AND STABLE HOUSING, LEGAL INCOME, PUBLIC BENEFITS, AND ACCESS TO HEALTH CARE. ACCORDING TO A 2023 STUDY, 62 PERCENT OF PARTICIPANTS REPORTED BOTH A MENTAL HEALTH CONDITION AND A SUBSTANCE USE DISORDER. MORE THAN 94% OF PEOPLE SURVEYED REPORTED THAT THEY HAD BEEN HOMELESS FOR MORE THAN A YEAR, WHILE 57% INDICATED THAT THEY HAD BEEN LIVING UNSHELTERED FOR FIVE OR MORE YEARS. IN THE ONE-YEAR FUNDED PERIOD, COLEAD WILL CONDUCT RAPID ASSESSMENTS FOR AT LEAST 200 PEOPLE WITH COMPLEX CONDITIONS LIVING UNSHELTERED IN THE IDENTIFIED AREAS OF FOCUS; PROVIDE HARM REDUCTION AND OVERDOSE PREVENTION SUPPLIES AND INSTRUCTION FOR AT LEAST 200 PEOPLE; PROVIDE INTENSIVE CASE MANAGEMENT SUPPORTS FOR AT LEAST 200 PEOPLE; ENROLL OR RENEW ENROLLMENT AT LEAST 100 PEOPLE IN MEDICAID AND/OR MEDICARE; AND PLACE AT LEAST 50 PEOPLE IN PERMANENT SUPPORTIVE HOUSING. BY COMBINING EVIDENCE-BASED WRAPAROUND CASE MANAGEMENT, MULTI-AGENCY COORDINATION, AND SHORT-TERM, NON-CONGREGATE, SUPPORTIVE SHELTER, COLEAD REDUCES BARRIERS TO SERVICES AND CARE FOR PEOPLE WHO OTHERWISE CANNOT ACCESS EXISTING RESOURCES; REDUCES RELIANCE ON POLICE AND THE CRIMINAL LEGAL SYSTEM TO ADDRESS PROBLEMS OF PUBLIC DISORDER; AND SERVES AS AN ALTERNATIVE OR SUPPLEMENT TO 911 AS A PRIMARY RESPONSE TO REQUESTS FOR SERVICE RELATED TO UNMET BEHAVIORAL HEALTH NEEDS.

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.

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

ACCOUNTABLE HEALTH COMMUNITIES, TRACK 3DIGNITY SJHMC 2MATCH PROJECT

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

IMMUNE MECHANISMS OF REJECTION IN HUMAN LUNG ALLOGRAFTS

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)

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

EARLY HEAD START ARRA EXPANSION

PRIMARY CARE TRAINING AND ENHANCEMENT-COMMUNITY PREVENTION AND MATERNAL HEALTH

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.

EARLY HEAD START/CHILD CARE PARTNERSHIP

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

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

FOREBRAIN CONTROL OF LOCOMOTION

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

HEAD START AND EARLY HEAD START

NK CELLS IN CNS INFLAMMATION AND AUTOIMMUNITY

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.

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

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

MOTONEURON POOL PLASTICITY FOLLOWING SPINAL CORD INJURY

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

PLASTICITY AND NEUROCIRCUIT REMODELING IN THE MEDIOBASAL HYPOTHALAMUS TO TREAT DIABETES

AFFORDABLE CARE ACT: PRIMARY CARE RESIDENCY EXPANSION

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

THE ROLE OF MAST CELLS IN THE PATHOPHYSIOLOGY OF INTRACRANIAL ANEURYSM

EARLY HEAD START/CHILD CARE PARTNERSHIP

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

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.

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

PEPTIDE AND PROTEIN BIOMARKERS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS)

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.

METABOLIC MECHANISMS OF FUNCTIONAL NEUROPROTECTION IN EPILEPTIC BRAIN

EARLY HEAD START-CHILD CARE PARTNERSHIPS

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

BARROW NEUROLOGICAL INSTITUTE APPLICATION TO BECOME A NEURONEXT SITE.

REDUCING CRIME AND DISORDER ASSOCIATED WITH UNMET BEHAVIORAL HEALTH NEEDS AND HOMELESSNESS THROUGH COORDINATED, WRAPAROUND STABILIZATION SERVICES IN SEATTLE/KING COUNTY, WA - SEATTLE-KING COUNTY LEAD (LAW ENFORCEMENT ASSISTED DIVERSION/LET EVERYONE ADVANCE WITH DIGNITY) REDUCES CRIME AND DISORDER ASSOCIATED WITH UNMET BEHAVIORAL HEALTH NEEDS AND HOMELESSNESS BY DIVERTING PEOPLE WITH UNMET BEHAVIORAL HEALTH NEEDS AWAY FROM ARREST AND INTO COORDINATED, COMMUNITY-BASED SYSTEMS OF RESPONSE AND CARE. LEAD CREATES A MECHANISM BY WHICH LAW ENFORCEMENT AND OTHER STAKEHOLDERS IN SEATTLE-KING COUNTY, WA, CAN DIVERT INDIVIDUALS AWAY FROM THE CRIMINAL LEGAL SYSTEM AND INTO INTENSIVE CASE MANAGEMENT SERVICES TO ADDRESS NEEDS RELATED TO MENTAL HEALTH, SUBSTANCE USE DISORDER, AND EXTREME POVERTY. SEATTLE-KING COUNTY LEAD IS A STRUCTURED, COLLABORATIVE PARTNERSHIP OF PUBLIC AGENCIES, NONPROFIT SERVICE PROVIDERS, LAW ENFORCEMENT AND CRIMINAL LEGAL ENTITIES, BUSINESS ASSOCIATIONS, GOVERNMENT OFFICIALS, AND OTHER COMMUNITY STAKEHOLDERS. PARTICIPANTS IN SEATTLE-KING COUNTY LEAD ARE INDIVIDUALS 18 YEARS AND OLDER WHO COMMIT, OR ARE AT HIGH RISK OF COMMITTING, LAW VIOLATIONS RELATED TO BEHAVIORAL HEALTH CHALLENGES AND/OR INCOME INSTABILITY. THEY ARE PEOPLE WHOSE BEHAVIORAL HEALTH ISSUES (MENTAL HEALTH CHALLENGES AND/OR SUBSTANCE USE) HAVE TYPICALLY BEEN MET WITH ARREST AND PROSECUTION; WHO HAVE DISPROPORTIONATELY HIGH RATES OF COMPLEX TRAUMA; WHO ARE COMMONLY ESTRANGED FROM ALL SYSTEMS OF CARE; AND WHO REQUIRE FIELD-BASED ENGAGEMENT AND RE-IMAGINATION OF ACCESS POINTS. THEY ARE TYPICALLY UNHOUSED; DISPROPORTIONATELY LACK ACCESS TO PUBLIC BENEFITS, HEALTHCARE, AND SOCIAL SERVICES; HAVE HIGH RATES OF CONTACT WITH THE CRIMINAL LEGAL SYSTEM AND WITH EMERGENCY RESPONSE SYSTEMS; AND HAVE MULTIPLE COMPOUNDING OR CO-OCCURRING CHALLENGES. IN THE ONE-YEAR FUNDED PERIOD, SEATTLE-KING COUNTY LEAD WILL PROVIDE CASE MANAGEMENT FOR AT LEAST 800 PARTICIPANTS; MAKE AT LEAST 300 REFERRALS TO BEHAVIORAL HEALTH RESOURCES; MAKE AT LEAST 30 REFERRALS TO LEAD LEGAL SERVICES; AND CONDUCT AT LEAST FIVE COMMUNITY MEETINGS RELATED TO HOMELESSNESS AND PUBLIC SAFETY TO EDUCATE A MINIMUM OF 50 UNDUPLICATED COMMUNITY MEMBERS ABOUT LEAD’S PURPOSE, ACTIVITIES, AND ACCESS.

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

ALPHA-CONOTOXIN MII: A SELECTIVE NICOTINIC RECEPTOR PROBE

BLOOD-BRAIN SIGNALING IN INFLAMMATION: LIPID MEDIATORS OF FEVER AND HYPOTHERMIA

THIS AWARD FUNDS THE APPROVED 2023?24 FGP PROGRAM. YOUR 2023?24 STATUTORY MATCH IS 10% AND YOUR BUDGETARY MATCH IS 19.88%.

ROLE OF MACROPHAGES IN HHT PATHOGENESIS AND THERAPY

ENGAGES PERSONS 55 AND OLDER IN SUPPORTIVE SERVICE TO CHILDREN IN NEED

CONTINUUM OF CARE PROGRAM

PURPOSE: THE CONTINUUM OF CARE (COC) PROGRAM IS DESIGNED TO PROMOTE COMMUNITY-WIDE COMMITMENT TO THE GOAL OF ENDING HOMELESSNESS; PROVIDE FUNDING FOR EFFORTS BY NONPROFIT PROVIDERS, STATES, AND LOCAL GOVERNMENTS TO QUICKLY HOUSE HOMELESS INDIVIDUALS AND FAMILIES WHILE MINIMIZING THE TRAUMA AND DISLOCATION CAUSED TO HOMELESS INDIVIDUALS, FAMILIES, AND COMMUNITIES BY HOMELESSNESS; PROMOTE ACCESS TO AND EFFECTIVE UTILIZATION OF MAINSTREAM PROGRAMS BY HOMELESS INDIVIDUALS AND FAMILIES; AND OPTIMIZE SELF-SUFFICIENCY AMONG INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS. THE MOST RECENT COC AWARD ANNOUNCEMENT LISTING AWARDS BY STATE AND COC IS ACCESSIBLE AT HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/COMM_PLANNING/COC/AWARDS. SELECT THE LINK UNDER THE FUNDING AND AWARD INFORMATION SECTION FOR THE APPROPRIATE FISCAL YEAR.; ACTIVITIES TO BE PERFORMED: CONTINUUM OF CARE PROGRAM FUNDS MAY BE USED TO PAY FOR THE ELIGIBLE COSTS USED TO ESTABLISH AND OPERATE PROJECTS UNDER FIVE PROGRAM COMPONENTS: (1) PERMANENT HOUSING, WHICH INCLUDES PERMANENT SUPPORTIVE HOUSING FOR PERSONS WITH DISABILITIES, AND RAPID REHOUSING; (2) TRANSITIONAL HOUSING; (3) SUPPORTIVE SERVICES ONLY; (4) HOMELESS MANAGEMENT INFORMATION SYSTEMS (HMIS), AND (5) IN SOME CASES, HOMELESSNESS PREVENTION. THIRTEEN TYPES OF ASSISTANCE MAY BE PROVIDED THROUGH THE CONTINUUM OF CARE (COC) PROGRAM: (1) COC PLANNING ACTIVITIES/COSTS FOR DESIGNING AND CARRYING OUT A COLLABORATIVE PROCESS FOR THE DEVELOPMENT OF AN APPLICATION TO HUD; (2) UNITED FUNDING AGENCY (UFA) COSTS FOR FISCAL CONTROL AND ACCOUNTING NECESSARY TO ASSURE THE PROPER DISBURSAL OF, AND ACCOUNTING FOR, FEDERAL FUNDS AWARDED TO SUBRECIPIENTS UNDER THE CONTINUUM OF CARE PROGRAM, (3) ACQUISITION OF REAL PROPERTY (INCLUDING STRUCTURES) FOR USE IN THE PROVISION OF HOUSING OR SUPPORTIVE SERVICES; (4) REHABILITATION OF STRUCTURES TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; (5) NEW CONSTRUCTION, INCLUDING THE BUILDING OF A NEW STRUCTURE OR BUILDING AN ADDITION TO AN EXISTING STRUCTURE FOR USE AS SUPPORTIVE HOUSING; (6) LEASING OF A STRUCTURE OR STRUCTURES, OR PORTIONS THEREOF, TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; (7) RENTAL ASSISTANCE, WHICH MAY BE SHORT-TERM, MEDIUM-TERM, OR LONG-TERM, AS WELL AS TENANT-BASED, PROJECT-BASED, OR SPONSOR-BASED, FOR TRANSITIONAL OR PERMANENT HOUSING; (8) SUPPORTIVE SERVICES TO ASSIST PROGRAM PARTICIPANTS OBTAIN AND MAINTAIN HOUSING; (9) OPERATING COSTS OF SUPPORTIVE HOUSING; (10) COSTS OF IMPLEMENTING AND OPERATING HMIS; (11) PROJECT ADMINISTRATIVE COSTS; (12) RELOCATION COSTS; AND (13) INDIRECT COSTS IN ACCORDANCE WITH 2 CFR PARTS 200, AS APPLICABLE. IN ADDITION TO USING GRANT FUNDS FOR THE ELIGIBLE COSTS DESCRIBED ABOVE, RECIPIENTS AND SUBRECIPIENTS IN CONTINUUMS OF CARE DESIGNATED AS HIGH PERFORMING COMMUNITIES MAY ALSO USE GRANT FUNDS TO PROVIDE HOUSING RELOCATION AND STABILIZATION SERVICES AND SHORT- AND/OR MEDIUM-TERM RENTAL ASSISTANCE TO INDIVIDUALS AND FAMILIES AT RISK OF HOMELESSNESS AS SET FORTH IN 24 CFR 576.103 AND 24 CFR 576.104, IF NECESSARY TO PREVENT THE INDIVIDUAL OR FAMILY FROM BECOMING HOMELESS. LIMITATION ON USE OF FUNDS: NO ASSISTANCE PROVIDED UNDER PROGRAM (OR ANY STATE OR LOCAL GOVERNMENT FUNDS USED TO SUPPLEMENT THIS ASSISTANCE) MAY BE USED TO REPLACE STATE OR LOCAL FUNDS PREVIOUSLY USED, OR DESIGNATED FOR USE, TO ASSIST HOMELESS PERSONS OR PERSONS AT-RISK OF HOMELESSNESS.; EXPECTED OUTCOMES: DECREASE IN THE NUMBER INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS, MORE SPECIFICALLY USING PERFORMANCE INDICATORS SUCH AS THE LENGTH OF TIME HOMELESS, RETURNS TO HOMELESSNESS OVER TIME, AND EXITS TO PERMANENT HOUSING. COC PERFORMANCE PROFILE REPORTS CAN BE FOUND AT HTTPS://WWW.HUDEXCHANGE.INFO/PROGRAMS/COC/COC-PERFORMANCE-PROFILE-REPORTS/.; INTENDED BENEFICIARIES: INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD.

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

FOSTER GRANDPARENT PROGRAM

EARLY HEAD START

STRUCTURAL DYNAMICS UNDERLYING RHO1 GABAC RECEPTOR ACTIVATION AND ANTAGONISM

GHANA APPAREL MANUFACTURING EXPANSION (GAME)

NURSE EDUCATION, PRACTICE, QUALITY AND RETENTION SIMULATION EDUCATION TRAINING PROGRAM

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.”

GENOTYPIC AND PHENOTYPIC EXAMINATION OF DISEASE PATHOGENEIS IN C8ORF72 FTD

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

PURPOSE: THE LEAD-BASED PAINT HAZARD REDUCTION (LHR) GRANT PROGRAM IS TO MAXIMIZE THE NUMBER OF CHILDREN UNDER THE AGE OF SIX PROTECTED FROM LEAD POISONING BY ASSISTING STATES, CITIES, COUNTIES/PARISHES, NATIVE AMERICAN TRIBES OR OTHER UNITS OF LOCAL GOVERNMENT IN UNDERTAKING COMPREHENSIVE PROGRAMS TO IDENTIFY AND CONTROL LEAD-BASED PAINT HAZARDS IN ELIGIBLE PRIVATELY-OWNED RENTAL OR OWNER-OCCUPIED HOUSING POPULATIONS. IN ADDITION, THERE IS HEALTHY HOMES SUPPLEMENTAL FUNDING AVAILABLE THAT IS INTENDED TO ENHANCE THE LEAD-BASED PAINT HAZARD CONTROL ACTIVITIES BY COMPREHENSIVELY IDENTIFYING AND ADDRESSING OTHER HOUSING HAZARDS THAT AFFECT OCCUPANT HEALTH. INFORMATION ABOUT WHERE THE SUPPLEMENTAL FUNDING CAN BE USED CAN BE FOUND AT. HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/HEALTHY_HOMES/PROJECT_DESCRIPTIONS; ACTIVITIES TO BE PERFORMED: PROGRAM FUNDS WILL BE AWARDED TO APPLICANTS TO ACCOMPLISH THE FOLLOWING OBJECTIVES: A. TARGETED UNITS: TARGET LEAD HAZARD CONTROL EFFORTS IN HOUSING UNITS WHERE CHILDREN LESS THAN 6 YEARS OF AGE ARE AT GREATEST RISK OF LEAD POISONING (PRE-1960, AND, ESPECIALLY, PRE-1940 CONSTRUCTION), WHICH HAS HISTORICALLY INCLUDED CHILDREN IN LOW-INCOME AND MINORITY NEIGHBORHOODS, TO REDUCE THE LIKELIHOOD OF ELEVATED BLOOD LEAD LEVELS IN THESE CHILDREN. B. COST EFFECTIVENESS: UTILIZE COST-EFFECTIVE LEAD HAZARD CONTROL METHODS AND APPROACHES THAT ENSURE THE LONG-TERM SAFETY OF THE BUILDING OCCUPANTS. C. CAPACITY: BUILD LOCAL CAPACITY OF TRAINED AND CERTIFIED INDIVIDUALS AND FIRMS TO ADDRESS LEAD HAZARDS SAFELY AND EFFECTIVELY DURING LEAD HAZARD CONTROL, RENOVATION, REMODELING, AND MAINTENANCE ACTIVITIES. ANOTHER CORE ELEMENT FOR CAPACITY INCLUDES THE DEVELOPMENT OF COMPREHENSIVE, COMMUNITY-BASED APPROACHES TO INTEGRATING THIS GRANT PROGRAM WITHIN OTHER LOCAL INITIATIVES THROUGH PUBLIC AND PRIVATE PARTNERSHIPS THAT ADDRESS HOUSING RELATED HEALTH AND SAFETY HAZARDS AND/OR SERVE LOW-INCOME FAMILIES WITH CHILDREN UNDER THE AGE OF SIX (6). D. AFFIRMATIVE MARKETING: ESTABLISH AND IMPLEMENT A DETAILED PROCESS OF MONITORING AND ENSURING THAT UNITS MADE LEAD-SAFE ARE AFFIRMATIVELY MARKETED, AND PRIORITY GIVEN, TO FAMILIES WITH CHILDREN UNDER AGE 6 YEARS FOR NOT LESS THAN THREE YEARS. E. DATA COLLECTION: GATHER PRE- AND POST-TREATMENT DATA THAT SUPPORTS AND VALIDATES LEAD HAZARD CONTROL INVESTMENTS. PROGRAM DATA COLLECTED SHOULD SUPPORT THE EVALUATION OF GRANT PROGRAM ACTIVITIES AND OUTCOMES. F. TARGETED OUTREACH AND EDUCATION: CONDUCTING TARGETED OUTREACH, AFFIRMATIVE MARKETING, EDUCATION OR OUTREACH PROGRAMS ON LEAD HAZARD CONTROL AND LEAD POISONING PREVENTION DESIGNED TO INCREASE THE ABILITY OF THE APPLICANT TO DELIVER THE SPECIFIED LEAD HAZARD CONTROL SERVICES THROUGH THIS PROGRAM; INCLUDING EDUCATING OWNERS OF ELIGIBLE RENTAL PROPERTIES, TENANTS, AND OTHERS ON THE BENEFITS AND EXPECTATIONS OF PARTICIPATING IN THIS PROGRAM PROVIDED BY "TITLE X" OF THE RESIDENTIAL LEAD-BASED PAINT HAZARD REDUCTION ACT OF 1992.; EXPECTED OUTCOMES: TO IDENTIFY AND CLEAN UP DANGEROUS LEAD IN LOW-INCOME FAMILIES’ HOMES WHERE LOW-INCOME FAMILIES WERE CHILDREN 6 AND UNDER RESIDE. THESE INVESTMENTS WILL PROTECT FAMILIES AND CHILDREN BY TARGETING SIGNIFICANT LEAD AND HEALTH HAZARDS IN OVER 3,700 LOW-INCOME HOMES FOR WHICH OTHER RESOURCES ARE NOT AVAILABLE.; INTENDED BENEFICIARIES: TO ASSIST STATES, CITIES, COUNTIES/PARISHES, NATIVE AMERICAN TRIBES OR OTHER UNITS OF LOCAL GOVERNMENT IN UNDERTAKING COMPREHENSIVE PROGRAMS TO IDENTIFY AND CONTROL LEAD-BASED PAINT HAZARDS IN ELIGIBLE PRIVATELY-OWNED RENTAL OR OWNER-OCCUPIED HOUSING POPULATIONS WERE CHILDREN UNDER 6 RESIDE.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD.

THE FOSTER GRANDPARENT PROGRAM (FGP) HAS VOLUNTEERS WHO WILL SERVE IN LOCAL SCHOOLS TO ASSIST LOW-ACHIEVING, AT-RISK YOUTH. RISK FACTORS, BASED ON LOCAL POVERTY LEVELS, INCLUDE PARENTAL ABSENCE, SUBSTANCE, AND OTHER FORMS OF ABUSE. PROTECTIVE FACTORS INCLUDE CARING RELATIONSHIPS, POSITIVE ACCEPTANCE, HIGH EXPECTATIONS, AND INTERACTIVE OPPORTUNITIES. SCHOOLS BENEFIT BY HAVING A NURTURING SENIOR AVAILABLE TO ENHANCE AND ENRICH THE CLASSROOM EXPERIENCE. YOUTH BENEFIT WITH AN IMPROVED SCHOOL PERFORMANCE. SERVICE ACTIVITY: 68 FOSTER GRANDPARENTS (FGPS) WILL WORK WITH 204 YOUTH IDENTIFIED BY THE TEACHERS. THEY WILL READ WITH THEIR YOUTH AND TUTOR IN LOW ACHIEVING SUBJECTS SUCH AS MATH, LANGUAGE ARTS, AND SOCIAL SKILLS. FGPS WILL HELP YOUTH THROUGH PRAISE, ONE-ON-ONE NURTURING, AND ENSURING EACH CHILD'S OPPORTUNITY TO INTERACT AND LEARN. AT THE TEACHER'S DIRECTION, FGPS WILL WORK BETWEEN 15 AND 40 HOURS EACH WEEK IN THEIR CLASSROOM. FGPS WILL WORK WITH ANY GRADE AT THE DISCRETION OF THE PRINCIPAL. LOCATION OF SERVICES: SHASTA, SISKIYOU, AND TRINITY COUNTIES OUTCOMES: 204 CHILDREN WILL BE SERVED IN MENTORING/TUTORING PROGRAMS WITH IMPROVED ACADEMIC ENGAGEMENT. NUMBER OF STATIONS: 36 FUNDING: CNCS FUNDING REQUESTED: $405,625 NON FEDERAL FUNDING: DIGNITY HEALTH PROVIDES IN-KIND THROUGH HUMAN RESOURCES, IT SUPPORT, AND OTHER CORPORATE CHARGES THAT COULD BE BILLED TO SENIOR CORPS GRANTS. ADDITIONAL IN-KIND FOR RENT, SPACE, BREAKFAST, LUNCHES AND RECOGNITION'S FOR VOLUNTEERS ARE SUPPORTED BY LOCAL SCHOOLS AND PARTNERING AGENCIES. EXCESS FUNDING: FEDERAL TRANSIT ADMINISTRATION -- 2017 EXPANDED 5310 GRANT - $63,034 FOR VOLUNTEER MILEAGE, SUPPLIES AND SALARIES.

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.

A COMPUTERIZED PLANNING TOOL FOR SPINE SURGERY

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

HEALTHY MARRIAGE INITIATIVE

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

CENTERS FOR INDEPENDENT LIVING

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

CENTERS FOR INDEPENDENT LIVING - CENTERS FOR INDEPENDENT LIVING

SECTION A. EXECUTIVE SUMMARY: THE FOSTER GRANDPARENT PROGRAM (FGP) HAS VOLUNTEERS WHO WILL SERVE IN LOCAL SCHOOLS TO ASSIST LOW-ACHIEVING, AT-RISK YOUTH. RISK FACTORS, BASED ON LOCAL POVERTY LEVELS, INCLUDE PARENTAL ABSENCE, SUBSTANCE, LOCAL AND NATIONAL DISASTERS (FIRE, COVID19) AND VARIOUS FORMS OF ABUSE. PROTECTIVE FACTORS INCLUDE CARING RELATIONSHIPS, POSITIVE ACCEPTANCE, HIGH EXPECTATIONS, AND INTERACTIVE OPPORTUNITIES. SCHOOLS BENEFIT BY HAVING A NURTURING SENIOR AVAILABLE TO ENHANCE AND ENRICH THE CLASSROOM EXPERIENCE. SERVICE ACTIVITY: 68 VOLUNTEERS TO PROVIDE SOCIAL AND EMOTIONAL SUPPORT TO ASSIGNED CHILDREN. LOCATION OF SERVICES: SHASTA, SISKIYOU, TEHAMA, LASSEN AND TRINITY COUNTIES OUTCOMES: 225 NUMBER OF STUDENTS WITH IMPROVED ACADEMIC ENGAGEMENT OR SOCIAL SKILLS. NUMBER OF STATIONS: 28 FUNDING: CNCS FUNDING REQUESTED: $454.753 GRANTEE SHARE: $69,732 NON-FEDERAL FUNDING: DIGNITY HEALTH CONNECTED LIVING (DHCL) PROVIDES IN-KIND THROUGH HUMAN RESOURCES, IT SUPPORT, AND OTHER CORPORATE CHARGES THAT COULD BE BILLED TO SENIOR CORPS GRANTS. ADDITIONAL IN-KIND FOR RENT, SPACE, BREAKFAST, LUNCHES, AND RECOGNITIONS FOR VOLUNTEERS ARE SUPPORTED BY LOCAL SCHOOLS AND PARTNERING AGENCIES. EXCESS FUNDING: FEDERAL TRANSIT ADMINISTRATION ? 2018 OPERATING ASSISTANCE MOBILITY MANAGEMENT 5310 GRANT - $17,554 TO HELP COVER THE COST OF VOLUNTEER MILEAGE, SUPPLIES, AND SALARIES.

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

HEALTH CARE AND OTHER FACILITIES

ASSESSMENT OF UTERINE CONTRACTILITY AND CERVICAL RIPENING DURING PREGNANCY

FY 2025 ILCL ~ STATE PLAN INDEPENDENT LIVING CENTERS

FY2024-2025 CENTERS FOR INDEPENDENT LIVING

FY2023-2024 CENTERS FOR INDEPENDENT LIVING

SURVIVOR ADVOCATES IN HEALTHCARE

TARGETING CNS EXPRESSION OF CHITINASES AS A NOVEL THERAPY FOR ALS

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.

PURPOSE: THE YOUTH HOMELESSNESS DEMONSTRATION PROGRAM (YHDP) AIMS TO SUPPORT SELECTED COMMUNITIES IN DEVELOPING AND IMPLEMENTING A COORDINATED COMMUNITY APPROACH TO PREVENTING AND ENDING YOUTH HOMELESSNESS. THE POPULATION TO BE SERVED BY THIS DEMONSTRATION PROGRAM IS YOUTH EXPERIENCING HOMELESSNESS, INCLUDING UNACCOMPANIED AND PREGNANT OR PARENTING YOUTH. THE DEMONSTRATION HAS SEVEN PRIMARY OBJECTIVES: • BUILD NATIONAL MOMENTUM. • PROMOTE EQUITY IN THE DELIVERY AND OUTCOMES OF HOMELESS ASSISTANCE. • HIGHLIGHT THE IMPORTANCE OF YOUTH LEADERSHIP. • EVALUATE THE COORDINATED COMMUNITY APPROACH. • EXPAND CAPACITY. • EVALUATE PERFORMANCE MEASURES. • ESTABLISH A FRAMEWORK FOR THE FEDERAL PROGRAM AND TECHNICAL ASSISTANCE COLLABORATION. BEGINNING IN 2016, NEW YHDP COMMUNITIES ARE SELECTED THROUGH A COMPETITIVE PROCESS DEPENDING ON THE ANNUAL FUNDING PROVIDED BY CONGRESS. A MAP OF CURRENTLY FUNDED YHDP SITES IS AVAILABLE AT THE LINK TITLED MAP OF YHDP-FUNDED COC AT HTTPS://WWW.HUDEXCHANGE.INFO/PROGRAMS/YHDP/FY-2022-APPLICATION-RESOURCES/. THE YOUTH HOMELESSNESS DEMONSTRATION PROGRAM (YHDP) AIMS TO SUPPORT SELECTED COMMUNITIES IN DEVELOPING AND IMPLEMENTING A COORDINATED COMMUNITY APPROACH TO PREVENTING AND ENDING YOUTH HOMELESSNESS. THE POPULATION TO BE SERVED BY THIS DEMONSTRATION PROGRAM IS YOUTH EXPERIENCING HOMELESSNESS, INCLUDING UNACCOMPANIED AND PREGNANT OR PARENTING YOUTH. THE DEMONSTRATION HAS SEVEN PRIMARY OBJECTIVES: • BUILD NATIONAL MOMENTUM. • PROMOTE EQUITY IN THE DELIVERY AND OUTCOMES OF HOMELESS ASSISTANCE. • HIGHLIGHT THE IMPORTANCE OF YOUTH LEADERSHIP. • EVALUATE THE COORDINATED COMMUNITY APPROACH. • EXPAND CAPACITY. • EVALUATE PERFORMANCE MEASURES. • ESTABLISH A FRAMEWORK FOR THE FEDERAL PROGRAM AND TECHNICAL ASSISTANCE COLLABORATION. BEGINNING IN 2016, NEW YHDP COMMUNITIES ARE SELECTED THROUGH A COMPETITIVE PROCESS DEPENDING ON THE ANNUAL FUNDING PROVIDED BY CONGRESS. A MAP OF CURRENTLY FUNDED YHDP SITES IS AVAILABLE AT THE LINK TITLED MAP OF YHDP-FUNDED COC (UNDER YHDP COMMUNITIES) AT HTTPS://WWW.HUDEXCHANGE.INFO/PROGRAMS/YHDP/.; ACTIVITIES TO BE PERFORMED: ELEVEN TYPES OF ASSISTANCE MAY BE PROVIDED THROUGH THE YHDP: 1. ACQUISITION OF REAL PROPERTY (INCLUDING STRUCTURES) FOR USE IN THE PROVISION OF HOUSING OR SUPPORTIVE SERVICES; 2. REHABILITATION OF STRUCTURES TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; 3. NEW CONSTRUCTION, INCLUDING THE BUILDING OF A NEW STRUCTURE OR BUILDING AN ADDITION TO AN EXISTING STRUCTURE FOR USE AS SUPPORTIVE HOUSING; 4. LEASING OF A NEW STRUCTURE OR STRUCTURES, OR PORTIONS THEREOF, TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; 5. RENTAL ASSISTANCE, WHICH MAY BE SHORT-TERM, MEDIUM-TERM, OR LONG-TERM, AS WELL AS TENANT-BASED, PROJECT-BASED, OR SPONSOR-BASED, FOR TRANSITIONAL OR PERMANENT HOUSING; 6. SUPPORTIVE SERVICES TO ASSIST PROGRAM PARTICIPANTS OBTAIN AND MAINTAIN HOUSING; 7. OPERATING COSTS OF SUPPORTIVE HOUSING; 8. COSTS OF IMPLEMENTING AND OPERATING HOMELESS MANAGEMENT INFORMATION SYSTEM (HMIS); 9. PROGRAM ADMINISTRATIVE COSTS; 10. RELOCATION COSTS; AND 11. INDIRECT COSTS IN ACCORDANCE WITH 2 CFR PART 200, AS APPLICABLE. NO ASSISTANCE PROVIDED UNDER THIS PROGRAM (OR ANY STATE OR LOCAL GOVERNMENT FUNDS USED TO SUPPLEMENT THIS ASSISTANCE) MAY BE USED TO REPLACE STATE OR LOCAL FUNDS PREVIOUSLY USED, OR DESIGNATED FOR USE, TO ASSIST HOMELESS PERSONS OR PERSONS AT-RISK OF HOMELESSNESS.; EXPECTED OUTCOMES: AS A RESULT OF DEVELOPING AND IMPLEMENTING A COORDINATED COMMUNITY APPROACH TO PREVENTING AND ENDING YOUTH HOMELESSNESS, THERE WILL BE: • SIGNIFICANT DECREASE IN THE NUMBER OF YOUTHS EXPERIENCING HOMELESSNESS. • INCREASED INCOME, EDUCATION, HEALTH, AND SOCIAL/EMOTIONAL WELL-BEING OF PARTICIPANTS. • COMMUNITY-LEVEL UNDERSTANDING OF THE NUMBER AND NEEDS OF YOUTH AT-RISK OF AND EXPERIENCING HOMELESSNESS. • NEW OR IMPROVED PARTNERSHIPS BETWEEN YOUTH-SERVING ORGANIZATIONS IN THE COMMUNITY.; INTENDED BENEFICIARIES: HOMELESS UNACCOMPANIED YOUTH (AGE 24 AND YOUNGER) AND HOMELESS YOUTH (AGE 24 AND YOUNGER) WITH CHILDREN.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD

FY2022-2023 CENTERS FOR INDEPENDENT LIVING

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.

2020 CILS

2019 CENTERS FOR INDEPENDENT LIVING

STROKE INDUCED-NK CELL DEFICIENCY: MECHANISMS AND CLINICAL IMPLICATIONS

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

2018 CENTERS FOR INDEPENDENT LIVING

PROMOTING REOPONSIBLE FATHERHOOD

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

2017 CENTERS FOR INDEPENDENT LIVING

ENHANCING ACMSD ACTIVITY AS A NOVEL GENE THERAPY FOR ALS

MULTIFAMILY HOUSING SERVICE COORDINATORS

2021 CILS

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

TARGETING THE PI3K/AKT PATHWAY IN HIGH GRADE GLIOMA

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

SAFE HAVEN FOR MENTAL HEALTH SERVICES PROJECT

VA IS PROVIDING PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

MODULATION OF MICROSACCADES AND CORRELATED NEURAL RESPONSES AS A FUNCTION OF VIEWING TASK

PATHOGEN-INSPIRED NANOPARTICLE DRUG DELIVERY TO MOTOR NEURONS

2020 ILC3 - CARES

2008 NSIP - NUTRITION SERVICES INCENTIVE PROGRAM

PEPTIDE AND PROTEIN BIOMARKERS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS)

ALLELIC EXPRESSION IMBALANCE IN TUBEROUS SCLEROSIS COMPLEX

A MINIATURIZED VALVE THAT MIMICS FUNCTIONAL ARACHNOID GRANULATIONS TO TREAT HYDROCEPHALUS

HCVNET ARIZONA: SCREENING AND LINKAGE TO CARE FOR PRIORITY AND UNDER-SERVED POPUL

HEALTH CARE AND OTHER FACILITIES

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.

PURPOSE: THE CONTINUUM OF CARE (COC) PROGRAM IS DESIGNED TO PROMOTE COMMUNITY-WIDE COMMITMENT TO THE GOAL OF ENDING HOMELESSNESS; PROVIDE FUNDING FOR EFFORTS BY NONPROFIT PROVIDERS, STATES, AND LOCAL GOVERNMENTS TO QUICKLY HOUSE HOMELESS INDIVIDUALS AND FAMILIES WHILE MINIMIZING THE TRAUMA AND DISLOCATION CAUSED TO HOMELESS INDIVIDUALS, FAMILIES, AND COMMUNITIES BY HOMELESSNESS; PROMOTE ACCESS TO AND EFFECTIVE UTILIZATION OF MAINSTREAM PROGRAMS BY HOMELESS INDIVIDUALS AND FAMILIES; AND OPTIMIZE SELF-SUFFICIENCY AMONG INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS. THE COC PROGRAM INCLUDES GRANTS THAT ARE AVAILABLE TO SPECIFIC SUBPOPULATIONS OF PEOPLE EXPERIENCING HOMELESSNESS. THE GRANTS SPECIFICALLY SERVE YOUTH, DEFINED AS HOUSEHOLDS WHERE NO PERSON IS OVER THE AGE OF 24 UNDER THE YOUTH HOMELESS DEMONSTRATION PROGRAM (YHDP). THE GOAL OF THE YOUTH HOMELESSNESS DEMONSTRATION PROGRAM (YHDP) IS TO SUPPORT THE DEVELOPMENT AND IMPLEMENTATION OF A COORDINATED COMMUNITY APPROACH TO PREVENTING AND ENDING YOUTH HOMELESSNESS AND SHARING THAT EXPERIENCE WITH AND MOBILIZING COMMUNITIES AROUND THE COUNTRY TOWARD THE SAME END. THE NOTICE OF FUNDING OPPORTUNITY (NOFO) FOR NEW YHDP GRANTS IS FOUND AT HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/COMM_PLANNING/YHDP (CHOOSE THE MOST RECENT YHDP NOFO LISTED). THE NOFO FOR YHDP RENEWALS AND REPLACEMENTS IS FOUND AT HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/COMM_PLANNING/COC/COMPETITION (CHOOSE THE MOST RECENT COC/YHDP RENEWAL OR REPLACEMENT NOFO LISTED).; ACTIVITIES TO BE PERFORMED: THESE GRANTS MAY BE USED TO PAY FOR THE ELIGIBLE COSTS USED TO ESTABLISH AND OPERATE PROJECTS UNDER FIVE PROGRAM COMPONENTS: 1. PERMANENT HOUSING, WHICH INCLUDES PERMANENT SUPPORTIVE HOUSING FOR PERSONS WITH DISABILITIES, AND RAPID REHOUSING; 2. TRANSITIONAL HOUSING; 3. SUPPORTIVE SERVICES ONLY; 4. HOMELESS MANAGEMENT INFORMATION SYSTEMS (HMIS); AND 5. HOMELESSNESS PREVENTION (IN SOME CASES). ELIGIBLE COSTS WITHIN THESE PROJECTS INCLUDE: 1. LEASING OF A STRUCTURE OR STRUCTURES, OR PORTIONS THEREOF, TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; 2. RENTAL ASSISTANCE, WHICH MAY BE SHORT-TERM, MEDIUM-TERM, OR LONG-TERM, AS WELL AS TENANT-BASED, PROJECT-BASED, OR SPONSOR-BASED, FOR TRANSITIONAL OR PERMANENT HOUSING; 3. SUPPORTIVE SERVICES TO ASSIST PROGRAM PARTICIPANTS OBTAIN AND MAINTAIN HOUSING; 4. OPERATING COSTS OF SUPPORTIVE HOUSING; 5. COSTS OF IMPLEMENTING AND OPERATING HMIS; 6. PROJECT ADMINISTRATIVE COSTS; 7. RELOCATION COSTS; AND 8. INDIRECT COSTS IN ACCORDANCE WITH 2 CFR PARTS 200, AS APPLICABLE. IN ADDITION TO USING GRANT FUNDS FOR THE ELIGIBLE COSTS DESCRIBED ABOVE, RECIPIENTS AND SUBRECIPIENTS IN CONTINUUMS OF CARE DESIGNATED AS HIGH PERFORMING COMMUNITIES MAY ALSO USE GRANT FUNDS TO PROVIDE HOUSING RELOCATION AND STABILIZATION SERVICES AND SHORT- AND/OR MEDIUM-TERM RENTAL ASSISTANCE TO YOUTH AT RISK OF HOMELESSNESS AS SET FORTH IN 24 CFR 576.103 AND 24 CFR 576.104, IF NECESSARY TO PREVENT YOUTH FROM BECOMING HOMELESS. NO ASSISTANCE PROVIDED UNDER PROGRAM (OR ANY STATE OR LOCAL GOVERNMENT FUNDS USED TO SUPPLEMENT THIS ASSISTANCE) MAY BE USED TO REPLACE STATE OR LOCAL FUNDS PREVIOUSLY USED, OR DESIGNATED FOR USE, TO ASSIST HOMELESS PERSONS OR PERSONS AT-RISK OF HOMELESSNESS.; EXPECTED OUTCOMES: DECREASE IN THE NUMBER OF YOUTH EXPERIENCING HOMELESSNESS, MORE SPECIFICALLY USING PERFORMANCE INDICATORS SUCH AS THE LENGTH OF TIME HOMELESS, RETURNS TO HOMELESSNESS OVER TIME, AND EXITS TO PERMANENT HOUSING. COC PERFORMANCE PROFILE REPORTS CAN BE FOUND AT: HTTPS://WWW.HUDEXCHANGE.INFO/PROGRAMS/COC/COC-PERFORMANCE-PROFILE-REPORTS/; INTENDED BENEFICIARIES: YOUTH DEFINED AS HOUSEHOLDS WHERE NO PERSON IS OVER THE AGE OF 24; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD

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.

CREATE TWO TRAUMA-SPECIFIC SURGERY SUITES AT ST. ROSE DOMINCAN HOSPITAL

HIGH-THROUGHPUT ASSAY DEVELOPMENT FOR NON-NICOTINE TOBACCO COMPONENTS

DEVELOPMENT OF NOVEL VIRAL VECTORS TO STUDY AND TREAT NEUROINFLAMMATION

MECHANISMS OF SEIZURE GENESIS IN HUMAN HYPOTHALAMIC HAMARTOMAS

THE NEURAL MECHANISMS UNDERLYING FLICKER FUSION

AMERICAN RESCUE PLAN

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.

ALPHA9*-NICOTINIC RECEPTORS IN AUTOIMMUNITY AND INFLAMMATION

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.

REPRESENTATION OF MEMORY FOR SPOKEN WORDS AND VOICE DETAIL BY SINGLE NEURONS IN T

CONSTRUCTION AND EXPRESSION OF CONCATEMERIC ALPHA6BETA2* NICOTINIC ACETYCHOLINE R

HEALTH CARE AND OTHER FACILITIES

EXOSOMES: ROLE IN ALLOGRAFT REJECTION AND POTENTIAL AS A BIOMARKER

THIS AWARD FUNDS THE APPROVED 2025-26 AMERICORPS SENIORS RSVP PROGRAM. YOUR 2025?26 STATUTORY MATCH REQUIREMENT IS 10% AND YOUR BUDGETED MATCH IS 15.37%.

RIC THERAPY-MEDIATED NEUROPROTECTION IN EYE TRAUMA

RETIRED AND SENIOR VOLUNTEER PROGRAM

HEALTH CARE AND OTHER FACILITIES

AXONAL TRANSPORT AND RAS ACTIVATION IN THE NF1 MOUSE MODEL

PARKINSON'S DISEASE NEUROPROTECTION TRIAL

FOOD SERVICES SUCH AS SENIOR BROWN BAG, HOME DELIVERED MEALS, AND COMMODITIES ARE AVAILABLE TO SENIORS WHO ARE LOW INCOME AND/OR HOMEBOUND AND ARE IN NEED OF ENOUGH FOOD TO LIVE AN ACTIVE HEALTHY LIFE. MOST HOME-DELIVERED MEAL PROGRAMS PROVIDE THEIR CLIENTS WITH A HOT MEAL FIVE DAYS A WEEK DELIVERED BY STAFF OR VOLUNTEER DRIVERS. BECAUSE OF THEIR FRAILTY, SENIORS RECEIVING HOME-DELIVERED MEALS ARE UNABLE TO MAKE THEIR OWN MEALS. SENIOR BROWN BAG AND COMMODITIES ARE DISTRIBUTED BY VOLUNTEERS SEVERAL TIMES A MONTH, WITHOUT WHICH MANY SENIORS WOULD GO WITHOUT NUTRITIONALLY ADEQUATE REGULAR MEALS. IN ADDITION, NUTRITION EDUCATION IS PROVIDED. SERVICE ACTIVITY: RSVP WITH THE ASSISTANCE OF PARTNERING STATIONS HAVE IDENTIFIED LOW INCOME AND HOME BOUND SENIORS NEEDING NUTRITION EDUCATION AND FOOD SERVICES. 109 VOLUNTEERS ARE NEEDED TO ASSIST WITH NUTRITION EDUCATION AND FOOD SUPPORT. LOCATION OF SERVICES: SHASTA, TEHAMA, TRINITY, GLENN AND SISKIYOU COUNTIES. OUTCOME: HEALTHY FUTURES IS THE PRIMARY FOCUS AREA OF THE RSVP PROJECT AND AT THE END OF THE THREE-YEAR GRANT CYCLE, 1,090 HOMEBOUND OR OLDER ADULTS AND INDIVIDUALS WITH DISABILITIES WILL HAVE BEEN SERVED. IN ADDITION, 150 RSVP VOLUNTEERS WILL SERVE IN OTHER COMMUNITY PRIORITIES BY SERVING AT LOCAL NON-PROFIT AGENCIES, HOSPITALS, THRIFT STORES, SCHOOLS, LIBRARIES, PUBLIC SAFETY AND MORE. FUNDING: REQUESTED: $109,638 NON FEDERAL FUNDING: DIGNITY HEALTH PROVIDES IN-KIND THROUGH HUMAN RESOURCES, IT SUPPORT, AND OTHER CORPORATE CHARGES THAT COULD BE BILLED TO SENIOR CORPS GRANTS. ADDITIONAL IN-KIND FOR RENT, SPACE, BREAKFAST, LUNCHES AND RECOGNITIONS FOR VOLUNTEERS ARE SUPPORTED BY LOCAL PARTNERING AGENCIES. EXCESS FUNDING: FEDERAL TRANSIT ADMINISTRATION -- 2019 OPERATING ASSISTANCE MOBILITY MANAGEMENT 5310 GRANT - $61,767 TO COVER THE COST OF VOLUNTEER MILEAGE, SUPPLIES AND SALARIES.

THIS AWARD FUNDS THE APPROVED 2022?23 RSVP PROGRAM. YOUR 2022?23 STATUTORY MATCH IS 30% AND YOUR BUDGETARY MATCH IS 33.9%.

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.

ENGAGES PERSONS 55 AND OLDER IN VOLUNTEER SERVICE IN THEIR COMMUNITIES

COGNITIVE AND NEURAL CORRELATES OF AGING IN AUTISM SPECTRUM DISORDER

RESIDENTIAL SHELTER SERVICES FOR UNACCOMPANIED CHILDREN

A NEW, QUANTITATIVE EEG TECHNIQUE FOR PREDICTION OF POST-TRAUMATIC EPILEPSY IN INDIVIDUAL SUBJECTS AFTER TRAUMATIC BRAIN INJURY

ENGAGES PERSONS 55 AND OLDER IN VOLUNTEER SERVICE IN THEIR COMMUNITIES

PURPOSE: THE CONTINUUM OF CARE (COC) PROGRAM IS DESIGNED TO PROMOTE COMMUNITY-WIDE COMMITMENT TO THE GOAL OF ENDING HOMELESSNESS; PROVIDE FUNDING FOR EFFORTS BY NONPROFIT PROVIDERS, STATES, AND LOCAL GOVERNMENTS TO QUICKLY HOUSE HOMELESS INDIVIDUALS AND FAMILIES WHILE MINIMIZING THE TRAUMA AND DISLOCATION CAUSED TO HOMELESS INDIVIDUALS, FAMILIES, AND COMMUNITIES BY HOMELESSNESS; PROMOTE ACCESS TO AND EFFECTIVE UTILIZATION OF MAINSTREAM PROGRAMS BY HOMELESS INDIVIDUALS AND FAMILIES; AND OPTIMIZE SELF-SUFFICIENCY AMONG INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS. THE MOST RECENT COC AWARD ANNOUNCEMENT LISTING AWARDS BY STATE AND COC IS ACCESSIBLE AT HTTPS://WWW.HUD.GOV/PROGRAM_OFFICES/COMM_PLANNING/COC/AWARDS. SELECT THE LINK UNDER THE FUNDING AND AWARD INFORMATION SECTION FOR THE APPROPRIATE FISCAL YEAR.; ACTIVITIES TO BE PERFORMED: CONTINUUM OF CARE PROGRAM FUNDS MAY BE USED TO PAY FOR THE ELIGIBLE COSTS USED TO ESTABLISH AND OPERATE PROJECTS UNDER FIVE PROGRAM COMPONENTS: (1) PERMANENT HOUSING, WHICH INCLUDES PERMANENT SUPPORTIVE HOUSING FOR PERSONS WITH DISABILITIES, AND RAPID REHOUSING; (2) TRANSITIONAL HOUSING; (3) SUPPORTIVE SERVICES ONLY; (4) HOMELESS MANAGEMENT INFORMATION SYSTEMS (HMIS), AND (5) IN SOME CASES, HOMELESSNESS PREVENTION. THIRTEEN TYPES OF ASSISTANCE MAY BE PROVIDED THROUGH THE CONTINUUM OF CARE (COC) PROGRAM: (1) COC PLANNING ACTIVITIES/COSTS FOR DESIGNING AND CARRYING OUT A COLLABORATIVE PROCESS FOR THE DEVELOPMENT OF AN APPLICATION TO HUD; (2) UNITED FUNDING AGENCY (UFA) COSTS FOR FISCAL CONTROL AND ACCOUNTING NECESSARY TO ASSURE THE PROPER DISBURSAL OF, AND ACCOUNTING FOR, FEDERAL FUNDS AWARDED TO SUBRECIPIENTS UNDER THE CONTINUUM OF CARE PROGRAM, (3) ACQUISITION OF REAL PROPERTY (INCLUDING STRUCTURES) FOR USE IN THE PROVISION OF HOUSING OR SUPPORTIVE SERVICES; (4) REHABILITATION OF STRUCTURES TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; (5) NEW CONSTRUCTION, INCLUDING THE BUILDING OF A NEW STRUCTURE OR BUILDING AN ADDITION TO AN EXISTING STRUCTURE FOR USE AS SUPPORTIVE HOUSING; (6) LEASING OF A STRUCTURE OR STRUCTURES, OR PORTIONS THEREOF, TO PROVIDE HOUSING OR SUPPORTIVE SERVICES; (7) RENTAL ASSISTANCE, WHICH MAY BE SHORT-TERM, MEDIUM-TERM, OR LONG-TERM, AS WELL AS TENANT-BASED, PROJECT-BASED, OR SPONSOR-BASED, FOR TRANSITIONAL OR PERMANENT HOUSING; (8) SUPPORTIVE SERVICES TO ASSIST PROGRAM PARTICIPANTS OBTAIN AND MAINTAIN HOUSING; (9) OPERATING COSTS OF SUPPORTIVE HOUSING; (10) COSTS OF IMPLEMENTING AND OPERATING HMIS; (11) PROJECT ADMINISTRATIVE COSTS; (12) RELOCATION COSTS; AND (13) INDIRECT COSTS IN ACCORDANCE WITH 2 CFR PARTS 200, AS APPLICABLE. IN ADDITION TO USING GRANT FUNDS FOR THE ELIGIBLE COSTS DESCRIBED ABOVE, RECIPIENTS AND SUBRECIPIENTS IN CONTINUUMS OF CARE DESIGNATED AS HIGH PERFORMING COMMUNITIES MAY ALSO USE GRANT FUNDS TO PROVIDE HOUSING RELOCATION AND STABILIZATION SERVICES AND SHORT- AND/OR MEDIUM-TERM RENTAL ASSISTANCE TO INDIVIDUALS AND FAMILIES AT RISK OF HOMELESSNESS AS SET FORTH IN 24 CFR 576.103 AND 24 CFR 576.104, IF NECESSARY TO PREVENT THE INDIVIDUAL OR FAMILY FROM BECOMING HOMELESS. LIMITATION ON USE OF FUNDS: NO ASSISTANCE PROVIDED UNDER PROGRAM (OR ANY STATE OR LOCAL GOVERNMENT FUNDS USED TO SUPPLEMENT THIS ASSISTANCE) MAY BE USED TO REPLACE STATE OR LOCAL FUNDS PREVIOUSLY USED, OR DESIGNATED FOR USE, TO ASSIST HOMELESS PERSONS OR PERSONS AT-RISK OF HOMELESSNESS.; EXPECTED OUTCOMES: DECREASE IN THE NUMBER INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS, MORE SPECIFICALLY USING PERFORMANCE INDICATORS SUCH AS THE LENGTH OF TIME HOMELESS, RETURNS TO HOMELESSNESS OVER TIME, AND EXITS TO PERMANENT HOUSING. COC PERFORMANCE PROFILE REPORTS CAN BE FOUND AT HTTPS://WWW.HUDEXCHANGE.INFO/PROGRAMS/COC/COC-PERFORMANCE-PROFILE-REPORTS/.; INTENDED BENEFICIARIES: INDIVIDUALS AND FAMILIES EXPERIENCING HOMELESSNESS.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD.

HTS ASSAY DEVELOPMENT FOR ALPHA6/3BETA2BETA3 SUBTYPE NICOTINIC RECEPTORS

CONTINUUM OF CARE PROGRAM

VA IS PROVIDING SPECIAL NEED PER DIEM FUNDING TO ASSIST WITH THE OPERATIONAL COSTS ASSOCIATED WITH TRANSITIONAL HOUSING BEDS FOR HOMELESS VETERANS.

ST. JOSEPH'S MEDICAL CENTER OF STOCKTON CALIFORNIA EXPANSION OF ITS DIGITAL MOBI

THE "WOMEN'S GET HEALTHY STAY HEALTHY" PROJECT WILL ADDRESS THE CAUSES OF PREMATU

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

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

THIS AWARD FUNDS THE APPROVED 2023?24 SCP PROGRAM. YOUR 2023?24 STATUTORY MATCH IS 10% AND YOUR BUDGETARY MATCH IS 17.4%

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

INDEPENDENT LIVING ARRA GRANTS

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

HOMELESS ASSISTANCE

HOMELESS ASSISTANCE

HOMELESS ASSISTANCE

HOMELESS ASSISTANCE

HOMELESS ASSISTANCE

CENTERS FOR INDEPENDENT LIVING

TOWARDS A UNIFIED THEORY OF MICROSACCADIC AND SACCADIC FUNCTION: DETERMINING THE SIGNIFICANCE OF MICROSACCADES FOR PERCEPTION, COGNITION, AND OCULOM

THE DESIGN, MANUFACTURE, AND TESTING OF A DISABILITY-ADAPTED BATHROOM MODULE

ENGAGES PERSONS 55 AND OLDER IN SUPPORTIVE SERVICES TO ADULTS WITH SPECIAL NEEDS

FY 2025 ILCL ~ STATE PLAN INDEPENDENT LIVING CENTERS

FY2024-2025 CENTERS FOR INDEPENDENT LIVING

FY2023-2024 CENTERS FOR INDEPENDENT LIVING

EDI SPECIAL PROJECTS