Cove Ltd

STATE FISCAL STABILIZATION FUND - EDUCATION GRANTS RECOVERY FUNDS

EDUCATION JOBS FUND

STATE FISCAL STABILIZATION FUND - GOVERNMENT SERVICES

CANCER CENTER SUPPORT GRANT

BURNHAM CENTER FOR CHEMICAL GENOMICS

HEALTH CENTER CLUSTER

HEALTH CENTER CLUSTER

HEALTH CENTER CLUSTER

PROTEIN GLYCOSYLATION IN THE COAGULOPATHY AND INFLAMMATION OF SEPSIS

HEALTH CENTER CLUSTER

HEALTH CENTER CLUSTER

HEALTH CENTER CLUSTER

GLOBAL INNATE IMMUNE RESPONSES TO HIV-1 INFECTION

TARGETING PTEN - AN UPSTREAM DOWNSTREAM AND OFFSTREAM APPROACH

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

IMPACT AID PROGRAM TITLE VIII SECTION 8003

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

IMPACT AID PROGRAM, TITLE VIII, SECTION 8003

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

AGING AS A RISK FACTOR AND TARGET FOR PREVENTION OF LIVER CANCER - PROJECT SUMMARY – OVERALL THE INCIDENCES OF LIVER CANCER (PRIMARILY HEPATOCELLULAR CARCINOMA (HCC)) ARE INCREASING AND DISEASE OUTCOME IS POOR. CONSEQUENTLY, THERE IS AN URGENT NEED FOR NEW THERAPIES AND BETTER PREVENTIVE STRATEGIES. AGE IS A MAJOR RISK FACTOR FOR HCC. IN LINE WITH THE GEROSCIENCE HYPOTHESIS, WE HYPOTHESIZE THAT AGING DRIVES A DYSFUNCTIONAL MITOCHONDRIAL, EPIGENETIC AND METABOLIC NETWORK THAT PROMOTES AND EXACERBATES AGE-ASSOCIATED DYSREGULATION OF IMMUNE FUNCTION AND INFLAMMATION IN LIVER. LOSS OF HOMEOSTASIS ACROSS MULTIPLE SYSTEMS IS PERMISSIVE FOR NEOPLASTIC LIVER DISEASE. WE FURTHER HYPOTHESIZE THAT DYSREGULATED CHRONIC INTERFERON SIGNALING IS CENTRAL TO THIS PATHOGENIC NETWORK. WE WILL DISSECT THIS NETWORK AND TEST THE CONSEQUENCE OF CHRONIC INTERFERON SIGNALING, TO UNDERSTAND WHY THE INCIDENCE OF LIVER CANCER INCREASES WITH AGE. WE WILL ALSO INVESTIGATE APPROACHES THAT TARGET THIS NETWORK FOR THEIR ABILITY TO PREVENT AND COMBAT LIVER CANCER. OUR OVERALL SPECIFIC OBJECTIVES ARE: OBJECTIVE 1. INVESTIGATE AGE-ASSOCIATED CHANGES TO MITOCHONDRIA, CHROMATIN, METABOLISM (SPECIFICALLY, BILE ACIDS) AND INNATE AND ADAPTIVE IMMUNITY, THEIR CAUSAL ROLE IN HCC AND UNDERLYING MECHANISMS. OBJECTIVE 2. INVESTIGATE HOW INTERACTIONS BETWEEN THESE DIFFERENT SYSTEMS AND AGE-DEPENDENT DYSREGULATION OF THESE INTERACTIONS CONTRIBUTES TO HCC. OBJECTIVE 3. TEST THE HYPOTHESIS THAT AT LEAST SOME OF THESE AGE-ASSOCIATED ALTERATIONS AND CONSEQUENT PREDISPOSITION TO HCC ARE DEPENDENT ON CHRONIC INTERFERON SIGNALING IN AGED TISSUE. OBJECTIVE 4. INVESTIGATE APPROACHES THAT TARGET AGE DYSREGULATION, FOR EXAMPLE SUPPRESSORS OF CHRONIC INTERFERON ACTIVATION, MITOHORMETIC INTERVENTIONS, RAPAMYCIN, SENOLYTICS, BILE ACID MODULATORS AND IMMUNE-MODULATORS, FOR THEIR ABILITY TO SUPPRESS THE ONSET OF LIVER CANCER AND BETTER COUNTER ESTABLISHED CANCER. SINCE AGE IS THE BIGGEST SINGLE RISK FACTOR FOR HCC, IT FOLLOWS THAT A MOLECULAR UNDERSTANDING OF THE AGE- DEPENDENCE OF HCC CAN LEAD TO IMPROVED DISEASE MANAGEMENT THROUGH RISK ASSESSMENT, EARLY DETECTION, PROGNOSTICATION AND THERAPY. MOREOVER, AN UNDERSTANDING OF HOW HCC DEVELOPS DURING AGING CAN ALSO LEAD TO PREVENTATIVE INTERVENTIONS. THIS PPG WILL DEFINE CRITICAL MOLECULAR MECHANISMS UNDERPINNING AGE-DEPENDENCE OF HCC. WE WILL ALSO PROMOTE APPROACHES FOR IMPROVED RISK ASSESSMENT THROUGH APPLICATION, TESTING AND REFINEMENT OF A TRANSCRIPTOME-BASED “TUMORIGENIC INDEX” TO QUANTITATE THE RISK OF HCC. FINALLY, BASED ON OUR DISCOVERIES, WE WILL TEST A PANEL OF CANDIDATE INTERVENTIONS FOR THOSE THAT CAN PREVENT AND COMBAT HCC.

HEAD START - CENTER BASED OPTION

IMPACT AID PROGRAM TITLE VIII SECTION 8003 AND SECTION 8007(A)

IMPACT AID PROGRAM TITLE VIII SECTION 8003

IMPACT AID PROGRAM TITLE VIII SECTION 8003

CLINICAL DEVELOPMENT OF AN MGLU2 POSITIVE ALLOSTERIC MODULATOR TO TREAT NICOTINE ADDICTION

UNKNOWN TITLE

ASSISTANCE TO HELP OFFSET LOSSES FOR COLORADO STATE HIGH RISK POOL.

SPATIAL MAPPING SENESCENT CELLS ACROSS THE MOUSE LIFESPAN BY MULTIPLEX TRANSCRIPTOMICS AND EPIGENOMICS - PROJECT SUMMARY CELLULAR SENESCENCE, CHARACTERIZED BY STABLE PROLIFERATION ARREST AND SECRETION OF PRO-INFLAMMATORY FACTORS, IS NOT ONLY A HALLMARK OF AGING, BUT ALSO A KEY CONTRIBUTOR TO AGE-ASSOCIATED DISEASES IN HUMANS. AS THE US POPULATION IS AGING, THERE IS AN ADDED URGENCY TO GAIN A BETTER UNDERSTANDING OF CELLULAR SENESCENCE IN DIFFERENT TISSUES OVER THE LIFESPAN. UNFORTUNATELY, WE STILL LACK THE KNOWLEDGE TO UNAMBIGUOUSLY DEFINE SENESCENCE AT THE MOLECULAR AND CELLULAR LEVELS, DUE TO ITS HETEROGENEOUS PHENOTYPES. TO ADDRESS THIS MAJOR GAP IN KNOWLEDGE, WE PROPOSE TO ESTABLISH A TISSUE MAPPING CENTER THAT FOCUSES ON THE IDENTIFICATION AND CHARACTERIZATION OF SENESCENT CELLS IN HEALTHY MOUSE BRAIN, BONE MARROW, BREAST, COLON AND LIVER. OUR RESEARCH STRATEGY BUILDS ON RECENT ADVANCES IN SINGLE CELL EPIGENOMICS TECHNOLOGIES THAT OUR TEAM DEVELOPED AND THE KNOWLEDGE THAT SENESCENT CELLS EXHIBIT CHARACTERISTIC CHANGES IN THE CHROMATIN LANDSCAPES AND HISTONE MODIFICATIONS ALONG WITH GENE EXPRESSION LEVELS AT MARKER GENES OF CELLULAR SENESCENCE. WE WILL DEPLOY CUTTING-EDGE SINGLE CELL IN SITU AND TISSUE DISSOCIATIVE MULTI-OMIC TOOLS THAT HAVE BEEN WELL ESTABLISHED IN OUR CENTER TO PRODUCE COMPREHENSIVE SINGLE CELL RESOLUTION MAPS OF THE TRANSCRIPTOME AND EPIGENOME IN MALE AND FEMALE MOUSE BRAIN, BONE MARROW, BREAST, COLON AND LIVER, AND TO PROVIDE QUALITATIVE AND QUANTITATIVE SPATIAL MAPS OF THE NORMAL BURDEN OF SENESCENT CELLS IN THESE VITAL ORGANS, ACROSS THE LIFESPAN OF TWO MOUSE STRAINS. WE WILL RIGOROUSLY VALIDATE THE NEWLY DEFINED SENESCENT CELL POPULATIONS USING PHARMACOLOGIC AND GENETIC APPROACHES TO ERADICATE SENESCENT CELLS OR SUPPRESS THEIR INFLAMMATORY PHENOTYPE, AND ORTHOGONAL STATE-OF-THE-ART AND CONVENTIONAL ASSAYS FOR CELLULAR SENESCENCE. WE WILL GENERATE WHOLE GENOME SINGLE CELL DNA METHYLATION DATA TO LINK OUR SPATIAL ATLAS TO MEASUREMENT OF EPIGENETIC AGE, A CANDIDATE PREDICTOR OF BENEFICIAL VERSUS DETRIMENTAL EFFECTS OF SENESCENT CELLS. WE EXPECT THAT COMPREHENSIVE SINGLE CELL ATLASES OF EPIGENOME AND TRANSCRIPTOME WILL ENABLE US TO IDENTIFY AND CHARACTERIZE CELLULAR SENESCENCE IN DIFFERENT TISSUE CONTEXTS AND DURING AGING. WE EXPECT THAT THE PLANNED RESEARCH WILL PROVIDE A REFERENCE FOR FUTURE STUDIES THAT SEEK TO CHARACTERIZE AND TARGET SENESCENT CELLS ASSOCIATED WITH OR PRECEDING DISEASE IN BRAIN, BONE MARROW, BREAST, COLON AND LIVER.

PRECLINICAL STUDIES FOR THE DEVELOPMENT OF SELECTIVE MGLU2 POSITIVE ALLOSTERIC MODULATORS TO TREAT SUBSTANCE USE DISORDERS

(NO IDC) FORT CAVAZOS TRUCK RAMP PROJECT

HEAD START

THE STATE OF ARIZONA HEALTH INFORMATION EXCHANGE

SAFETY/TOXICOLOGY, ADME AND CMC ACTIVITIES TO SUPPORT THE ASSESSMENT OF THE MGLU2 PAM SBP-9330 IN A PHASE 2 CLINICAL STUDY IN SMOKERS - PROJECT SUMMARY THIS RESUBMISSION APPLICATION, “SAFETY/TOXICOLOGY, ADME AND CMC ACTIVITIES TO SUPPORT THE ASSESSMENT OF THE MGLU2 PAM SBP-9330 IN A PHASE 2 CLINICAL STUDY IN SMOKERS”, IS IN RESPONSE TO PAR-22-202 AND REPRESENTS THE CONTINUATION OF OUR CURRENT WORK FUNDED THROUGH 07/31/2023 BY U01 DA051077 “CLINICAL DEVELOPMENT OF AN MGLU2 POSITIVE ALLOSTERIC MODULATOR TO TREAT NICOTINE ADDICTION”. CIGARETTE SMOKING REMAINS ONE OF THE LEADING CAUSES OF DEATH AND DISEASE WORLDWIDE. ONLY THREE TYPES OF MEDICATIONS FOR SMOKING CESSATION HAVE BEEN APPROVED BY THE UNITED STATES FOOD AND DRUG ADMINISTRATION (FDA) (BUPROPION, VARENICLINE, AND NICOTINE REPLACEMENT THERAPY), ALL OF WHICH HAVE POOR EFFICACY AND TOLERABILITY. POSITIVE ALLOSTERIC MODULATORS (PAMS) OF THE METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 2 (MGLU2) DECREASE NICOTINE SELF-ADMINISTRATION AND CUE-INDUCED REINSTATEMENT OF NICOTINE SEEKING IN ANIMAL MODELS, PROVIDING SUPPORT FOR MGLU2 AS A VALID TARGET FOR THE TREATMENT OF NICOTINE ADDICTION. OUR INVESTIGATIONAL DRUG, THE SMALL MOLECULE MGLU2 PAM SBP-9330 (CHARACTERIZED DURING PRIOR GRANT U01 DA041731), HAS RECENTLY BEEN EVALUATED IN HEALTHY NONSMOKERS AND SMOKERS IN A PLACEBO- CONTROLLED, RANDOMIZED, AND DOUBLE-BLIND PHASE 1 CLINICAL STUDY (NCT04948827). TO DATE, THE DATA FOR THE HEALTHY NONSMOKERS HAVE BEEN UNBLINDED AND ANALYZED, REVEALING THAT SBP-9330 WAS WELL TOLERATED, WITH NO SERIOUS ADVERSE EVENTS OR SAFETY CONCERNS. HUMAN PHARMACOKINETIC DATA REVEALED THAT PLASMA EXPOSURES WERE NEARLY DOSE-PROPORTIONAL, ACCUMULATED APPROXIMATELY 2-FOLD OVER 14 DAYS OF DOSING, AND WERE SUFFICIENTLY HIGH FOR POTENTIAL EFFICACY. THESE PROMISING DATA SUPPORT CONTINUATION OF THE CLINICAL DEVELOPMENT OF SBP-9330.THE STUDIES PROPOSED IN THIS GRANT APPLICATION ARE REQUIRED BY THE FDA BEFORE WE CAN DOSE SBP-9330 FOR LONGER DURATION IN TOBACCO SMOKERS IN A PHASE 2 STUDY AND BEYOND. TO THIS END, OUR SPECIFIC AIMS ARE: (1) PERFORM THE PRECLINICAL ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) STUDIES NEEDED TO SUPPORT THE PHASE 2 CLINICAL DEVELOPMENT OF SBP-9330 IN SMOKERS; (2) PERFORM THE PRECLINICAL TOXICOLOGY STUDIES NEEDED TO SUPPORT PHASE 2 CLINICAL DEVELOPMENT OF SBP-9330 IN SMOKERS; AND (3) PERFORM THE CHEMISTRY, MANUFACTURING, AND CONTROLS (CMC) ACTIVITIES NEEDED TO SUPPORT PHASE 2 CLINICAL DEVELOPMENT IN SMOKERS. TO ACHIEVE THESE SPECIFIC AIMS, WE HAVE RETAINED THE SAME HIGHLY EXPERIENCED AND QUALIFIED MULTIDISCIPLINARY TEAM OF INVESTIGATORS THAT HAS COLLABORATED PRODUCTIVELY DURING THE PREVIOUS GRANT (U01 DA041731) AND THE CURRENTLY ACTIVE GRANT (U01 DA051077). WE HAVE ALSO COMPILED AN EXTENSIVE DATA PACKAGE TO SUPPORT THE FURTHER CLINICAL DEVELOPMENT OF SBP-9330. ACHIEVEMENT OF THE MILESTONES IN THIS PROPOSAL WILL PROVIDE THE ADDITIONAL DATA AND DRUG SUBSTANCE NEEDED TO ADVANCE SBP-9330 INTO A PHASE 2 PROOF-OF-CONCEPT CLINICAL STUDY IN SMOKERS. OUR TEAM HAS THE DEPTH AND BREADTH OF EXPERTISE AND EXPERIENCE TO EXECUTE THE PROPOSED RESEARCH PLAN, AS EVIDENCED BY THE COMPLETE AND TIMELY ACHIEVEMENT OF THE MILESTONES FOR BOTH U01 DA041731 AND U01 DA051077 IN THE PAST SIX YEARS.

UNKNOWN TITLE

FYHS FULL DAY & PART DAY HEAD START ANDSERVICES TO HANDICAPPED CHILDREN

GENETIC CONTROL OF THE HEART BY TINMAN AND NEUROMANCER

LA JOLLA-PARKINSON'S DISEASE CENTER GRANT

HEAD START

HEAD START

HEALTH CENTER PROGRAM

HEALTH CENTER PROGRAM

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

ULTRASTRUCTURAL BASIS OF MECHANOTRANSDUCTION IN MATRIX ADHESIONS

REWIRED SIGNALING AT THE NEXUS OF MELANOMA METASTASIS AND RESISTANCE

GLYCOSYLTRANSFERASE FUNCTION IN DEVELOPMENT AND DISEASE

CARBOHYDRATE-DEPENDENT ADHESION IN NORMAL AND TUMOR CELLS

LA JOLLA INTERDISCIPLINARY NEUROSCIENCE CENTER CORES

CLERMONT COUNTY FAST TRAC (SYSTEM OF CARE)

GENE TO STRUCTURE FOR $10K (GTS10K)

BIASED MU-OPIOID RECEPTOR ANALGESICS TO PREVENT OVERDOSE AND OPIOID USE DISORDERS

TARGETING EPH RECEPTORS IN CANCER

HEAD START

ENHANCEMENT OF A PREDICTIVE TOXICOLOGY TOOLBOX VIA MULTI-PARAMETRIC DATA INFORMED QSAR MODELING OF BENCHMARK TOXINS

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

MOLECULAR PATHOBIOLOGY OF SOLUBLE TREM2 IN ALZHEIMER'S DISEASE.

EPIGENETICS & SIGNALING IN HESC COMMITMENT AND DIFFERENTIATION INTO MUSCLE

CHARACTERIZATION, OPTIMIZATION, AND DEVELOPMENT OF DUAL MGLU2/3 POSITIVE ALLOSTERIC MODULATORS FOR OPIOID USE DISORDER - PROJECT SUMMARY OPIOID USE DISORDER (OUD) IS A SIGNIFICANT PROBLEM WORLDWIDE AND A SURGE IN METHAMPHETAMINE (MA) USE HAS EMERGED IN CHRONIC OPIOID USERS. GIVEN RECENT INCREASES IN CO-ABUSE, THERE IS A DIRE NEED FOR NOVEL TREATMENT STRATEGIES THAT PREVENT RELAPSE TO DRUG USE IN BOTH OUD AND MA USE DISORDER (MUD). LONG-TERM DRUG EXPOSURE INDUCES ENHANCED GLUTAMATE (GLU)-MEDIATED SYNAPTIC PLASTICITY, WHICH UNDERLIES EXCESSIVE PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO DRUG-RELATED CUES. OPIOID AND MA EXPOSURE ALSO ACTIVATE MICROGLIA AND ASTROCYTES, PROMOTING RELEASE OF PRO-INFLAMMATORY CYTOKINES. ALL THESE FACTORS INCREASE THE RISK OF RELAPSE TO DRUG USE. NORMALIZATION OF ABERRANT GLU ACTIVITY CAUSED BY CHRONIC DRUG USE REPRESENTS A NOVEL THERAPEUTIC STRATEGY TO PREVENT RELAPSE IN OUD/MUD. THE ACTIVATION OF METABOTROPIC GLU RECEPTOR SUBTYPES 2 AND 3 (MGLU2/3) USING AGONISTS OR POSITIVE ALLOSTERIC MODULATORS (PAMS) DECREASES PSYCHOSTIMULANT SELF-ADMINISTRATION (SA) AS WELL AS CUE-INDUCED REINSTATEMENT (RI) IN ANIMALS. MOREOVER, PRECLINICAL STUDIES INDICATE THAT MGLU2/3 ACTIVATION HAS PROMISE FOR TREATING STRESS- AND ANXIETY-RELATED DISORDERS IN HUMANS AND CAN SYSTEMATICALLY AUGMENT SLEEP. HOWEVER, THE RELATIVE CONTRIBUTION OF MGLU2 VERSUS MGLU3 ACTIVATION FOR TREATING OUD/MUD IS NOT YET KNOWN. ACTIVATION OF PRESYNAPTIC MGLU2 AUTORECEPTORS RESULTS IN DOWNSTREAM INHIBITION OF GLU RELEASE IN THE NUCLEUS ACCUMBENS, WHICH IN TURN ATTENUATES DRUG RI. IN ADDITION, ACTIVATION OF MGLU3, WHICH IS HIGHLY EXPRESSED IN ASTROCYTES, LEADS TO THE RELEASE OF THE ANTI-INFLAMMATORY CYTOKINE TRANSFORMING GROWTH FACTOR BETA (TGF-SS). THE SPECIFIC LOCALIZATION AND SIGNAL TRANSDUCTION OF MGLU2 AND MGLU3 RECEPTORS LEAD TO OUR OVERARCHING HYPOTHESIS THAT DUAL ACTIVATION OF BOTH MGLU2 AND MGLU3 WILL PROVIDE A CLEAR ADVANTAGE FOR THE TREATMENT FOR OUD AND MUD OVER MGLU2 ACTIVATION ALONE. WE HAVE RECENTLY SYNTHESIZED AND CHARACTERIZED SBI-0799220, A PAM WITH EQUAL POTENCY FOR MGLU2 AND MGLU3 AND SBI-0801315, A PAM WITH >50-FOLD SELECTIVITY FOR MGLU2 VS MGLU3. PRELIMINARY DATA INDICATE THAT SBI-0801315 ATTENUATES OXY CUE-INDUCED RI AND SA, AND THAT SBI-0799220 ATTENUATES MA SA. HOWEVER, A DIRECT COMPARISON OF MGLU2/3 WITH MGLU2 PAMS IN MODELS OF OUD AND MUD HAS NOT YET BEEN CONDUCTED. THE GOAL OF THIS APPLICATION IS TO ADVANCE MGLU2/3 PAMS AS A NOVEL TREATMENT FOR PREVENTING RELAPSE TO OUD, EXAMINE THEIR POTENTIAL FOR TREATING MUD, AND SIMULTANEOUSLY OPTIMIZE MGLU2/3 PAMS. WE WILL DETERMINE THE IN VIVO EFFICACY OF MGLU2/3 AND MGLU2-PREFERRING PAMS TO ATTENUATE OXY/MA SA AND RI, OXY/MA-INDUCED WITHDRAWAL, MA-INDUCED NEUROINFLAMMATION, AND OPIOID-INDUCED ANTINOCICEPTION IN RATS. SIMULTANEOUSLY, WE WILL OPTIMIZE THE PHARMACOLOGICAL AND PHARMACEUTICAL PROPERTIES OF OUR MGLU2/3 PAM SERIES INCLUDING ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION, AND PHARMACOKINETICS. WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM OF INVESTIGATORS THAT HAS THE KNOWLEDGE AND EXPERIENCE TO ACHIEVE THESE OUTCOMES. SUCCESSFUL COMPLETION OF THESE STUDIES WILL EXPEDITE DEVELOPMENT OF A NOVEL MGLU2/3 PAM TOWARDS INVESTIGATIONAL NEW DRUG (IND)-ENABLING STUDIES AND ULTIMATELY, A NOVEL TREATMENT FOR PREVENTING RELAPSE IN OUD.

ASSEMBLY, DYNAMICS AND EVOLUTION OF CELL-CELL AND CELL-MATRIX ADHESIONS

PDE4B INHIBITORS FOR TREATING MAJOR DEPRESSION

DEVELOPMENT OF SBI-553, AN ALLOSTERIC MODULATOR OF NTR1, FOR THE TREATMENT OF SUBSTANCE USE DISORDERS - PROJECT SUMMARY OPIOID USE DISORDER (OUD) IS A MAJOR PUBLIC HEALTH CRISIS IN THE UNITED STATES, WITH >50,000 OVERDOSE DEATHS IN 2017 ALONE. ADDICTION TO OPIOIDS IS INTIMATELY RELATED TO THE PHYSIOLOGY OF THE BRAIN’S DOPAMINE-BASED REWARDING SYSTEM. THE NEUROTENSIN 1 RECEPTOR (NTR1) IS FOUND AMONG DOPAMINE PRE AND POST-SYNAPTIC NEURONS IN THE CENTRAL NERVOUS SYSTEM, AND ACTS AS A MODULATOR OF DOPAMINERGIC SYSTEMS. EVEN THOUGH SUBSTANTIAL EVIDENCE POINTS TOWARDS NTR1 AS A MOLECULAR TARGET FOR TREATING ADDICTION DISORDERS, FEW NON- PEPTIDE BRAIN PENETRANT NEUROTENSIN MODULATORS HAVE BEEN IDENTIFIED, AND ORTHOSTERIC NTR1 LIGANDS DISPLAY SIDE EFFECTS INCLUDING HYPOTENSION AND HYPOTHERMIA THAT HAVE LIMITED THEIR CLINICAL DEVELOPMENT. RECENTLY, WE HAVE DISCOVERED A SERIES OF BRAIN-PENETRANT NTR1 MODULATORS, INCLUDING A LEAD COMPOUND SBI-553, WITH A UNIQUE MECHANISM OF ACTION AT NTR1. SBI-553 IS AN ORALLY AVAILABLE AND BRAIN PENETRANT B-ARRESTIN BIASED ALLOSTERIC MODULATOR OF NTR1, WHICH SHOWS EFFICACY IN A RANGE OF ADDICTION MODELS. THE LITERATURE CONTAINS NO DOCUMENTED REPORTS OF SUCH MOLECULES AMONG POSITIVE OR NEGATIVE ALLOSTERIC MODULATORS OF GPCRS. IN ADDITION, THE UNIQUE PROFILE OF SBI-553 APPEARS TO CIRCUMVENT THE CLINICALLY LIMITING SIDE EFFECTS OF HYPOTHERMIA AND HYPOTENSION DISPLAYED BY ORTHOSTERIC NTR1 LIGANDS. WHILE POTENTIALLY HIGH RISK, THE ACTIVITY OF SBI-553 HAS BEEN VALIDATED IN VITRO AND IN VIVO, AND THE INITIAL SAFETY PROFILING INDICATES NO ISSUES THAT WOULD PRECLUDE FURTHER DEVELOPMENT. THE GOAL OF THE APPLICATION IS TO DEVELOP SBI-553 AS A TREATMENT FOR OPIOID USE DISORDERS. A 2-YEAR UG3 PHASE IS PROPOSED WITH THE PRIMARY OBJECTIVE OF DETERMINING THE SUITABILITY OF SBI-553 (OR A BACKUP COMPOUND) ENTERING IND-ENABLING STUDIES FOLLOWED BY A 2-YEAR UH3 PHASE WITH THE PRIMARY OBJECTIVE OF COMPLETING A PHASE 1 SINGLE ASCENDING DOSE STUDY. DURING THE UG3 PHASE, THE TEAM WILL COMPLETE PHARMACOKINETIC (PK) STUDIES AND THE PRECLINICAL SAFETY PROFILE OF SBI-553 IN A RELEVANT SPECIES; IDENTIFY A BACKUP COMPOUND TO SBI-553; AND CONDUCT DEFINITIVE CELLULAR AND IN VIVO PHARMACOLOGY STUDIES WITH SBI-553 (AND/OR POTENTIAL BACKUP) IN MODELS OF ADDICTION TO INFORM BEST CLINICAL INDICATION AND CLINICAL ENDPOINTS (PK/PHARMACODYNAMIC). DURING THE UH3 PHASE, THE TEAM WILL ENSURE COMPLETION OF GMP SYNTHESIS, STABILITY TESTING AND FORMULATION; GLP TOXICOLOGY STUDIES; AND THE PHASE 1 SINGLE ASCENDING DOSE STUDY.

GENETIC ANALYSIS OF DROSOPHILA FUNCTIONAL AGING

MOLECULAR PATHOGENESIS AND TREATMENT OF HYPOPHOSPHATASIA

NEW CONGENITAL DISORDERS OF GLYCOSYLATION: THERAPY AND MODELS

NANOTHERAPY FOR VULNERABLE PLAQUE

NEURON-GLIA COMMUNICATION IN DEVELOPMENT

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

FUNCTION OF CD19 IN B-CELL DEVELOPMENT & DIFFERENTIATION

AMERICAN RESCUE PLAN ACT FUNDING FOR HEALTH CENTERS

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

COVENANT HOUSE INTERNATIONAL WILL STRENGTHEN PROTECTION AND PREVENTION SERVICES FOR MIGRANTS, TRAFFICKING SURVIVORS, AND YOUTH AT-RISK IN GUATEMALA, HONDURAS, AND MEXICO.

COUNSELING & RECOVERY SERVICES OF OKLAHOMA CMHC - COUNSELING & RECOVERY SERVICES OF OKLAHOMA (CRSOK) PROPOSES TO EXPAND ITS CRISIS SERVICES TO INCLUDE A CRISIS RESPONSE PROGRAM THROUGH THE COMMUNITY MENTAL HEALTH CENTERS (CMHC) GRANT PROGRAM TO TREAT SCHOOL-AGED YOUTH EXPERIENCING BEHAVIORAL HEALTH CRISES. CRSOK IS LICENSED BY THE STATE OF OKLAHOMA AS A MENTAL HEALTH AND SUBSTANCE USE DISORDER TREATMENT FACILITY FOR ADULTS, FAMILIES, AND CHILDREN IN TULSA COUNTY. THERE ARE SIGNIFICANT HEALTH DISPARITIES AMIDST TULSA CHILDREN WITH UNMET BEHAVIORAL HEALTH NEEDS AND AN INCREASING RATE OF CHILDREN'S CRISES DUE TO THE COVID-19 PANDEMIC. CRSOK PROPOSES TO BUILD ON ITS EXISTING CRISIS SERVICES TO INCLUDE IMMEDIATE CRISIS ASSESSMENT, 23:59 CHAIRS, AND TRIAGE TO DIVERT CLIENTS AWAY FROM INPATIENT HOSPITALS AND LAW ENFORCEMENT. WE PLAN TO SERVE 500 INDIVIDUALS EACH YEAR, 1,000 OVER THE LIFE OF THE GRANT. THIS WILL REQUIRE MINIMAL INVESTMENT IN INFRASTRUCTURE, WITH MOST OF OUR INVESTMENT GOING TOWARD RESOURCES THAT WILL PROVIDE DIRECT SERVICES TO OUR CLIENTS. THE FOCUS OF OUR PROPOSED PROJECT IS TO INCREASE ACCESS TO YOUTH IN CRISIS DUE TO THE PANDEMIC AND GET THEM BACK INTO THEIR COMMUNITY WITHOUT FURTHER HARM OR DISTRESS. OUR SELECTED OBJECTIVES ALIGN WITH OUR STATED GOALS: 1) EXPAND THE CAPACITY FOR IMMEDIATE CHILD CRISIS ASSESSMENT, EMERGENCY RESPONSE, AND TRIAGE IN TULSA TO DECREASE THE OVERUTILIZATION OF EMERGENCY ROOMS AND INPATIENT HOSPITALS AND 2) EXPAND INTERNAL CAPACITY FOR CRISIS RESPONSE BY ESTABLISHING A CHILDREN'S CRISIS RESPONSE TEAM. THE OBJECTIVES FOR THIS PROJECT WILL BE ACCOMPLISHED THROUGH THE FRAMEWORK OUTLINED IN THIS GRANT. IT WILL BE LED BY EXPERIENCED AND QUALIFIED PERSONNEL OVERSEEN BY CRSOK'S SENIOR LEADERSHIP AND ADVISED BY THE BOARD OF DIRECTORS. WE WILL MANAGE, MONITOR, AND APPLY OUR DATA COLLECTION AND PERFORMANCE MEASUREMENT TO NOT ONLY MEET REPORTING REQUIREMENTS, BUT ALSO TO INFORM OF BROADER PERFORMANCE ASSESSMENT AND CQI EFFORTS TO ENHANCE OUR PROGRAMS.

THE SSVF PROGRAM'S PURPOSE IS TO PROVIDE SUPPORTIVE SERVICES GRANTS TO PRIVATE NON-PROFIT ORGANIZATIONS AND CONSUMER COOPERATIVES, WHO WILL COORDINATE OR PROVIDE SUPPORTIVE SERVICES TO VERY LOW-INCOME VETERAN FAMILIES WHO ARE RESIDING IN PERMANENT HOUSING, ARE HOMELESS AND SCHEDULED TO BECOME RESIDENTS OF PERMANENT HOUSING WITHIN A SPECIFIED TIME PERIOD; OR AFTER EXITING PERMANENT HOUSING WITHIN A SPECIFIED TIME PERIOD, ARE SEEKING OTHER HOUSING THAT IS RESPONSIVE TO SUCH VERY LOW-INCOME VETERAN FAMILY'S NEEDS AND PREFERENCES. GRANTEES WILL USE SUPPORTIVE SERVICES GRANT FUNDS TO PROVIDE SUPPORTIVE SERVICE. ALL GRANTEES ARE REQUIRED TO PROVIDE OUTREACH SERVICES, CASE MANAGEMENT SERVICES, ASSISTANCE IN OBTAINING VA BENEFITS AND ASSISTANCE IN OBTAINING AND COORDINATING OTHER PUBLIC BENEFITS. IN ADDITION TO THE REQUIRED SERVICES, GRANTEES MAY ALSO PROVIDE TEMPORARY FINANCIAL ASSISTANCE PAID DIRECTLY TO A THIRD PARTY ON BEHALF OF A PARTICIPANT FOR CHILD CARE, EMERGENCY HOUSING ASSISTANCE, TRANSPORTATION, RENTAL ASSISTANCE, UTILITY-FEE PAYMENT ASSISTANCE, SECURITY DEPOSITS, UTILITY DEPOSITS, MOVING COSTS, AND GENERAL HOUSING STABILITY ASSISTANCE (WHICH INCLUDES EMERGENCY SUPPLIES), IN ACCORDANCE WITH 38 CFR PART 62. ADDITIONAL OPTIONAL SUPPORTIVE SERVICES MAY INCLUDE LEGAL ASSISTANCE AND FINANCIAL MANAGEMENT SERVICES. GRANTEES WILL USE SUPPORTIVE SERVICES GRANT FUNDS TO PROVIDE SUPPORTIVE SERVICE. ALL GRANTEES ARE REQUIRED TO PROVIDE OUTREACH SERVICES, CASE MANAGEMENT SERVICES, ASSISTANCE IN OBTAINING VA BENEFITS AND ASSISTANCE IN OBTAINING AND COORDINATING OTHER PUBLIC BENEFITS. IN ADDITION TO THE REQUIRED SERVICES, GRANTEES MAY ALSO PROVIDE TEMPORARY FINANCIAL ASSISTANCE PAID DIRECTLY TO A THIRD PARTY ON BEHALF OF A PARTICIPANT FOR CHILD CARE, EMERGENCY HOUSING ASSISTANCE, TRANSPORTATION, RENTAL ASSISTANCE, UTILITY-FEE PAYMENT ASSISTANCE, SECURITY DEPOSITS, UTILITY DEPOSITS, MOVING COSTS, AND GENERAL HOUSING STABILITY ASSISTANCE (WHICH INCLUDES EMERGENCY SUPPLIES), IN ACCORDANCE WITH 38 CFR PART 62. ADDITIONAL OPTIONAL SUPPORTIVE SERVICES MAY INCLUDE LEGAL ASSISTANCE AND FINANCIAL MANAGEMENT SERVICES.

HEPARAN SULFATE IN SKELETAL DEVELOPMENT AND DISEASES

ALTERED REVERSE TRANSCRIPTASE-DEPENDENT GENE DIVERSIFICATION MECHANISMS IN ALZHEIMER'S DISEASE BRAINS

A NOVEL ROLE FOR THE UPR COMPONENT, ATF6 IN AD-ASSOCIATED NEUROPROTECTIVE PATHWAYS

THE SSVF PROGRAM'S PURPOSE IS TO PROVIDE SUPPORTIVE SERVICES GRANTS TO PRIVATE NON-PROFIT ORGANIZATIONS AND CONSUMER COOPERATIVES, WHO WILL COORDINATE OR PROVIDE SUPPORTIVE SERVICES TO VERY LOW-INCOME VETERAN FAMILIES WHO ARE RESIDING IN PERMANENT HOUSING, ARE HOMELESS AND SCHEDULED TO BECOME RESIDENTS OF PERMANENT HOUSING WITHIN A SPECIFIED TIME PERIOD; OR AFTER EXITING PERMANENT HOUSING WITHIN A SPECIFIED TIME PERIOD, ARE SEEKING OTHER HOUSING THAT IS RESPONSIVE TO SUCH VERY LOW-INCOME VETERAN FAMILY'S NEEDS AND PREFERENCES. GRANTEES WILL USE SUPPORTIVE SERVICES GRANT FUNDS TO PROVIDE SUPPORTIVE SERVICE. ALL GRANTEES ARE REQUIRED TO PROVIDE OUTREACH SERVICES, CASE MANAGEMENT SERVICES, ASSISTANCE IN OBTAINING VA BENEFITS AND ASSISTANCE IN OBTAINING AND COORDINATING OTHER PUBLIC BENEFITS. IN ADDITION TO THE REQUIRED SERVICES, GRANTEES MAY ALSO PROVIDE TEMPORARY FINANCIAL ASSISTANCE PAID DIRECTLY TO A THIRD PARTY ON BEHALF OF A PARTICIPANT FOR CHILD CARE, EMERGENCY HOUSING ASSISTANCE, TRANSPORTATION, RENTAL ASSISTANCE, UTILITY-FEE PAYMENT ASSISTANCE, SECURITY DEPOSITS, UTILITY DEPOSITS, MOVING COSTS, AND GENERAL HOUSING STABILITY ASSISTANCE (WHICH INCLUDES EMERGENCY SUPPLIES), IN ACCORDANCE WITH 38 CFR PART 62. ADDITIONAL OPTIONAL SUPPORTIVE SERVICES MAY INCLUDE LEGAL ASSISTANCE AND FINANCIAL MANAGEMENT SERVICES. GRANTEES WILL USE SUPPORTIVE SERVICES GRANT FUNDS TO PROVIDE SUPPORTIVE SERVICE. ALL GRANTEES ARE REQUIRED TO PROVIDE OUTREACH SERVICES, CASE MANAGEMENT SERVICES, ASSISTANCE IN OBTAINING VA BENEFITS AND ASSISTANCE IN OBTAINING AND COORDINATING OTHER PUBLIC BENEFITS. IN ADDITION TO THE REQUIRED SERVICES, GRANTEES MAY ALSO PROVIDE TEMPORARY FINANCIAL ASSISTANCE PAID DIRECTLY TO A THIRD PARTY ON BEHALF OF A PARTICIPANT FOR CHILD CARE, EMERGENCY HOUSING ASSISTANCE, TRANSPORTATION, RENTAL ASSISTANCE, UTILITY-FEE PAYMENT ASSISTANCE, SECURITY DEPOSITS, UTILITY DEPOSITS, MOVING COSTS, AND GENERAL HOUSING STABILITY ASSISTANCE (WHICH INCLUDES EMERGENCY SUPPLIES), IN ACCORDANCE WITH 38 CFR PART 62. ADDITIONAL OPTIONAL SUPPORTIVE SERVICES MAY INCLUDE LEGAL ASSISTANCE AND FINANCIAL MANAGEMENT SERVICES.

SREBPS IN REGULATION OF LIPID METABOLISM

MEB-1170: A NEW CHEMICAL ENTITY FOR THE TREATMENT OF OPIOID USE DISORDER - PROJECT SUMMARY / ABSTRACT MEBIAS DISCOVERY, INC. IS DEVELOPING A NEW CHEMICAL ENTITY, MEB-1170, TO TREAT OPIOID USE DISORDER (OUD) AS A MAINTENANCE MEDICATION. CURRENTLY, ALL OF THE FDA-APPROVED MEDICATIONS FOR TREATING OUD (MOUD) – BUPRENORPHINE, METHADONE, AND NALTREXONE – COME WITH LIABILITIES (ABUSE POTENTIAL, MEDICATION DIVERSION, NEED FOR DETOXIFICATION PRIOR TO ADMINISTRATION, RISK OF RESPIRATORY DEPRESSION, ETC.) AND ~50% OF PATIENTS DISCONTINUE TREATMENT AFTER 6 MONTHS.1,2 MEB-1170 IS A FULL MU OPIOID RECEPTOR AGONIST AND PARTIAL KAPPA OPIOID RECEPTOR AGONIST THAT HAS A UNIQUE PHARMACOLOGICAL PROFILE. SPECIFICALLY, IT PRODUCES A ROBUST ANALGESIC RESPONSE THAT IS MEDIATED THROUGH MU OPIOID RECEPTORS BUT HAS NO ABUSE LIABILITY AS MEASURED IN MULTIPLE PRECLINICAL ASSAYS (CONDITIONED PLACE PREFERENCE, INTRAVENOUS DRUG SELF-ADMINISTRATION, DRUG DISCRIMINATION) AND NO TYPICAL OPIOID-RELATED ADVERSE EFFECTS SUCH AS RESPIRATORY DEPRESSION, CONSTIPATION, AND SEDATION. A PHASE 1 SINGLE ASCENDING DOSE STUDY SUPPORTED ITS SAFETY AND TOLERABILITY IN HEALTHY ADULT VOLUNTEERS. IN THE UG3 PHASE OF THE PROPOSED RESEARCH, WE WILL COMPLETE PRECLINICAL STUDIES IN RODENTS AND NON-HUMAN PRIMATES TO EVALUATE THE EFFICACY OF MEB-1170 AS AN MOUD. WE WILL ASSESS THE ABILITY OF MEB-1170 TO REDUCE FENTANYL SELF- ADMINISTRATION, AS WELL AS ITS PROPENSITY TO PRODUCE RESPIRATORY DEPRESSION AND PRECIPITATE OPIOID WITHDRAWAL IN OPIOID- DEPENDENT ANIMALS. IN THE UH3 PHASE, WE WILL CONDUCT A PHASE 1 MULTIPLE ASCENDING DOSE CLINICAL TRIAL TO FURTHER EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF MULTIPLE DOSES OF MEB-1170 IN HEALTHY ADULT VOLUNTEERS OVER A 10-DAY REGIMEN. IN ADDITION, WE WILL CONDUCT A PHASE 1B CLINICAL STUDY TO ASSESS THE ABILITY OF MEB-1170 TO REDUCE FENTANYL-INDUCED RATINGS OF DRUG LIKING AND PRECIPITATE OPIOID WITHDRAWAL IN OPIOID-DEPENDENT INDIVIDUALS WITH OUD WHO ARE NOT CURRENTLY NOT SEEKING TREATMENT FOR OUD. OUR OVERARCHING GOAL IS TO DEVELOP MEB-1170 AS A SAFE AND EFFECTIVE MOUD TO PREVENT RELAPSE AND FACILITATE LONG-TERM RECOVERY. 1 MONTOYA, I. D. & VOLKOW, N. D. IUPHAR REVIEW: NEW STRATEGIES FOR MEDICATIONS TO TREAT SUBSTANCE USE DISORDERS. PHARMACOL RES 200, 107078, DOI:10.1016/J.PHRS.2024.107078 (2024). 2 MARSDEN, J. ET AL. MEASUREMENT-BASED CARE USING DSM-5 FOR OPIOID USE DISORDER: CAN WE MAKE OPIOID MEDICATION TREATMENT MORE EFFECTIVE? ADDICTION 114, 1346-1353, DOI:10.1111/ADD.14546 (2019).

REGULATION OF NUTRIENT STRESS-INDUCED MACROPINOCYTOSIS IN PANCREATIC DUCTAL ADENOCARCINOMA

ROLE OF HYPERNUTRITION AND METABOLIC STRESS IN NON-ALCOHOLIC STEATOHEPATITIS (NASH) DRIVEN HEPATOCELLULAR CARCINOMA (HCC) - PROJECT SUMMARY – OVERALL HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON PRIMARY LIVER CANCER AND A RISING CAUSE OF CANCER MORTALITY. HCC RELATED TO METABOLIC STRESS IS ON THE RISE, WITH NONALCOHOLIC STEATOHEPATITIS (NASH) RAPIDLY BECOMING THE DOMINANT ETIOLOGY. WE HYPOTHESIZE THAT STRESS-INDUCED METABOLIC REPROGRAMMING VIA NRF2 AND ATF6 ALTERS, GLUCOSE, LIPID, AND CHOLESTEROL METABOLISM TO AUGMENT GLYCOLYSIS AND INDUCE MITOCHONDRIAL DYSFUNCTION THROUGH STARD1 AND SAB, WHICH COLLABORATES WITH GENETIC ALTERATIONS TO ACCELERATE NASH PROGRESSION TO HCC THROUGH A SELF-SUSTAINED DOWNWARD SPIRAL. INTERFERENCE WITH KEY COMPONENTS OF THIS NETWORK MAY SUPPRESS HCC PROGRESSION AND CAN YIELD NOVEL INTERCEPTIVE STRATEGIES. OUR PRELIMINARY DATA INDICATE THAT INTERACTIONS BETWEEN THE CYTOSOL AND NUCLEUS (AKT;NRF2), THE ENDOPLASMIC RETICULUM (ER; ATF6) AND MITOCHONDRIA (STARD1+SAB) CONTRIBUTE SYNERGISTICALLY TO NASH-DRIVEN HCC. ELIMINATION OF ANY OF THESE COMPONENTS ATTENUATES HCC AND THEIR ACTIVATION EXACERBATES HCC PROGRESSION IN MURINE MODELS. TOGETHER, OUR OUTSTANDING TEAM OF INVESTIGATORS WILL ADDRESS THE PATHOLOGICAL SIGNIFICANCE AND MECHANISMS UNDERLYING THE CROSSTALK BETWEEN THESE PATHWAYS VIA 3 PROJECTS: PROJECT 1 WILL INTERROGATE HOW THE NEWLY DISCOVERED NRF2- FBP1 TUG-OF-WAR IS REGULATED TO SUPPORT HCC PROGRESSION. IT WILL IDENTIFY THE FIRST CELLS IN WHICH NRF2 AND AKT ARE ACTIVATED TO DRIVE FBP1 DEGRADATION AND THE CUES THAT TRIGGER THIS SWITCH. LINEAGE TRACING WILL DETERMINE WHETHER NRF2-HIGH HCC DIRECTLY ORIGINATES FROM FBP1-HIGH SENESCENT NASH HEPATOCYTES AND THE ROLE OF DIET- INDUCED DNA DAMAGE IN HEPATOCYTE SENESCENCE AND MUTAGENESIS WILL BE ELUCIDATED. PROJECT 2 WILL DEFINE HOW ATF6 DRIVES HCC IN RESPONSE TO METABOLIC STRESS. IT WILL UNCOVER THE MECHANISM BY WHICH ER STRESS AND THE UNFOLDED PROTEIN RESPONSE TRANSDUCER ATF6 PROMOTES NASH PROGRESSION TO HCC, LIKELY THROUGH NRF2 AND FBP1 DEGRADATION, THE REPROGRAMMING OF LIPID AND CHOLESTEROL METABOLISM, AND WILL TEST WHETHER AND HOW ATF6 ABLATION OR INHIBITION ABROGATE NASH-DRIVEN HCC. PROJECT 3 WILL EXPLORE HOW METABOLIC STRESS AND CHOLESTEROL TRIGGER MITOCHONDRIAL DYSFUNCTION THROUGH STARD1 AND SAB TO DRIVE HCC. MITOCHONDRIAL OUTER MEMBRANE PROTEINS STARD1 AND SAB MAY CONTRIBUTE TO NASH AND HCC DEVELOPMENT THROUGH ALTERED CHOLESTEROL TRAFFICKING AND BILE ACID SYNTHESIS, MITOCHONDRIAL DYSFUNCTION THAT TRIGGERS ROS PRODUCTION, RESULTING IN NRF2 AND ATF6 ACTIVATING OXIDATIVE AND/OR ER STRESS. THIS PPG OFFERS AN UNPRECEDENTED OPPORTUNITY FOR ADVANCED UNDERSTANDING OF NASH-DRIVEN HCC VIA PROXIMAL METABOLIC REGULATORS AND DNA DAMAGE CONTROLLED BY NRF2, ATF6, AND STARD1/SAB. EXTENSIVE COLLABORATIVE INTERACTIONS AND COORDINATED ADMINISTRATIVE RESOURCES (CORE A), SHARED USE OF DIETARY AND TRANSGENIC MOUSE MODELS, METABOLIC PROFILING/FLUX STUDIES (CORE 1) AND EXTENSIVE “OMIC” AND BIOINFORMATIC ANALYSES (CORE 2) WILL FURTHER ENHANCE COLLABORATIONS AND ENSURE UNIFORM SUCCESS THROUGHOUT ALL PROJECTS. THIS P01 OFFERS A UNIQUE TRANSLATIONAL OPPORTUNITY TO DEFINE HOW ENERGY RICH DIETS IMPACT REGULATORS THAT PROMOTE NASH PROGRESSION TO HCC, GENERATING NEW PREVENTIVE AND THERAPEUTIC STRATEGIES.

TRANSFORMATIVE RESEARCH ON SOMATIC GENE RECOMBINATION IN THE NORMAL AND ALZHEIMER'S DISEASE-RELATED DEMENTIA BRAIN

ROLE OF THE UNFOLDED PROTEIN RESPONSE IN BETA CELL

AMERICAN RESCUE PLAN ACT FUNDING FOR HEALTH CENTERS

REGULATION OF FACTOR VIII SECRETION

A PHARMACOCHAPERONE-BASED STRATEGY FOR IDENTIFYING CHEMICAL PROBES OF BRAIN-DERIVED ORPHAN GPCRS

PRESENILINS IN PROTEIN TRAFFICKING

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

HEAD START

CENTER ON PROTEOLYTIC PATHWAYS(RMI)

POINT-OF-CARE IMMUNOASSAY FOR EARLY DIAGNOSIS OF PERTUSSIS

DETROIT RECOVERY PROJECT CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (DRP CCBHC)

MODIFIERS OF PROINSULIN INFLUENCE T2D SUSCEPTIBILITY

CONTROL OF LIPOGENESIS AND HEPATIC STEATOSIS BY CASPASE-2

REDISCOVER CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) IMPROVEMENT AND ADVANCEMENT PROJECT - REDISCOVER, A CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC, SERVING RESIDENTS OF JACKSON COUNTY, MISSOURI, PROPOSED TO IMPLEMENT A CCBHC IMPROVEMENT AND ADVANCEMENT PROJECT TO ENHANCE THEIR CAPACITY TO SERVE INDIVIDUALS WITH SERIOUS EMOTIONAL DISTURBANCE, SERIOUS MENTAL ILLNESS, SUBSTANCE USE DISORDER, OR WHO HAVE A CO-OCCURRING DISORDER LIKE SMI AND SUD, ESPECIALLY THOSE WHO ARE IN CRISIS WITH PEER SUPPORT SERVICES. THIS PROJECT WILL SERVE 278 CLIENTS IN YEAR ONE, 360 CLIENTS IN YEAR TWO, 440 CLIENTS IN YEAR THREE, 560 CLIENTS IN FOUR, FOR A TOTAL OF 1,638 UNDUPLICATED CLIENTS OVER FOUR YEARS. BASED ON THE REQUIREMENT OF PEER SUPPORT SPECIALISTS TO BE 18 YEARS OR OLDER, 95% OF CLIENTS TO BE SERVED IN THIS PROGRAM ARE EXPECTED TO BE 18 YEARS AND OLDER. IDEALLY, AT LEAST 80% OF CLIENTS REACHED BY THIS PROGRAM WILL BE UNDERREPRESENTED, MOST LIKELY LATINX AND AFRICAN AMERICAN, TO ADDRESS HEALTH DISPARITIES FOR THESE POPULATIONS IN THE REGION. THE GOALS OF THIS PROJECT ARE TO INCREASE REDISCOVER’S CAPACITY 1) TO IDENTIFY AND ENGAGE UNDERREPRESENTED POPULATIONS IN TREATMENT SERVICES; 2) CONNECT INDIVIDUALS TO APPROPRIATE ONGOING SERVICES AND RESOURCES BEFORE THEY ESCALATE INTO CRISIS; AND 3) ENGAGE INDIVIDUALS IN CRISIS IN ONGOING TREATMENT SERVICES; AND INCREASE INDIVIDUALS’ CAPACITY 4) TO NAVIGATE THEIR BEHAVIORAL HEALTHCARE OPTIONS. OBJECTIVES INCLUDE INCREASING THE SHOW RATE FOR INTAKES, ENGAGEMENT IN PRE-TREATMENT SERVICES, SUCCESSFUL CONNECTION TO OUTPATIENT, CLINICAL, AND/OR RECOVERY TREATMENT SERVICES AND MAINTENANCE OF THESE SERVICES, AND DECREASING PRE-SERVICE CRISIS INTERACTIONS AND THE ESCALATION INTO CRISIS WHILE IN SERVICES. TO ACHIEVE THESE GOALS AND OBJECTIVES, REDISCOVER WILL HIRE TWENTY-SIX PEER SUPPORT SPECIALISTS, FAMILY SUPPORT PROVIDERS, AND TEAM LEADS OVER THE FOUR-YEAR PERIOD; TRAIN THEM IN EVIDENCE-BASED PRACTICES; AND INTEGRATE THEM INTO FIVE SUBSTANCE USE SERVICE PROGRAMS AND EIGHT CRISIS SERVICE PROGRAMS. IN ADDITION, PEER SUPPORT SPECIALISTS WILL WORK WITH THE QUALITY IMPROVEMENT DEPARTMENT TO DESIGN AND DISTRIBUTE SURVEYS AND CONDUCT FOCUS GROUPS WITH INDIVIDUALS WHO HAVE CHOSEN NOT TO PARTICIPATE IN SERVICES OR WHO HAVE STRUGGLED TO STAY ENGAGED IN SERVICES, INCLUDING INDIVIDUALS FROM LATINX AND BLACK ETHNIC AND RACIAL BACKGROUNDS TO IMPROVE THE NEEDS ASSESSMENTS CONDUCTED BY REDISCOVER.

DRP CCBHC EXPANSION - DETROIT RECOVERY PROJECT (DRP), A CARF ACCREDITED BEHAVIORAL HEALTH HOME, A RECIPIENT OF A 2020 CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC EXPANSION GRANT, IS SEEKING FY 2022 SUBSTANCE ABUSE AND MENTAL HEALTH SERVICES ADMINISTRATION (SAMHSA), CENTER FOR MENTAL HEALTH SERVICES (CMHS) FUNDING FOR CCBHC IMPROVEMENT AND ADVANCEMENT GRANT (CCBHC-IA) TO CONTINUE EXPANDING AND SOLIDIFYING ITS BEHAVIORAL HEALTH SERVICES. DRP IS LOCATED IN DETROIT, THE LARGEST CITY IN WAYNE COUNTY, MICHIGAN (WC). THE POPULATION OF DETROIT IS 672,000 AND IS A MAJORITY-MINORITY CITY WITH 77% OF ITS RESIDENTS BEING AFRICAN AMERICAN AND 8% BEING LATINX. ACCORDING TO THE DETROIT WAYNE MENTAL HEALTH AUTHORITY 2017-2018 ANNUAL REPORT, PREVALENCE RATE IS FOR SUD 7,879 (10.7%); SMI 39,398 (53.53%), AND SED 12, 274(16.6%). OVER 414,000 OUT OF 1.74 MILLION PERSONS ARE LIVING IN POVERTY WITH WC. DETROIT IS ONE OF THREE MOST IMPOVERISHED COMMUNITIES ABOVE THE NATIONAL AVERAGE FOR POVERTY: DETROIT 39.8% WITH CLOSELY NEIGHBORING CITIES, HIGHLAND PARK 40.9%, AND HAMTRAMCK 50.9%. WITHIN THESE HIGH-RISK COMMUNITIES AND IN OTHER WC AREAS MANY INDIVIDUALS HAVE LIMITED OR NO ACCESS TO A COMPREHENSIVE, INTEGRATED ARRAY OF BEHAVIORAL AND PHYSICAL HEALTH SERVICES DUE TO A LACK OF OR INADEQUATE HEALTH CARE COVERAGE. THE MICHIGAN DEPARTMENT OF HEALTH & HUMAN SERVICES (MDHHS) CARE CONNECT 360 DATA IDENTIFIED THAT OVER 4% OF THE INDIVIDUALS SERVED BY EMS HAVE A CHRONIC COMORBID CONDITION AND 40% HAVE FIVE OR MORE. THIS EQUATES TO APPROXIMATELY 3,500 INDIVIDUALS REQUIRING MORE COMPREHENSIVE INTEGRATED CARE COORDINATION. OTHER SUBPOPULATIONS AT RISK INCLUDING VETERANS AND YOUTH SUICIDE, AS IDENTIFIED BY THE DETROIT WAYNE MENTAL HEALTH AUTHORITY, WITH 25.4% SERIOUSLY CONSIDERING ATTEMPTING SUICIDE AND 18.6% COMMITTING SUICIDE BASED ON THE MICHIGAN PROFILE HEALTH YOUTH 2016-2017 SURVEY. DRP WILL FURTHER EXPAND AND ENHANCE SERVICES TO THE TARGET POPULATION BY 1) INCREASING ACCESS TO PRIMARY AND BEHAVIORAL HEALTH CARE THROUGH DRP CCBHC INTEGRATED SERVICES; 2) ENHANCING CCBHC INFRASTRUCTURE AND SUSTAINABILITY TO SUPPORT THE PROVISION OF AN INTEGRATED CONTINUUM OF CARE; 3) DECREASING OVERDOSE DEATHS THROUGH MAT AND SUD TREATMENT SERVICES AND 4) ENHANCING THE QUALITY OF LIFE FOR INDIVIDUALS IN THE TARGET POPULATION. DRP ANTICIPATES SERVING 950 INDIVIDUALS (150 INDIVIDUALS IN YEAR ONE, 200 IN YEAR 2, AND 300 IN YEARS 3 AND 4 OVER THE FOUR-YEAR PROGRAM. DRP MET THE CCBHC ATTESTATION CRITERIA IN 2021 AND IT IS THE ONLY PEER-LED, PEER-RAN, PEER-DRIVEN ORGANIZATION IN WC THAT IS CONTRACTED, LICENSED AND CURRENTLY PROVIDING A FULL CCBHC CONTINUUM OF SERVICES TO ALL TARGET (SMI, SUD SED, COD, RECOVERY SERVICES) POPULATIONS.

CAPE COD CCBHC - THE CAPE COD CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) WILL SERVE AS A MUCH NEEDED SUPPLEMENT TO EXISTING SERVICES BY CREATING A ROBUST CONTINUUM OF INTEGRATED BEHAVIORAL AND PHYSICAL HEALTH SERVICES FOR VULNERABLE POPULATIONS RESIDING IN CAPE COD, MA. OUR TARGET POPULATION WILL BE LOW-INCOME, UNINSURED AND UNDER-INSURED ADULTS WITH SERIOUS MENTAL ILLNESS , SUBSTANCE USE DISORDERS, AND CO-OCCURRING DISORDERS, AND CHILDREN AND ADOLESCENTS WITH SERIOUS EMOTIONAL DISTURBANCE. WE WILL ADDRESS THE IMPACT OF CHALLENGES RELATED TO ACCESS TO CARE FELT BY THE REGION'S MOST VULNERABLE RESIDENTS, WHO FREQUENTLY CONTEND WITH THE OVERWHELMING CIRCUMSTANCES OF LIVING IN POVERTY AND THE INSIDIOUS IMPACTS OF SOCIAL DETERMINANTS OF HEALTH(SDOH). IN MANY WAYS, THERE ARE TWO CAPE CODS – ONE A POPULAR TOURIST DESTINATION THAT SEES UPWARDS OF 5 MILLION VISITORS ANNUALLY AND CATERS TO WEALTHY SEASONAL RESIDENTS AND VISITORS AND THE OTHER A RURAL, INSULAR COMMUNITY OF 228,996 YEAR ROUND RESIDENTS, WITH 14,176 PEOPLE LIVING BELOW THE POVERTY LEVEL. WITH THE WEALTH OF THE REGION HIDING THE PROBLEM, ACCESS TO SERVICES CAN BE MORE CHALLENGING THAN IN PLACES WITH HIGHER POVERTY. BAY COVE HAS BEEN PROVIDING FOR THE URGENT BEHAVIORAL HEALTH (BH) NEEDS FOR CAPE COD AS THE STATE CONTRACTED EMERGENCY SERVICE PROVIDER (ESP) FOR FIVE YEARS WHERE WE PERFORM AN AVERAGE OF 3,000 CRISIS EVALUATIONS ANNUALLY. SINCE 2019, OUR ESP HAS OPERATED A FOLLOW UP PROGRAM FOR INDIVIDUALS WHO HAD SOUGHT CRISIS SERVICES. ENGAGING IN THIS FOLLOW-UP WORK HAS GIVEN US AN IN-DEPTH UNDERSTANDING OF THE DEMAND FOR SERVICES, THE COMMUNITY BH PROVIDER LANDSCAPE AND THE MOST PRESSING SDOH NEEDS OF THE PEOPLE WE SERVE IN THIS COMMUNITY. WHAT WE HAVE SEEN FIRST HAND IS THE LACK OF OPTIONS FOR ONGOING CARE ON CAPE COD DESPITE THE SIGNIFICANT NEED FOR BH SERVICES. GIVEN OUR EXPERIENCE ON THE CAPE, BAY COVE IS WELL POSITIONED TO BE THE IDEAL AGENCY TO SUCCESSFULLY BRING CCBHC SERVICES TO CAPE COD. IN BECOMING A CCBHC, BAY COVE SEEKS TO ADDRESS GAPS BY PROVIDING OPEN ACCESS TO CULTURALLY RESPONSIVE, INTEGRATED BEHAVIORAL HEALTHCARE REGARDLESS OF INSURANCE STATUS. THE CCBHC WILL PROVIDE CRISIS SERVICES, SAME-DAY TREATMENT, PSYCHOPHARMACOLOGY TREATMENT, INTEGRATED PRIMARY CARE, ENHANCED CARE NAVIGATION AND COORDINATION, AND INCREASED OUTREACH EFFORTS AND SUPPORT SERVICES FOR THOSE NOT YET READY TO ENGAGE IN CARE. THE GOALS OF THE PROJECT ARE: 1) TO ADDRESS THE UNDER RESOURCED AND OVERLY IMPACTED CONTINUUM OF CARE FOR CAPE COD RESIDENTS BY BUILDING A BH OUTPATIENT SERVICE LOCATION AT OUR HYANNIS SITE TO BE WOVEN INTO THE EXISTING OVER BURDENED CARE SYSTEM; 2) TO BUILD A ROBUST CCBHC CONTINUUM OF CARE TO FURTHER DEVELOP BAY COVE’S CAPACITY TO RAPIDLY TRIAGE, ASSESS, PRIORITIZE AND ADDRESS THE MOST PRESSING BH NEEDS FOR SERVICES ON THE CAPE; 3) TO DEVELOP AND IMPLEMENT THE INFRASTRUCTURE NECESSARY FOR BAY COVE TO BECOME A CCBHC ON CAPE COD; AND 4) TO EVALUATE THE CAPE COD CCBHC ON SAMHSA AND OTHER QUALITY MEASURES WITH A VIEW TO SUSTAINABILITY. OUR MEASURABLE OBJECTIVES INCLUDE: ESTABLISHING PROTOCOLS AND DATA SHARING AGREEMENTS FOR COLLABORATION WITH OUR DCOS, CHILD AND FAMILY SERVICES AND DUFFY HEALTH CARE AND OUR COMMUNITY SUPPORTERS CAPE COD VET CENTER AND THE NATIONAL ALLIANCE FOR MENTAL ILLNESS; HIRING NEW BH PROFESSIONALS, INCLUDING CLINICIANS, PSYCHIATRISTS, AND COMMUNITY WORKERS; IMPLEMENTING A CO-LOCATED PRIMARY CARE CLINIC; INITIATING BASELINE AND FOLLOW-UP ADMINISTRATION OF NOMS TOOL AND STANDARDIZED MEASURES OF PSYCHIATRIC SYMPTOMS; AND COMPLETING QUARTERLY REPORTS AND ANNUAL OUTCOME EVALUATIONS. WE WILL ENROLL A MINIMUM OF 100 PARTICIPANTS A YEAR, FOR A TOTAL OF A OF 400 CLIENTS THROUGHOUT THE LIFE OF THE PROJECT. THE PROCESS EVALUATION WILL ASSESS PROJECT IMPLEMENTATION IN RELATION TO TIMELINES ON STANDARDIZED MEASURES OF MENTAL HEALTH SYMPTOMS AND QUALITY OF LIFE, AS WELL AS ON NOMS MEASURES AND UTILIZATION OF ACUTE CARE SERVICES.

FY 2021 CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC EXPANSION GRANTS - CCBHC EXPANSION GRANTS - FREEDOM HOUSE PROPOSES TO IMPLEMENT A PROJECT THAT WILL SERVE CHILDREN AND YOUTH WITH SERIOUS EMOTIONAL DISTURBANCES (SED), ADULTS WITH SEVERE MENTAL ILLNESS (SMI), INDIVIDUALS WITH SUBSTANCE USE DISORDERS (SUD) INCLUDING OPIOID USE DISORDERS (OUD) AND THOSE WITH CO-OCCURRING MENTAL HEALTH AND SUBSTANCE USE DISORDERS (COD) PROJECT IN WARREN, ORANGE, AND PERSON COUNTIES IN THE CENTRAL PORTION OF NORTH CAROLINA. FOLLOWING ARE THE GOALS AND OBJECTIVES OF THE PROPOSED PROJECT. GOAL 1: TO INCREASE AVAILABILITY AND ACCESSIBILITY OF SERVICES OBJECTIVE 1: USE MOBILE CRISIS TEAMS IN RURAL COMMUNITIES OBJECTIVE 2: EMBED MOBILE CRISIS TEAMS IN THE COMMUNITY OBJECTIVE 3: INSTITUTE POLICIES TO HAVE MOBILE CRISIS TEAMS WORK SEAMLESSLY WITH FACILITY-BASED CRISIS FOR INTAKE AND ADMISSION WHEN INPATIENT CRISIS AND/OR DETOX IS REQUIRED GOAL 2: TO PROVIDE A COMPREHENSIVE ARRAY OF MEDICAL AND MENTAL HEALTH SERVICES TO SUPPORT LONG TERM WELLNESS AND RECOVERY OBJECTIVE 1: PROVIDE PHYSICAL AND MENTAL HEALTH SCREENINGS, ASSESSMENT, AND DIAGNOSIS WITHIN 48 HOURS OF ADMISSION OBJECTIVE 2: COORDINATE CARE AND PEER SUPPORT SERVICES AS PART OF INPATIENT CRISIS TREATMENT PLANNING OBJECTIVE 3: PROVIDE SCREENINGS FOR HIV, VIRAL HEPATITIS (A, B, AND C), DIABETES AND OTHER CHRONIC MEDICAL CONDITIONS OBJECTIVE 4: INCREASE EARLY INTERVENTION AND EDUCATION ABOUT CHRONIC CO-MOBILITIES THAT NEGATIVELY IMPACT OVERALL HEALTH AND WELLNESS GOAL 3: TO PARTNER WITH LOCAL LAW ENFORCEMENT TO DECREASE EMERGENCY ROOM USAGE FOR MENTAL HEALTH/SUBSTANCE USE CRISIS OBJECTIVE 1. INCREASE AWARENESS AMONG LOCAL LAW ENFORCEMENT OF THE AVAILABILITY AND ACCESSIBILITY OF CRISIS SERVICES, OBJECTIVE 2. CONDUCT AT LEAST THREE MENTAL HEALTH AWARENESS TRAINING EVENTS OBJECTIVE 3. PRODUCE AND DISTRIBUTE BUSINESS CARDS AND/OR FLYERS WITH THE MOBILE CRISIS CALL LINE NUMBER FOR LAW ENFORCEMENT AND EMS. GOAL 4: TO EVALUATE THE PROJECT OBJECTIVE 1. GATHER, ANALYZE, AND MONITOR PROJECT OUTCOMES AGAINST STATED GOALS AND OBJECTIVES OBJECTIVE 2. COLLECT DATA USING THE GPRA INSTRUMENT REQUIRED FOR THE PROJECT. OBJECTIVE 3. ANALYZE AND PRODUCE REPORTS AT LEAST MONTHLY TO DISSEMINATE TO THE PROJECT MANAGEMENT TEAM AND ADVISORY COMMITTEE FOR CONTINUOUS QUALITY IMPROVEMENT GOAL 5: POSITION FREEDOM HOUSE FOR PROJECT SUSTAINABILITY BEYOND THE TWO-YEAR FUNDING BY SECURING ALL CREDENTIALLING AND FUNDER APPROVALS TO BILL FOR SERVICES OBJECTIVE 1. ESTABLISH AN ADVISORY WORK GROUP LED BY THE DIRECTOR OF CREDENTIALLING AND FACILITIES AND COMPRISED OF INDIVIDUALS WITH MENTAL AND SUBSTANCE USE DISORDERS, AND FAMILY MEMBERS TO MEET MONTHLY TO PROVIDE INPUT AND GUIDANCE TO THE CCBHC ON IMPLEMENTATION AND SUSTAINABILITY. OBJECTIVE 2. WORK WITH UTILIZATION MANAGEMENT AND BILLING TO UNDERSTAND AND OVERCOME BARRIERS TO REIMBURSEMENT THE PROPOSED PROJECT WILL SERVE 400 INDIVIDUALS IN THE FIRST YEAR AND 800 IN THE SECOND YEAR FOR A TOTAL OF 1,200 OVER THE GRANT FUNDING PERIOD.

RCA CCBHC EXPANSION

COMMUNITY CENTER FOR INTEGRATED HEALTH

BOSTON CERTIFIED COMMUNITY BEHAVIORAL HEALTH CENTER - THE BOSTON CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) WILL INCREASE ACCESS TO ROBUST CONTINUUM OF INTEGRATED BEHAVIORAL AND PHYSICAL HEALTH SERVICES FOR VULNERABLE POPULATIONS RESIDING IN BOSTON, MA. OUR POPULATION OF FOCUS WILL BE LOW-INCOME, UNINSURED AND UNDER-INSURED ADULTS WITH SERIOUS MENTAL ILLNESS (SMI), SUBSTANCE USE DISORDERS (SUDS), AND CO-OCCURRING DISORDERS (CODS), AND CHILDREN AND ADOLESCENTS WITH SERIOUS EMOTIONAL DISTURBANCE (SED). BOSTON'S CURRENT COMMUNITY-BASED BEHAVIORAL HEALTH (BH) CARE SYSTEM DOES NOT WORK WELL FOR THE CITY'S MOST VULNERABLE RESIDENTS, WHO FREQUENTLY CONTEND WITH THE OVERWHELMING CIRCUMSTANCES OF LIVING IN POVERTY AND THE INSIDIOUS IMPACTS OF SOCIAL DETERMINANTS OF HEALTH. AS SUCH, THERE REMAIN SEVERAL GAPS IN CARE, SUCH AS A LACK OF 24/7 ACCESS TO URGENT BEHAVIORAL HEALTH SERVICES, INCLUDING PSYCHOPHARMACOLOGY; INSUFFICIENT PRIMARY CARE INTEGRATION; AND A LACK OF ON-SITE SERVICES FOR YOUTH WITH SED AND THEIR FAMILIES. BAY COVE HUMAN SERVICES, INC., IN PARTNERSHIP WITH BOSTON MEDICAL CENTER (BMC) AND BOSTON HEALTH CARE FOR THE HOMELESS PROGRAM (BHCHP), SEEKS TO FILL THOSE GAPS BY IMPLEMENTING AN ACCESSIBLE SYSTEM OF BH CARE PROVIDING CRISIS SERVICES, SAME-DAY TREATMENT, NAVIGATION, CARE COORDINATION, PSYCHOPHARMACOLOGY TREATMENT, INTEGRATED PRIMARY CARE, AND RECOVERY SUPPORTS. THIS SYSTEM WILL PROVIDE "TREATMENT ON DEMAND" FOR THOSE READY TO ENGAGE IN CARE THROUGH A "NO WRONG DOOR APPROACH" FACILITATED BY ENHANCED CARE NAVIGATION AND COORDINATION, AND INCREASE OUTREACH EFFORTS AND SUPPORTS FOR THOSE NOT YET READY TO ENGAGE IN CARE. THE GOALS OF THE PROJECT ARE: 1) TO EXPAND THE CAPACITY OF BAY COVE'S EXISTING BEHAVIORAL HEALTH URGENT CARE CENTER (BHUCC) TO PROVIDE 24/7 SCREENING, INITIAL ASSESSMENT, AND FACILITATED REFERRALS TO THE BOSTON CCBHC'S MULTIDISCIPLINARY TEAM; 2) TO DEVELOP AND IMPLEMENT THE INFRASTRUCTURE NECESSARY FOR BAY COVE TO BECOME A CCBHC; AND 3) TO EVALUATE THE BOSTON CCBHC ON SAMHSA AND OTHER QUALITY MEASURES WITH A VIEW TO SUSTAINABILITY. OUR MEASURABLE OBJECTIVES INCLUDE: ESTABLISHING PROTOCOLS AND DATA SHARING AGREEMENTS FOR COLLABORATION WITH BMC AND BHCHP; HIRING NEW BEHAVIORAL HEALTH PROFESSIONALS, INCLUDING CLINICIANS, PSYCHIATRISTS, AND COMMUNITY HEALTH WORKERS; IMPLEMENTING AN ON-SITE PRIMARY CARE CLINIC; INITIATING BASELINE AND FOLLOW-UP ADMINISTRATION OF NOMS TOOL AND STANDARDIZED MEASURES OF PSYCHIATRIC SYMPTOMS; AND COMPLETING QUARTERLY REPORTS AND ANNUAL OUTCOME EVALUATIONS. WE WILL ENROLL A MINIMUM OF 400 PARTICIPANTS A YEAR, FOR A TOTAL OF 800 CLIENTS THROUGHOUT THE LIFE OF THE PROJECT. THE PROCESS EVALUATION WILL ASSESS PROJECT IMPLEMENTATION IN RELATION TO TIMELINES ON STANDARDIZED MEASURES OF MENTAL HEALTH SYMPTOMS AND QUALITY OF LIFE, AS WELL AS ON NOMS MEASURES AND UTILIZATION OF ACUTE CARE SERVICES. ANNUALLY, THE EVALUATOR WILL INTERVIEW CCBHC STAFF AND ADVISORY BOARD MEMBERS TO YIELD QUALITATIVE DATA ON BARRIERS AND FACILITATORS AND PERCEIVED CHALLENGES, SUCCESSES, AND EFFECTIVENESS.

ONE STOP WELLNESS OF THE FINGER LAKES - THE ONE STOP WELLNESS OF THE FINGER LAKES THROUGH OF THE FINGER LAKES AREA COUNSELING AND RECOVERY AGENCY (FLACRA) IS AN ESTABLISHED AND ATTESTED CCBHC SEEKING TO ENGAGE IN THE IMPROVEMENT AND ADVANCEMENT ACTIVITIES TO ENHANCE AND EXPAND SERVICES AT THE CURRENT SITES YATES AND ONTARIO COUNTIES. THE POPULATION(S) OF FOCUS FOR THIS PROJECT IS ADULTS, YOUTH AND CHILDREN WITH A SMI, SED, SUD OR COD, PRIMARILY LOW-INCOME/MEDICAID RECIPIENTS. THE PROJECT WILL CONTINUE, ENHANCE AND EXPAND COMPREHENSIVE CCBHC SERVICES DIRECTLY AND THROUGH DESIGNATED COLLABORATING ORGANIZATIONS AND PARTNERING PROVIDERS. THE KEY CONTEXTS FOR THE GOALS AND OBJECTIVES ARE THE CHARACTERISTICS OF THE POPULATION(S) OF FOCUS, THE SOCIO-ECONOMIC AND ENVIRONMENTAL FACTORS THAT SURROUND THESE POPULATIONS, DISPARITIES AND INEQUITY BROUGHT TO LIGHT DURING THE PANDEMIC AND THE RESULTING TRAUMA AND STRESSORS IMPACTING ON MENTAL WELLNESS AND USE OF SUBSTANCES, HIGHLIGHTING THE NEED FOR AN INTEGRATED, TRAUMA-INFORMED, RECOVERY-ORIENTED AND EQUITY FOCUSED APPROACH. THESE SERVICES WILL BE ENHANCED THROUGH THE ESTABLISHMENT AND EXPANSION OF SCHOOL-BASED SITES AND DEVELOPMENT EVIDENCE-BASED APPROACHES AND PRACTICES, SUCH AS APPLIED BEHAVIORAL ANALYSIS (ABA) TO SERVE THE COHORT OF CHILDREN AND YOUTH WITH SERIOUS BEHAVIORAL CONCERNS. THE ABILITY TO PROVIDE OFF-SITE SERVICES WILL ALLOW FOR SERVICES TO BE PROVIDED AT HOME OR AT ALTERNATIVE SITES, MEETING THE NEEDS OF STUDENTS ON OUT-OF-SCHOOL SUSPENSION DUE TO THEIR BEHAVIORS. THE ADDITION OF SCHOOL-BASED OUTPATIENT SERVICES IS EXPECTED TO SUPPORT SCHOOLS WITH EARLIER TREATMENT INTERVENTIONS AND LINKAGE TO RECOVERY SUPPORT SERVICES BEING MADE AVAILABLE BEFORE CONCERNS ESCALATE TO A LEVEL PROMPTING SUSPENSION. PARTNERSHIPS WILL BE FOSTERED FOR THE ESTABLISHMENT OF PRO-SOCIAL OPPORTUNITIES FOR YOUTH THROUGH RECOVERY CENTERS OR ALTERNATE SITES. FURTHER DEVELOPMENT OF STAFF KNOWLEDGE AND CAPACITY TO EXTRACT DATA FROM THE EHR AND OTHER SYSTEMS TO MAKE DATA-DRIVEN DECISIONS, IDENTIFY AND IMPROVE PRACTICE PATTERNS, DRIVE QUALITY AND PROMOTE AN INTERDISCIPLINARY TEAM APPROACH THROUGH INFORMATION SHARING WITHIN THE EHR WILL OCCUR. ADHERENCE TO SPARS AND NOMS REQUIREMENTS AND ACCURACY AND IDENTIFICATION OF DISPARITIES WILL BE AN AREA OF FOCUS. ADDITIONAL STAFF/CONSULTANT SUPPORT WILL BE NEEDED TO MONITOR FIDELITY TO EBP PRACTICES. A TOTAL OF 1,266 UNDUPLICATED AND 2,961 DUPLICATED (ACROSS GRANT YEARS) INDIVIDUALS WILL BE SERVED BY THE PROJECT OVER THE 4-YEAR PERIOD, YEAR 1: 593, YEAR 2: 682, YEAR 3: 784; YEAR 4: 902. FLACRA IS A NY STATE OFFICE OF MENTAL HEALTH (OMH) AND OFFICE OF ADDICTIONS SERVICES AND SUPPORTS (OASAS) LICENSED PROVIDER OF A RANGE OF SERVICES AT MULTIPLE SITES IN THE FINGER LAKES REGION OF NY, INCLUDING OUTPATIENT CLINICS, CRISIS OVERDOSE RESPONSE, STABILIZATION, DETOXIFICATION, RESIDENTIAL, RECOVERY SUPPORT, CARE MANAGEMENT AND HOME AND COMMUNITY-BASED SERVICES (HCBS). FLACRA IS INNOVATIVE AND THE AGENCY LEAD FOR FINGER LAKES AND SOUTHERN TIER BEHAVIORAL HEALTH CARE COLLABORATIVE (FLST BHCC/IPA) AND AN ACTIVE, FOUNDING MEMBER OF THE FINGER LAKES IPA (FLIPA). SERVICES WILL BE GROUNDED IN PERSON-CENTERED PLANNING APPROACHES, ATTENTION TO THE CULTURAL NORMS AND BELIEFS, AND TRAUMA-INFORMED PRACTICES. EVIDENCE-BASED PRACTICES AND APPROACHES WILL BE USED AS APPROPRIATE TO EACH INDIVIDUAL, INCLUDING MOTIVATIONAL INTERVIEWING, COGNITIVE BEHAVIORAL THERAPY, RATIONAL EMOTIVE BEHAVIOR THERAPY, SOLUTION FOCUSED THERAPY, MATRIX MODEL, SEEKING SAFETY, LIVING IN BALANCE, ABA AND CRAFT. CERTIFIED RECOVERY PEER ADVOCATES (CRPA) AND PEER SPECIALISTS (NYCPS) WILL BE EMBEDDED IN OUTPATIENT AND ALL IN-COMMUNITY AND CO-LOCATED LOCATIONS PROVIDING ADDITIONAL SUPPORT TO INDIVIDUALS AND FAMILIES.

SEE NOTICE OF AWARD, ATTACHMENT 1 - TERMS AND CONDITIONS, ATTACHMENT D, STATEMENT OF WORK, ABSTRACT.

RWJBARNABAS HEALTH SBIRT PROGRAM - THE RWJBARNABAS HEALTH (RWJBH) INSTITUTE FOR PREVENTION AND RECOVERY (IFPR) WILL IMPLEMENT THE SAMHSA FY 2021 SCREENING, BRIEF INTERVENTION AND REFERRAL TO TREATMENT (SBIRT) PROJECT TO PROVIDE SBIRT SERVICES FOR RWJBH PATIENTS AGES 12 AND OLDER AND TO EXPAND AND ENHANCE THE CONTINUUM OF CARE FOR SUBSTANCE USE DISORDER (SUD) SERVICES. NEW JERSEY HAS STRUGGLED WITH THE SUBSTANCE USE CRISIS IN THE LAST DECADE, WITH A 125.0% INCREASE IN THE NUMBER OF DRUG OVERDOSE DEATHS FROM 2013 TO 2018. RWJBH'S CATCHMENT AREA PRIMARILY CONSISTS OF URBAN AND SUBURBAN LOCALES IN NEW JERSEY. IT IS RACIALLY AND ETHNICALLY DIVERSE, WITH LESS THAN HALF (48.4%) OF THE POPULATION BEING NON-HISPANIC WHITE. APPROXIMATELY ONE-QUARTER (22.7%) OF THE POPULATION IS HISPANIC/LATINO, 15.2% IS BLACK OR AFRICAN-AMERICAN, AND 11.0% IS ASIAN. THE GOALS OF THE SBIRT PROGRAM ARE TO: 1) INSTITUTE A COMPREHENSIVE EDUCATION AND TRAINING PROGRAM TO EDUCATE CLINICAL STAFF ON PROTOCOLS AND BEST PRACTICES OF SBIRT; 2) INCREASE SCREENING AND BRIEF INTERVENTIONS FOR INDIVIDUALS WITH SUD AND THOSE AT RISK FOR DEVELOPING SUD ; 3) EVALUATE THE IMPACT OF SBIRT IN THE EMERGENCY DEPARTMENT, INPATIENT, AND OUTPATIENT SETTINGS ON PATIENT AND SYSTEM OUTCOMES; AND 4) CREATE A SUSTAINABLE SBIRT IMPLEMENTATION PROJECT FOR THE EMERGENCY DEPARTMENT, INPATIENT, AND OUTPATIENT SETTINGS. THE PROJECT WILL UTILIZE FIVE EVIDENCE-BASED PRACTICES-SBIRT, SBIRT TRAINING OF TRAINERS, HILTON ADOLESCENT SBIRT, SBIRT-MOBILE HEALTH AND TELEHEALTH INTERVENTIONS, AND SYSTEMS-LEVEL IMPLEMENTATION OF SBIRT-TO EFFECTIVELY ASSESS AND INTERVENE WITH PATIENTS DISPLAYING MODERATE TO HIGH RISK BEHAVIORS FOR SUD. THE PROJECT PROPOSES TO SERVE 2,250,000 UNDUPLICATED INDIVIDUALS IN YEAR 1, 2,500,000 UNDUPLICATED INDIVIDUALS IN YEAR 2, 3,000,000 UNDUPLICATED INDIVIDUALS IN YEAR 3, 3,000,000 UNDUPLICATED INDIVIDUALS IN YEAR 4, AND 3,000,000 UNDUPLICATED INDIVIDUALS IN YEAR 5. 3,000,000 UNDUPLICATED INDIVIDUALS WILL BE SERVED OVER THE ENTIRE PROJECT PERIOD. THE PROJECT WILL MEASURE PROGRESS TOWARDS GOALS AND OBJECTIVES BY UTILIZING RWJBH'S SHARED ELECTRONIC HEALTH RECORD, THE GPRA TOOL, AND A PARTNERSHIP WITH RTI INTERNATIONAL, WHICH HAS CONDUCTED THREE NATIONAL CROSS-SITE EVALUATION OF SAMHSA'S SBIRT PROGRAM OVER THE LAST TWO DECADES AND WILL SERVE AS THE PROJECT'S EVALUATOR.

COUNTERMEASURES FOR BIOTERROISM TARGETING CELLULAR HOST FACTORS

ROLES OF AN APP-BINDING PRO-APOPTOTIC PROTEIN IN MEDIATING NEURONAL CELL DEATH

DEFINING CHROMOSTASIS - A CANDIDATE REGULATOR OF HEALTHY AGING AND LONGEVITY

NEUROTENSIN 1 ALLOSTERIC MODULATOR FOR THE TREATMENT OF PAIN - PROJECT SUMMARY THE NIH HEAL INITIATIVE AIMS TO TACKLE TWO ONGOING HEALTH CARE CRISES: OPIOID USE DISORDER AND UNCONTROLLED PAIN. PHARMACOLOGICAL APPROACHES TARGETING BOTH CRISES ARE URGENTLY NEEDED. THE NEUROTENSIN RECEPTOR 1 (NTR1) HAS BEEN A SOUGHT-AFTER TARGET FOR THE TREATMENT OF BOTH PAIN AND ADDICTION, BUT DEVELOPMENT OF BALANCED NTR1 AGONISTS IS PRECLUDED BY THEIR SEVERE SIDE EFFECTS. AS A G PROTEIN-COUPLED RECEPTOR (GPCR) NTR1 SIGNALS THROUGH THE ACTIVATION OF G PROTEINS AND Β-ARRESTINS (E.G., ARRB2). ARRB2 ATTENUATES DRUG REWARD AND SUPPRESSES PAIN VIA REGULATION OF BOTH GPCRS AND NON-GPCRS, INCLUDING THE NMDA RECEPTOR. WE HAVE DEMONSTRATED IN RODENTS THAT SBI-553, A NOVEL ARRB2-BIASED ALLOSTERIC MODULATOR (BAM) OF NTR1, ATTENUATES OPIOID REWARD AND THE REINFORCING EFFECTS OF PSYCHOSTIMULANTS WITHOUT THE SIDE EFFECTS CHARACTERISTIC OF BALANCED NTR1 SIGNALING. CRYO- EM STUDIES DEMONSTRATE THAT SBI-553 BINDS AT AN INTRACELLULAR ALLOSTERIC SITE AND ACTS LIKE A MOLECULAR GLUE, DIRECTING SIGNALING TO ARRB2 IN THE PRESENCE OR ABSENCE OF AGONISTS. RECENTLY WE HAVE SHOWN THAT NTR1 BAMS PRODUCE POTENT ANTINOCICEPTION IN RODENT MODELS, A FINDING THAT BUILDS OFF PREVIOUS REPORTS THAT NEUROTENSIN, NTR1’S ENDOGENOUS LIGAND PROVIDED MORE POTENT PAIN RELIEF THAN MORPHINE THROUGH A MECHANISM THAT IS INDEPENDENT OF OPIOID RECEPTORS. NTR1 BAMS RAISE NOCICEPTIVE THRESHOLDS IN WILD-TYPE MICE, BUT NOT IN NTSR1−/−OR ARRB2−/− (KNOCKOUT) MICE, CONFIRMING THE MECHANISTIC REQUIREMENT FOR NTR1 AND ARRB2. LOCAL OR SYSTEMIC DELIVERY OF NTR1 BAMS REDUCED HYPERSENSITIVITY IN MOUSE MODELS OF POSTOPERATIVE AND NEUROPATHIC PAIN AND SUPPRESSED EXCITATORY SYNAPTIC TRANSMISSION AND NMDAR/ERK SIGNALING IN SPINAL CORD NOCICEPTIVE NEURONS. ADDITIONALLY, NTR1 BAMS SUPPRESSED C-FIBER-INDUCED RESPONSES IN VIVO AND ACTION POTENTIAL FIRING IN MOUSE AND HUMAN NOCICEPTIVE SENSORY NEURONS IN VITRO. COLLECTIVELY, OUR FINDINGS INDICATE THAT NTR1 BAMS ARE AN EXCITING AND NOVEL APPROACH TO DEVELOP A FIRST-IN-CLASS NON-OPIOID DRUG FOR THE TREATMENT OF PAIN. IN THIS APPLICATION WE OUTLINE OUR PLAN TO OPTIMIZE AND DEVELOP SUCH A DRUG FOR POSTOPERATIVE PAIN. IN THE UG3 STAGE, WE WILL LEVERAGE THE STRUCTURE ACTIVITY RELATIONSHIPS DEVELOPED AROUND SBI-553 AND, THROUGH A STRUCTURE-BASED DESIGN LEAD OPTIMIZATION PROCESS, REFINE AND IMPROVE THE PROPERTIES OF THE LEADS. CO-STRUCTURES OF LEADS WITH NTR1 WILL BE DETERMINED THROUGH CRYOEM, SUCH THAT THE ITERATIVE MEDICINAL CHEMISTRY, DESIGN-MAKE-TEST CYCLE IS INFORMED BY COMPUTATIONAL PREDICTIONS USING BOTH ARTIFICIAL INTELLIGENCE AND STRUCTURE-BASED DRUG DESIGN. IN THE UH3 PHASE THE OBJECTIVE IS TO DERIVE ADVANCED LEADS WITH EXCELLENT IN VIVO POTENCY IN ACUTE INFLAMMATORY PAIN, SURGICAL PAIN, AND CHRONIC NEUROPATHIC PAIN MODELS, OUTSTANDING DRUG-LIKE PROPERTIES, AND NO LIMITING CV OR CNS SAFETY RISK. IN THE UH3 PHASE, THE SELECTED CLINICAL CANDIDATE WILL BE SUBJECTED TO A STANDARD BATTERY OF REQUIRED IND-ENABLING STUDIES, LEADING TO AN INVESTIGATIONAL NEW DRUG APPLICATION (IND). UPON ACCEPTANCE OF THE IND, WE WILL CONDUCT A PHASE I, SINGLE ASCENDING DOSE STUDY IN HEALTHY VOLUNTEERS TO ASSESS THE SAFETY, TOLERABILITY AND PK OF OUR CLINICAL CANDIDATE.

SURVIVAL MECHANISMS FOR APOPTOTIC CASPASE

CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC AT VETERANS RECOVERY RESOURCES (CCBHC-VRR) - VETERANS RECOVERY RESOURCES (VRR) PROPOSES THE CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC AT VETERANS RECOVERY RESOURCES (CCBHC-VRR) PROJECT TO EXPAND ITS EVIDENCE-BASED MENTAL HEALTH (MH) AND SUD SERVICES TO INDIVIDUALS WITH SMI, SUD, OR COD ALONG WITH CHILDREN AND ADOLESCENTS WITH SED. VRR’S INTERDISCIPLINARY, TRAUMA-INFORMED AND PEER-INFUSED OUTPATIENT TREATMENT PROGRAM SERVES A VIBRANT AND DIVERSE COMMUNITY OF SERVICE MEMBERS, VETERANS, AND THEIR FAMILIES (SMVF) AS WELL AS NON-VETERANS, FIRST RESPONDERS, AND OTHER UNDER-SERVED POPULATIONS IN SOUTHWEST ALABAMA. BY THE END OF THE GRANT PERIOD, VRR WILL PROVIDE WHOLE-PERSON, WHOLE-FAMILY, AND COMMUNITY-BASED CCBHC SERVICES TO 700 UNDUPLICATED INDIVIDUALS IN MOBILE AND BALDWIN COUNTIES (A HEALTH RESOURCES AND SERVICES ADMINISTRATION IDENTIFIED HIGH-NEED AREA) AND BE POISED TO SUSTAIN CCBHC SERVICES IN THE FUTURE. IN ALIGNMENT WITH NEEDS OF THE FOCUS POPULATIONS, PROJECT GOALS INCLUDE: (1) INCREASING TIMELY ACCESS TO ALL CCBHC SERVICES; (2) INCREASING ACCESS TO INTEGRATED MH/SUD TREATMENT WITH PRIMARY CARE SERVICES BY CO-LOCATING AND INTEGRATING SERVICES; (3) ENSURING QUALITY CARE BY PROVIDING EBP EDUCATION AND TRAINING TO STAFF AND MONITORING USE OF EBPS, AND (4) EXPANDING PEER SUPPORT AND COMMUNITY INTEGRATION INTO EVIDENCE-BASED, INTEGRATED PRIMARY CARE. OBJECTIVES TO SUPPORT GOAL 1 INCLUDE PROVIDING ALL REQUIRED CCBHC SERVICES TO FOCUS POPULATIONS; PROVIDING ASSISTED OUTPATIENT TREATMENT (AOT); CONDUCTING EVIDENCE-BASED, AGE-APPROPRIATE SCREENING FOR SUICIDE RISK, DEPRESSION, AND SUD FOR ALL CCBHC ADULTS AND ADOLESCENTS DURING INITIAL INTAKE; ESTABLISHING AN EVIDENCE-BASED PROTOCOL AND FREQUENCY INTERVALS FOR RE-SCREENING CLIENTS, AND IMPLEMENTING AGE-APPROPRIATE SCREENING, BRIEF INTERVENTION AND REFERRAL TO TREATMENT (SBIRT) FOR ALL CCBHC CLIENTS. OBJECTIVES TO SUPPORT GOAL 2 INCLUDE ESTABLISHING A PARTNERSHIP WITH A PEDIATRIC CLINIC TO PROVIDE PEDIATRIC PRIMARY CARE; ENGAGING A LOCAL EMERGENCY DEPARTMENTS (ED) TO LOCATE PEER SUPPORT SPECIALISTS WITHIN THE CARE SETTING; PROVIDING AGE-APPROPRIATE UNIVERSAL SCREENING FOR OVERWEIGHT/OBESITY AND TOBACCO USE TO ALL CCBHC CLIENTS. OBJECTIVES TO SUPPORT GOAL 3 INCLUDE PROVIDING EDUCATION AND TRAINING TO ALL CCBHC-VRR CLINICAL STAFF ON ACCEPTANCE AND COMMITMENT THERAPY (ACT), PRINCIPLES OF TRAUMA-INFORMED CARE, OTHER EBPS, AND THE FOUNDATIONAL BUILDING BLOCKS OF OUR UNIQUE MODEL SUCH THAT 100% OF VRR CLINICAL STAFF WILL REPORT USE OF AT LEAST TWO EBPS IN YEAR 1, AS MEASURED THROUGH A SEMI-ANNUAL SURVEY. OBJECTIVES TO SUPPORT GOAL 4 INCLUDE CONDUCTING A NEEDS ASSESSMENT USING A COMMUNITY-BASED PARTICIPATORY ACTION RESEARCH APPROACH TO IMPROVE THE QUALITY OF LIVES FOR YOUTH VIA DESIGNING A PEER-TO-PEER PROGRAM FOR YOUTH AND ADVANCING INTEGRATION BETWEEN VRR AND THE COMMUNITY; CREATING A COMMUNITY-INTEGRATION ADVISORY BOARD WITH MEMBERS FROM COMMUNITY-BASED, FAITH-BASED, AND SOCIAL SUPPORT ORGANIZATIONS TO CREATE AN ACTION PLAN FOR VRR COMMUNITY PARTNERSHIPS AND PURSUING A PARTNERSHIP WITH THE JUVENILE COURT SYSTEM TO PLACE A PEER SUPPORT SPECIALIST IN THE COURT SYSTEM TO CONNECT JUVENILES AND FAMILIES TO CCBHC AND OTHER COMMUNITY-BASED SERVICES.

TARGETED NANOPARTICLES FOR BREAST CANCER DIAGNOSIS AND THERAPY

NATIONAL PEER RUN TRAINING AND TECHNICAL ASSISTANCE CENTER FOR ADDICTION RECOVERY SUPPORT - ONE WORLD RECOVERY NETWORK (OWRN), A PEER-LED, BLACK-LED, WOMAN-LED RECOVERY COMMUNITY ORGANIZATION (RCO), WILL COORDINATE A NATIONAL PEER-RUN TRAINING AND TECHNICAL ASSISTANCE CENTER FOR ADDICTION RECOVERY SUPPORT (CARS) WITH EFFORTS DRIVEN BY A NATIONAL STEERING COMMITTEE COMPOSED OF PERSONS WITH LIVED EXPERIENCE IN RECOVERY FROM SUBSTANCE USE DISORDERS. CARS AIMS TO PLAY A LEADING ROLE IN SUCCESSFULLY INTEGRATING RECOVERY SUPPORT SERVICES INTO A MYRIAD OF TRADITIONAL AND NON-TRADITIONAL ORGANIZATIONAL AND COMMUNITY SETTINGS AND BUILDING LEADERSHIP AND CAPACITY TO IMPLEMENT RECOVERY SUPPORT SERVICES IN UNDERSERVED AND HISTORICALLY EXCLUDED COMMUNITIES. OWRN WILL COLLABORATE WITH SIX SUPPORTING ORGANIZATIONS FROM THE CURRENT PEER RECOVERY CENTER OF EXCELLENCE WITH DEEP EXPERTISE AND EXPERIENCE IN TRAINING AND TECHNICAL ASSISTANCE (TTA) DELIVERY AND RECOVERY SUPPORT SERVICES TO IMPLEMENT THE PROJECT: THE UNIVERSITY OF MISSOURI KANSAS CITY, THE UNIVERSITY OF WISCONSIN, THE UNIVERSITY OF TEXAS, THE NATIONAL COUNCIL FOR BEHAVIORAL HEALTH, THE ASSOCIATION FOR RECOVERY SCHOOLS, AND THE ASSOCIATION OF RECOVERY IN HIGHER EDUCATION. SUPPORTING ORGANIZATIONS WILL ALSO MENTOR & BUILD THE CAPACITY OF RCOS AND PEER-RUN ORGANIZATIONS (PROS) WHO ALREADY PROVIDE LOCALIZED, TAILORED TTA IN THEIR GEOGRAPHIC AREAS. OWRN WILL ESTABLISH THESE RCOS/PROS AS REGIONAL RECOVERY HUBS TO PROVIDE CULTURALLY RELEVANT TTA & EXPAND THE ENGAGEMENT OF CARS AT THE GRASSROOTS LEVEL. LEVERAGING THE CAPACITY OF MULTIPLE INSTITUTIONS, THIS PEER-RUN CENTER WILL SERVE FOUR MAJOR GROUPS: A) PEER SUPPORT WORKERS AND NETWORKS, B) RCOS/PROS, C) STATE OFFICIALS, INCLUDING CERTIFICATION BOARDS AND SINGLE STATE AUTHORITIES, AND C) OTHER ORGANIZATIONS IN THE ECOSYSTEM OF RECOVERY. CARS ANTICIPATES SERVING 6,262 INDIVIDUALS OVER 5 YEARS (Y1-1,000; Y2-1,248; Y3-1,298; Y4-1,348; AND Y5-1,368) AND WILL COLLECT PERFORMANCE MEASURES THROUGH SAMHSA’S GOVERNMENT PERFORMANCE AND RESULTS ACT (GPRA) AS WELL AS OUTCOME AND PROCESS EVALUATIONS. PROPOSED ACTIVITIES WILL ADDRESS THREE MAJOR SERVICE GAPS: 1) THE DEARTH OF INFRASTRUCTURE AND RESOURCES FOR ROBUST PEER WORKFORCE DEVELOPMENT; 2) THE NEED TO BUILD RECOVERY-RICH COMMUNITIES ACROSS MYRIAD SERVICE SETTINGS AND PURPOSE-FOCUSED SETTINGS; AND 4) THE SHORTAGE OF MECHANISMS TO DISSEMINATE EXISTING AND FUTURE RECOVERY SUPPORT EVIDENCE-BASED PRACTICES. FOUR GOALS FOR ADDRESSING THESE GAPS ARE: 1) TO ENHANCE THE CAPACITY & EFFECTIVENESS OF THE GENERAL PEER WORKFORCE BY DEVELOPING & PROVIDING TARGETED TTA IN PEER SUPPORT CERTIFICATION, DIGITAL RECOVERY, & COMPREHENSIVE PROFESSIONAL SUPPORT INCLUDING FINANCING, SUPERVISION, WORKPLACE CULTURE, & CAREER DEVELOPMENT; 2) TO PROMOTE COMPREHENSIVE RECOVERY SOLUTIONS ACROSS VARIOUS SERVICE SETTINGS BY DEVELOPING & PROVIDING SPECIALIZED TTA FOR COURT, CORRECTIONS, & RE-ENTRY PROGRAMS, CLINICAL TREATMENT, RECOVERY HOUSING, & RCOS/PROS; 3) TO FOSTER & SUPPORT RECOVERY IN PURPOSE-FOCUSED ENVIRONMENTS BY DEVELOPING & PROVIDING SPECIALIZED TTA FOR RECOVERY-READY WORKPLACES, RECOVERY IN HIGHER EDUCATION, & RECOVERY IN HIGH SCHOOLS; AND 4) TO STRENGTHEN THE FOUNDATION OF RECOVERY PRACTICES BY PROVIDING COMPREHENSIVE TTA THAT SUPPORTS BOTH RESEARCH-BASED EVIDENCE & PRACTICE-BASED RESEARCH ACROSS THE CORE TOPIC AREA. KEY ACTIVITIES WILL INCLUDE CONDUCTING CAPACITY/NEEDS ASSESSMENTS AND ENVIRONMENTAL SCANS; DEVELOP AND MAINTAIN A WEB-BASED RESOURCE LIBRARY; PROVIDING TTA TO REQUESTERS; CREATE AND DISSEMINATE TOOLKITS, CURRICULA, PODCASTS, ONLINE COURSES, AND OTHER RESOURCES; HOST WEBINARS, POLICY ACADEMIES, AND OTHER IN-PERSON AND VIRTUAL EDUCATIONAL AND LEADERSHIP DEVELOPMENT EVENTS.

STARK COUNTY SYSTEM OF CARE EXPANSION & SUSTAINABILITY PROJECT

HVEM-BTLA SYSTEM IN INFLAMMATION

ANTI-HERPESVIRUS SIGNALING BY LTALPHABETA/LIGHT CYTOKINES

COMPARATIVE RESISTOMICS OF GRAM-NEGATIVE BACTERIAL PATHOGENS - ABSTRACT INCREASING ANTIBIOTIC RESISTANCE NECESSITATES EXPANDING RESEARCH INTO THE MECHANISMS BY WHICH BACTERIAL PATHOGENS ACQUIRE AND PERPETUATE DRUG RESISTANCE. DESPITE RAPIDLY EXPANDING GENOMIC MAPPING OF RESISTANCE-CONFERRING MUTATIONS IN CLINICAL ISOLATES AND LABORATORY STUDIES, OUR KNOWLEDGE OF DYNAMICS AND MECHANISMS UNDERLYING EVOLUTION OF ANTIMICROBIAL RESISTANCE IS STILL INSUFFICIENT. TO FILL-IN THIS GAP, THE AUTHORS OF THIS PROPOSAL COMBINE EXPERIMENTAL EVOLUTION IN A CONTINUOUS CULTURING DEVICE, MORBIDOSTAT, WITH TIME- RESOLVED ULTRADEEP GENOMIC SEQUENCING OF EVOLVING BACTERIAL CULTURES. THE UTILITY OF THE DEVELOPED MORBIDOSTAT-BASED WORKFLOW IS SUPPORTED BY PUBLISHED AND ONGOING STUDIES WITH ESTABLISHED ANTIMICROBIALS AND EXPERIMENTAL DRUG CANDIDATES. THE PRELIMINARY RESULTS OF COMPARATIVE RESISTOMICS STUDIES OVER A RANGE OF GRAM-NEGATIVE BACTERIAL SPECIES PROVIDED INITIAL SUPPORT TO A PREMISE THAT EVOLUTION OF DRUG RESISTANCE IN MORBIDOSTAT PROCEEDS VIA A LIMITED SET OF TRAJECTORIES DEFINED BY A COMBINATION OF RESISTANCE AND FITNESS CONSTRAINS APPROXIMATING CLINICAL EVOLUTION, WHICH FAVORS SELECTION OF LOW-FREQUENCY/HIGH-FITNESS OVER HIGH- FREQUENCY/LOW-FITNESS MUTANTS. A COMPARATIVE RESISTOMICS APPROACH ENABLES MAPPING OF BOTH UNIVERSAL AND STRAIN-SPECIFIC MECHANISMS AS DEMONSTRATED IN A RECENT PROOF-OF-CONCEPT STUDY ON EXPERIMENTAL EVOLUTION OF CIPROFLOXACIN RESISTANCE IN THREE GRAM-NEGATIVE BACTERIA. THE PROPOSED 5-YEAR PROJECT WILL TEST THE CENTRAL HYPOTHESIS AND EXTEND EXPLORATION OF ANTIMICROBIAL RESISTOME BY PURSUING THE FOLLOWING SPECIFIC AIMS: (I) IN AIM 1, THE ESTABLISHED MORBIDOSTAT-BASED WORKFLOW WILL BE USED TO DETERMINE MAJOR MECHANISMS DRIVING RESISTANCE TO BROAD-SPECTRUM CLINICAL ANTIBIOTICS, CIPROFLOXACIN, COLISTIN, TIGECYCLINE AND MEROPENEM, IN FOUR DIFFICULT-TO-TREAT GRAM-NEGATIVE BACTERIAL PATHOGENS, ACINETOBACTER BAUMANNII ATCC17978, P. AERUGINOSA ATCC27853, E. COLI ATCC25922, AND K. PNEUMONIAE ATCC13883; (II) IN AIM 2, A REPRESENTATIVE PANEL OF SELECTED CLONES WILL BE SYSTEMATICALLY CHARACTERIZED TO ASSESS THE EFFECTS OF INDIVIDUAL MUTATIONS AND COMBINATIONS THEREOF ON ACQUIRED RESISTANCE AND FITNESS; (III) AIM 3 WILL LEVERAGE A MORIBIDOSTAT-BASED WORKFLOW TO MAKE FIRST STEPS TOWARD EXPERIMENTAL EVOLUTION OF MULTIDRUG RESISTANCE FOCUSING ON A. BAUMANNII AND STARTING FROM CLONES SELECTED IN SINGLE-DRUG EVOLUTION STUDIES. THE RESULTS THAT WILL BE OBTAINED IN ALL PLANNED STUDIES WILL BE A SUBJECT OF IN-DEPTH BIOINFORMATICS ANALYSIS (INCLUDING COMPARISON WITH PUBLIC DATA FOR CLINICAL ISOLATES), PREDICTIVE MODELING, INTEGRATION AND SHARING WITH BROAD RESEARCH COMMUNITY VIA A SPECIALIZED WEB-SITE ON INTEGRATIVE GENOMICS OF EVOLUTION OF ANTIMICROBIAL RESISTANCE (IGEAR). THE PROPOSED STUDY IS EXPECTED TO HAVE TRANSLATIONAL IMPACTS IN ADVANCING METHODOLOGY TO SUPPORT RATIONAL OPTIMIZATION OF ANTIBIOTIC TREATMENT REGIMENS AND DEVELOPMENT OF NEW DRUGS WITH MINIMIZED RESISTIBILITY.

COUNSELING & RECOVERY SERVICES OF OKLAHOMA CCBHC - COUNSELING & RECOVERY SERVICES OF OKLAHOMA (CRSOK) PROPOSES TO EXPAND ITS CURRENT SERVICES DELIVERY MODEL OF INTEGRATED CARE THROUGH THE CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) EXPANSION GRANT TO SERVE INDIVIDUALS WITH SERIOUS MENTAL HEALTH ILLNESS (SMI) OR SUBSTANCE USE (INCLUDING OPIOID) DISORDERS (SUD); CHILDREN WITH SERIOUS EMOTIONAL DISTURBANCES (SED); AND INDIVIDUALS WITH CO-OCCURRING DISORDERS (COD). CRSOK IS LICENSED BY THE STATE OF OKLAHOMA AS A MENTAL HEALTH (MH) AND SUBSTANCE USE DISORDER (SUD) TREATMENT FOR ADULTS, FAMILIES, AND CHILDREN IN TULSA COUNTY. THERE ARE SIGNIFICANT HEALTH DISPARITIES AMIDST TULSA RESIDENTS WITH UNMET BEHAVIORAL HEALTH NEEDS AND ONE OF THE HIGHEST RATES OF HOMELESSNESS IN THE STATE. CRSOK PROPOSES TO BUILD ON ITS SUBSTANTIAL EXISTING OPERATIONS TO PROVIDE ALL THE REQUIRED CCBHC ACTIVITIES THROUGH EXPANSION OF IN-HOUSE SERVICES AND OUR DCO PARTNERS. THIS WILL REQUIRE MINIMAL INVESTMENT IN INFRASTRUCTURE DEVELOPMENT WITH MOST OF OUR INVESTMENT GOING TOWARD RESOURCES THAT WILL PROVIDE DIRECT SERVICES TO OUR CLIENTS AND EXPAND OUR CARE COORDINATION CAPACITY. THE FOCUS OF OUR PROPOSED PROJECT IS TO INCREASE CLIENT WELLNESS, CARE COORDINATION, AND EXPANDED ACCESS, CONSISTENT WITH THE CCBHC MODEL. OUR SELECTED OBJECTIVES ALIGN WITH OUR FOUR STATED GOALS: 1) EXPAND CAPACITY FOR SCREENING AND MONITORING OF PHYSICAL HEALTH CONDITIONS, 2)IMPROVE CARE COORDINATION WITH PRIMARY CARE PARTNERS, 3) INCREASE TARGETED CASE MANAGEMENT CAPACITY AND SERVICES IN THE INDIVIDUAL PLACEMENT & SUPPORT AND HOUSING FIRST PROGRAMS, 4) INCREASE CLIENTS SERVED IN OUR SUD PROGRAM. CRSOK WILL CONTINUE TO USE EVIDENCE-BASED MODELS TO PROVIDE COMPREHENSIVE OUTPATIENT MH AND SUD DIAGNOSTIC AND TREATMENT PRACTICES. THE OBJECTIVES FOR THIS PROJECT WILL BE ACCOMPLISHED THROUGH THE FRAMEWORK PROVIDED BY THE CCBHC MODEL. IT WILL BE LED BY EXPERIENCED AND QUALIFIED PERSONNEL OVERSEEN BY CRSOK'S SENIOR LEADERSHIP AND ADVISED BY OUR BOARD OF DIRECTORS; A REPRESENTATIVE SAMPLE OF THE INDIVIDUALS SERVED BY THE ORGANIZATION. CRSOK'S PLAN FOR SUSTAINABILITY IS TO SECURE THE PPS RATE AVAILABLE TO CCBHCS IN OKLAHOMA, A DEMONSTRATION STATE. WE WILL MANAGE, MONITOR, AND APPLY OUR DATA COLLECTION AND PERFORMANCE MEASUREMENTS TO NOT ONLY MEET REPORTING REQUIREMENTS, BUT ALSO TO INFORM OUR BROADER PERFORMANCE ASSESSMENT AND CQI EFFORTS TO ENHANCE OUR PROGRAMS. AS A CCBHC, CRSOK WILL BE ABLE TO EXPAND MUCH NEEDED BEHAVIORAL HEALTH SERVICES, SCREENING AND MONITORING FOR PHYSICAL HEALTH ISSUES, EMPLOYMENT SUPPORT AND HOUSING SERVICES FOR TULSANS LIVING WITH MENTAL ILLNESS AND/OR SUBSTANCE USE DISORDERS. WE WILL DO THIS BY INVESTING IN DIRECT CARE SERVICES, PHYSICAL HEALTH SCREENING INFRASTRUCTURE AND COMMUNITY OUTREACH.

MOLECULAR MECHANISM OF BCL2-DEPENDENT APOPTOSIS

DACCO CERTIFIED CLINIC EXPANSION PROJECT (CCEP)

DEVELOPMENT OF SBI-553, AN ALLOSTERIC MODULATOR OF NTR1, FOR THE TREATMENT OF SUBSTANCE USE DISORDERS

PRECLINICAL DISCOVERY OF NOVEL FARNESYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND RELATED TAUOPATHIES - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) IS A FATAL DISEASE THAT CURRENTLY AFFLICTS ALMOST SIX MILLION AMERICANS. WITH AN AGING POPULATION, WE RISK A PUBLIC HEALTH CRISIS BY 2050, UNLESS EFFECTIVE TREATMENTS ARE IDENTIFIED. DESPITE EXTENSIVE RESEARCH, THERE ARE CURRENTLY NO DRUGS THAT SLOW OR ALTER THE COURSE OF DISEASE. AD IS DEFINED BY THE PRESENCE OF SS-AMYLOID (ASS) PLAQUES AND INTRANEURONAL TAU INCLUSIONS CALLED NEUROFIBRILLARY TANGLES (NFTS) IN THE BRAIN. DRUG CANDIDATES THAT REDUCE ASS PLAQUES HAVE NOT, YET, BEEN SHOWN TO HAVE CLINICAL BENEFIT, AND GROWING DATA SUGGESTS THAT IT MAY BE MORE IMPORTANT TO TARGET NFTS OVER ASS PLAQUES TO PREVENT COGNITIVE DECLINE. RECENTLY, THE MACROAUTOPHAGY-LYSOSOMAL PATHWAY OF PROTEIN DEGRADATION HAS EMERGED AS A COMPELLING TARGET FOR REDUCING PATHOGENIC TAU IN THE BRAIN. OUR HYPOTHESIS IS THAT INCREASING THE RATE OF TAU DEGRADATION WILL REDUCE TAU LEVELS AND STOP, OR GREATLY SLOW, THE RATE OF TAU AGGREGATION. WE RECENTLY DISCOVERED A NOVEL PATHWAY TO ACCOMPLISH THIS OBJECTIVE. INHIBITING THE FARNESYLATION OF RHES, A GTPASE PROTEIN IN THE RAS FAMILY, ACTIVATES THE LYSOSOME AND RESULTS IN THE SELECTIVE DEGRADATION OF PATHOLOGICAL TAU. CONFIRMATION OF THE THERAPEUTIC HYPOTHESIS WAS ACHIEVED BY ADMINISTERING A FARNESYLTRANSFERASE INHIBITOR (FTI) IN A MOUSE MODEL OF TAUOPATHY, WHICH REDUCED TAU PATHOLOGY AND ATTENUATED BEHAVIORAL ABNORMALITIES IN THE MICE. KNOWN FTIS ARE NOT SUITABLE FOR HUMAN DEVELOPMENT AS CNS DRUGS. OPTIMIZED FOR CANCER INDICATIONS, THEY ARE EFFICIENTLY PUMPED OUT OF THE BRAIN BY EFFLUX PROTEINS. WE PROPOSE A THREE-PRONGED APPROACH TO IDENTIFY CHEMICAL MATTER THAT CAN REACH PHARMACOLOGICALLY SIGNIFICANT AND DOSE-PROPORTIONAL BRAIN LEVELS. FOR TWO OF THE KNOWN INHIBITORS, L-778,123 AND LONAFARNIB, WE WILL MAKE STRATEGIC CHANGES TO THE STRUCTURES, ELIMINATING FUNCTIONAL GROUPS THAT SERVE AS RECOGNITION SUBSTRATES FOR THE EFFLUX PUMPS. CONCURRENTLY, WE WILL INITIATE A HIGH- THROUGHPUT SCREEN OF A CHEMICAL LIBRARY WITH CHEMICAL PROPERTIES CONSISTENT WITH KNOWN CNS DRUGS. AS A THIRD STEP, WE WILL ENGAGE IN A MULTI-MILLION COMPOUND ARTIFICIAL INTELLIGENCE-BASED VIRTUAL SCREEN WITH ATOMWISE TO IDENTIFY NOVEL FTIS. BY GENERATING X-RAY CO-CRYSTAL STRUCTURES OF THE MOST PROMISING HITS AND USING COMPUTER- AIDED DRUG DESIGN, WE PLAN TO ACCELERATE THE PROCESS OF HIT VALIDATION, LEAD DISCOVERY, AND OPTIMIZATION TO IDENTIFY SMALL MOLECULE DRUG CANDIDATES. WE WILL ADVANCE INHIBITORS TO AN IN VIVO PHARMACODYNAMIC MODEL AND SELECT COMPOUNDS WITH LINEAR PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) RELATIONSHIPS THAT CAN BE ADVANCED INTO THE CLINIC. THREE OF THE TOP COMPOUNDS WILL BE TESTED FOR EFFICACY IN A TAUOPATHY ANIMAL MODEL USING DOSES DERIVED FROM THE PK/PD RELATIONSHIP. SHORT-TERM STUDIES WILL IDENTIFY COMPOUNDS THAT REDUCE ALL PATHOGENIC TAU SPECIES. THE MOST EFFICACIOUS COMPOUND WILL BE MOVED INTO LONG-TERM DOSING STUDIES TO EVALUATE LIFE-SPAN EXTENSION AND REDUCTION IN NFT FORMATION.

THIS EDA INVESTMENT WILL LEVERAGE MANUFACTURING AND TECHNOLOGY-BASED ECONOMIC DEVELOPMENT IN CORYELL COUNTY, TEXAS. THE CITY OF COPPERAS COVE IS ADDRESSING THE LOCAL AND REGIONAL NEED FOR HIGH PAYING HIGH QUALITY JOBS BY IMPROVING WATER, SEWAGE, AND ROAD INFRASTRUCTURE TO DEVELOP TWO 22-ACRE SITES FOR INDUSTRIAL USE, SPECIFICALLY THE COMPUTER CHIP INDUSTRY. THE ECONOMIC IMPACT WILL PROVIDE STABLE WELL-PAYING JOBS TO THE RESIDENTS OF CORYELL COUNTY AS WELL AS ADDRESS THE LONGER-TERM INVESTMENTS NEEDED IN INFRASTRUCTURE TO ALLOW FOR MORE ROBUST DEVELOPMENT AND THE PRODUCTION OF NEEDED MICROPROCESSORS AND COMPUTER CHIPS IN THE DOMESTIC MARKET. THIS PROJECT WAS MADE POSSIBLE BY THE REGIONAL PLANNING EFFORTS LED BY THE DEVELOPMENT DISTRICT OF CENTRAL TEXAS. EDA FUNDS THE DEVELOPMENT DISTRICT OF CENTRAL TEXAS TO BRING TOGETHER THE PUBLIC AND PRIVATE SECTORS TO CREATE AN ECONOMIC DEVELOPMENT ROADMAP TO STRENGTHEN THE REGIONAL ECONOMY, SUPPORT PRIVATE CAPITAL INVESTMENT AND CREATE JOBS.

NORTHERN OHIO RECOVERY ASSOCIATION CCBHC (N-CCBHC) PROJECT - THE NORTHERN OHIO RECOVERY ASSOCIATION (NORA) PROPOSED NORA CCBHC (N-CCBHC) PROJECT WILL SIGNIFICANTLY EXPAND CAPACITY TO SERVE RESIDENTS OF CUYAHOGA COUNTY WITH SERIOUS MENTAL ILLNESS (SMI) OR SUBSTANCE USE DISORDERS (SUD), INCLUDING OPIOID USE DISORDERS; CHILDREN AND ADOLESCENTS WITH SERIOUS EMOTIONAL DISTURBANCE (SED); AND INDIVIDUALS WITH CO-OCCURRING MENTAL AND SUBSTANCE DISORDERS (COD). NORA WILL QUALIFY FOR CERTIFICATION AS A CCBHC. GRANT FUNDS WILL HELP NORA ADDRESS THE SIGNIFICANT SHORTFALL IN CAPACITY OF CUYAHOGA COUNTY’S BEHAVIORAL HEALTH SERVICES DELIVERY SYSTEM TO MEET THE NEEDS OF ITS MOST VULNERABLE CITIZENS WHOSE PLIGHT IS EXACERBATED BY THEIR RESIDENCE IN ONE OF THE MOST ECONOMICALLY DISTRESSED AREAS IN THE NATION. NORA WILL USE GRANT FUNDS TO ADDRESS THIS SITUATION BY EXPANDING ITS EXISTING SERVICE ARRAY TO INCLUDE SMI SERVICES, AS WELL AS SED SERVICES TARGETED TO DIFFERENT AGE LEVELS: YOUNG CHILDREN (AGES 0-6), SCHOOL AGE (AGES 6-12), AND ADOLESCENTS (AGES 12-17). THE N-CCBHC PROJECT WILL SERVE 355 UNDUPLICATED INDIVIDUALS IN YEAR 1 AND 360 IN YEAR TWO. NORA WILL SUBCONTRACT WITH THE NATIONAL COUNCIL FOR BEHAVIORAL HEALTH FOR TECHNICAL ASSISTANCE TO MEET ALL CCBHC CRITERIA BY THE 4TH MONTH SUBSEQUENT TO GRANT AWARD. NORA WILL ALSO CONTRACT WITH THE CENTER FOR EVIDENCE-BASED PRACTICES (CEBP) AT CASE WESTERN RESERVE UNIVERSITY (CWRU) TO PROVIDE TRAINING IN ASSERTIVE COMMUNITY TREATMENT (ACT) TO PROJECT STAFF TO SERVE THE SMI POPULATION. NORA WILL IMPLEMENT A CONTINUUM OF AGE-SPECIFIC DEVELOPMENTALLY APPROPRIATE EBPS FOR CHILDREN/ADOLESCENTS WITH SED. THE CENTER FOR INNOVATIVE PRACTICE (CIP), ALSO HOUSED AT CWRU, WILL TRAIN PROJECT STAFF IN INTEGRATED CO-OCCURRING TREATMENT (ICT), TO SERVE ADOLESCENTS (AGES 12-17). NORA WILL IMPLEMENT ALTERNATIVES FOR FAMILIES: A CBT TO TREAT CHILDREN, AGES 6-12, , AND EARLY PATHWAYS WILL BE DELIVERED TO CHILDREN, AGES 0 TO 6. SERVING AS DCOS WILL BE 1) FRONTLINE SERVICE, WHICH WILL PROVIDE CRISIS SERVICES AND THE VA NORTHEAST OHIO HEALTHCARE SYSTEM, WHICH WILL ACCEPT REFERRALS OF VETERANS FOR TREATMENT. PROJECT GOALS ARE: 1) ACHIEVE FULL COMPLIANCE WITH CCBHC STANDARDS; 2) EXPAND ACCESS TO BEHAVIORAL HEALTH SERVICES; 3) FILL IN IDENTIFIED GAPS IN PROFESSIONAL STAFF CAPACITY TO SERVE THE NEEDS OF THE TARGET POPULATIONS; 4) EXPAND PROGRAMMING TO SERVE NEW TREATMENT POPULATIONS; 5) PROVIDE CARE COORDINATION FOR EVERY INDIVIDUAL/FAMILY ASSESSED TO BENEFIT FROM THIS SERVICE; 6) IMPROVE PARTICIPANTS' MENTAL HEALTH; 7) DECREASE PARTICIPANTS’ SUBSTANCE USE, AND 9) FOSTER PARTICIPANT SATISFACTION WITH THEIR CARE.

SIGNAL TRANSDUCTION AND CELL DEATH REGULATION

CYCLIC EPHA4 PEPTIDE ANTAGONISTS FOR NEUROPROTECTION IN ALS

DESCRIPTION:THIS AGREEMENT PROVIDES FUNDING TO THE CITY OF GLEN COVE TO IMPLEMENT ITS PROJECT TO CONSTRUCT A PACKED TOWER AERATION SYSTEM (PTAS) FOR THE REMOVAL OF CONTAMINANTS IN ITS DRINKING WATER AS DIRECTED IN THE 2023 CONSOLIDATED APPROPRIATIONS ACT OR AS IDENTIFIED IN AN APPROVED TECHNICAL CORRECTION IF ONE HAS BEEN APPROVED FOR THIS PROJECT.ACTIVITIES:THE ACTIVITIES TO BE PERFORMED ARE CONSTRUCTION OF 2 PERMANENT PTAS FOR 3 WELLS, CONFIGURED ALONGSIDE GRANULAR ACTIVATED CARBON SYSTEMS. SUBRECIPIENT:NO SUBAWARDS ARE INCLUDED IN THIS ASSISTANCE AGREEMENT.OUTCOMES:THE ANTICIPATED DELIVERABLES ARE PTAS AND GAC SYSTEMS FOR 3 WELLS, WHICH ARE EXPECTED TO LEAD TO DECREASED CONTAMINATION OF THE DRINKING WATER FOR THE RESIDENTS OF GLEN COVE.

ER STRESS AND UPR IN NON-ALCOHOLIC STEATOHEPATITIS AND HEPATOCELLULAR CARCINOMA

IMPACT AID PROGRAM, TITLE VII, SECTION 7003

NOVEL ROLES FOR THE ALZHEIMER'S DISEASE (AD) RISK GENE, SORLA IN NEUROPROTECTION IN AD

CONTROL OF MUSCLE GENE EXPRESSION BY SIGNALING PATHWAYS

TARGETING NEUROINFLAMMATION IN AD WITH NOVEL CX3CR1 AGONISTS

LIGAND FUNCTIONAL SELECTIVITY IN EPHA2 RECEPTOR SIGNALING

DEVELOPMENT OF SMAC MIMETICS AS LATENCY-REVERSING AGENTS

BRAIN PATHOLOGY AND FUNCTION IN A CHRONIC MOUSE MODEL OF ZIKV TRANSMISSION

HEALTH CENTER PROGRAM

BLOOD TEST TO AID TREATMENT DECISIONS FOR PERINATAL ASPHYXIATION

COVE BEHAVIORAL HEALTH CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC IMPROVEMENT AND ADVANCEMENT - COVE BEHAVIORAL HEALTH, INC. (COVE) IS SEEKING A CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) IMPROVEMENT AND ENHANCEMENT GRANT. THIS GRANT WILL STRATEGICALLY ENHANCE COVE’S EXISTING ACHIEVEMENTS AND PARTNERSHIPS EXPERIENCED THROUGH THE ORIGINAL CCBHC AWARD TO INCREASE ACCESS TO AND IMPROVE THE QUALITY OF COMMUNITY BEHAVIORAL HEALTH TREATMENT. WE INTEND TO BUILD ON OUR EMERGING SUCCESS IN IDENTIFYING AND SERVING OUR POPULATION OF FOCUS – MINORITY INDIVIDUALS WITH CO-OCCURRING MENTAL HEALTH AND SUBSTANCE USE DISORDERS WITH SPECIFIC FOCUS ON THOSE WITH OPIOID USE DISORDERS, AS WELL AS ADOLESCENTS, YOUNG ADULTS, PREGNANT WOMEN, AND VETERANS WITH EMERGING MENTAL HEALTH AND SUBSTANCE USE ISSUES IN HILLSBOROUGH COUNTY, FLORIDA. OVER THE FOUR-YEAR FUNDING PERIOD, WE WILL IDENTIFY 4,000 PARTICIPANTS, SCREEN 3,000 PATIENTS FOR BEHAVIORAL HEALTH ISSUES USING OUR PATIENT PATHWAYS AND DIGITAL DOORWAY ESTABLISHED DURING OUR INITIAL CCBHC IMPLEMENTATION AND ENGAGE 2,250 PATIENTS FOR INDICATED TREATMENT AND CARE COORDINATION SERVICES. COVE HAS SERVED RESIDENTS OF HILLSBOROUGH COUNTY SINCE 1973 AND HAS ESTABLISHED STRONG COMMUNITY PARTNERSHIPS WITH OTHER PROVIDERS, SOCIAL SERVICE ORGANIZATIONS, SCHOOLS, FAITH-BASED ORGANIZATIONS, AND BUSINESSES. THROUGH THE YEARS OF COLLABORATION WITH OUR STAKEHOLDERS COVE HAS DEMONSTRATED THE ABILITY TO ENGAGE AND MAINTAIN PARTNERSHIPS AND HAS ACHIEVED A REPUTATION FOR EXCELLENCE IN THE FIELD OF BEHAVIORAL HEALTH. COVE LOOKS FORWARD TO USING THIS GRANT OPPORTUNITY TO IMPROVE AND ADVANCE OUR CCBHC.

CHARACTERIZING THE NUCLEAR PORE COMPLEX-T CELL RECEPTOR CONNECTION

DESCRIPTION:THIS AGREEMENT PROVIDES FUNDING FOR SEWER LINE EXTENSION FROM THE COVENTRY HIGH SCHOOL TO THE EXISTING SEWER CONVEYANCE SYSTEM IN ORDER TO DISCONTINUE DISCHARGING TO A FAILED SEPTIC SYSTEM AS DIRECTED IN THE 2024 CONSOLIDATED APPROPRIATIONS ACT OR AS IDENTIFIED IN AN APPROVED TECHNICAL CORRECTION IF ONE HAS BEEN APPROVED FOR THIS PROJECT. ACTIVITIES:THE ACTIVITIES TO BE PERFORMED INCLUDE THE EXECUTION AND IMPLEMENTATION OF A WASTEWATER INFRASTRUCTURE CONSTRUCTION PROJECT. WORKPLAN ACTIVITIES CONSIST OF EXTENDING SEWER LINE FROM THE COVENTRY HIGH SCHOOL TO THE EXISTING SEWER CONVEYANCE SYSTEM. SUBRECIPIENT:NO SUBAWARDS ARE INCLUDED IN THIS ASSISTANCE AGREEMENT.OUTCOMES:THE ANTICIPATED DELIVERABLES AND OUTCOME INCLUDE THE EXTENSION OF SEWER LINE AND CONNECTION TO EXISTING SEWER CONVEYANCE SYSTEM. THE INTENDED BENEFICIARIES INCLUDE THE RESIDENTS OF THE TOWN OF COVENTRY.

PLEKHA7 AND BETA-CATENIN INTERACT TO REGULATE MUTANT KRAS

ONE STOP WELLNESS OF THE FINGER LAKES

HEALTH CENTER PROGRAM

ROLE OF FBXW7-MEDIATED PROTEASOMAL DEGRADATION IN MYOFIBERS IN DETERMINING MUSCLE STEM CELL POOL SIZE

MECHANISMS OF INITATION OF SKELETAL MINERALIZATION

SOMATIC GENE RECOMBINATION OF MAPT IN SINGLE CELLS FROM FRONTOTEMPORAL LOBAR DEMENTIA (FTLD) BRAINS WITH TAU PATHOLOGY

MECHANISMS THAT COUPLE IRREGULAR DEVELOPMENT OF FETAL MELANOBLASTS TO PREMATURE EXHAUSTION OF ADULT MELANOCYTE STEM CELLS - PROJECT SUMMARY MAINTENANCE OF TISSUE FUNCTION DURING ADULTHOOD, AND HENCE SUPPRESSION OF TISSUE DEGENERATION AND DISEASE, DEPENDS ON MAINTENANCE OF STEM CELL POPULATIONS. ADULT STEM CELLS ARE EPIGENETICALLY PROGRAMMED AND A CULMINATION OF A SERIES OF DEVELOPMENTAL DECISIONS INITIATED IN THE EMBRYO. IN UTERO ENVIRONMENTAL EXPOSURES ON THE EMBRYO CAN INFLUENCE ADULT AND LATE-LIFE DISEASE, LIKELY IN PART VIA EFFECTS ON STEM CELL DEVELOPMENT THAT ARE TRANSMITTED TO MAINTENANCE AND FUNCTION OF STEM CELLS IN THE ADULT. HOWEVER, THE MOLECULAR LINKS BETWEEN EMBRYONIC DEVELOPMENT AND LONG-TERM MAINTENANCE OF STEM CELL FUNCTION AND PHENOTYPE IN ADULTS ARE POORLY DEFINED. WE WILL EMPLOY LINEAGE-SPECIFIC GENETIC INACTIVATION OF A HISTONE CHAPERONE TO UNDERSTAND HOW EMBRYONIC DEVELOPMENTAL INTEGRITY OF MELANOBLASTS (MB) IMPACTS ON MAINTENANCE ADULT MELANOCYTE (MC) STEM CELLS (MCSC). THE HISTONE CHAPERONE HIRA DEPOSITS HISTONE VARIANT H3.3 INTO ACTIVE GENES, PROMOTERS AND ENHANCERS. THROUGH IN VITRO AND IN VIVO STUDIES AND SINGLE CELL RNA-SEQ OF MOUSE EMBRYO MELANOBLASTS (MBS) FROM WILD TYPE MICE AND MICE LACKING EXPRESSION OF HIRA IN EMBRYONIC MBS, WE HAVE UNCOVERED A ROLE FOR HIRA IN SUSTAINING THE PAX3/SOX10-MITF MB SPECIFICATION PATHWAY. INACTIVATION OF HIRA IN MBS DEPLETES THE NUMBER OF MBS IN EARLY/MID STAGE EMBRYOS. HOWEVER, THIS EMBRYONIC DEFECT IS RESCUED BY BIRTH AND YOUNG MICE EXHIBIT NORMAL NUMBERS OF MELANOCYTIC CELLS, AND ONLY A VERY SUBTLE PIGMENTATION DEFECT. NEVERTHELESS, IN NEW-BORN MICE, HIRA KNOCK OUT (KO) MELANOCYTIC CELLS EXHIBIT A HIGHER FREQUENCY OF TELOMERE-ASSOCIATED DNA DAMAGE FOCI, INDICATING THAT HIRA KNOCK OUT MCSC AND/OR MELANOCYTES HARBOR MOLECULAR DAMAGE, EVEN IN NEW-BORN MICE. INDEED, MELANOBLASTS AND MELANOCYTES FROM NEW-BORN HIRA KO MICE RESPOND POORLY TO PRO-PROLIFERATIVE CHALLENGE IN VITRO AND IN VIVO, AND THESE MICE SHOW MARKED ACCELERATED MCSC AND MELANOCYTE DEPLETION AND DRAMATICALLY ACCELERATED HAIR GREYING DURING ADULTHOOD. BUILDING ON THESE EXTENSIVE PRELIMINARY DATA, WE WILL INVESTIGATE THE ROLE OF HIRA IN DIFFERENTIATION AND DEVELOPMENT OF THE MELANOCYTIC LINEAGE, AND INVESTIGATE THE LINKS BETWEEN ABNORMAL EMBRYONIC DEVELOPMENT AND ADULT STEM CELL DEPLETION DURING ADULTHOOD AND AGING. DYSREGULATION OF THE PAX3/SOX10-MITF SIGNALING PATHWAY CONTRIBUTES TO DEVELOPMENTAL DISORDERS AND MELANOMA. THESE STUDIES TO DEFINE HIRA'S ROLE IN THE PAX3/SOX10-MITF AXIS CAN PROMOTE THERAPEUTIC INTERVENTIONS TO COMBAT THESE DEVELOPMENTAL AND NEOPLASTIC DISORDERS. MOREOVER, COMPLETION OF THESE SPECIFIC AIMS WILL ADDRESS HOW THE INTEGRITY OF EMBRYONIC DEVELOPMENT OF TISSUE SPECIFIC STEM CELLS IMPACTS MAINTENANCE OF THOSE STEM CELLS DURING ADULTHOOD.

RURAL BEHAVIORAL HEALTH WORKFORCE COORDINATING CENTERS ? NORTHERN BORDER REGION

YOUTH HOMELESSNESS DEMONSTRATION PROGRAM

REGULATION OF ER STRESS-INDUCED CELL DEATH

IMPROVING PROINSULIN FOLDING TO AMELIORATE TYPE II DIABETES - PROJECT SUMMARY DIABETES IS AMONG THE FASTEST GROWING HEALTH CHALLENGES OF THE 21ST CENTURY, AFFECTING >30 MILLION PEOPLE, WITH =80,000 DEATHS ANNUALLY, AND INVOLVING ~15% OF U.S. NATIONAL HEALTH EXPENDITURES. TYPE 2 DIABETES (T2D) IS THE MOST COMMON FORM OF DIABETES, WHICH IS LINKED TO AN INSUFFICIENT AMOUNT OF CIRCULATING INSULIN BECAUSE OF THE BODY’S INSENSITIVITY TO THE HORMONE. MAINTENANCE OF THE INSULIN STORAGE POOL REQUIRES SYNTHESIS OF ~6000 PROINSULIN (PI) MOLECULES/SS-CELL/SECOND, EACH DELIVERED TO THE ENDOPLASMIC RETICULUM (ER) FOR FOLDING. EVEN MORE MOLECULES ARE NEEDED IN STATES OF INSULIN RESISTANCE. SIGNIFICANTLY, WE DISCOVERED THAT PI ENTERS ABERRANT DISULFIDE-LINKED INTERMOLECULAR COMPLEXES, EVEN IN HEALTHY (HUMAN AND MURINE) ISLETS. UNDER CONDITIONS THAT DEMAND INCREASED INSULIN PRODUCTION (EVEN PREDIABETES), THESE COMPLEXES DRAMATICALLY INCREASE, THUS LIMITING INSULIN PRODUCTION. WE SHOW NEW KEY EVIDENCE THAT THESE ABERRANTLY FOLDED PI COMPLEXES CAN BE RESOLVED TO MONOMERIC PI WITHIN THE ER. WE RECENTLY ELUCIDATED THE FIRST MAP OF THE HUMAN PI INTERACTOME IDENTIFYING PI FOLDING MODIFIERS. THE MOST SIGNIFICANT PI INTERACTOR IN HUMAN ISLETS IS THE ER CHAPERONE BIP AND WE PRESENT NEW EVIDENCE (BOTH GAIN OF FUNCTION, AND LOSS OF FUNCTION) THAT THIS INTERACTION, SUPPORTED BY BIP CO- CHAPERONES, IS ABSOLUTELY REQUIRED FOR PRODUCTIVE PROINSULIN FOLDING (AND LIMITING MISFOLDING), LEADING TO SUCCESSFUL ANTEROGRADE TRANSPORT. FOR OUR STUDIES WE GENERATED A NOVEL BIP-TAGGED MOUSE THAT CAN FOR THE FIRST TIME IDENTIFY FUNDAMENTAL STEPS IN PI FOLDING ESSENTIAL FOR INSULIN PRODUCTION. MOREOVER, WE SHOW THAT INCREASED EXPRESSION OF BIP AND ITS CO-CHAPERONE P58IPK DRAMATICALLY REDUCES ACCUMULATION OF THE HIGH MOLECULAR WEIGHT PI COMPLEXES. THUS, OUR DISCOVERIES OPEN THE POSSIBILITY THAT PHARMACOLOGIC INTERVENTION MAY IMPROVE CHAPERONE-DEPENDENT PI FOLDING, AND THIS MAY ATTENUATE T2D. AS WE BEGIN TO ELUCIDATE THE HUMAN PI FOLDING PATHWAY, WE ARE DEVELOPING PARALLEL ANIMAL MODELS TO DETERMINE HOW PI FOLDS/MISFOLDS. HERE WE PROPOSE TO: 1) MECHANISTICALLY DISSECT HOW BIP AND ADDITIONAL PI INTERACTORS IN THE ER ORCHESTRATE SUCCESSFUL PI FOLDING AND DETERMINE WHICH STEP(S) OF PI FOLDING GO AWRY IN T2D; 2) IDENTIFY HOW THE PI INTERACTOME CHANGES IN HUMAN T2D; DETERMINE THE FUNCTION OF ALTERED PI INTERACTIONS IN ISLETS FROM PATIENTS WITH T2D; AND UTILIZE NOVEL ASSAYS TO MEASURE PRODUCTIVE PI FOLDING/TRAFFICKING IN SS-CELLS. WE WILL INTEGRATE PHYSIOLOGIC STUDIES OF HUMAN ISLETS WITH NOVEL GENETIC AND BIOCHEMICAL APPROACHES TO GENERATE A COMPREHENSIVE UNDERSTANDING OF HOW PI FOLDING HOMEOSTASIS IMPACTS SS-CELL FUNCTION IN HEALTH AND DISEASE. WE BELIEVE THAT THIS HYPOTHESIS IS A HIGH-IMPACT IDEA ESSENTIAL TO THE MISSION OF THE NIDDK, AND WE NOW BRING TOOLS, ASSAYS, AND APPROACHES THAT ARE NOT CURRENTLY AVAILABLE ANYWHERE ELSE.

NG2-PG IN TUMOR VASCULARIZATION AND PROGRESSION

OVERRIDING THE IMMUNE EVASION TACTICS OF CORONAVIRUS

DISCOVERY OF SELECTIVE INHIBITORS FOR THE EPHA4 KINASE

VIRULENCE FACTORS AND CELL DEATH

DESCRIPTION:THIS AGREEMENT PROVIDES FUNDING TO DISCOVERY CLEAN WATER ALLIANCE IN WASHINGTON TO IMPLEMENT ITS PROJECT FOR SALMON CREEK WASTEWATER TREATMENT PLANT UPGRADES AS DIRECTED IN THE 2024 CONSOLIDATED APPROPRIATIONS ACT. ACTIVITIES:THE ACTIVITIES TO BE PERFORMED INCLUDE THE EXECUTION AND IMPLEMENTATION OF A WASTEWATER INFRASTRUCTURE CONSTRUCTION PROJECT. WORKPLAN ACTIVITIES CONSIST OF THE INSTALLATION OF A NEW ULTRAVIOLET (UV) DISINFECTION SYSTEM. SUBRECIPIENT:NO SUBAWARDS ARE INCLUDED IN THIS ASSISTANCE AGREEMENT.OUTCOMES:THE ANTICIPATED DELIVERABLES INCLUDE THE INSTALLATION OF TWO UV DISINFECTION CHANNELS AND INTEGRATION INTO THE EXISTING WASTEWATER TREATMENT SYSTEM. THE EXPECTED OUTCOMES INCLUDE IMPROVED WASTEWATER QUALITY, REDUCED ENERGY USE, REDUCED MAINTENANCE COSTS, AND INCREASED RELIABILITY. THE INTENDED BENEFICIARIES INCLUDE THE RESIDENTS OF CLARK COUNTY, WASHINGTON AS WELL AS THE GREATER ENVIRONMENT.

RWJBARNABAS HEALTH INSTITUTE FOR PREVENTION AND RECOVERY - MAT-PDOA - THE RWJBARNABAS HEALTH (RWJBH) INSTITUTE FOR PREVENTION AND RECOVERY (IFPR) WILL PARTNER WITH NEWARK BETH ISRAEL MEDICAL CENTER (NBIMC), CLARA MAASS MEDICAL CENTER (CMMC), RWJBH MEDICAL GROUP, INTEGRITY HOUSE, AND THE CENTER FOR GREAT EXPECTATIONS (CGE) TO IMPLEMENT SAMHSA FY 2022 MEDICATION-ASSISTED TREATMENT - PRESCRIPTION DRUG AND OPIOID ADDICTION (MAT-PDOA) TO EXPAND AND ENHANCE ACCESS TO MEDICATION FOR OPIOID USE DISORDER (MOUD) FOR PERSONS WITH AN OPIOID USE DISORDER (OUD) SEEKING OR RECEIVING MOUD. NBIMC AND CMMC PRIMARILY SERVE THE EASTERN AND SOUTHEASTERN PORTIONS OF ESSEX COUNTY, NEW JERSEY, WHICH IS COMPOSED OF URBAN COMMUNITIES AND SUBURBAN TOWNS. THIS AREA HAS DISPARITIES IN SOCIOECONOMIC STATUS, HEALTH STATUS, AND ACCESS TO SERVICES. ESSEX COUNTY HAS A LARGER PROPORTION OF AFRICAN-AMERICAN AND HISPANIC/LATINO RESIDENTS THAN NEW JERSEY AS A WHOLE-38.0% OF THE POPULATION IS NON-HISPANIC AFRICAN-AMERICAN AND 23.3% OF THE POPULATION IS HISPANIC OR LATINO, COMPARED TO 12.6% AND 20.4% STATEWIDE, RESPECTIVELY. NEW JERSEY HAS STRUGGLED WITH THE OPIOID OVERDOSE CRISIS IN THE PAST DECADE, WITH A 133.8% INCREASE IN DRUG OVERDOSE DEATHS FROM 2013 TO 2021. ESSEX COUNTY HAS BEEN PARTICULARLY AFFECTED, WITH A 208.3% INCREASE IN THE SAME TIMEFRAME. IN 2021, ESSEX COUNTY HAD 407 SUSPECTED OVERDOSE DEATHS, THE MOST IN THE STATE. IN THE SAME YEAR, PROVIDERS IN THE COUNTY WROTE 243,920 OPIOID PRESCRIPTIONS, AND LAW ENFORCEMENT AND EMERGENCY MEDICAL SERVICES ADMINISTERED NALOXONE 2,085 TIMES, A FOURFOLD INCREASE FROM 2015. IN 2020, ESSEX COUNTY HAD THE SECOND HIGHEST NUMBER OF RESIDENTS ADMITTED FOR TREATMENT FOR OPIOID USE. THE GOALS OF THE MAT-PDOA PROGRAM ARE TO: 1) INCREASE THE CAPACITY OF RWJBH STAFF TO PROVIDE MOUD IN COMBINATION WITH COMPREHENSIVE CLINICALLY APPROPRIATE SERVICES FOR INDIVIDUALS WITH OUD SEEKING OR RECEIVING MOUD IN THE EMERGENCY DEPARTMENT (ED), 2) INCREASE THE NUMBER OF INDIVIDUALS WITH OUD RECEIVING MOUD, AND 3) DECREASE ILLICIT OPIOID DRUG USE AND PRESCRIPTION OPIOID MISUSE AMONG INDIVIDUALS WITH OUD RECEIVING MOUD. THE PROJECT WILL UTILIZE THREE EVIDENCE-BASED PRACTICES (EBPS)-BUPRENORPHINE AS TREATMENT FOR OUD, THE EMERGENCY DEPARTMENT-INITIATED BUPRENORPHINE FOR OPIOID USE DISORDER (EMBED) CLINICAL DECISION SUPPORT (CDS) INTERVENTION, AND THE BRIDGE MODEL FOR BUPRENORPHINE INITIATION IN THE ED-TO INCREASE ED STAFF CAPACITY TO ASSESS PATIENTS WITH OUD AND PROVIDE MOUD, INCREASE THE NUMBER OF PATIENTS RECEIVING MOUD, AND IMPROVE PATIENT OUTCOMES. THE PROJECT PROPOSES TO SERVE 360 UNDUPLICATED INDIVIDUALS IN YEAR 1, 420 UNDUPLICATED INDIVIDUALS IN YEAR 2, 480 UNDUPLICATED INDIVIDUALS IN YEAR 3, 540 UNDUPLICATED INDIVIDUALS IN YEAR 4, AND 600 UNDUPLICATED INDIVIDUALS IN YEAR 5, TOTALING 2,400 UNDUPLICATED INDIVIDUALS SERVED OVER THE ENTIRE PROJECT PERIOD WITH GRANT FUNDS. THE PROJECT WILL MEASURE PROGRESS TOWARDS GOALS AND OBJECTIVES BY UTILIZING RWJBH'S ELECTRONIC HEALTH RECORD AND THE GPRA TOOL.

ALLEN COUNTY CHILDREN'S MENTAL HEALTH INITIATIVE - THE MENTAL HEALTH & RECOVERY SERVICES BOARD (MHRSB) OF ALLEN, AUGLAIZE & HARDIN COUNTIES, A GOVERNMENTAL ENTITY FORMED BY THE STATE OF OHIO, PROPOSES TO PARTNER WITH COLEMAN HEALTH SERVICES (CHS) AND OTHER BEHAVIORAL HEALTH PROVIDERS AND COMMUNITY ORGANIZATIONS WITHIN THE ALLEN COUNTY SYSTEM OF CARE TO IMPROVE OUTCOMES FOR 600 CHILDREN, YOUTH AND YOUNG ADULTS, AGES 0-21, WHO EXPERIENCE OR ARE AT RISK FOR SERIOUS EMOTIONAL DISORDERS (SED). THE TARGET POPULATION ARE AT-RISK YOUTH AND THEIR FAMILIES IN ALLEN COUNTY, OHIO, MANY OF WHOM WILL LIVE IN THE CITY OF LIMA, A SMALL RUSTBELT CITY WITH BIG CITY PROBLEMS, INCLUDING POVERTY, STRESSED SINGLE-PARENT FAMILIES, CONCENTRATION OF RACIAL MINORITIES, AND HIGH CRIME RATES, AS WELL AS A PERVASIVELY HIGH LEVEL OF VIOLENCE EXPERIENCED BY YOUTH. ALLEN COUNTY HAS SUFFERED HIGH RATES OF EARLY MORBIDITY AND RANKS #60 OF 88 OHIO COUNTIES ON PHYSICAL AND MENTAL HEALTH MEASURES. IN RECENT YEARS THE RESULTING TRAUMA AND POOR MENTAL HEALTH HAVE BECOME BEHAVIORALLY EXPRESSED THROUGH CHILD-TO-PARENT DOMESTIC VIOLENCE. PARENTS OR CAREGIVERS IN THIS CONSERVATIVE SOCIOPOLITICAL CULTURE, HAVE TRADITIONALLY TURNED TO LAW ENFORCEMENT AT CRISIS POINTS TO DE-ESCALATE FAMILY CONFLICT AND MITIGATE THEIR CHILD'S BAD BEHAVIOR. IN RESPONSE TO RISING NUMBERS OF CHILDREN AS YOUNG AS AGE 7 BEING ARRESTED, DETAINED AND CHARGED WITH DOMESTIC VIOLENCE, THE ALLEN COUNTY COMMON PLEAS COURT, JUVENILE DIVISION, HAS DEVELOPED A DIVERSIONARY PROGRAM. AT THE HEART OF THE PROGRAM IS AN ACCESS CENTER WHERE YOUTH, REFERRED BY POLICE, SCHOOLS, COMMUNITY ORGANIZATIONS, AND DIRECTLY BY PARENTS, ARE SCREENED FOR SED AND ADVERSE CHILDHOOD EXPERIENCES THAT PUT THEM AT RISK FOR SED. MANY OF THESE YOUTH ARE REFERRED TO COMMUNITY-BASED SERVICES AND RESOURCES. WHILE PARENTS PARTICIPATE IN THE ASSESSMENTS, FEW ELECT TO RECEIVE SERVICES THEMSELVES, AND MOST DO NOT RECOGNIZE THE ROLE OF THE FAMILY SYSTEM IN THE YOUTH'S BEHAVIORAL PROBLEMS. SERVICES FOR YOUTH IN THE COMMUNITY FREQUENTLY HAVE WAITING LISTS, AND MANY YOUTH DO NOT RECEIVE THE RECOMMENDED TREATMENT OR SERVICE COORDINATION. THE ALLEN COUNTY CMHI PROJECT WILL PROVIDE CULTURALLY APPROPRIATE FAMILY ADVOCACY AND ENGAGEMENT ACTIVITIES, AS WELL AS CONNECT FAMILIES TO 24/7/365 MOBILE CRISIS SERVICES. THE PROJECT WILL ALSO INCREASE THE CAPACITY OF THE COMMUNITY TO PROVIDE MORE RAPID ACCESS TO YOUTH- AND FAMILY-FOCUSED EVIDENCE-BASED MENTAL HEALTH CARE AND SERVICE COORDINATION, AS WELL AS CONNECTION TO SERVICES FOR PARENTS WITH UNMET BEHAVIORAL HEALTH NEEDS. GOALS INCLUDE IMPROVING FAMILY STABILIZATION, WHILE REDUCING THE OVERRELIANCE ON LAW ENFORCEMENT AND THE JUVENILE JUSTICE DETENTION SYSTEM. THE PROGRAM WILL SEEK TO IMPROVE MENTAL HEALTH AND LIFE OUTCOMES FOR CHILDREN AND YOUTH, HELP YOUTH AND FAMILIES HEAL FROM TRAUMA, AND DEVELOP STRONGER PATHWAYS TO SUCCESSFULLY TRANSITION YOUTH TO ADULT SERVICES, ROLES AND RESPONSIBILITIES. IT ALSO AIMS TO CHANGE THE CULTURE FROM ONE OF PUNISHMENT THAT CAN ITSELF BE TRAUMATIZING, TO ONE THAT RECOGNIZES THAT BAD BEHAVIORS ARE OFTEN SYMPTOMS OF A TREATABLE MENTAL HEALTH CONDITION. THE ALLEN COUNTY FAMILY AND CHILDREN FIRST COUNCIL WILL SERVE AS THE GOVERNING ORGANIZATION FOR THIS SYSTEM-OF-CARE PROGRAM.

ROSECRANCE JACKSON RECOVERY CENTERS WOODBURY COUNTY CCBHC - PDI - ROSECRANCE JACKSON’S CCBHC PLANNING, DEVELOPMENT, AND IMPLEMENTATION (PDI) INITIATIVE WILL SEEK TO IMPROVE ACCESS TO CRITICAL, COMMUNITY-BASED BEHAVIORAL HEALTH (BH) CARE FOR INDIVIDUALS OF ALL AGES WITH MENTAL (MH) CONDITIONS AND SUBSTANCE USE DISORDERS (SUD) IN WOODBURY COUNTY, IOWA. OUR CCBHC’S CATCHMENT AREA IN WOODBURY COUNTY IS APPROXIMATELY 880 SQUARE MILES ON THE WESTERN EDGE OF IOWA, LOCATED IN THE SIOUXLAND REGION. WE ANTICIPATE THAT OUR CCBHC CLIENT POPULATION WILL BE 69.8% WHITE, 9.5% AMERICAN INDIAN OR ALASKAN NATIVE, AND 6.6% BLACK, AND 6% WILL IDENTIFY AS HISPANIC OR LATINO. FURTHER, 56% WILL BE MALE AND 44% WILL BE FEMALE, WITH LESS THAN 1% OF CLIENTS BEING TRANSGENDER. WE EXPECT 3.6% WILL IDENTIFY AS LGBTQ+. MOST (90%) OF OUR CCBHC CLIENTS WILL BE OVER THE AGE OF 18, WITH ONLY 10% BEING MINORS. THE MAJORITY OF CLIENTS (72%) WILL BE MEDICAID ENROLLEES LIVING AT OR BELOW 133% OF THE FEDERAL POVERTY LINE, AND 25% OF OUR CCBHC CLIENT POPULATION IS EXPECTED TO BE EXPERIENCING HOMELESSNESS. BASED ON THEIR LOW ACCESS TO BH CARE AND COMPLEX, INTERSECTING NEEDS, WE WILL SEEK TO REDUCE DISPARITIES FOR TWO PRIORITY POPULATIONS THROUGH OUR CCBHC PROGRAM: 1) WOMEN WITH SUD WHO ALSO HAVE CHILDREN, WHO WE EXPECT TO REPRESENT ABOUT 20% OF OUR CCBHC CLIENTS SERVED; AND 2) INDIVIDUALS OF ANY AGE WITH BH NEEDS AND ARE INVOLVED WITH THE CRIMINAL JUSTICE (CJ) SYSTEM, WHICH WE EXPECT TO BE ABOUT 40% OF OUR CCBHC CLIENTS SERVED. WE WILL SERVE 1,700 INDIVIDUALS OVER THE GRANT PERIOD, INCLUDING 300 IN Y1, 400 IN Y2, AND 500 IN YS 3 AND 4, RESPECTIVELY. THROUGH OUR CCBHC-PDI INITIATIVE, ROSECRANCE JACKSON SEEKS TO ACHIEVE THE FOLLOWING: GOAL 1: BUILD CAPACITY TO ALIGN WITH THE NEWLY REVISED CCBHC CRITERIA WITHIN ONE YEAR OF GRANT AWARD, INCLUDING: 1.A: ONBOARDING TWO CLINICIANS, TWO CASE MANAGERS, TWO PEER SPECIALISTS, AND A MEDICAL ASSISTANT TO SUPPORT OUR CCBHC SERVICES; 1.B: ATTAINING CHAPTER 24 ACCREDITATION FROM IOWA DEPARTMENT OF HEALTH AND HUMAN SERVICES TO DELIVER OUTPATIENT MH SERVICES; 1.C: ENTERING INTO A DCO AGREEMENT WITH SIOUXLAND MH FOR CCBHC MOBILE CRISIS AND SPECIALTY MH SERVICES; AND 1.D: COMPLETING AN ATTESTATION ILLUSTRATING HOW OUR CCBHC MEETS ALL CRITERIA, AS MEASURED BY PROGRAM RECORDS. GOAL 2: INCREASE ACCESS TO INTEGRATED BH CARE FOR INDIVIDUALS WHO ARE INVOLVED WITH THE CJ SYSTEM, INCLUDING: 2.A: ANNUALLY CONDUCTING SIX OUTREACH AND EDUCATIONAL SESSIONS WITH PARTNERS SERVING THE CJ-INVOLVED POPULATION (E.G., PROBATION, DEPT. OF CORRECTIONS, SUD AND JUVENILE COURTS), TO EDUCATE THEM ABOUT OUR CCBHC; AND 2.B: ESTABLISHING AN AGREEMENT WITH THE WOODBURY COUNTY SHERIFF’S DEPARTMENT TO PROVIDE UNIVERSAL MH AND SUD SCREENING AND CONNECTION TO CARE FOR INDIVIDUALS BEING RELEASED FROM THE COUNTY JAIL. GOAL 3: INCREASE ACCESS TO INTEGRATED BH CARE FOR INDIVIDUALS WHO ARE WOMEN WITH SUD, INCLUDING 3.A: ANNUALLY CONDUCTING SIX OUTREACH AND EDUCATIONAL SESSIONS WITH PARTNERS SERVING WOMEN WITH SUD (E.G., HOSPITALS, CHILD WELFARE, HOUSING PROVIDES, WIC), TO EDUCATE THEM ABOUT OUR CCBHC; AND 3.B: ESTABLISHING A PARTNERSHIP WITH SIOUXLAND COMMUNITY HEALTH CENTER TO PROVIDE TRAINING TO THEIR OBGYN AND PRIMARY CARE PROVIDERS TO SCREEN WOMEN FOR SUD AND CONNECT INDIVIDUALS TO OUR CCBHC FOR CARE WHEN RISKS ARE IDENTIFIED. GOAL 4: IMPROVE BH OUTCOMES FOR WOODBURY COUNTY RESIDENTS LIVING WITH BH NEEDS SERVED BY OUR CCBHC, INCLUDING: 4.A: IMPROVING RETENTION IN OUR CCBHC SERVICES; 4.B: OFFERING OVERDOSE RESPONSE TRAINING AND NARCAN TO 100% OF CLIENTS WITH OUD AND THEIR FAMILIES TO REDUCE RISK OF DEATH FROM OVERDOSE; 4.C: SUPPORTING CLIENTS TO DECREASE THEIR DEPRESSION-RELATED RISKS; AND 4.D: SUPPORTING CLIENTS TO IMPROVE THEIR OVERALL QUALITY OF LIFE.

ONE STOP WELLNESS OF MONROE COUNTY - FINGER LAKES AREA COUNSELING & RECOVERY AGENCY (FLACRA) PROPOSES TO EXPAND ITS CURRENT INTEGRATED CARE SERVICE DELIVERY MODEL THROUGH THE CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) PLANNING, DEVELOPMENT, AND IMPLEMENTATION (PDI) GRANT. CURRENTLY, FLACRA'S EAST AVE CLINIC PROVIDES SERVICES FOR INDIVIDUALS WITH SERIOUS MENTAL ILLNESS (SMI) AND SUBSTANCE USE DISORDERS (SUD) AND IS IN THE APPROVAL PROCESS FOR THE EXPANSION OF SERVICES FOR CHILDREN AND ADOLESCENTS WITH SERIOUS EMOTIONAL DISTURBANCES (SED) AND IS CURRENTLY DESIGNATED TO PROVIDE SERVICES FOR INDIVIDUALS WITH CO-OCCURRING DISORDERS (COD) AND IS SEEKING SUPPORT TO EXPAND ITS SERVICE. A TOTAL OF 2,761 UNDUPLICATED INDIVIDUALS (ACROSS GRANT YEARS) WILL BE SERVED OVER THE 4-YEAR PERIOD THROUGH THIS CCBHC: YEAR 1- 596, YEAR 2- 665, YEAR 3- 720 AND YEAR 4- 780. THE EAST AVE CLINIC IS APPROVED FOR THE NYS OMH INTEGRATED OUTPATIENT SERVICES (IOS) DESIGNATION AND IS PROVIDING FULLY INTEGRATED SUBSTANCE USE DISORDER TREATMENT AND MENTAL HEALTH SERVICES AND IS PENDING APPROVAL TO SERVE CHILDREN AGES 5 AND OLDER FOR MENTAL HEALTH TREATMENT AND PSYCHIATRIC SUPPORT. AS A RESULT OF OBTAINING THE CURRENT IOS DESIGNATION, SERVICES ALREADY OFFERED INCLUDE SEVERAL OF THE REQUIRED CCBHC CORE SERVICES INCLUDING CARE COORDINATION AND PRIMARY CARE SERVICES. WE WILL EXPAND OUR CCBHC SERVICES THROUGH DESIGNATED COLLABORATING ORGANIZATIONS (DCO) PARTNERSHIPS TO EXTEND CRISIS CARE, PSYCHIATRIC EMERGENCY AND INPATIENT CARE AND PRIMARY CARE SERVICES. SINCE THE PANDEMIC, THE SOCIO-ECONOMIC AND ENVIRONMENTAL FACTORS IN THE CITY OF ROCHESTER SERVICE AREA POPULATIONS HAVE WIDENED HEALTH DISPARITIES AND INEQUITABLE ACCESS TO CARE, AS WELL AS COMPOUNDED TRAUMA AND STRESSORS EXACERBATING BEHAVIORAL HEALTH (BH) AND SUBSTANCE USE DISORDERS (SUD). THE RESIDENTS OF THE MOST SIGNIFICANTLY IMPACTED ZIP CODES IN THE CITY OF ROCHESTER WILL BENEFIT FROM THE ADDITION OF A CCBHC THAT IS INTEGRATED, TRAUMA-INFORMED, RECOVERY-ORIENTED AND OPERATES FROM AN EVIDENCE-BASED AND EQUITY FOCUSED APPROACH. FLACRA HAS EXTENSIVE EXPERIENCE PROVIDING TREATMENT AND RECOVERY SUPPORT FOR MILD TO SERIOUS MENTAL ILLNESS AND SERIOUS EMOTIONAL DISTURBANCES, SUDD AND CO-OCCURRING DISORDERS. THE CCBHC PDI GRANT WILL BE USED TO BUILD ON EXISTING COMPREHENSIVE SERVICES AND EXPAND SUPPORT FOR ADULTS AND CHILDREN WITH THE CLINIC AND THROUGH SCHOOL-BASED SERVICES AND COLLABORATIONS. SERVICES WILL BE GROUNDED IN EVIDENCE-BASED CARE, PERSON-CENTERED PLANNING APPROACHES, ATTENTION TO CULTURAL NORMS AND BELIEFS AND TRAUMA-INFORMED PRACTICES. THE GOALS AND OBJECTIVES OF THE PDI GRANT INCLUDE: (1) IMPLEMENTING AND ENHANCING SERVICES ALIGNED WITH A CCBHC MODEL; (2) INCREASING THE NUMBER OF PROVIDERS WITH DIVERSE SPECIALTY AREAS AND CULTURAL SKILLSETS, TRAINED IN EVIDENCE-BASED INTERVENTIONS SUCH AS COGNITIVE BEHAVIORAL THERAPY (CBT), DIALECTICAL BEHAVIORAL THERAPY FOR ADULTS (DBT) AND ADOLESCENTS (DBT-A), TRAUMA FOCUSED CBT (TF-CBT), CBT FOR PSYCHOSIS (CBTP), FAMILY PSYCHOEDUCATION, SOCIAL SKILLS TRAINING (SST), FUNCTIONAL FAMILY THERAPY (FFT), MATRIX MODEL FOR TEENS AND YOUNG ADULTS, PEER ADVOCACY/SUPPORT, SEEKING SAFETY, LIVING IN BALANCE, COMMUNITY REINFORCEMENT AND FAMILY TRAINING (CRAFT), MOTIVATIONAL INTERVIEWING (MI) AS WELL AS MEDICATION ASSISTED THERAPY (MAT); (3) EXPANDING OFF-SITE SERVICES TO MEET THE BH NEEDS OF CHILDREN AND FAMILIES IN HIGH NEED SCHOOL SETTINGS; (4) INCREASING PEER AND RECOVERY SUPPORT SERVICES; (5) AUGMENTING TECHNOLOGY TO SUPPORT EMR DATA EXTRACTION TO MAKE DATA-DRIVEN DECISIONS THAT IDENTIFY AND IMPROVE PRACTICE PATTERNS, DRIVE QUALITY AND PROMOTE AND INTERDISCIPLINARY TEAM-BASED CARE APPROACH; AND (6) ADHERING TO SPARS AND NOMS REQUIREMENTS AND ACCURACY THROUGH TRACKING PERFORMANCE AND CLINICAL QUALITY METRICS THAT HELP IMPROVE QUALITY OF LIFE PERCEPTIONS, IMPROVE OUTCOMES AND REDUCE DISPARITIES IN BOTH ACCESS AND OUTCOMES.

RECOVERY CONSULTANTS OF ATLANTA CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC - RECOVERY CONSULTANTS OF ATLANTA, INC. (RCA) PROPOSES AN ADVANCEMENT OF ITS CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) TO INCLUDE COMMUNITY-BASED BEHAVIORAL HEALTH SERVICES FOR UNDERSERVED CHILDREN AND FAMILIES IN DEKALB AND FULTON COUNTIES, GEORGIA INCLUDING THOSE WITH CHRONIC HEALTH DISEASES, SERIOUS MENTAL ILLNESS (SMI), SUBSTANCE USE DISORDER (SUD), AND CO-OCCURRING DISORDERS (COD). RCA CURRENTLY PROVIDES EVIDENCE-BASED INTERVENTIONS TO ADULTS WITHIN THE SERVICE AREA INCLUDING PRIMARY AND PREVENTATIVE CARE, BEHAVIORAL HEALTH SERVICES, PEER SUPPORT, TRANSITIONAL HOUSING, AND RECOVERY SUPPORT SERVICES. THROUGH PARTNERSHIPS WITH CORNERS OUTREACH, CBOS AND OTHER COMMUNITY LOCATIONS, RCA WILL EXTEND EVIDENCE-BASED INTERVENTIONS TO WHERE CHILDREN AND FAMILIES ARE MOST COMFORTABLE, AND SERVICES ARE DESPERATELY NEEDED. WITHIN THESE COMMUNITY-BASED SETTINGS, RCA WILL PROVIDE OUTREACH, ENGAGEMENT, CASE MANAGEMENT, AND BEHAVIORAL HEALTH SERVICES TO METRO-ATLANTA CHILDREN AND FAMILIES FOR 100 INDIVIDUALS IN YEAR 1, 115 IN YEAR 2, 125 IN YEAR 3, AND 140 IN YEAR 4 FOR A TOTAL OF 480 INDIVIDUALS SERVED DURING THE GRANT PERIOD. THE GOALS OF THIS CCBHC ADVANCEMENT ARE TO: (1) PROVIDE CHILDREN AND FAMILIES WITH ACCESS TO A FULLY INTEGRATED CARE TEAM INCLUDING CASE MANAGEMENT, PRIMARY CARE, BEHAVIORAL HEALTH CARE, PEER SUPPORT, AND RECOVERY SUPPORT SERVICES; (2) CONTINUE TO OPERATE THE CCBHC PROGRAM IN COMPLIANCE WITH ALL CERTIFICATION CRITERIA; (3) PROVIDE PHYSICAL HEALTH CARE THROUGH SCREENING, MONITORING, AND FOLLOW-UP OF KEY HEALTH INDICATORS TO DECREASE HEALTH RISKS AND IMPROVE PHYSICAL HEALTH OUTCOMES OF THE POPULATION OF FOCUS; (4) PROVIDE BEHAVIORAL HEALTH SCREENING, ASSESSMENT, DIAGNOSIS, AND DEVELOP RECOVERY-ORIENTED TREATMENT PLANS FOR BEHAVIORAL HEALTH, SUD, AND COD; AND (5) DEMONSTRATE CONSISTENT, PERSON AND FAMILY-CENTERED APPROACH IN DELIVERY OF BEHAVIORAL HEALTH AND PRIMARY CARE SERVICES.

MCKINLEY COUNTY CCBHC-PDI PROJECT TO ADDRESS DISPARITIES IMPACTING NATIVE AMERICANS - SANTA FE RECOVERY CENTER, INC. (SFRC) PROPOSES TO ESTABLISH A CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) IN MCKINLEY COUNTY, NEW MEXICO (NM), MANAGED BY SFRC’S FOUR CORNERS DETOX RECOVERY CENTER (FCDRC) IN GALLUP. THE POPULATION OF FOCUS ARE THE INDIVIDUALS OF ALL AGES LIVING IN AND AROUND THE COUNTY WITH SERIOUS MENTAL ILLNESS (SMI), SUBSTANCE USE DISORDER (SUD) INCLUDING OPIOID USE; CHILDREN WITH SERIOUS EMOTIONAL DISTURBANCE (SED); INDIVIDUALS WITH CO-OCCURRING MENTAL AND SUBSTANCE USE DISORDERS (COD); AND INDIVIDUALS EXPERIENCING A MENTAL HEALTH OR SUBSTANCE USE-RELATED CRISIS. THE CATCHMENT AREA IS MCKINLEY COUNTY, NM, IN THE HEART OF INDIAN COUNTRY. DESCRIPTION OF SPECIFIC POPULATIONS: WITH A TOTAL POPULATION OF 69,830, 79.9% OF MCKINLEY COUNTY RESIDENTS ARE NATIVE AMERICANS, PRIMARILY OF THE FEDERALLY RECOGNIZED NAVAJO NATION AND ZUNI PUEBLO. HISPANIC RESIDENTS ARE 14.6% OF THE COUNTY’S POPULATION, AND 7.8% ARE WHITE. MCKINLEY COUNTY IS THE STATE’S “UNHEALTHIEST COUNTY" AND HAS NM’S HIGHEST RATE OF CLIENTS RECEIVING “NO TREATMENT” FOR THEIR BEHAVIORAL HEALTH NEEDS AT 36.5%. ACCORDING TO A 2022 COMMUNITY HEALTH NEEDS ASSESSMENT, SURVEY RESPONDENTS INDICATED SUBSTANCE ABUSE (85.7%) AND MENTAL HEALTH PROBLEMS (71.4%) AS THE COUNTY’S TOP TWO HEALTH PROBLEMS – AHEAD OF OBESITY, DIABETES, AND HEART DISEASE. IN YEAR 1, SFRC WILL PROVIDE 700 UNDUPLICATED MCKINLEY COUNTY RESIDENTS A COMPREHENSIVE RANGE OF OUTREACH, SCREENING, ASSESSMENT, TREATMENT, CARE COORDINATION, AND RECOVERY SUPPORTS BY PROVIDING ACCESS TO HIGH-QUALITY MENTAL HEALTH AND SUD SERVICES, REGARDLESS OF AN INDIVIDUAL’S ABILITY TO PAY. THE PROJECT WILL FOCUS ON GROUPS CURRENTLY FACING HEALTH DISPARITIES, AS IDENTIFIED IN A COMMUNITY NEEDS ASSESSMENT TO BE COMPLETED WITHIN SIX MONTHS OF THE PROJECT START DATE. SFRC'S GOALS AND IMPLEMENTATION PLAN ADDRESS THE NINE CORE CCBHC SERVICES AND ALL REQUIRED ACTIVITIES. GOAL 1. SFRC SUCCESSFULLY IMPLEMENTS CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC) SERVICES TO ADDRESS INDIVIDUALS’ MENTAL HEALTH AND SUBSTANCE USE DISORDERS IN MCKINLEY COUNTY. GOAL 2. SFRC PROVIDES A COMPREHENSIVE RANGE OF SERVICES, TREATMENT AND RECOVERY SUPPORTS TO IMPROVE CONSUMERS’ PHYSICAL AND BEHAVIORAL HEALTH OUTCOMES. GOAL 3. SFRC INCREASES ACCESS TO HIGH-QUALITY MENTAL HEALTH AND SUD SERVICES, REGARDLESS OF AN INDIVIDUAL’S ABILITY TO PAY.

ECONOMIC DEVELOPMENT INITIATIVE, COMMUNITY PROJECT FUNDING, AND MISCELLANEOUS GRANTS

DESCRIPTION:THE PURPOSE OF THIS GRANT IS TO FUND THE CITY OF KING COVE'S CONSTRUCTION OF A SOLID WASTE PROCESSING FACILITY ADJACENT TO THE EXISTING LANDFILL, APPROXIMATELY 1.8 MILES FROM THE CITY CENTER. ACTIVITIES:PROJECT COMPONENTS WILL INCLUDE EXCAVATION OF 40,000 CUBIC YARDS OF MATERIAL, SITE PREPARATION FOR BUILDING PAD, CONSTRUCTION OF A 40' BY 50' SOLID WASTE HANDLING BUILDING, PROCUREMENT AND INSTALLATION OF TWO AIR CURTAIN BURNERS (FOR OPERATIONAL FLEXIBILITY AND REDUNDANCY), AND THE PROCUREMENT OF SOLID WASTE HANDLING EQUIPMENT, SUCH AS A SKID STEER. THE PROJECT WILL ALSO INCLUDE INSTALLATION OF WATER AND ELECTRICAL UTILITIES TO SERVICE THE SOLID WASTE HANDLING BUILDING, ROADWAY IMPROVEMENTS, DEVELOPMENT OF SPACE FOR PARKING AND STORING EQUIPMENT AS WELL AS APPROPRIATE SETBACKS FROM PROPERTY BOUNDARIES. AN EPA NATIONAL ENVIRONMENTAL POLICY ACT REVIEW AND PUBLIC COMMENT PROCESS WERE COMPLETED FOR THIS PROCESS, WITH A FINAL FINDING OF NO SIGNIFICANT IMPACT (FONSI) AND STATE HISTORIC PRESERVATION OFFICE (SHPO) APPROVAL.SUBRECIPIENT:NO SUBAWARDS ARE INCLUDED IN THIS ASSISTANCE AGREEMENT.OUTCOMES:SHORT-TERM OUTCOMES: A SOLID WASTE MANAGEMENT PLAN WILL BE DEVELOPED, SPECIFIC TO THE NEW KING COVE SOLID WASTE PROCESSING FACILITY. THE WIDER KING COVE COMMUNITY WILL BE EDUCATED ABOUT HOW TO USE THE NEW SOLID WASTE PROCESSING FACILITY (SORTING, COLLECTION DAYS, ETC). CITY STAFF WILL BE EDUCATED ABOUT HOW TO USE THE AIR CURTAIN BURNERS AND SORTING FACILITY TO BEST EFFECT. MEDIUM-TERM OUTCOMES: A SOLID WASTE MANAGEMENT PLAN SPECIFIC TO THE KING COVE SOLID WASTE PROCESSING FACILITY WILL BE IMPLEMENTED. A REDUCTION OF 80% IN SOLID WASTE STREAM WILL BE ACHIEVED, AS WASTE IS THERMALLY-TREATED AND REDUCED TO ASH. OUTREACH WILL BE CONDUCTED TO KING COVE CITIZENS ABOUT ADDITIONAL WAYS/TYPES OF WASTE TO RECYCLE. THERE WILL BE AESTHETIC IMPROVEMENTS, AS SOLID WASTE IN AND AROUND THE LANDFILL IS REDUCED. PUBLIC SAFETY WILL BE INCREASED, DUE TO A REDUCED MIGRATION OF BEARS TO FOOD SOURCES IN THE LANDFILL. DISEASE VECTORS WILL BE REDUCED. LONG-TERM OUTCOMES: THE CITY'S CONSULTING ENGINEERS HAVE DESIGNED THE LANDFILL EXPANSION TO ACCOMMODATE KING COVE SOLID WASTE NEEDS FOR THE NEXT 20-25 YEARS. LONG-TERM ENVIRONMENTAL OUTCOMES WILL INCLUDE IMPROVED AIR AND WATER QUALITY. OPERATIONAL OUTCOMES WILL INCLUDE INTEGRATED SOLID WASTE MANAGEMENT PLANS TO INCLUDE BOTH NON-RECYCLABLES AND MAXIMUM RECYCLABLES. THE PROJECT WILL BENEFIT ALL CITIZENS OF THE CITY OF KING COVE, AK, THE TWO INDIAN TRIBES IN KING COVE (THE AGDAAGUX TRIBE AND THE BELKOFSKI TRIBE), AND ENVIRONMENT.

NOVEL ANTI-VIRAL AGENTS TO TREAT INFLUENZA

THE MBDA CAPITAL READINESS PROGRAM (PROGRAM) IS DESIGNED TO HELP CLOSE THE ENTREPRENEURSHIP GAP BETWEEN SOCIALLY AND ECONOMICALLY DISADVANTAGED INDIVIDUALS (SEDI) AND NON-SEDI. THE RECIPIENTS ARE WERE SELECTED TO: (1) HELP SEDI ENTREPRENEURS BUILD CAPACITY; (2) ATTRACT AND PROVIDE ACCESS TO CAPITAL OPPORTUNITIES; AND (3) ATTRACT AND PROVIDE ACCESS TO NETWORKS. THE PROPOSED ACTIVITIES MAY RESEMBLE THE SERVICE MODELS OF INCUBATORS (FOCUSING ON EARLY-STAGE TECHNICAL ASSISTANCE FOR NEW ENTREPRENEURS) OR ACCELERATORS (PROVIDING EMERGING-STAGE TECHNICAL ASSISTANCE TO BUSINESSES READY TO EXPAND OR SCALE), OR PROVIDE A COMBINATION OF BOTH SERVICE MODELS.

LINKING THE MICROBIOME AND IMMUNE-CHECKPOINT IN MELANOMA BY RNF5

RURAL COMMUNITIES OPIOID RESPONSE PROGRAM - MEDICATION ASSISTED TREATMENT ACCESS

SIMPLIFYING ENCODING OF BIOASSAYS TO ACCELERATE TRANSLATIONAL DRUG DISCOVERY

HEALTH RECOVERY SERVICES, INC. - MEDICATION ASSISTED TREATMENT - HEALTH RECOVERY SERVICES, INC. MEDICATION-ASSISTED TREATMENT (HRS-MAT) PROJECT WILL ALLOW HEALTH RECOVERY SERVICES (HRS) TO EXPAND SERVICES IN ATHENS, HOCKING, VINTON, GALLIA, JACKSON, AND MEIGS COUNTIES IN SOCIOECONOMICALLY DISADVANTAGED AND RURAL SOUTHEASTERN OHIO BY PROVIDING MOUD IN COMBINATION WITH PSYCHOSOCIAL SERVICES TO THOSE WITH OUD. THE GEOGRAPHIC CATCHMENT AREA IS LARGELY RURAL AND LOCATED IN APPALACHIAN OHIO. THE COMBINED POPULATION OF ALL SIX COUNTIES IS APPROXIMATELY 192,705, JUST 1.7% OF OHIO’S POPULATION OVER A COMBINED LAND AREA OF 2,232.9 SQUARE MILES. THIS EQUATES TO AN AVERAGE POPULATION DENSITY (FOR THE SIX COUNTIES) OF APPROXIMATELY 87 PEOPLE PER SQUARE MILE. RESIDENTS OF THE SIX COUNTIES ARE PRIMARILY WHITE AND THE PERCENT OF POPULATION LIVING BELOW POVERTY LEVEL IS HIGHER THAN THAT OF THE STATE OF OHIO FOR ALL SIX COUNTIES. THE APPALACHIAN REGION COMPARED TO THE NON-APPALACHIAN REGION HAS SEEN HIGHER RATES OF OPIOID PRESCRIBING AND OPIOID OVERDOSE DEATHS (NATIONAL ASSOCIATION OF COUNTIES AND APPALACHIAN REGIONAL COMMISSION, 2019). OVERPRESCRIBING OF OPIOIDS BY PHYSICIANS AND THE ADDITION OF SYNTHETIC OPIOIDS SUCH AS FENTANYL AND CARFENTANYL TO THE SYSTEM IS CONTINUING TO IMPACT APPALACHIA, ATTRIBUTING INCREASING DRUG OVERDOSE DEATHS (SCHALKOFF ET AL, 2021). ADDITIONALLY, THERE HAS BEEN A GROWING USE OF NITAZENES (ALSO TERMED FRANKENSTEIN OPIOIDS), WHICH ARE SYNTHETIC OPIOIDS THAT CAN BE UP TO 40 TIMES MORE POTENT THAN FENTANYL THAT HAS AFFECTED MEIGS, GALLIA, AND JACKSON COUNTIES (OHIO ATTORNEY GENERAL, 2022). THE GOALS OF HRS-MAT ARE (1) PROVIDE MAT SERVICES, USING FDA-APPROVED MEDICATIONS, COMBINATION WITH COMPREHENSIVE AND EVIDENCE-BASED PSYCHOSOCIAL SERVICES TO AT LEAST 350 (50 IN THE YEAR ONE, AND 75 EACH FOR YEARS TWO THROUGH FIVE) ADDITIONAL PATIENTS; (2) CONDUCT CLINICAL ASSESSMENTS TO DETERMINE PATIENTS MEETING ELIGIBLE CRITERIA FOR MAT; (3) CHECK THE PDMP FOR EACH NEW ADMISSION TO PREVENT MEDICATION DIVERSION; (4) CONDUCT SCREENINGS AND ASSESSMENTS FOR CO-OCCURRING SUBSTANCE USE DISORDERS AND MENTAL HEALTH DISORDERS AND ENSURE ADEQUATE DELIVERY AND COORDINATION OF SERVICES; (5) DEVELOP AND IMPLEMENT OUTREACH AND ENGAGEMENT STRATEGIES TO INCREASE ACCESS TO MOUD AND RELATED SERVICES FOR DIVERSE POPULATIONS WITH OUD IN SOUTHEASTERN OHIO; (6) ENSURE ALL APPLICABLE PRACTITIONERS OBTAIN A DATA WAIVER; (7) BUILD FUNDING MECHANISMS AND SERVICE DELIVERY MODELS WITH RURAL AND RESOURCE-LIMITED AREAS/MUNICIPALITIES AND ORGANIZATIONS TO PROVIDE ROBUST TREATMENT AND RSS TO EFFECTIVELY IDENTIFY, ENGAGE, AND RETAIN INDIVIDUALS IN OUD TREATMENT AND FACILITATE LONG-TERM RECOVERY; (8) USE TELEHEALTH SERVICES OR OTHER INNOVATIVE INTERVENTIONS, AS CLINICALLY APPROPRIATE, TO REACH, ENGAGE, AND RETAIN OUD PATIENTS IN TREATMENT; (9) PROVIDE RSS, INCLUDING PEER RECOVERY SERVICES, DESIGNED TO IMPROVE ACCESS TO AND RETENTION IN MAT AND FACILITATE LONG-TERM RECOVERY FOR MAT PATIENTS; AND (10) PROVIDE HARM REDUCTION SERVICES ON SITE, EITHER SINGULARLY OR IN COLLABORATION WITH A COMMUNITY-BASED HARM REDUCTION ORGANIZATION.

FRAGMENT-BASED DISCOVERY OF STEP MODULATORS IN ALZHEIMER'S DISEASE ADMINISTRATIVE SUPPLEMENT - PROJECT SUMMARY STRIATAL-ENRICHED TYROSINE PHOSPHATASE (STEP) IS A NEURON-SPECIFIC PROTEIN TYROSINE PHOSPHATASE (PTP) AND A NOVEL THERAPEUTIC TARGET FOR ALZHEIMER’S DISEASE (AD), A DEBILITATING NEURODEGENERATIVE DISORDER FOR WHICH NO CURE CURRENTLY EXISTS. MULTIPLE STUDIES INDICATE THAT LEVELS OF STEP ARE ELEVATED IN AD AND OTHER NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISORDERS, INCLUDING PARKINSON’S DISEASE, SCHIZOPHRENIA, AND FRAGILE X SYNDROME. THE DATA SUGGEST THAT INCREASED STEP ACTIVITY INTERFERES WITH SYNAPTIC FUNCTION AND CONTRIBUTES TO THE CHARACTERISTIC COGNITIVE AND BEHAVIORAL DEFICITS IN THESE DEVASTATING DISEASES. CROSSING STEP KO MICE WITH MOUSE MODELS OF AD, SCHIZOPHRENIA, OR FRAGILE X SYNDROME COMPLETELY REVERSED THE COGNITIVE AND BEHAVIORAL DEFICITS, GENERATING PROGENY WITH LOWER STEP LEVELS INDISTINGUISHABLE FROM WT MICE. SIMILAR EFFECTS WERE OBSERVED WHEN STEP WAS PHARMACOLOGICALLY INHIBITED BY OUR TOOL COMPOUND TC-2153. THESE STUDIES VALIDATE STEP AS A NOVEL DRUG TARGET FOR THE TREATMENT OF AD AND OTHER NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISORDERS. TC-2153 IS THE ONLY REPORTED STEP INHIBITOR WITH CELLULAR AND IN VIVO ACTIVITY. HOWEVER, TC-2153 AND SIMILAR COMPOUNDS ARE KNOWN TO REACT WITH CELLULAR THIOLS AND MODIFY DNA, PRECLUDING THIS INHIBITOR FROM FURTHER PRECLINICAL STUDIES. OTHER REPORTED STEP INHIBITORS SUFFER FROM POOR SELECTIVITY FOR STEP AND LACK OF EFFICACY UNDER PHYSIOLOGICAL CONDITIONS. TO OVERCOME THESE TYPICAL CHALLENGES FOR INHIBITORS TARGETING PTPS - ENZYMES THAT HAVE A HIGHLY CONSERVED AND HIGHLY CHARGED ACTIVE SITE - WE SET OUT TO DISCOVER SMALL MOLECULES THAT BIND TO LESS CONSERVED, ALLOSTERIC SITES IN STEP. USING INNOVATIVE FRAGMENT-BASED SCREENING TECHNOLOGIES, WE IDENTIFIED 19 FRAGMENTS, LOW MOLECULAR WEIGHT COMPOUNDS ADHERING TO THE “RULE OF 3”, THAT SELECTIVELY BIND TO NOVEL, LESS CONSERVED SITES IN STEP WITH UP TO SINGLE DIGIT MICROMOLAR AFFINITY. THESE FRAGMENTS ARE IDEAL STARTING POINTS FOR GENERATING STEP-TARGETED DEGRADERS SUCH AS PROTEOLYSIS TARGETING CHIMERAS (PROTACS) WITH PHYSICOCHEMICAL PROPERTIES SUITABLE FOR CROSSING THE BLOOD-BRAIN BARRIER (BBB). IN FACT, IN PRELIMINARY EXPERIMENTS WE HAVE DEMONSTRATED THAT A PROTAC BASED ON OUR BEST FRAGMENT CAN EFFECTIVELY REDUCE STEP LEVELS IN VIVO. BASED ON THESE EXCITING RESULTS, WE PROPOSE A STEP-TARGETED PROTEIN DEGRADATION APPROACH AS A THERAPEUTIC STRATEGY IN AD. IN AIM 1, WE WILL OPTIMIZE OUR FRAGMENT BINDERS FOR LIGAND EFFICIENCY AND STEP SELECTIVITY. IN AIM 2, WE WILL GENERATE STEP PROTACS FROM THE MOST PROMISING BINDERS, ASSESS THEM IN OUR ESTABLISHED TESTING FUNNEL, AND OPTIMIZE THEM FOR DRUG METABOLISM AND PHARMACOKINETICS (DMPK), PHARMACODYNAMICS (PD), AND TOXICITY (TOX) PROPERTIES. THE GOAL IS TO GENERATE NON-TOXIC STEP DEGRADERS WITH EXPOSURE AND EFFICACY IN THE BRAIN. IN AIM 3, WE WILL TEST WHETHER CANDIDATE PROTACS ARE ABLE TO IMPROVE COGNITION IN MOUSE AD MODELS. OUR STUDIES ARE DESIGNED TO PROVIDE PROOF-OF-CONCEPT (POC) FOR STEP DEGRADERS AS NOVEL THERAPEUTICS IN AD. WE EXPECT TO DEVELOP AT LEAST ONE LEAD SERIES AND ONE BACKUP SERIES OF EFFECTIVE PROTACS THAT ARE READY FOR PRECLINICAL DEVELOPMENT TOWARDS A FIRST-IN-CLASS EARLY TREATMENT OPTION FOR AD.

FAMILY RECOVERY PROJECT CENTRAL

A GENOMIC/METABOLOMIC STRATEGY TO CHARACTERIZE CARDIAC MITOCHONDRIAL DYSFUNCTION

HOMEOSTATIC ROLE OF IRE1A-XBP1-PDI1 IN HEPATIC LIPID METABOLISM

IMPROVE ACCESS TO BEHAVIORAL AND PHYSICAL HEALTH SERVICES BY TRANSFORMING VALEO BEHAVIORAL HEALTH CARE FROM A COMMUNITY MENTAL HEALTH CENTER TO A CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC - VALEO BEHAVIORAL HEALTH CARE, INC. WILL IMPROVE ACCESS TO BEHAVIORAL AND PHYSICAL HEALTH SERVICES BY TRANSFORMING VALEO FROM A COMMUNITY MENTAL HEALTH CENTER (CMHC) TO A CERTIFIED COMMUNITY BEHAVIORAL HEALTH CLINIC (CCBHC). VALEO'S PRIMARY POPULATION OF FOCUS ARE ADULTS (18+) IN SHAWNEE COUNTY, KANSAS WITH MENTAL HEALTH CONDITIONS, SUBSTANCE USE DISORDERS OR CO-OCCURRING DISORDERS WHO LACK HEALTH INSURANCE COVERAGE, ARE UNDERINSURED, OR CANNOT AFFORD SUBSIDIZED HEALTH INSURANCE, WITH AN EMPHASIS ON INDIVIDUALS WHO ARE 65 AND OLDER, INDIVIDUALS EXPERIENCING HOMELESSNESS, AND THOSE WHO HAVE SERIOUS MENTAL ILLNESS. TOPEKA, THE KANSAS CAPITAL, LIES WITHIN THE BOUNDARIES OF SHAWNEE COUNTY WHICH ENCOMPASSES THE CCBHC SERVICE AREA. SHAWNEE COUNTY IS HOME TO AN ESTIMATED 176,875 RESIDENTS. THERE ARE NO CCBHCS IN THE SERVICE AREA, THOUGH THERE IS ANOTHER CMHC THAT PROVIDES BEHAVIORAL HEALTH SERVICES FOR CHILDREN UP TO 18 YEARS OLD. FOR INDIVIDUALS WITHOUT INSURANCE, VALEO IS ONE OF FOUR PROVIDERS IN THE AREA FOR ADULTS (18+). VALEO IS THE ONLY ADULT PROVIDER WHO WILL PROVIDE SERVICES REGARDLESS OF AN INDIVIDUAL'S ABILITY TO PAY. APPROXIMATELY 17.4% OF THE COUNTY'S POPULATION IS WITHOUT INSURANCE DUE, IN PART, TO KANSAS NOT EXPANDING MEDICAID. THROUGH A SURVEY CONDUCTED BY THE SHAWNEE COUNTY HEALTH DEPARTMENT, RESPONDENTS IDENTIFIED MENTAL HEALTH ISSUES, ALCOHOL/ILLEGAL DRUG ABUSE, PRESCRIPTION DRUG ABUSE/DEPENDENCE, AND OBESITY AS SIGNIFICANT COMMUNITY ISSUES. VALEO WILL SERVE AN ADDITIONAL 2,000 INDIVIDUALS OVER THE COURSE OF THE FOUR-YEAR GRANT PERIOD (500 IN YEAR ONE, 500 IN YEAR TWO, 500 IN YEAR THREE, AND 500 IN YEAR FOUR). THE PROJECT'S FIRST GOAL IS TO INCREASE THE INTEGRATION OF HEALTHCARE SERVICES TO IMPROVE THE OVERALL HEALTH OF THE POPULATION OF FOCUS. OBJECTIVES INCLUDE COLLECTING PRIMARY PROVIDER CARE INFORMATION ON 75% OF CONSUMERS BY THE END OF YEAR ONE AND 100% BY THE END OF YEAR TWO. IN YEAR ONE, 50% OF CONSUMERS WILL RECEIVE PRIMARY CARE SCREENINGS, 75% IN YEAR TWO, 85% IN YEAR THREE, AND 95% IN YEAR FOUR. IN YEAR ONE, 50% OF CONSUMERS WILL RECEIVE CARE COORDINATION, 65% IN YEAR TWO, 75% IN YEAR THREE, AND 95% IN YEAR FOUR. AN ASSERTIVE COMMUNITY TREATMENT (ACT) TEAM WILL BE IMPLEMENTED AND SERVE 25 CONSUMERS IN YEAR ONE, 50 IN YEAR TWO, 75 IN YEAR THREE, AND 100 IN YEAR FOUR. BY YEAR THREE, 50% OF CONSUMERS WITH A BODY MASS INDEX (BMI) OUTSIDE NORMAL PARAMETERS WILL RECEIVE REFERRALS TO APPROPRIATE SUPPORTS, AND 75% WILL RECEIVE REFERRALS BY YEAR FOUR. THE SECOND GOAL IS TO INCREASE TIMELY ACCESS TO SERVICES AND EVIDENCE-BASED PRACTICES TO REDUCE THE NEED FOR MORE RESTRICTIVE LEVELS OF CARE FOR THE POPULATION OF FOCUS. TIME FROM REFERRAL TO SERVICE PROVISION WILL BE DECREASED TO 10 DAYS IN YEAR ONE AND DECREASED TO SEVEN DAYS IN YEAR TWO. SIXTY PERCENT OF CONSUMERS WILL RECEIVE AN EVIDENCE-BASED PRACTICED IN YEAR ONE, 70% IN YEAR TWO, 80% IN YEAR THREE, AND 90% IN YEAR FOUR. VALEO WILL PROVIDE SERVICES TO AN ADDITIONAL 20 INDIVIDUALS 65 YEARS AND OLDER IN YEAR ONE, 40 IN YEAR TWO, 60 IN YEAR THREE, AND 80 IN YEAR FOUR. ACCESS TO SERVICES WILL INCREASE, WITH THE NUMBER OF BILLABLE EVENTS INCREASING BY 10% IN YEAR TWO, 20% IN YEAR THREE, AND 25% IN YEAR FOUR. VALEO WILL ACCOMPLISH THESE OBJECTIVES BY UTILIZING SHORTER-TERM, MORE EFFECTIVE EVIDENCE-BASED PRACTICES, FULLY IMPLEMENTING SAME DAY ACCESS INTAKE, IMPLEMENTING JUST-IN-TIME PSYCHIATRIC PRESCRIBING, UTILIZING A NEW ELECTRONIC HEALTH RECORD WITH A CCBHC MODULE, IMPLEMENTING A FULLY INTEGRATED TREATMENT PLAN, UTILIZING A LEVEL OF CARE INSTRUMENT, ENHANCING AGENCY TRAININGS, EXPANDING THE USE OF SAFETY PLANS, AND IMPROVING ENGAGEMENT OF INDIVIDUALS 65 YEARS AND OLDER.

BIOCOMPUTATION ACROSS DISTRIBUTED PRIVATE DATASETS TO ENHANCE DRUG DISCOVERY

FOUR COUNTY SYSTEMS OF STRENGTH AND WELLNESS - THE FOUR COUNTY SYSTEMS OF STRENGTH AND WELLNESS (4SOSW) PROVIDES INFRASTRUCTURE FOR CARE MANAGEMENT AND SERVICE COORDINATION PLUS AN ARRAY OF BEHAVIORAL HEALTH SERVICES ACROSS A FOUR-COUNTY RURAL REGION OF OHIO.

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

GENERATION OF RETINOID SIGNALS DURING DEVELOPMENT

MICROGLIAL HEPARAN SULFATE IN THE MODULATION OF APOE FUNCTION AND NEURODEGENERATION - HEPARAN SULFATE (HS), A SULFATED GLYCAN EXPRESSED AT THE CELL SURFACE AND IN EXTRACELLULAR MATRIX, HAS LONG ATTRACTED ATTENTION AS A PUTATIVE FACTOR INVOLVED IN ALZHEIMER'S DISEASE (AD), BASED ON CIRCUMSTANTIAL EVIDENCE FROM IN VITRO AND CLINICOPATHOLOGICAL STUDIES. NEVERTHELESS, THE FUNCTIONAL SIGNIFICANCE OF HS IN AD, ESPECIALLY IN THE LATE-ONSET TYPE (LOAD) THAT COMPRISES MORE THAN 90% OF AD CASES, IS ELUSIVE. RECENT HUMAN GENOMIC STUDIES IMPLICATE APOE AND MICROGLIA AS DOMINANT CONTRIBUTORS TO NEURODEGENERATION IN LOAD. THE APOE GENE IS THE STRONGEST KNOWN GENETIC RISK FACTOR FOR LOAD. ACCUMULATING DATA INDICATE THAT APOE PROTEINS EXERT IMMUNOMODULATORY EFFECTS ON MICROGLIA, AND THAT THIS FUNCTION OF APOE IS AT LEAST PARTLY MEDIATED BY THE TREM2 RECEPTOR, ANOTHER AD RISK FACTOR THAT IS EXPRESSED BY MICROGLIA. AMONG THE THREE HUMAN APOE ALLELES, THE APOE4 ALLELE CONFERS AN INCREASED RISK FOR LOAD, WHILE THE APOE2 ALLELE CONFERS A DECREASED RISK RELATIVE TO THE MORE COMMON APOE3 ALLELE. THE MOLECULAR BASIS OF THESE ALLELE- SPECIFIC RISK VARIATIONS IS ONE OF THE KEY UNANSWERED ISSUES IN AD RESEARCH. IN THIS CONTEXT, IT IS INTERESTING TO NOTE THAT APOE PROTEINS BIND HS IN AN ISOFORM-SPECIFIC MANNER — APOE4 EXHIBITS 2- TO 3-FOLD GREATER AFFINITY FOR HS THAN APOE2 AND APOE3, THUS APPARENTLY CORRELATING WITH THEIR RELATIVE AD RISKS. FURTHERMORE, A RECENT REPORT REGARDING THE UNIQUE CASE OF A COLUMBIAN WOMAN, WHO CARRIES A HIGHLY DETRIMENTAL PSEN1E280A MUTATION, SUGGESTS THAT HER APOE3 "CHRISTCHURCH" MUTATION, WHICH ABOLISHES THE AFFINITY OF APOE3 FOR HS, CONFERS STRONG PROTECTION AGAINST NEURODEGENERATION AND COGNITIVE IMPAIRMENT. ALSO SUGGESTING THE FUNCTIONAL INVOLVEMENT OF HS IN LOAD ARE RECURRENT REPORTS OF GENETIC ASSOCIATION OF HS SULFOTRANSFERASE GENES WITH LOAD. IN A SERIES OF PRELIMINARY STUDIES, WE HAVE OBTAINED MULTIPLE PIECES OF EVIDENCE SUGGESTING THAT THE STRONG INTERACTION OF HS WITH APOE4, RELATIVE TO ITS INTERACTIONS WITH APOE2 AND APOE3, IS THE KEY UNDERLYING MECHANISM BY WHICH APOE4 EXERTS A DETRIMENTAL EFFECT ON THE BRAIN. SIGNIFICANTLY, WE HAVE FOUND THAT HAPLOINSUFFICIENT REDUCTION IN HS EXPRESSION LEADS TO THE MITIGATION OF SYNAPSE LOSS AND MICROGLIAL ACTIVATION IN THE PS19 TAUP310S MOUSE MODEL. WE HYPOTHESIZE THAT HS PLAYS A CRITICAL ROLE IN MEDIATING THE APOE4 EFFECT ON MICROGLIAL RESPONSE AND FUNCTION, AND THAT THE DETRIMENTAL EFFECT OF THE APOE4 ALLELE IS MAINLY DUE TO ITS STRONGER INTERACTION WITH THE 3-O SULFATE-RICH HS SPECIES EXPRESSED IN MICROGLIA. WE WILL: (1) DETERMINE THE ROLE OF HS IN APOE-TREM2 INTERACTION AND SIGNALING IN MICROGLIA; (2) DETERMINE THE ROLE OF MICROGLIAL HS IN APOE/ABCA1-MEDIATED CHOLESTEROL EFFLUX; AND (3) EXAMINE IN VIVO EFFECTS OF MICROGLIAL HS ON BRAIN PATHOLOGY AND FUNCTION IN AD MOUSE MODELS. THIS RESEARCH WILL PROVIDE ENTIRELY NOVEL INSIGHTS INTO THE ROLE OF HS IN MICROGLIA, AND MOREOVER, INTO LONG-TERM QUESTIONS REGARDING THE ISOFORM-SPECIFIC RISK OF APOE VARIANTS. SUCCESSFUL COMPLETION OF THIS PROJECT WILL REVEAL THE APOE4-HS INTERACTION AS A PROMISING THERAPEUTIC TARGET FOR REDUCING AD RISK IN APOE4 CARRIERS.

UNLOCKING REGENERATIVE POTENTIAL THROUGH IN VIVO GENETIC REPROGRAMMING

REGULATION AND FUNCTION OF STROMAL MACROPINOCYTOSIS IN PANCREATIC DUCTAL ADENOCARCINOMA - PROJECT SUMMARY RECENT YEARS HAVE WITNESSED AN APPRECIATION OF THE ROLE THAT METABOLIC ADAPTATION PLAYS IN CONFERRING SURVIVAL ADVANTAGES TO CELLS THAT ENCOUNTER THE HARSH NUTRIENT-POOR CONDITIONS OF THE TUMOR MICROENVIRONMENT. OF PARTICULAR RELEVANCE TO THIS PROPOSAL IS THE NOW WIDELY ACCEPTED NOTION THAT MACROPINOCYTOSIS, AN ENDOCYTIC MECHANISM OF FLUID-PHASE UPTAKE, FUNCTIONS IN TUMORS AS AN AMINO ACID SUPPLY ROUTE. BY STIMULATING THE UPTAKE OF EXTRACELLULAR PROTEIN AND TARGETING IT FOR LYSOSOMAL DEGRADATION, MACROPINOCYTOSIS PROVIDES CELLS WITH A SOURCE OF PROTEIN-DERIVED AMINO ACIDS, ALLOWING TUMORS TO CIRCUMVENT AMINO ACID DEPLETION AND SURVIVE NUTRIENT STRESS. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) TUMORS ARE DEFICIENT IN GLUTAMINE, A VITAL NUTRIENT THAT SUPPORTS TUMOR GROWTH. OUR PUBLISHED WORK IN PDAC CELLS HAS ESTABLISHED THAT GLUTAMINE DEPLETION HAS THE CAPACITY TO MODULATE MACROPINOCYTOSIS – DIALING THE PROCESS UP OR DOWN AS REQUIRED. INTERESTINGLY, OUR PRELIMINARY DATA PRESENTED IN THIS PROPOSAL DEMONSTRATE FOR THE FIRST TIME THAT GLUTAMINE SCARCITY CAN ALSO STIMULATE MACROPINOCYTOSIS IN CANCER-ASSOCIATED FIBROBLASTS (CAFS). MECHANISTICALLY, WE HAVE ATTRIBUTED GLUTAMINE STRESS-INDUCED MACROPINOCYTIC UPTAKE IN CAFS TO A CAMKK2-AMPK SIGNAL THAT LEADS TO THE RAC1- DEPENDENT ACTIN CYTOSKELETON DYNAMICS THAT ARE REQUIRED FOR MACROPINOCYTOSIS. AMPK IS A BIOENERGETIC STRESS SENSOR THAT IS MOST OFTEN STUDIED IN THE CONTEXT OF GLUCOSE STARVATION, WHICH UNLIKE GLUTAMINE DEPLETION, DOES NOT BOOST CAF MACROPINOCYTOSIS. NOTABLY, NOT MUCH IS KNOWN ABOUT AMPK ACTIVATION AND FUNCTION DURING GLUTAMINE DEPLETION. OUR PRELIMINARY STUDIES SUGGEST THAT MACROPINOCYTOSIS HAS A DUAL PURPOSE IN CAFS – IT CAN SERVE TO SUSTAIN CAF VIABILITY AND FUNCTION, AND IT CAN PROVIDE SECRETED AMINO ACIDS TO NOURISH THE TUMOR CELLS. IMPORTANTLY, OUR IN VIVO AND IN VITRO EXAMINATIONS OF MACROPINOCYTOSIS IN NORMAL FIBROBLASTS, AS WELL AS IN CAFS ORIGINATING FROM OTHER TUMOR TYPES, SUGGEST THAT GLUTAMINE DEPLETION-INDUCED STROMAL UPTAKE IS UNIQUE TO PANCREATIC CAFS. BASED ON THESE DATA, OUR CENTRAL HYPOTHESIS IS THAT GLUTAMINE SCARCITY SELECTIVELY DRIVES CAMKK2-AMPK-DEPENDENT MACROPINOCYTOSIS IN CAFS, AND THAT STROMAL MACROPINOCYTOSIS IS A PROCESS THAT CAN BE HARNESSED IN PDAC THERAPY. IN THIS PROPOSAL, WE WILL 1) EXAMINE THE MOLECULAR MECHANISMS DRIVING THE SELECTIVE ROLE OF GLUTAMINE IN CAF MACROPINOCYTOSIS, 2) FUNCTIONALLY CHARACTERIZE STROMAL MACROPINOCYTOSIS IN PDAC, AND 3) DETERMINE WHETHER THE STROMAL REORGANIZATION THAT OCCURS WITH MACROPINOCYTOSIS INHIBITION CAN BE LEVERAGED FOR PDAC THERAPY. THIS PROJECT WILL BE OF GREAT SIGNIFICANCE, NOVELTY AND IMPACT, AS IT WILL CONSTITUTE THE FIRST EVALUATION OF THE ROLE OF MACROPINOCYTOSIS IN THE PDAC TUMOR STROMA AND THE FIRST ANALYSIS TO SELECTIVELY LINK GLUTAMINE STARVATION TO CAMKK2-AMPK SIGNALING. MOREOVER, BECAUSE MACROPINOCYTOSIS IS IMPORTANT IN BOTH THE TUMOR CELLS AND THE STROMA, OUR WORK COULD HAVE TREMENDOUS IMPACT ON THE DEVELOPMENT OF NOVEL THERAPEUTIC MODALITIES FOR PDAC.

DEVELOPING ER STRESS INHIBITORS FOR TREATING ALS

HYBRID NANOTECHNOLOGIES FOR DETECTION AND SYNERGISTIC THERAPIES FOR BREAST CANCER

ELUCIDATING A MICROGLIAASSOCIATED ROLE FOR SORLA IN MODULATING AD PATHOGENESIS - PROJECT SUMMARY MUTATIONS IN SORLA (ENCODED BY SORL1) IDENTIFIED THROUGH GWAS AND WHOLE EXOME SEQUENCING ANALYSIS HAVE BEEN LINKED TO INCREASED ALZHEIMER’S DISEASE (AD) RISK. ALTHOUGH A NEURONAL ROLE FOR SORLA IN SUPPRESSING AMYLOIDOGENIC APP PROCESSING AND CONSEQUENT ASS GENERATION HAS BEEN ESTABLISHED, SORLA EXPRESSION IS ~8-FOLD HIGHER IN HUMAN MICROGLIA COMPARED TO NEURONS, THUS IMPLICATING A MICROGLIAL ROLE FOR SORLA IN AD PATHOGENESIS. SO FAR, FUNCTIONAL ROLES FOR SORLA IN MICROGLIA HAVE NOT YET BEEN DESCRIBED. HERE, WE USED CRISPR/CAS9 EDITING METHODS TO INTEGRATE AD-ASSOCIATED A528T AND R744X MUTATIONS INTO THE SORL1 (ENCODING SORLA) LOCUS IN HUMAN H9 EMBRYONIC STEM CELLS, WHICH WERE SUBSEQUENTLY DIFFERENTIATED INTO HUMAN MICROGLIA-LIKE (HMGL) CELLS. COMPARING TRANSCRIPTOMIC PROFILES BETWEEN WILDTYPE AND AD-ASSOCIATED SORL1 (A528T, R744X) AND TREM2 (R47H) MUTANT HMGLS REVEALS PATHOGENIC MICROGLIA GENE SIGNATURES SUCH AS INDUCED APOE EXPRESSION PREVIOUSLY DESCRIBED IN AD MOUSE MODELS AND HUMAN AD BRAIN. OUR RESULTS ALSO SHOW THAT CULTURED SORL1R744X AND TREM2R47H HMGLS FEATURE DEFECTS IN ASS UPTAKE IN AN APOE-DEPENDENT MANNER, ALONG WITH IMPAIRED ASS CLEARANCE AND PLAQUE ASSOCIATION IN MOUSE BRAIN XENOTRANSPLANTS BY MICRODIALYSIS/HISTOLOGY. THESE RESULTS PROVIDE PIONEERING EVIDENCE THAT SORLA DYSFUNCTION CAN CONFER PATHOGENIC EXPRESSION SIGNATURES AND IMPAIR MICROGLIAL FUNCTION. WE HYPOTHESIZE THAT MICROGLIAL DYSFUNCTION WILL VARY ACCORDING TO DOMAIN-SPECIFIC MUTATIONS IN THE SORLA EXTRACELLULAR REGION, AND THAT EARLY AND LATE ONSET SORLA MUTATIONS MAY SHOW DIFFERENTIAL EFFECTS ON MICROGLIA DYSREGULATION AND MICROGLIA/NEURON INTERACTION. USING OUR GENE EDITING/HUMAN MICROGLIAL MODELING AND ANALYSIS PLATFORM, WE WILL EXPAND OUR SORLA MUTANT EMBRYONIC STEM CELL (ESC) PANEL TO INCLUDE REPRESENTATIVE EARLY AND LATE AD ONSET MUTATIONS WITHIN EACH OF THE FUNCTIONAL DOMAINS IN THE SORLA EXTRACELLULAR REGION. WE WILL CHARACTERIZE GENE EXPRESSION PROFILES OF WILDTYPE (WT) AND SORLA MUTANT ESC-DERIVED MICROGLIA (“XHMGS”) IN VIVO BY RNASEQ/PROTEOMIC ANALYSIS, AS WELL AS FUNCTIONAL ASPECTS OF MICROGLIAL FUNCTION (ASS UPTAKE, CYTOKINE PROFILES) IN XHMGS XENOTRANSPLANTED IN AD MOUSE BRAIN. AS OUR RESULTS INDICATE THAT SORLA MUTATIONS SUCH AS R744X AND A528T UPREGULATE APOE WHICH MAY TRIGGER CERTAIN ASPECTS OF MICROGLIA FUNCTION, WE WILL ALSO TEST WHETHER APOE AND OTHER POTENTIAL DRIVERS OF MICROGLIA DYSFUNCTION EPISTATICALLY MEDIATE DOWNSTREAM PATHOGENIC BEHAVIOR IN SORLA MUTANT MICROGLIA XENOTRANSPLANTS IN AD MOUSE BRAIN. WE WILL ALSO EXPLORE CELLULAR MECHANISMS ASSOCIATED WITH VARIOUS SORLA MUTATIONS THAT DRIVE CELLULAR DYSFUNCTION IN ESC-DERIVED MICROGLIA AND NEURONS; TO THIS END, WE WILL INVESTIGATE HOW SORLA MUTATIONS IN HUMAN MICROGLIA (XHMGS) INTERACT WITH NEURONS IN MOUSE AD BRAIN XENOTRANSPLANTS, AS WELL AS WT AND SORLA MUTANT HMGLS/NEURONS IN CO-CULTURE. THESE RESULTS WILL PROVIDE US WITH MECHANISTIC INSIGHT INTO HOW VARIOUS MUTATIONS CAN TRIGGER MICROGLIA DYSFUNCTION, AND POTENTIALLY DESCRIBE HOW ASPECTS OF MICROGLIAL AND NEURONAL-RELATED SORLA PATHWAYS ARE AFFECTED TO ALTER AGE-RELATED ONSET IN AD PATHOGENESIS.

MECHANISMS OF NUP210 REGULATION OF MUSCLE DEVELOPMENT AND REGENERATION

MULTIMARKER SURFACE SIGNATURES OF HUMAN ISLET DERIVED EXTRACELLULAR VESICLES - WE PROPOSE AN INDUSTRIAL-ACADEMIC COLLABORATION IN RESPONSE TO RFA-DK-21-016 TITLED “CHARACTERIZATION OF ISLET- DERIVED EXTRACELLULAR VESICLES FOR IMPROVED DETECTION, MONITORING, CLASSIFICATION, AND TREATMENT OF TYPE 1 DIABETES”. THE OBJECTIVES ARE TO IDENTIFY COMBINATIONS OF SURFACE MARKERS THAT DEFINE POPULATIONS OF EV ORIGINATING FROM THE MAJOR CELLS OF THE ISLETS OF LANGERHANS AND EXOCRINE PANCREATIC TISSUE AND TO APPLY NOVEL TECHNOLOGIES FOR ISOLATING AND DEEPLY CHARACTERIZING THESE UNIQUE EV POPULATIONS. WE WILL BUILD UPON RECENT SUCCESSES AT MSD IN DEVELOPING A NOVEL TECHNIQUE FOR EV SURFACE MARKER SCREENING AND A MULTIMARKER IMMUNOAFFINITY TECHNIQUE FOR ISOLATING HIGHLY SPECIFIC EV POPULATIONS. THESE TECHNIQUES WILL BE ADAPTED TO THE SPECIFIC EV POPULATIONS OF THE PANCREAS, WHICH WILL ENABLE US TO OBSERVE CHANGES TO THE EV REPERTOIRE RELATED TO PATHOLOGICAL EVENTS AND TO IDENTIFY POPULATIONS OF EVS OR SPECIFIC EV CARGO THAT MAY SERVE AS A REMOTE BIOMARKER FOR ISLET RELATED EVENTS. WE WILL APPLY OUR EXPERTISE IN ULTRASENSITIVE ECL-BASED ASSAYS TO DEVELOP ASSAYS THAT ENABLE DETECTION OF THESE PANCREAS-SPECIFIC EVS FROM PERIPHERAL BLOOD. THIS PROPOSAL COMBINES THE TECHNICAL EXPERTISE OF MESO SCALE DIAGNOSTICS, LLC., WITH EXPERTISE IN THE BIOLOGY OF ISLET-DERIVED EXTRACELLULAR VESICLES OF OUR COLLABORATOR, DR. EDWARD PHELPS AT THE UNIVERSITY OF FLORIDA.

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

BRAIN-PENETRANT GPR88 AGONISTS AS NOVEL THERAPEUTICS FOR OPIOID ABUSE - SUMMARY SUBMITTED IN RESPONSE TO RFA-DA-22-031, THIS APPLICATION DESCRIBES A MULTIDISCIPLINARY EFFORT TO DEVELOP NOVEL, BRAIN-PENETRANT, SMALL-MOLECULE GPR88 AGONISTS TO ATTENUATE ADDICTION-RELEVANT BEHAVIORAL RESPONSES TO OPIOID DRUGS AND AMELIORATE WITHDRAWAL SYNDROME IN OPIOID-DEPENDENT INDIVIDUALS. GPR88 IS AN ORPHAN G-PROTEIN COUPLED RECEPTOR (GPCR) WITH CONCENTRATED EXPRESSION IN STRIATOPALLIDAL (INDIRECT PATHWAY) MEDIUM SPINY NEURONS (MSNS) IN THE STRIATUM. RECENT OBSERVATIONS IN TRANSGENIC MICE DEMONSTRATE THAT GPR88 EXERTS AN INHIBITORY INFLUENCE OVER OPIOID RECEPTOR SIGNALING IN THE STRIATUM. BUILDING ON THIS AND OTHER RECENT PROMISING PRECLINICAL OBSERVATIONS, WE PROPOSE TO LEVERAGE OUR EXPERTISE IN NEUROBIOLOGICAL MECHANISMS OF OPIOID USE DISORDERS AND SMALL-MOLECULE DRUG DISCOVERY TO FORMALLY VALIDATE GPR88 AS A DRUG TARGET FOR OPIOID USE DISORDERS (OUD) AND ESTABLISH A DRUG DEVELOPMENT PATH FORWARD BY DISCOVERING GPR88 AGONIST LEAD COMPOUNDS. WE WILL LEVERAGE AN IN VIVO MURINE MODEL OF OPIOID DEPENDENCE WE HAVE DEVELOPED AND GPR88-/- MICE ALONG WITH AVAILABLE GPR88 PHARMACOLOGICAL TOOLS. UNFORTUNATELY, PUBLISHED GPR88 AGONISTS HAVE LIMITATIONS THAT RESTRICT THEIR UTILITY IN VIVO AND PREVENT THEIR DEVELOPMENT INTO THERAPEUTICS. TO ADDRESS THIS SHORT COMING WE WILL DEVELOP NOVEL, POTENT GPR88 AGONISTS WITH PROPERTIES OPTIMIZED FOR THE TREATMENT OF OPIOID DEPENDENCE. WE ARE WELL POSITIONED TO ACCOMPLISH THIS TASK. WE RECENTLY CONDUCTED A GPR88 HIGH THROUGHPUT SCREEN (HTS), USING AN INNOVATIVE PHARMACOCHAPERONE ASSAY FORMAT, AND IDENTIFIED A NOVEL CHEMICAL SCAFFOLD EXEMPLIFIED BY SBI-‘2037 AS A VALIDATED GPR88 AGONIST. IN ADDITION, WE HAVE ALREADY DEVELOPED ROBUST CELL-BASED ASSAYS (AND APPROPRIATE COUNTER-SCREENS) TO RELIABLY MONITOR GPR88 FUNCTION AND ITS IMPACT ON OPIOID RECEPTORS. LEVERAGING THESE ASSETS, WE WILL CONDUCT A MEDICINAL CHEMISTRY CAMPAIGN TO INCREASE POTENCY AND SELECTIVITY OF THE SBI-‘2037 SCAFFOLD WITH A CRITICAL PATH CONSISTING OF CELLULAR ASSAYS FOCUSED ON THEIR UTILITY IN OUD THAT INCLUDES EARLY ASSESSMENT OF ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION (ADME) AND BRAIN PENETRATION PROPERTIES. TO INCREASE THE OVERALL PROBABILITY OF SUCCESS, WE INTEND TO CONDUCT AN ADDITIONAL GPR88 HTS SCREENING CAMPAIGN IN SEARCH OF ONE OR MORE BACK UP SERIES. WE HAVE ESTABLISHED A STRINGENT SET OF CRITERIA FOR GPR88 AGONIST LEADS, AND ONLY COMPOUNDS THAT MATCH THIS PROFILE WILL BE ADVANCED INTO EFFICACY TESTING IN THE INTRAVENOUS OXYCODONE SELF- ADMINISTRATION PROCEDURE IN WILD-TYPE AND GPR88 KNOCKOUT MICE. THIS MULTIDISCIPLINARY RESEARCH PLAN CAPITALIZES ON THE UNIQUELY RELEVANT SCIENTIFIC AND DRUG DISCOVERY EXPERTISE OF OUR TEAM OF COMMITTED INVESTIGATORS AND IS AN INITIAL STEP TOWARDS OUR ULTIMATE GOAL OF DEVELOPING GPR88 AGONISTS AS NOVEL THERAPEUTICS TO FACILITATE ABSTINENCE IN OPIOID-DEPENDENT INDIVIDUALS.

DEVELOPMENT OF AN EFFECTIVE THERAPY AGAINST POST-EXPOSURE ANTHRAX

BUILDING RESILIENCE THROUGH INTERVENTION: GROWING HEALTHIER TGTHR (PROJ BRIGHT)

EPIGENETIC CONTROL OF HEMATOPOIETIC STEM CELLS

LEAD OPTIMIZATION OF NOVEL ML-IAP ANTAGONISTS TO TREAT LUNG CANCER

MAGNETIC RESONANCE OF CARDIAC C13 FLUX & METABOLISM RATE

ENHANCED SERVICES TO RESIDENTS AT PROJECT PRIDE, THEIR CHILDREN, THEIR PARTNERS AND EXTENDED FAMILY MEMBERS.

NEW DOWN SYNDROME BRAIN ORGANIZATION REVEALED BY SINGLE-CELL GENOMICS - PROJECT SUMMARY/ABSTRACT NEARLY 100% OF DOWN SYNDROME (DS; TRISOMY OF HUMAN CHROMOSOME 21) INDIVIDUALS THAT LIVE INTO THEIR 5TH DECADE OF LIFE AND BEYOND, SHOW ALZHEIMER’S DISEASE (AD)-LIKE DEMENTIA AND NEUROPATHOLOGY (DS-AD), REPRESENTING A PROMINENT DS COMORBIDITY THAT HAS RECENTLY BEEN REPORTED AS THE LEADING CAUSE OF DEATH FOR DS ADULTS. BEYOND TRISOMY OF CHROMOSOME 21, WHICH INCLUDES THE KEY AD GENE, AMYLOID PRECURSOR PROTEIN (APP), THE MOLECULAR MECHANISMS UNDERLYING DS-AD HAVE RESISTED IDENTIFICATION. THERE ARE NO DISEASE-MODIFYING THERAPIES (DMTS) TO PREVENT OR TREAT DS-AD, WHICH COULD IMPROVE DS QUALITY OF LIFE AND LIFESPAN. THIS INCLUDE PROPOSAL WILL TRANSFORM OUR UNDERSTANDING OF DS BY REVEALING THE TRANSCRIPTOMIC (RNA) AND GENOMIC (DNA) SINGLE-CELL LANDSCAPE OF THE AGING DS INDIVIDUAL, AND ESPECIALLY THE DS-AD BRAIN, BY CENTERING UPON A NOVEL HUMAN BRAIN MOLECULAR MECHANISM THAT MIGHT UNDERLIE DS-AD: SOMATIC GENE RECOMBINATION (SGR) AND RESULTANT GENOMIC AND TRANSCRIPTOMIC HETEROGENEITY. SGR HAS THE POTENTIAL TO CHANGE THE DNA BLUEPRINT OF DS BRAIN CELLS RESULTING IN FUNCTIONAL CONSEQUENCES FOR BRAIN CELLS THAT COULD EXPLAIN DS-AD ONSET AS WELL AS OTHER DS BRAIN COMORBIDITIES SUCH AS AUTISM AND EPILEPSY. SGR HAS NOT BEEN EXAMINED IN DS BRAINS, WHICH IF OPERATIONAL, WOULD PROVIDE A FUNDAMENTALLY NEW VIEW ON HOW GENES AND GENE DOSAGE ACT TO PROMOTE DS-AD OVER TIME. SGR IS KNOWN TO ACT ON APP IN NORMAL AND SPORADIC AD NEURONS, RESULTING IN THOUSANDS OF NEW APP VARIANTS WITHIN INDIVIDUAL HUMAN BRAINS AND HAS BEEN INDEPENDENTLY CONFIRMED IN THE SCIENTIFIC LITERATURE. THE PROVEN INCREASES IN DS BRAIN GENE EXPRESSION, COMBINED WITH THE IDENTIFIED LINKAGE OF GENE EXPRESSION TO SGR, IMPLICATES GENES TRANSCRIPTIONALLY INCREASED BY TRISOMY 21 AS NEW TARGETS FOR SGR IN DS-AD. APP IS LIKELY THE “TIP OF THE ICEBERG” FOR DS-AFFECTED GENES IN NEURONS AND NON-NEURONAL CELLS, WITH IMPLICATIONS FOR BOTH DS AS WELL AS OTHER STATES OF THE NORMAL AND DISEASED HUMAN BRAIN. THREE INDEPENDENT, BUT DEEPLY-CONNECTED, RESEARCH ELEMENTS (RES) WILL BE COMPLETED BY A PROVEN, COLLABORATIVE TEAM OF MOLECULAR BIOLOGISTS, NEUROSCIENTISTS, NEUROLOGISTS, BIOENGINEERS, AND BIOINFORMATICIANS TO TEST THE HYPOTHESIS THAT SGR CONTRIBUTES TO DS BRAIN DEFICITS AND DS-AD BY ALTERING KNOWN AND UNKNOWN DISEASE GENES AT THE SINGLE-CELL TRANSCRIPTOMIC AND GENOMIC LEVEL WITHIN THE DS BRAIN. RE1 AND RE2 WILL USE CUTTING-EDGE SEQUENCING TECHNOLOGIES TO INTERROGATE THE TRANSCRIPTOMIC AND GENOMIC HETEROGENEITY OF SINGLE NUCLEI FROM DS AND DS-AD BRAINS COMPARED TO CONTROLS, AND WILL INFORMATICALLY INTEGRATE TRANSCRIPTOMIC EXPRESSION, CHROMATIN ACCESSIBILITY, NOVEL ISOFORM DETECTION AND GENOMIC MOSAICISM FORMS, INCLUDING GENCDNAS, WITHIN SINGLE CELLS ACROSS CELL TYPES AND WITH AGE. RE3 WILL EXPLORE THE FUNCTIONAL CONSEQUENCES SGR IN PRIMARY NEURONAL AND INDUCED PLURIPOTENT STEM CELL (IPSC) MODELS TOWARDS UNDERSTANDING THE FUNCTIONAL IMPLICATIONS OF DISEASE ENHANCED SGR, AND THE THERAPEUTIC OPPORTUNITIES THAT SGR UNVEILS.

ARCC- ADOLESCENTS IN RECOVERY AND COMMUNITY CONNECTIONS - THE VILLAGE VIRGIN ISLAND PARTNERS IN RECOVERY, INC., (THE VILLAGE) ADOLESCENTS IN RECOVERY AND COMMUNITY CONNECTIONS (ARCC) PROGRAM PURPOSE IS TO PROVIDE EARLY INTERVENTION, RECOVERY SUPPORT SERVICES, AND COMPREHENSIVE SUD/COD OUTPATIENT TREATMENT TO TRADITIONALLY UNDER-SERVED, PRIMARILY MINORITY YOUTH AND THEIR FAMILIES/PRIMARY CAREGIVERS ON THE US VIRGIN ISLANDS. SUBSTANCE USE IS ACCELERATING IN USVI. FENTANYL-INVOLVED OVERDOSE DEATHS HAVE STEADILY INCREASED; FENTANYL DEATHS BALLOONED NEARLY 900% BETWEEN 2016 AND 2017: FROM 12 TO 106. THIS PROJECT WILL INCREASE ACCESS TO CARE BY PROVIDING CULTURALLY COMPETENT AND YOUTH-CENTERED EVIDENCE-BASED SUD/COD TREATMENT AND ENHANCE THE SOCIAL AND BEHAVIORAL HEALTH FUNCTIONING OF PRIMARILY MINORITY YOUTH (12-25) AND THEIR FAMILIES. THIS WILL BE ACCOMPLISHED BY OFFERING THE REQUIRED ACTIVITIES, INCLUDING EVIDENCE-BASED (EBP) OUTPATIENT TREATMENT, WRAPAROUND SERVICES, AND CASE MANAGED COMMUNITY-BASED SUPPORT SERVICES. THIS WILL INCLUDE EXPANSION OF THE EXISTING CONTINUUM OF CARE TO INCLUDE OUTPATIENT SERVICES AND WRAPAROUND CARE WHICH WILL PROVIDE THE YOUTH AND FAMILY WITH EVERYTHING THEY NEED TO BE SUCCESSFUL.

SANTA FE RECOVERY CENTER'S SUBSTANCE USE DISORDER RESIDENTIAL TREATMENT FOR PREGNANT AND POSTPARTUM WOMEN GRANT

DEVELOPMENT OF STEP ALLOSTERIC INHIBITORS AS NOVEL THERAPEUTICS FOR ALZHEIMER'S DISEASE

MOLECULAR DETERMINANTS OF TLR TRAFFICKING