Rush University Medical Center

RUSH ALZHEIMER'S DISEASE CORE CENTER

EPIDEMIOLOGIC STUDY OF NEURAL RESERVE AND NEUROBIOLOGY OF AGING

MIND DIET INTERVENTION TO PREVENT ALZHEIMER'S DISEASE

RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF AD

MIND DIET AND DEMENTIA PREVENTION IN ISCHEMIC STROKE PATIENTS

RISK FACTORS FOR COGNITIVE DECLINE IN AFRICAN AMERICANS

RUSH ALZHEIMER'S DISEASE RESEARCH CENTER - ABSTRACT – OVERALL THE OVERALL GOAL OF THE PROPOSED RUSH ADRC IS TO CREATE AN INTER-DISCIPLINARY ENVIRONMENT THAT SUPPORTS INNOVATIVE RESEARCH ON THE CAUSES, TREATMENTS, AND PREVENTION OF AD/ADRD. WHILE THE PROPOSED RUSH ADRC IS FOR A NEW GRANT, IT BUILDS ON THREE DECADES OF WORK BY THE CURRENT RUSH ADCC. THE RUSH ADRC HAS EIGHT CORES AND ONE COMPONENT, WHICH ALIGN WITH THE RECOMMENDATIONS OF THE 2017 NIA STRATEGIC PLAN, INCLUDING STUDIES THAT: 1) RECOGNIZE THE HETEROGENEITY AND MULTIFACTORIAL NATURE OF DEMENTIAS; 2) SUPPORT EXTENSIVE MOLECULAR PROFILING TO FILL THE GAPS IN LARGE-SCALE HUMAN DATA NEEDED TO BUILD PREDICTIVE MODELS OF DISEASE AND WELLNESS; 3) EMPLOY NEW RESEARCH PARADIGMS, E.G., SYSTEMS BIOLOGY, HUMAN CELL MODELING; 4) ENABLE RAPID AND EXTENSIVE SHARING OF DATA, DISEASE MODELS, SPECIMENS, AND SUPPORT OPEN AND TEAM SCIENCE; 5) DEVELOP COMPUTATIONAL TOOLS AND INFRASTRUCTURE FOR STORAGE, INTEGRATION, AND ANALYSIS OF LARGE-SCALE BIOLOGICAL AND PATIENT-RELEVANT DATA; 6) BUILD MULTIDISCIPLINARY TRANSLATIONAL TEAMS IN VIRTUAL AND REAL SPACES; 7) DEVELOP NEW PRE-COMPETITIVE PUBLIC-PRIVATE PARTNERSHIPS; 8) CHANGE ACADEMIC, PUBLISHING, AND FUNDING INCENTIVES TO PROMOTE COLLABORATIVE, TRANSPARENT, AND REPRODUCIBLE RESEARCH; AND 9) ENGAGE PATIENTS, CAREGIVERS, AND CITIZENS AS DIRECT PARTNERS IN RESEARCH. THE ADMINISTRATIVE CORE WILL PROVIDE SCIENTIFIC LEADERSHIP TO THE RUSH ADRC AS A WHOLE. THE RELIGIOUS ORDERS STUDY (ROS) CORE WILL RECRUIT AND CONDUCT ANNUAL EVALUATIONS OF CATHOLIC CLERGY WITHOUT DEMENTIA WHO AGREE TO ORGAN DONATION. THE CLINICAL AND LATINO CORES WILL COLLECT DATA HARMONIZED WITH ON BLACKS AND LATINOS WITHOUT DEMENTIA AND WORK TO OBTAIN BRAIN AUTOPSY. THE NEUROPATHOLOGY CORE WILL PROCESS, STORE, EVALUATE AND DISTRIBUTE BIOSPECIMENS OBTAINED BY THE CLINICAL, ROS, AND LATINO CORES. THE OUTREACH, RECRUITMENT, AND ENGAGEMENT CORE WILL PROVIDE A WIDE RANGE OF EDUCATIONAL PROGRAMS TO SUPPORT OUTREACH AND RECRUITMENT OF RACIAL AND ETHNIC MINORITIES INTO THE CLINICAL, ROS AND LATINO CORES, AND OTHER NIA FUNDED INITIATIVES. THE BIOMARKER/NEUROIMAGING CORE WILL PROCESS NEUROIMAGING GENERATED WITH OTHER FUNDS FROM ALL THREE CORES AND AFFILIATED STUDIES, AND DOCUMENT NEUROIMAGING AND BIOFLUID BIOMARKER DATA. THE NEW RESEARCH AND EDUCATION COMPONENT WILL PROVIDE STRUCTURED MENTORING OF STUDENTS AND FACULTY AT ALL LEVELS. THE DATA MANAGEMENT AND STATISTICAL CORE WILL PROVIDE THE INFRASTRUCTURE THAT ALLOWS ALL OTHER CORES AND THE REC TO BE MAXIMALLY SUCCESSFUL AND IMPACTFUL AND WILL PROVIDE STATISTICAL SUPPORT TO USERS OF ADRC RESOURCES ESPECIALLY JUNIOR INVESTIGATORS AND TRAINEES.

IMPACT OF COVID-19 ON AD OCCURRENCE: A BIRACIAL INTERGENERATIONAL POPULATION STUDY - THE CHICAGO HEALTH AND AGING PROJECT (CHAP) HAS MADE SEVERAL SIGNIFICANT CONTRIBUTIONS TO ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD) EPIDEMIOLOGY. THESE AREAS INCLUDE RACIAL DISPARITIES, PREVALENCE, AND INCIDENCE OF DEMENTIA TRENDS, SOCIAL, LIFESTYLE, VASCULAR, GENETIC RISK FACTORS, AND NEUROIMAGING AND BLOOD BIOMARKERS IN A LARGE POPULATION-BASED COMMUNITY STUDY OF AFRICAN AMERICANS (AAS) AND EUROPEAN AMERICANS (EAS). USING THE OLDER CHAP PARENT AND THE ONGOING MIDLIFE OFFSPRING COHORTS, WE WILL TEST SEVERAL NOVEL AND INNOVATIVE HYPOTHESES ON THE IMPACT OF COVID-19 ON ADRD, MCI, COGNITIVE DECLINE, AND STRUCTURAL MRI BRAIN INJURY. BY EXTENDING THE AWARDED NIA NOSI ADMINISTRATIVE SUPPLEMENT, THE INTERGENERATIONAL STUDY PROVIDES SIGNIFICANT ADVANTAGES BY INVESTIGATING: (1) THE DIRECT EFFECT OF SARS-COV-2 INFECTIONS AMONGST THOSE WITH HIGHER INFLAMMATORY CYTOKINES, ESPECIALLY IN FAMILIES WITH A HIGH RISK OF COVID-19 TRANSMISSION, WHICH LEADS TO ADVERSE COGNITIVE OUTCOMES; AND (2) AN INDIRECT EFFECT OF COVID-19 OUTBREAK-IMPOSED CHANGES IN PHYSICAL AND COGNITIVE ACTIVITIES, SOCIAL ENGAGEMENT, AND VASCULAR RISK FACTORS IN A SHARED FAMILY ENVIRONMENT IN DIVERSE COMMUNITIES. TO ADDRESS THIS SCIENTIFIC AREA OF RESEARCH, WE PROPOSE TO CONDUCT A BIRACIAL POPULATION-BASED COMMUNITY STUDY OF 4,000 OLDER CHAP PARENTS WITH TWO POPULATION COGNITIVE ASSESSMENTS AND DETAILED CLINICAL EVALUATIONS FOR ADRD IN 1,200 PARTICIPANTS WITH THE FOLLOWING SPECIFIC AIMS: (1) ESTIMATE THE 2020 US CENSUS DEMOGRAPHIC ADJUSTED OVERALL AND DEMOGRAPHIC-SPECIFIC (AGE, RACE/ETHNICITY, AND GENDER) PREVALENCE AND INCIDENCE OF ADRD, MCI, AND DEMENTIA LIKELIHOOD AND TEST WHETHER THE PREVALENCE AND INCIDENCE HAVE CHANGED BEFORE AND AFTER COVID-19. ALSO, TEST WHETHER THE 5-YEAR RISK OF ADRD AMONG HIGH-RISK AA PARENTS HAS HIGH-RISK OFFSPRING COMPARED TO EAS; (2) EXAMINE THE CHANGE IN PHYSICAL AND COGNITIVE ACTIVITIES, SOCIAL ENGAGEMENT, BMI, AND HYPERTENSION FROM PRE- TO POST-COVID AND THE IMPACT OF THESE CHANGES ON THE RISK OF ADRD, MCI, COGNITIVE DECLINE, AND MRI BRAIN INJURY. ALSO, TEST WHETHER THESE ASSOCIATIONS ARE HIGHER BY AGE, SEX (MALES VS. FEMALES), AND AMONG AA PARENTS AND OFFSPRING COMPARED TO EA PARENTS AND OFFSPRING; (3) TEST WHETHER PARTICIPANTS WITH SARS-COV-2 RNA INFECTIONS AND SEROLOGY ANTIBODIES AND ELEVATED CONCENTRATIONS OF INFLAMMATORY CYTOKINES AMONG THOSE WITH HIGHER VASCULAR RISK FACTORS HAVE A HIGHER RISK OF ADRD, MCI, COGNITIVE DECLINE, AND STRUCTURAL MRI BRAIN INJURY. ALSO, TEST WHETHER THESE ASSOCIATIONS ARE HIGHER AMONG AA PARENTS AND OFFSPRING COMPARED TO EAS. THIS PROPOSAL HAS AN ENORMOUS PUBLIC HEALTH IMPACT IN DEVELOPING PREVENTIVE STRATEGIES AND THERAPEUTIC STUDIES ON THE IMPACT OF COVID-19 ON POPULATION HEALTH ACROSS GENERATIONS FROM MIDLIFE TO LATE-LIFE IN A DIVERSE POPULATION WITH SOCIALLY DISADVANTAGED AA MINORITIES.

PRESERVING COGNITIVE RESILIENCE: A BIRACIAL PARENT-OFFSPRING STUDY (18-4674) - FEASIBILITY STUDY

MAPPING THE JOINT-NERVE INTERACTOME OF THE KNEE - PROJECT SUMMARY OUR MULTIDISCIPLINARY TEAM ASSEMBLES BASIC AND TRANSLATIONAL RESEARCHERS WITH EXPERTISE IN JOINT BIOLOGY AND NEUROSCIENCE, PROPOSING A HOLISTIC APPROACH TO MAPPING THE SENSORY INNERVATION OF MURINE AND HUMAN KNEE JOINTS. WE WILL USE STATE-OF-THE-ART IMAGING TECHNIQUES, COMBINED WITH TRANSCRIPTOMICS TO CONSTRUCT 3D MODELS OF THE SENSORY INNERVATION OF THE KNEE, COMPOSE A CELL ATLAS IN WHICH KNEE AFFERENTS ARE TRANSCRIPTIONALLY PROFILED AT A SINGLE CELL RESOLUTION, AND DOCUMENT THE NERVE-JOINT CELL INTERACTOME AT THE TRANSCRIPTIONAL LEVEL. OUR OVERARCHING OBJECTIVE IS TO PRECISELY DESCRIBE THE SENSORY INNERVATION OF THE KNEE, AND THE DYNAMIC CHANGES OCCURRING WITH AGING, JOINT INJURY, AND OSTEOARTHRITIS (OA). THIS WILL PROVIDE THE CONSORTIUM WITH A RICH ANATOMICAL AND MOLECULAR RESOURCE TO STUDY MECHANISMS UNDERLYING JOINT PAIN AND GUIDE THE DEVELOPMENT OF NOVEL ANALGESIC STRATEGIES. AIM 1. DOCUMENTING THE SENSORY INNERVATION OF THE HEALTHY AND DISEASED MOUSE KNEE: ANATOMICAL AND MOLECULAR PERSPECTIVES. USING FLUORESCENT REPORTER MICE TO LABEL NOCICEPTORS, C-FIBER SUBSETS, AND PROPRIOCEPTORS, WE WILL MAP THE ANATOMICAL INNERVATION OF THE MOUSE KNEE IN (A) NAÏVE MICE OF DIFFERENT AGES; (B) AFTER JOINT INJURY; (C) IN SURGICALLY INDUCED OA. WE WILL USE RIBBON SCANNING CONFOCAL AND CLEARING-ENABLED LIGHTSHEET MICROSCOPY TO CONSTRUCT HIGH-RESOLUTION 3-D ANATOMICAL MODELS OF JOINT INNERVATION. WE WILL BACKLABEL KNEE-INNERVATING AFFERENTS AND USE SPATIAL TRANSCRIPTOMICS TO DESCRIBE THEIR MOLECULAR PHENOTYPES COMPARED TO OTHER NON-KNEE INNERVATING DRG NEURONS. AIM 2. DOCUMENTING THE SENSORY INNERVATION OF THE HEALTHY AND DISEASED HUMAN KNEE: ANATOMICAL AND MOLECULAR PERSPECTIVES. WE WILL USE A UNIQUE SET OF POST MORTEM KNEE/DRG SAMPLES FROM (1) HEALTHY KNEES, AGE 20-40 (N=15/SEX); (2) KNEES FROM DONORS OVER 70 (N=15/SEX), IN WHICH WE ANTICIPATE 80-90% TO EXHIBIT OA PATHOLOGY. KNEE TISSUES WILL BE COLLECTED IN A STANDARDIZED FASHION, INCLUDING SYNOVIUM, OSTEOCHONDRAL PLUGS (MEDIAL TIBIAL PLATEAU), MENISCUS, ACL, FAT PAD, AND QUADRICEPS MUSCLE. IN EACH TISSUE, WE WILL PERFORM (1) HISTOPATHOLOGY; (2) IHC FOR SENSORY INNERVATION; (3) BULK AND SCRNASEQ; (4) SPATIAL TRANSCRIPTOMICS. MATCHED DRGS WILL BE USED FOR BULK RNASEQ TO IDENTIFY DIFFERENTIALLY EXPRESSED GENES (DEG) BETWEEN THE GROUPS PROVIDE INFORMATION FOR LIGAND-RECEPTOR ANALYSIS. AIM 3. IDENTIFYING MEDIATORS IN THE KNEE SYNOVIUM THAT DRIVE DISEASE- ASSOCIATED NEUROPLASTICITY. (1) WE WILL RECONSTRUCT THE CELLULAR INTERACTOME BETWEEN SYNOVIAL CELLS AND DRG NEURONS IN MOUSE MODELS OF AGING, JOINT INJURY, AND OA USING SCRNASEQ OF MATCHED SYNOVIUM AND DRG SAMPLES. (2) WE WILL COMPARE PATIENT REPORTS OF OA KNEE PAIN AT THE TIME OF TKR TO MATCHED SYNOVIAL HISTOLOGY, INCLUDING EXTENT OF LINING HYPERPLASIA, SINGLE-CELL TRANSCRIPTIONAL CHANGES, AND INNERVATION. OVERALL, THIS PROJECT WILL PROVIDE THE COMMUNITY WITH COMPREHENSIVE DATABASES OF THE NEURO-ARTICULAR ENVIRONMENT, WHICH CAN BE MINED TO (1) UNDERTAKE MECHANISTIC STUDIES TO INHIBIT PATHOLOGICAL NEUROPLASTICITY AND (2) IDENTIFY AND TEST NEW DRUGGABLE TARGETS. THIS STRATEGY WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL, TARGETED, NON-ADDICTIVE, AND SAFE ANALGESIC THERAPEUTICS FOR THE TREATMENT OF JOINT PAIN.

EFFECTS OF AFQ056 ON LANGUAGE LEARNING IN YOUNG CHILDREN WITH FRAGILE X SYNDROME (FXS)

WHOLE GENOME SEQUENCING AND ADMIXTURE ANALYSES OF NEUROPATHOLOGIC TRAITS IN DIVERSE COHORTS IN USA AND BRAZIL - ABSTRACT IDENTIFYING MOLECULAR DRIVERS OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD) PATHOLOGIES IS AN URGENT PUBLIC HEALTH PRIORITY. THIS IS ESPECIALLY IMPORTANT IN PERSONS OF AFRICAN ANCESTRY. THE OVERALL GOAL OF THE PROPOSED STUDY IS TO IDENTIFY GENES AND PROTEINS THAT DRIVE COMMON AD/ADRD PATHOLOGIC TRAITS. WE PREVIOUSLY USED MULTI-LEVEL OMICS TO IDENTIFY MOLECULAR DRIVERS OF AD/ADRD PATHOLOGIC TRAITS IN NON-LATINX WHITES. THE PROPOSED STUDY, SUBMITTED IN RESPONSE TO NOT-AG-18-053 WILL EXTEND THIS WORK BY LEVERAGING AN UNIQUE, ONGOING, DIVERSE STUDY BEING CONDUCTED IN SAO PAULO, BRAZIL, CALLED “PATHOLOGY, ALZHEIMER´S AND RELATED DEMENTIAS STUDY” (PARDOS) AND FIVE OTHER DIVERSE COHORTS IN THE USA, WITH WHOLE GENOME SEQUENCING (WGS) ON MORE THAN 1350 DIVERSE AUTOPSIED PARTICIPANTS. PARDOS IS PROSPECTIVELY GENERATING NEUROPATHOLOGIC AND CLINICAL AD/ADRD TRAITS, AND DNA ON ADMIXED BRAZILIANS OF EUROPEAN AND AFRICAN, AND TO A LESSER EXTENT NATIVE BRAZILIAN ANCESTRY. THE PROPOSAL HAS THE FOLLOWING AIMS. AIM 1 WILL GENERATE WGS ON AN ADDITIONAL 7650 PERSONS IN COLLABORATION WITH THE ALZHEIMER’S DISEASE SEQUENCING PROJECT (ADSP). AIM 2 WILL PERFORM DEEP ADMIXTURE MAPPING OF KNOWN SNPS FOR ALZHEIMER’S DEMENTIA, TO DETERMINE THEIR ASSOCIATIONS WITH AD/ADRD NEUROPATHOLOGIC PHENOTYPES IN 6500 ADMIXED BRAZILIAN BRAINS FOLLOWED GENERALIZATION TO 300 DIVERSE BRAINS FROM THE USA, AND DISCOVERY ANALYSES FOR 5500 BRAZILIANS FOLLOWED BY GENERALIZATION TO 2000 DIVERSE SAMPLES IN THE USA. AIM 3 WILL COMPUTATIONALLY DETERMINE TELOMERE LENGTH (TL) AND EXAMINE THEIR ASSOCIATION WITH AD/ADRD CLINICAL AND PATHOLOGIC TRAITS. AN EXPLORATORY ANALYSIS WILL EXAMINE FOR RARE VARIANT ASSOCIATIONS WITH AD/ADRD NEUROPATHOLOGIC TRAITS. AIM 5 WILL EXAMINE THE ASSOCIATION OF MITOCHONDRIAL DNA TO AD/ADRD TRAITS.

HIV SUSCEPTIBILITY AND PATHOGENESIS IN THE FEMALE GENITAL TRACT

RUSH CENTER FOR URBAN HEALTH EQUITY

RISK FACTORS FOR INCIDENT ALZHEIMER'S DISEASE

CHARACTERIZING THE BEHAVIOR PROFILE OF HEALTHY COGNITIVE AGING

TRANSITION FROM ACUTE TO CHRONIC PAIN IN TOTAL KNEE ARTHROPLASTY PATIENTS: IDENTIFYING RESILIENCE AND VULNERABILITY PROFILES

AFRICAN ANCESTRY AND THE GENOMIC ARCHITECTURE OF AD AND OTHER COMMON NEURODEGENERATIVE DISEASE NEUROPATHOLOGIES

EPIDEMIOLOGIC STUDY OF IMPAIRED DECISION-MAKING IN PRECLINICAL ALZHEIMER'S DISEAS

OSTEOARTHRITIS PROGRESSION AND SENSORY PATHWAY ALTERATIONS

CHICAGO PREVENTION AND INTERVENTION EPICENTER II (CPIE-II)

CK20-004, CHICAGO PREVENTION AND INTERVENTION EPICENTER III (CPIE-III)

DEVELOPING AN INTERVENTION TO PREVENT VISCERAL FAT IN PREMENOPAUSAL WOMEN: (CBID)

IDENTIFYING RESILIENCE PROTEINS IN KEY MOTOR TISSUES THAT DRIVE MOTOR AND COGNITIVE DECLINE AND OFFSET THE NEGATIVE EFFECTS OF ADRD PATHOLOGIES WITHIN AND OUTSIDE THE BRAIN - MOVEMENT IS A VOLITIONAL BEHAVIOR LINKED TO ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD). THOUGH MANY OLDER ADULTS SHOW SOME DEGREE OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES, THE EXTENT THAT THESE PATHOLOGIES DEGRADE MOVEMENT VARIES. THE SAME AMOUNT OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES MAY BE RELATED TO RAPID DECLINE IN ONE ADULT AND LITTLE LOSS IN ANOTHER. AN ADULT WHO MAINTAINS MOVEMENT OR HAS A SLOWER RATE OF DECLINE IN THE PRESENCE OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES MANIFESTS MOTOR RESILIENCE. TO PROMOTE MOTOR RESILIENCE, IT IS CRUCIAL TO IDENTIFY RISK FACTORS OR PROTEINS THAT OFFSET THE NEGATIVE EFFECTS OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES. SHARED NEURAL SUBSTRATE UNDERLIES MOTOR AND COGNITIVE RESOURCES THAT CONTROL MOVEMENT. SO, IT’S NOT SURPRISING THAT COGNITIVE RESILIENCE PROTEINS ARE RELATED TO MOTOR RESILIENCE. THIS STUDY WILL COMPLEMENT OUR ONGOING DISCOVERY OF RESILIENCE USING DEEP OMICS IN “COGNITIVE” BRAIN REGIONS WITH DEEP OMICS IN KEY “MOTOR REGIONS” TO IDENTIFY NEW GENES AND PROTEINS THAT MAY PROVIDE MOTOR AND COGNITIVE RESILIENCE. THIS STUDY RESPONDS TO NOT-AG-20-053. WE SELECTED 3 KEY MOTOR TISSUES IN WHICH TO IDENTIFY MOTOR RESILIENCE PROTEINS THAT MAY OFFSET THE NEGATIVE EFFECTS OF PATHOLOGIES OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) AND DEGENERATION IN MOTOR SYSTEMS. WE WILL THEN TEST IF SOME OF THESE PROTEINS ALSO PROVIDE COGNITIVE RESILIENCE. COMPELLING DATA SUPPORT THIS STUDY: 1) ALZHEIMER’S DISEASE PATHOLOGY IN BRAINSTEM AND SPINAL CORD IS RELATED TO A HIGHER ODDS OF DEMENTIA. 2) LARGE INDIVIDUAL DIFFERENCES IN DEGENERATION OF SPINAL MOTONEURONS, NERVE AND MUSCLE, HIGHLIGHT THE NEED TO MEASURE THEIR DEGENERATION TO ISOLATE MOTOR RESILIENCE. 3) OUR SYSTEMS BIOLOGY AND PROTEIN VALIDATION APPROACH APPLIED TO RNASEQ IN DORSAL LATERAL PREFRONTAL CORTEX (DLPFC) IDENTIFIED COGNITIVE RESILIENCE GENES AND PROTEINS IN PRIOR WORK. 4) THIS APPROACH CAN SUCCEED IN MOTOR TISSUES AS HIGH QUALITY RNASEQ DATA, SUMMARIZED AS CO-EXPRESSION MODULES, WAS OBTAINED FROM 3 KEY MOTOR TISSUES (BRAIN [SMA], SPINAL CORD AND MUSCLE) FROM THE SAME DECEDENTS. 5) AS HYPOTHESIZED, AFTER ISOLATING MOTOR RESILIENCE, WE IDENTIFIED PROTEINS IN DLPFC THAT PROVIDE RESILIENCE FOR MOTOR OR COGNITIVE DECLINE AND SOME THAT PROVIDE RESILIENCE FOR BOTH. MOTOR RESILIENCE MANIFESTS AS SLOWER MOTOR DECLINE. WE WILL QUANTIFY ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES IN BRAIN, BRAINSTEM, SPINAL CORD, NERVE AND MUSCLE TO ISOLATE MOTOR RESILIENCE I.E., MOTOR DECLINE NOT EXPLAINED BY ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES AND DEGENERATION. AIM 1 WILL APPLY A SYSTEMS BIOLOGY APPROACH TO TRANSCRIPTOME DATA FROM 3 KEY MOTOR TISSUES (BRAIN, SPINAL CORD AND MUSCLE) TO DISCOVER GENES THAT MAY PROVIDE MOTOR RESILIENCE. AIM 2 WILL VERIFY THESE GENES WITH SRM PROTEINS AND VALIDATE THAT THESE PROTEINS ARE RELATED TO MOTOR DECLINE IN AN INDEPENDENT SAMPLE OF ADULTS. AIM 3 WILL TEST IF MOTOR RESILIENCE PROTEINS ALSO PROVIDE COGNITIVE RESILIENCE AND IF AGGREGATING MULTIPLE PROTEINS INTO A PERSON-SPECIFIC INDEX QUANTIFIES HIGH AND LOW RESILIENCE RELATED TO ALZHEIMER’S DISEASE PHENOTYPES. AIM 4 WILL TEST IF RESILIENCE PROTEINS LINK RISK FACTORS WITH MOTOR AND COGNITIVE DECLINE. RESILIENCE PROTEINS ARE HIGH VALUE TARGETS FOR DRUG DISCOVERY TO MAINTAIN MOTOR AND COGNITIVE FUNCTION DESPITE THE PRESENCE OF UNTREATABLE ALZHEIMER’S DISEASE AND RELATED PATHOLOGIES. THESE DATA WILL ALSO INFORM ON MECHANISMS UNDERLYING MOTOR AND COGNITIVE DECLINE AND RISK FACTORS WHICH PROVIDE RESILIENCE.

CHARACTERIZING TDP-43 RELATED HIPPOCAMPAL DEGENERATION AND MEMORY LOSS IN AGING

RACIAL DIFFERENCES IN LATE-LIFE COGNITIVE DECLINE AND RISK OF ALZHEIMER'S DISEASE

STUDY OF WOMEN'S HEALTH ACROSS THE NATION-CHICAGO, RUSH

CONTROL MECHANISMS OF CA-INDUCED CA RELEASE

RUSH CENTER OF EXCELLENCE ON DISPARTIES IN HIV AND AGING (CEDHA)

RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF AD

MOLECULAR PATHWAYS OF PAIN GENERATION IN OSTEOARTHRITIS

EXPLORING THE ROLE OF THE BRAIN EPIGENOME: COGNITIVE DECLINE AND LIFE EXPERIENCES

LONGITUDINAL VALIDATION OF CEREBRAL SMALL VESSEL DISEASE BIOMARKERS IN DIVERSE COMMUNITY-BASED OLDER ADULTS WITHOUT DEMENTIA - ABSTRACT CEREBRAL SMALL VESSEL DISEASE (SVD) ENCOMPASSES A RANGE OF COMMON PROCESSES AND PATHOLOGIES (ARTERIOLOSCLEROSIS, CEREBRAL AMYLOID ANGIOPATHY, SMALL VESSEL ATHEROSCLEROSIS, SMALL AND MICROSCOPIC INFARCTS AND BLEEDS, ENLARGED PERIVASCULAR SPACES, AND WHITE MATTER DISEASE) THAT WE AND OTHERS HAVE SHOWN ARE ASSOCIATED WITH IMPAIRED COGNITION AND DEMENTIA (VCID). HIGH-QUALITY BIOMARKERS OF SVD ARE CRITICALLY NEEDED TO ADVANCE THE DIAGNOSIS, PREVENTION, AND TREATMENT OF SMALL VESSEL VCID. THE MISSION OF THE MARKVCID CONSORTIUM HAS BEEN TO IDENTIFY THE MOST PROMISING BIOMARKERS OF SVD AND CONDUCT ANALYTICAL (INSTRUMENTAL) VALIDATION AND PRELIMINARY CLINICAL VALIDATION. OUR TEAM AT RUSH UNIVERSITY MEDICAL CENTER AND ILLINOIS INSTITUTE OF TECHNOLOGY WAS PRIVILEGED TO BE ACTIVE PARTICIPANTS IN THIS INITIAL WORK. WE ARE NOW EAGER TO CONTINUE THIS COLLABORATIVE EFFORT WITH THIS PROPOSAL. THE OBJECTIVE OF THE PROPOSED PROJECT IS TO CONDUCT RIGOROUS LONGITUDINAL CLINICAL VALIDATION OF MARKVCID-SELECTED BIOMARKERS IN A DIVERSE COHORT FREE OF DEMENTIA, AND TO INVESTIGATE THE ASSOCIATIONS OF THESE BIOMARKERS WITH SVD NEUROPATHOLOGIC INDICES, WORKING SYNERGISTICALLY WITH OTHER CONSORTIUM SITES AND CONTRIBUTING SCIENTIFIC EXPERTISE, EXPERIMENTAL INFRASTRUCTURE, AND SCIENTIFIC GUIDANCE. SPECIFICALLY, WE PROPOSE TO RECRUIT, ENROLL, AND LONGITUDINALLY ASSESS A LARGE, DIVERSE, COMMUNITY-BASED GROUP OF OLDER ADULTS WITHOUT DEMENTIA USING MARKVCID CLINICAL EVALUATION AND BIOMARKERS, TO TEST THE HYPOTHESES THAT THE BIOMARKERS ARE ASSOCIATED WITH COGNITIVE DECLINE AND SVD NEUROPATHOLOGIC INDICES. THIS WILL BE A NESTED SUB-STUDY OF PARTICIPANTS OF THE RUSH MEMORY AND AGING PROJECT (MAP), MINORITY AGING RESEARCH STUDY (MARS), RELIGIOUS ORDERS STUDY (ROS), CLINICAL CORE (CC), AND LATINO CORE (LATC) OF THE RUSH ALZHEIMER’S DISEASE RESEARCH CENTER, WHICH ARE ON-GOING LONGITUDINAL, CLINICAL-PATHOLOGIC COHORT STUDIES OF AGING THAT RECRUIT NON-DEMENTED INDIVIDUALS AND HAVE HIGH FOLLOW-UP RATES. MARS AND CC RECRUIT EXCLUSIVELY AFRICAN AMERICANS, AND LATC RECRUITS LATINO OLDER ADULTS. OUR PAST CONTRIBUTIONS TO MARKVCID SUPPORT OUR CURRENT AIMS. FIRST, WE DEMONSTRATED OUR ABILITY TO RECRUIT AND FOLLOW A LARGE AND DIVERSE GROUP OF NON-DEMENTED OLDER ADULTS, SOME OF WHOM DIED, ENABLING AUTOPSY STUDIES. SECOND, WE DEVELOPED AND MADE PUBLICLY AVAILABLE A NOVEL BIOMARKER OF ARTERIOLOSCLEROSIS WITH HIGH PERFORMANCE, NAMED ARTS, WHICH WE TRAINED USING MACHINE LEARNING ON MRI AND PATHOLOGY DATA. THIRD, WE CONTRIBUTED TO THE ANALYTICAL AND INITIAL CLINICAL VALIDATION OF MULTIPLE MARKVCID BIOMARKERS. FOURTH, WE LED THE MARKVCID IMAGING BIOMARKERS COMMITTEE AND WERE ACTIVE IN ALL FUNCTIONS OF THE CONSORTIUM. WE PROPOSE TO LEVERAGE OUR EXPERTISE AND INFRASTRUCTURE TO CONDUCT RIGOROUS LONGITUDINAL CLINICAL VALIDATION OF MARKVCID BIOMARKERS IN A DIVERSE POPULATION, AND TO INVESTIGATE THE ASSOCIATIONS OF THESE BIOMARKERS WITH SVD NEUROPATHOLOGIC INDICES.

GENETIC EPIDEMIOLOGY OF COGNITIVE DECLINE IN AN AGING POPULATION SAMPLE

ADVANCED NURSING EDUCATION WORKFORCE

MEXICAN TEACHERS COHORT STUDY: GENETICS AND COGNITIVE FUNCTION - ABSTRACT THIS IS A RESUBMISSION OF A U01 APPLICATION FOR THE “ALZHEIMER’S DISEASE SEQUENCING PROJECT (ADSP) FOLLOW- UP STUDY 2.0: THE DIVERSE POPULATION INITIATIVE” (PAR-21-212). THE OVERALL GOALS ARE TO: (I) CONTRIBUTE NEARLY 20,000 GWAS AND 5000 WHOLE GENOME SEQUENCES TO ADSP FROM PARTICIPANTS OF THE “ESTUDIO DE LA SALUD DE LAS MAESTRAS” (MEXICAN TEACHERS COHORT), AND (II) DETECT NOVEL GENETIC DRIVERS OF COGNITIVE FUNCTION IN THIS LARGE MEXICAN COHORT, IN COMBINATION WITH EXISTING ADSP COHORTS. US HISPANICS ARE PROJECTED TO EXPERIENCE THE LARGEST INCREASE IN ADRDS OF ANY ETHNIC GROUP. MOREOVER, DEMENTIA ONSET OCCURS AT YOUNGER AGES, ON AVERAGE, IN HISPANIC/LATINX (HL) POPULATIONS IN THE US; EXPECTED YEARS LIVED WITH COGNITIVE IMPAIRMENT IS UP TO 4-8 YEARS LONGER FOR OLDER HL INDIVIDUALS, THAN NON-HISPANIC WHITES. MEXICAN-AMERICANS REPRESENT 65% OF US HISPANICS; COHORTS IN MEXICO CAN THUS COMPLEMENT THOSE IN THE US TO MAXIMIZE DEMENTIA RESEARCH IN DIVERSE POPULATIONS. MEXICAN TEACHERS COHORT (MTC) WAS ESTABLISHED IN 2006, AND IS AN ONGOING COHORT OF FEMALE TEACHERS, WHICH HAS MAINTAINED HIGH FOLLOWUP. MTC SPANS 12 CULTURALLY DIVERSE STATES IN MEXICO AND WAS DESIGNED TO SUPPORT RESEARCH ON GENETIC AND SOCIAL DETERMINANTS OF HEALTH. IN PARTICULAR, ANCESTRY ANALYSES DEMONSTRATE GENETIC SEPARATION OF MEXICAN FROM CENTRAL AND SOUTH AMERICAN BACKGROUNDS (MEXICANS HAVE DISTINCT AMERINDIAN SUBSTRUCTURE). THUS, ADDITION OF MTC TO ADSP CAN SUBSTANTIALLY CONTRIBUTE TO IDENTIFICATION OF NOVEL AND RELEVANT GENES/PATHWAYS UNDERLYING HEALTH. CENTRAL TO THIS U01, WE PROPOSE TO EXTEND MTC BY (I) IMPLEMENTING UP TO 2 WAVES OF COGNITIVE EVALUATIONS IN 13,500 EXISTING WOMEN PLUS 3,500 NEWLY-RECRUITED MEN, AGE 55+ YEARS, AND (II) COLLECTING BLOOD SPECIMENS IN ALL PARTICIPANTS. IN AIM 1, WE WILL GENOTYPE 17,000 PARTICIPANTS USING THE ILLUMINA GLOBAL SCREENING ARRAY; PERFORM WHOLE GENOME SEQUENCING IN 5000 PARTICIPANTS AGE 65+ YEARS; PROCESS/HARMONIZE ARRAY AND SEQUENCING DATA. IN AIM 2, WE WILL PERFORM DISCOVERY ADMIXTURE ANALYSES TO IDENTIFY GLOBAL ANCESTRY, AND THEN LOCAL ANCESTRY-ASSOCIATED REGIONS, RELATED TO THE POWERFUL QUANTITATIVE TRAIT OF GLOBAL COGNITIVE FUNCTION, AND SECONDARILY TO COGNITIVE IMPAIRMENT (MCI+DEMENTIA); THIS WILL INCLUDE FINE MAPPING TO IDENTIFY CREDIBLE CAUSAL VARIANTS, AND REPLICATION IN ADSP COHORTS. WE WILL ALSO EXAMINE KNOWN AD-RELATED SNPS IN THIS LARGE HL POPULATION. IN AIM 3, WE WILL GENERATE MEASURES OF TELOMERE LENGTH USING TELSEQ ON WGS, AND MEASURES OF MITOCHONDRIAL DNA (MTDNA) VARIATION (MTDNA COPY NUMBER AND MTDNA HETEROPLASMY) FROM WGS; WE WILL EXAMINE ASSOCIATIONS WITH COGNITIVE FUNCTION AND COGNITIVE IMPAIRMENT, ADDRESSING DIFFERENCES BY ANCESTRY. FINALLY, IN AIM 4, WE WILL SHARE ALL SPECIMENS VIA THE NCRAD REPOSITORY, AND DATA VIA NIAGADS. IMPACT: THE PROPOSED APPLICATION WILL PROVIDE A STRONG AND SUSTAINED IMPACT ON THE FIELD BY SUBSTANTIALLY BROADENING THE PLATFORM FOR DISCOVERY REGARDING COGNITIVE AGING IN HISPANIC/LATINX INDIVIDUALS.

GEOGRAPHIC UTILIZATION OF ARTIFICIAL INTELLIGENCE IN REAL-TIME FOR DISEASE IDENTIFICATION AND NOTIFICATION (GUARDIAN)

INTERPLAY BETWEEN NEUROPROTECTIVE PATHWAYS, HIV, AND ASTROCYTES

ALCOHOL AND CIRCADIAN DISRUPTION IN SHIFT WORKERS DECREASES THEIR RESILIENCY TO COVID-19

CHICAGO D-CFAR

PREPARING FOR PARENTHOOD: A FATHER INCLUSIVE MODEL OF PRENATAL CARE

COGNITIVE NEUROPSYCHOLOGY OF HIV AND DRUG ABUSE

MOLECULAR BASIS OF INTESTINAL CRYPTOSPORIDIOSIS

CHARACTERIZING THE NATURAL HISTORY OF FRAGILE X SYNDROME TO INFORM THE DEVELOPMENT OF INTERVENTION,OUTCOME MEASURES

PROGRAM PROJECT GRANT

EXPLORING THE ROLE OF THE BRAIN EPIGENOME: COGNITIVE DECLINE AND LIFE EXPERIENCES

EVALUATING SPECIFIC AND NON-SPECIFIC MECHANISMS IN TWO DISTINCT COMPLEMENTARY/INT

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

CHICAGO CENTER ON MUSCULOSKELETAL PAIN (C-COMP) (OVERALL APPLICATION) - PROJECT SUMMARY WE SEEK TO ESTABLISH A NEW RESOURCE-BASED CENTER TO FOSTER AND SUPPORT RESEARCH AND TRAINING AIMED AT UNDERSTANDING THE MECHANISMS UNDERLYING PAIN ASSOCIATED WITH MUSCULOSKELETAL (MSK) AND RHEUMATIC DISEASES, WITH THE ULTIMATE GOAL OF BETTER MANAGING AND PREVENTING IT. ONE THIRD OF THE WORLD’S POPULATION IS AFFECTED BY CHRONIC PAIN, AND THE MSK SYSTEM IS THE MOST PREVALENT SOURCE OF PAIN AND DISABILITY. CURRENTLY AVAILABLE ANALGESIC DRUGS ACT ON A LIMITED NUMBER OF TARGETS, AND THEY DO NOT PROVIDE SUSTAINED PAIN RELIEF AND THEIR CHRONIC USE IS ASSOCIATED WITH SERIOUS ADVERSE EFFECTS. ONE OF THE MAJOR OBSTACLES IN IDENTIFYING SAFE AND EFFICACIOUS DRUGS FOR PRODUCING PAIN RELIEF IS OUR GENERAL LACK OF UNDERSTANDING OF THE MECHANISMS UNDERLYING MSK PAIN, AND HOW THESE MECHANISMS MAY OVERLAP OR DIFFER BETWEEN DIFFERENT TYPES OF RHEUMATIC AND MSK DISEASES. THE CHICAGO CENTER ON MUSCULOSKELETAL PAIN (C-COMP) WILL ADDRESS THIS NEED IN A TIMELY AND UNIQUE MANNER, CAPITALIZING ON THE WORLD CLASS EXPERTISE THAT IS AVAILABLE TO US IN THE AREAS OF MSK RESEARCH, PAIN AND NEUROBIOLOGY TO ACHIEVE THE FOLLOWING BROAD LONG-TERM GOALS: (1) TO INTEGRATE BASIC, TRANSLATIONAL AND CLINICAL EXPERTISE IN A MULTIDISCIPLINARY CENTER WHICH WILL PROVIDE THE LEADERSHIP AND RESOURCES FOR PROMOTING MSK PAIN RESEARCH; (2) TO ENHANCE THE RESEARCH ENVIRONMENT FOR THE MSK RESEARCH COMMUNITY BY PROVIDING ACCESS TO WORLD-CLASS EXPERTISE AND STATE-OF-THE-ART RESOURCES, TECHNOLOGIES, AND INFRASTRUCTURE FOR STUDYING PAIN; (3) TO PROMOTE INTERDISCIPLINARY RESEARCH BETWEEN THE MSK RESEARCH FIELD AND THE FIELD OF PAIN/NEUROSCIENCE; (4) TO EXPAND THE MSK PAIN RESEARCH COMMUNITY BY ATTRACTING EARLY CAREER AS WELL AS ESTABLISHED RESEARCHERS INTO THIS AREA OF STUDY. WE ENVISION THREE CORES OPERATING IN SUPPORT OF THESE OVERALL GOALS. THE ADMINISTRATIVE CORE A (PI: A.M. MALFAIT; CO-DIRECTOR: J.J. JACOBS) WILL PROVIDE LEADERSHIP, MAINTAIN EFFECTIVE COMMUNICATION, PARTNER WITH RELATED CENTERS TO STIMULATE HUMAN TRANSLATION OF FINDINGS, AND IMPLEMENT A DYNAMIC ENRICHMENT PROGRAM. THE BEHAVIORAL RESOURCE CORE B (PI: R.E. MILLER; CO-DIRECTOR: D.R. SUMNER) WILL PROVIDE A CENTRALIZED RESOURCE TO FACILITATE BEHAVIORAL ASSAYS IN A BROAD ARRAY OF ANIMAL MODELS OF RHEUMATIC AND MSK DISEASES, INCLUDING TRAINING FOR BEHAVIORAL TESTS, ACCESS TO CUSTOMIZED PROTOCOLS, EQUIPMENT, AND SPACE TO PERFORM TESTING, A CONSULTATION SERVICE AND A CUSTOMIZED, FULL-SERVICE OPTION FOR BEHAVIORAL TESTING. THE NEUROBIOLOGY CORE C (PI: RJ MILLER; CO- DIRECTOR: D.R. SUMNER) WILL OFFER STATE-OF-THE-ART TECHNIQUES FOR ASSESSMENT AND MANIPULATION OF NEURONAL CIRCUITRY INVOLVED IN PAIN PHYSIOLOGY, SUCH AS IN VIVO CALCIUM IMAGING, ELECTROPHYSIOLOGY, CHEMO/OPTOGENETICS, TRANSCRIPTOMICS/BIOINFORMATICS AND NEUROANATOMICAL TECHNIQUES. THIS WILL ALLOW THE CENTER’S RESEARCH COMMUNITY TO ENGAGE IN CUTTING-EDGE INVESTIGATIONS OF THE MECHANISMS OF PAIN IN ANIMAL MODELS OF MSK DISEASE. IN SUMMARY, C-COMP WILL PROVIDE (1) UNIQUE RESOURCES AND INFRASTRUCTURE FOR SUPPORTING HIGH-QUALITY EXTERNALLY FUNDED RESEARCH AND (2) PILOT FUNDING, EDUCATION, AND TRAINING IN A MULTIDISCIPLINARY AND COLLABORATIVE FASHION. THIS INTEGRATED APPROACH IS EXPECTED TO ACCELERATE RESEARCH IN PAIN ASSOCIATED WITH MSK AND RHEUMATIC DISEASE.

ANATOMIC, PHYSIOLOGIC, AND COGNITIVE PATHOLOGY OF AD

LINKING PERIPHERAL AND BRAIN INSULIN RESISTANCE TO AD NEUROPATHOLOGY AND COGNITION

EPIDEMIOLOGIC STUDY OF BRAIN VITAMIN E, DIET & AGE-RELATED NEUROLOGIC DISEASES

INVESTIGATING THE EFFECT OF APOE ALLELES ON NEURO-IMMUNITY OF HUMAN BRAIN BORDERS IN NORMAL AGING AND ALZHEIMER'S DISEASE USING SINGLE-CELL MULTI-OMICS AND IN VITRO ORGANOIDS - PROJECT SUMMARY NEUROINFLAMMATION AND INNATE IMMUNE RESPONSE HAVE EMERGED AS THE FOREFRONT PATHOLOGY OF ALZHEIMER’S DISEASE (AD). ACCUMULATED EVIDENCE HAS SHOWN THAT APOLIPOPROTEIN E4 (APOE4), THE MOST SIGNIFICANT AD GENETIC RISK FACTOR, CONFERS A PRO-INFLAMMATORY STATE IN THE NORMAL AGING AND AD BRAINS. HOWEVER, MOST STUDIES HAVE CENTERED AROUND THE ROLES OF APOE4 IN DISRUPTING THE HOMEOSTATIC FUNCTIONS OF ASTROCYTES AND MICROGLIA IN BRAIN PARENCHYMA. RECENT DISCOVERIES OF A LYMPHATIC SYSTEM IN THE DURA MENINGES AND A REPERTOIRE OF IMMUNE CELLS AT BRAIN BORDERS HAVE HIGHLIGHTED THE CRITICAL ROLE OF BORDER IMMUNITY IN BRAIN AGING AND AD. APOE IS HIGHLY EXPRESSED IN THE BORDER-ASSOCIATED MACROPHAGES (BAMS), DURA LYMPHATIC VESSELS, AND CHOROID PLEXUS. THUS, THOSE STUDIES RAISE A CRITICAL QUESTION ON WHETHER APOE4 REGULATES THE BORDER-ASSOCIATED IMMUNITY IN NORMAL AGING AND AD. DESPITE THE RECENT SINGLE-CELL TRANSCRIPTOMIC STUDY ON MOUSE BAMS18, LITTLE INFORMATION EXISTS ON CELL STATES OF HUMAN BRAIN BORDERS RELATED TO NORMAL AGING AND AD, NEITHER THE APOE4’S EFFECTS ON BORDER CELL STATES, IMMUNITY, AND FUNCTIONS. THE OVERALL GOAL OF THIS APPLICATION IS TO INVESTIGATE THE EFFECT OF APOE ALLELES ON CELL STATES AND FUNCTIONS OF HUMAN BRAIN BORDERS IN NORMAL AGING AND AD. OUR CENTRAL HYPOTHESIS IS THAT AD AND APOE4 ALTER CELL STATES IN BRAIN BORDER REGIONS, AND APOE4 EXACERBATES MOLECULAR AND CELLULAR PHENOTYPES IN CONTROL AND AD ISOGENIC BORDER CELL MODELS. WE FORMULATED THIS HYPOTHESIS BASED ON LITERATURE AS MENTIONED ABOVE AND OUR TRANSCRIPTOMIC ANALYSIS SHOWING DISTINCT CELL TRANSCRIPTOMIC SIGNATURE AND STRONG APOE EXPRESSION IN BAMS AT HUMAN BRAIN BORDERS. WE WILL TEST THIS HYPOTHESIS BY COMBINING SINGLE-CELL MULTI-OMICS PROFILING OF EX VIVO HUMAN BORDER REGIONS AND IN VITRO BORDER REGION MODELING. SPECIFICALLY, WE WILL FIRST PROFILE THE SINGLE-CELL TRANSCRIPTOME AND CHROMATIN ACCESSIBILITY FROM THE SAME CELLS OF POSTMORTEM MENINGES AND CHOROID PLEXUS OF APOE4 AND NON-APOE4 CARRIERS FROM CONTROL AND AD INDIVIDUALS. THIS AIM WILL ENABLE US TO REVEAL CELL TYPES, CELL STATES, REGIONAL SPECIFICITY, AND INTERCELLULAR COMMUNICATIONS AT HUMAN BRAIN BORDERS AND IDENTIFY UPSTREAM MASTER REGULATORS OF AD- AND APOE4-SPECIFIC CELL STATES (AIM 1). TO STUDY THE APOE4’S FUNCTIONS IN HUMAN BRAIN BORDERS, WE WILL DEVELOP MULTICELLULAR CHOROID PLEXUS 3D MODELS BY INTRODUCING IPSC-DERIVED IMMUNE CELLS TO CHOROID PLEXUS ORGANOIDS. WE WILL THEN GENERATE CONTROL AND AD ISOGENIC CHOROID PLEXUS MODELS CARRYING EITHER APOE3 OR APOE4 ALLELES TO EXAMINE THE APOE4’S CELLULAR, MOLECULAR, AND FUNCTIONAL EFFECTS IN BOTH CELL-AUTONOMOUS AND NON-CELL-AUTONOMOUS MANNERS (AIM 2). OUR STUDY WILL SHED SIGNIFICANT INSIGHTS INTO HUMAN BORDER-ASSOCIATED IMMUNITY AND REVEAL A NOVEL MECHANISM UNDERLYING AD PATHOPHYSIOLOGY. THE UPSTREAM REGULATORS OF AD- AND APOE4-SPECIFIC CELL STATES IDENTIFIED IN THIS STUDY WILL SERVE AS IDEAL THERAPEUTIC TARGETS FOR MODULATING THE BRAIN BORDER IMMUNITY. OUR CHOROID PLEXUS MODEL PROVIDES A TRACTABLE SYSTEM TO TEST OTHER GENETIC TARGETS, EXTRINSIC FACTORS, AND CANDIDATE DRUGS, OPENING A NEW AVENUE OF TARGETING THE BRAIN BORDERS FOR AD THERAPEUTIC INTERVENTIONS.

DYNAMIC INTERACTION BETWEEN HIV IN THE CNS AND PERIPHERAL ORGANS

A NOVEL EPIGENETIC CLOCK FOR BRAIN AGING - ABSTRACT BIOMARKERS OF AGING ARE CRITICAL TO EFFECTIVE RESEARCH PROMOTING THE HEALTHSPAN. THERE IS A PARTICULARLY URGENT NEED FOR MOLECULAR BIOMARKERS OF BRAIN AGING; DEATHS DUE TO NEURODEGENERATIVE DISEASES HAVE INCREASED, IN CONTRAST TO DECREASES IN HEART DISEASE AND CANCER MORTALITY. EPIGENETIC DYSREGULATION IS CLEARLY IMPLICATED IN BRAIN AGING, ALZHEIMER DEMENTIA, AND OTHER NEUROLOGIC DISEASES. EPIGENETIC CLOCK BIOMARKERS COMBINE DNAM LEVELS ACROSS SELECT CPG SITES TO ESTIMATE BIOLOGIC AGE; EPIGENETIC CLOCKS STRONGLY PREDICT MORTALITY, AND SEVERAL ARE MODESTLY ASSOCIATED WITH NEUROLOGIC OUTCOMES. HOWEVER, WHILE SPECIFIC PEDIATRIC CLOCKS HAVE NOW BEEN DEVELOPED TO TARGET BIOLOGIC AGING IN YOUNGER AGE GROUPS, NO CLOCKS TO DATE TARGET OLDER POPULATIONS OR FOCUS ON PATHWAYS MECHANISTICALLY IMPLICATED IN AGING. WE PROPOSE HERE A NOVEL EPIGENETIC CLOCK, BUILT ON RIBOSOMAL DNA METHYLATION (RDNAM). THE RDNA LOCUS HARBORS FUNDAMENTAL, EVOLUTIONARILY CONSERVED AGING MECHANISMS, AND RDNAM HAS GREATER ASSOCIATION WITH AGE THAN ANY OTHER SEGMENT OF THE GENOME - YIELDING AN EFFICIENT AND EFFECTIVE EPIGENETIC CLOCK BIOMARKER. IN INITIAL WORK, WE REPORTED AN RDNAM CLOCK TRAINED IN MOUSE BLOOD WAS WELL-CALIBRATED IN HUMANS AND CANIDS. THUS, THE RDNA MAY REPRESENT A COMPELLING DIMENSION OF EPIGENETIC REGULATION, PROVIDING COMPLEMENTARY STRENGTHS TO ESTABLISHED CLOCKS. WE PROPOSE RESEARCH CONSTRUCTING A RDNAM CLOCK OF BRAIN AGING. INDEED, A RECENT REVIEW OF EPIGENETIC CLOCKS RECOMMENDED NEW DEVELOPMENT OF SUCH SPECIALIZED CLOCKS, ROOTED IN SPECIFIC TISSUES AND PATHWAYS, TO ADVANCE RESEARCH IN THE FIELD. THE PROPOSED AIMS UTILIZE THE RELIGIOUS ORDERS STUDY AND RUSH MEMORY AND AGING PROJECT (ROSMAP), WITH 1450 BRAIN SPECIMENS (INCLUDING A SUBSET WITH BLOOD SAMPLES), AND EXTENSIVE PHENOTYPIC DATA. IN AIM 1, WE WILL DOCUMENT RDNAM STATES IN DORSOLATERAL PRE-FRONTAL CORTEX (DLPFC), AND TRAIN A RDNAM CLOCK IN 800 SPECIMENS AGE >65 YEARS, TO ENHANCE APPLICATIONS TO AGING BRAIN. WE WILL THEN TEST RELATIONS OF THE RDNAM BRAIN CLOCK TO ALZHEIMER DISEASE NEUROPATHOLOGIC TRAITS IN THE REMAINING 650 ROSMAP DLPFC. IN AIM 2, WE WILL EVALUATE THE RDNAM BRAIN CLOCK IN TWO FURTHER BRAIN REGIONS (PRIMARY OCCIPITAL CORTEX, INFERIOR ANTERIOR TEMPORAL CORTEX), AND IN BLOOD SAMPLES AS A MORE ACCESSIBLE TISSUE FOR RESEARCH. IN AIM 3, WE WILL CONTRAST THE RDNAM BRAIN CLOCK TO EXISTING CLOCKS. IMPACT: OUR FOCUS ON THE HIGHLY CONSERVED RDNA LOCUS MAY IMPROVE APPLICATION OF THE RDNAM CLOCK ACROSS TISSUES, WHILE LINKS OF RDNA TO AGING AND NEUROBIOLOGY COULD ENHANCE APPLICATIONS TO BRAIN HEALTH. PROPOSED AIMS CAN YIELD NOVEL TOOLS TO EVALUATE BRAIN AGE, PREDICT RISK OF NEURODEGENERATIVE DISEASES, PROVIDE NEW INSIGHTS INTO MECHANISMS UNDERLYING NEURO-DEGENERATION, AND IDENTIFY INTERVENTIONS TO DELAY BRAIN AGING. ADDITIONALLY, GIVEN THE CENTRALITY OF RDNA IN CELLULAR METABOLISM AND AGING, WE WILL ADD TO A WEALTH OF HIGH-DIMENSIONAL DATA FOR LARGER RESEARCH IN THESE COHORTS.

UNCOVERING CELL-TYPE-SPECIFIC DRIVER GENES OF ALZHEIMER'S DISEASE BY PATHOLOGY-INDEXING SCRNA-SEQ, SPATIAL TRANSCRIPTOMICS, AND CRISPR SCREENS - PROJECT SUMMARY ALTHOUGH AMYLOID-SS PLAQUES AND NEUROFIBRILLARY TANGLES ARE THE CURRENT CRITERIA FOR PATHOLOGIC DIAGNOSIS OF ALZHEIMER’S DISEASES (AD), ONLY 9% OF CLINICALLY DIAGNOSED AD PATIENTS HAVE "PURE" AD PATHOLOGY AND MOST AD CASES HAVE MIXED PATHOLOGIES, WHICH SIGNIFICANTLY INCREASE THE ODDS OF DEMENTIA . BECAUSE DIVERSE INTRA- AND EXTRACELLULAR PATHOLOGIES AND STRESSORS CONTRIBUTE TO AD PROGRESSION, IT IS ESSENTIAL TO TRACK HOW THEY AFFECT THE VARIOUS CELL TYPES OF THE BRAIN BY CATALOGING CELL-TYPE-SPECIFIC TRANSCRIPTOMIC RESPONSES TO BOTH INTRA- AND EXTRACELLULAR PATHOLOGIES IN AD PATHOGENESIS. THEREFORE, THIS PROPOSAL AIMS TO MEASURE THE EFFECTS OF MULTIPLE PATHOLOGIES ON EACH CELL TYPE IN THEIR NATIVE ENVIRONMENT, THEN MAKE THIS INFORMATION ACTIONABLE BY COMPUTATIONALLY IDENTIFYING THE DRIVERS OF THESE EFFECTS AND TESTING THEM IN HUMAN CELL MODELS. TO THIS END, WE PROPOSE TWO APPROACHES TO SIMULTANEOUSLY MEASURE THE CELL TRANSCRIPTOMES AND MULTIPLE PATHOLOGIES IN MILLIONS OF INDIVIDUAL CELLS IN THEIR NATIVE CONTEXT. THE FIRST APPROACH, “PATHOLOGY-INDEXING SCRNA-SEQ,” IS DESIGNED FOR INTRACELLULAR PATHOLOGIES. IT COMBINES SINGLE-CELL RNA-SEQ (SCRNA-SEQ) WITH A SET OF OLIGO- BARCODED ANTIBODIES AGAINST INTRACELLULAR PATHOLOGIES. THIS APPROACH ENABLES US TO SIMULTANEOUSLY MEASURE GENE EXPRESSION AND MULTIPLE INTRACELLULAR PATHOLOGIES ALL IN THE SAME CELL. THE SECOND APPROACH, “PATHOLOGY SPATIAL TRANSCRIPTOMICS,” IS DESIGNED FOR EXTRACELLULAR PATHOLOGIES. IT OBTAINS GENE EXPRESSION OF 1~10 CELLS (55- ΜM RESOLUTION) IN SPATIAL REGISTRATION WITH EXTRACELLULAR PATHOLOGY. THIS ENABLES US TO QUANTIFY THE EFFECTS OF EXTRACELLULAR PATHOLOGIES AND MICROENVIRONMENT ON CELL DISEASE STATES. WE WILL APPLY THESE TWO INNOVATIVE SEQUENCING TECHNOLOGIES TO TWO BRAIN REGIONS, THE DORSAL LATERAL PREFRONTAL CORTEX AND HIPPOCAMPUS OF POSTMORTEM BRAINS OF DEEPLY-PHENOTYPED ROSMAP PARTICIPANTS. USING UNIVARIATE, SYSTEMS BIOLOGY, AND DEEP LEARNING COMPUTATIONAL METHODS, WE WILL IDENTIFY CANDIDATE GENES THAT DRIVE CELL-TYPE-SPECIFIC DISEASE STATES. TO TEST PREDICTED EARLY DRIVER GENES AND PROVIDE THERAPEUTIC TARGETS, WE WILL CONDUCT CRISPR SCREENS IN HUMAN CORTICAL CELL MODELS DERIVED FROM CONTROL AND AD ISOGENIC IPSC LINES. COLLECTIVELY, OUR STUDY WILL SHED IMPORTANT LIGHT ON THE CELL-TYPE-SPECIFIC DRIVER GENES IN AD PATHOGENESIS, DEFINE MOLECULAR PATHWAYS LEADING TO CELL DISEASE-STATES, AND PROVIDE EXPERIMENTALLY VALIDATED TARGETS FOR PREVENTING THE DISEASE-STATE TRANSITION DURING EARLY AD DEVELOPMENT.

CULTURALLY RELEVANT CONTRIBUTORS TO COGNITIVE AND MRI CHANGES IN OLDER LATINOS

MRI MARKERS OF BRAIN AGING AND RISK FACTORS FOR COGNITIVE DECLINE IN OLDER AFRICAN AMERICANS

BUILDING EARLY CONNECTIONS

BLUE LIGHT AND MELATONIN FOR TREATMENT OF CIRCADIAN RHYTHM DISORDERS AND JET LAG

ELUCIDATING THE MOLECULAR DRIVERS OF IMPAIRED MOBILITY WITHIN AND OUTSIDE THE CNS IN ALZHEIMER?S DISEASE AND RELATED DISORDERS

IMPAIRED GAIT IN OLDER ADULTS: PATHOLOGIES OF ALZHEIMER'S DISEASE AND RELATED DISORDERS

GEOGRAPHIC UTILIZATION OF ARTIFICIAL INTELLIGENCE IN REAL-TIME FOR DISEASE IDENTIFICATION AND NOTIFICATION (GUARDIAN)

ENGAGE, EDUCATE, EMPOWER FOR EQUITY: E4, THE RUSH CENTER OF EXCELLENCE FOR BEHAVIORAL HEALTH DISPARITIES IN AGING

MITIGATING COVID-19 TRANSMISSION IN U.S. JAILS

DEVELOPMENT OF CO-MORBID PTSD AND CHRONIC PAIN AMONG INNER-CITY WOMEN

REDUCING DISPARITY IN RECEIPT OF MOTHER?S OWN MILK IN VERY LOW BIRTH WEIGHT INFANTS: AN ECONOMIC INTERVENTION TO IMPROVE ADHERENCE TO SUSTAINED MATERNAL BREAST PUMP USE

3/4: IMPROVING THE PART C EARLY INTERVENTION SERVICE DELIVERY SYSTEM FOR CHILDREN WITH ASD: A RANDOMIZED CLINICAL TRIAL

GERIATRICS WORKFORCE ENHANCEMENT PROGRAM

VALUE AND MECHANISMS OF HOME VISITATION IN OBESITY INTERVENTIONS FOR LOW-INCOME CHILDREN

THE ROLE OF BLOOD AND BRAIN 5-HYDROXYMETHYLCYTOSINE IN LINKING VASCULAR RISK FACTORS TO ADRD IN OLDER WHITE AND BLACK PERSONS - PROJECT SUMMARY/ ABSTRACT ALZHEIMER’S DISEASE (AD) IS A CHRONIC AND DISABLING CONDITION, THE 6TH LEADING CAUSE OF DEATH IN THE US, AND A MAJOR CAUSE OF PERSONAL, SOCIETAL, AND GLOBAL BURDEN. YET, OUR UNDERSTANDING OF PATHOBIOLOGIC MECHANISMS UNDERLYING DEMENTIA AND COGNITIVE IMPAIRMENT IN AGING REMAINS INCOMPLETE, AND THIS GAP IN KNOWLEDGE HINDERS SCIENTIFIC ADVANCEMENT AND IMPROVED CLINICAL CARE AND PREVENTION. VASCULAR CONDITIONS SUCH AS DIABETES MELLITUS (DM) ARE COMMON, ESPECIALLY AMONG MINORITY RACIAL GROUPS, AND RECOGNIZED AS INCREASING DEMENTIA RISK. BECAUSE THESE FACTORS ARE MODIFIABLE BY TREATMENT AND LIFESTYLE APPROACHES, RESEARCH LINKING VASCULAR FACTORS TO ALZHEIMER’S DISEASE/ ALZHEIMER’S DISEASE-RELATED DEMENTIAS (AD/ADRD) IS MORE IMPORTANT THAN EVER. EMERGING DATA SUGGESTS THAT THE EPIGENOME LIKELY PLAYS A ROLE IN THIS LINK, AND NOVEL METHODS TO STUDY THE EPIGENOME ARE NOW AVAILABLE. 5-HYDROXYMETHYLCYTOSINE (5HMC) IS AN EPIGENETIC MODIFICATION OF CYTOSINE FOR WHICH WE CAN NOW MEASURE GENOME-WIDE CHANGES IN CIRCULATING CELL-FREE DNA (CFDNA) IN BLOOD AND GENOMIC DNA (GDNA) IN TISSUES. OUR GROUP HAS DEVELOPED A HIGHLY SENSITIVE AND SELECTIVE ANALYTIC APPROACH TO CAPTURE AND SEQUENCE 5HMC-CONTAINING DNA FRAGMENTS IN ORDER TO MAP GENOME-WIDE DISTRIBUTIONS, AND HAVE SUCCESSFULLY USED THIS APPROACH TO DEVELOP 5HMC SCORES WHICH DISTINGUISH BETWEEN PATIENTS WITH AND WITHOUT DIFFERENT CONDITIONS, INCLUDING IN RECENT STUDIES OF AD AND DM. IN RESPONSE TO THE PRESSING NEED TO BETTER UNDERSTAND THE PATHOBIOLOGIC UNDERPINNINGS OF AD/ADRD, WE PROPOSE A COLLABORATIVE PROJECT WITH THE OVERALL GOAL OF ELUCIDATING EPIGENETIC MECHANISMS LINKING VASCULAR RISK FACTORS TO AD/ADRD CLINICAL AND PATHOLOGICAL PHENOTYPES, IN OLDER WHITES AND BLACKS. THE PROPOSED STUDY WILL LEVERAGE AVAILABLE RESOURCES FROM TWO COMMUNITY-BASED COHORT STUDIES, INCLUDING RESEARCH PARTICIPANTS FROM WHICH TO COLLECT BLOOD SPECIMENS, AS WELL AS EXTENSIVE LONGITUDINAL CLINICAL DATA AND POSTMORTEM NEUROPATHOLOGIC DATA, AND BIOSPECIMENS (E.G., FROZEN BRAIN TISSUE SAMPLES). AMONG WHITE AND BLACK PERSONS, WE WILL COLLECT NEW GENOME-WIDE 5HMC DATA TO GENERATE SERUM-SPECIFIC (AIMS 1 AND 4) AND BRAIN-SPECIFIC 5HMC SCORES (AIMS 2 AND 4), USING DISCOVERY AND VALIDATION EXPERIMENTS IN DIFFERENT SETS OF PERSONS, THAT DISTINGUISHES BETWEEN PERSONS WITH AND WITHOUT DEMENTIA. WE WILL THEN LINK THE BLOOD AND BRAIN 5HMC DATA TO AD/ADRD CLINICAL AND PATHOLOGIC PHENOTYPES, INCLUDING INCIDENT DEMENTIA AND COGNITIVE DECLINE (AIMS 1 AND 4), CEREBROVASCULAR AND AD PATHOLOGY (AIM 2). WE WILL FURTHER EXAMINE IF RELATIONS ARE DIFFERENTIAL BY VASCULAR RISK FACTORS (DM, BLOOD PRESSURE [BP], AND BODY MASS INDEX [BMI]) AND BY OTHER FACTORS (E.G., SEX; AIMS1-4), AND IF GENERALIZABLE TO BLACK PERSONS (AIM 4). BECAUSE VASCULAR RISK FACTORS ARE COMMON AND MODIFIABLE, THIS STUDY WHICH WILL ELUCIDATE 5HMC MECHANISMS IN AD/ADRD AND VASCULAR DISEASES AMONG WHITE AND BLACK OLDER PERSONS, WILL FILL A MAJOR GAP IN SCIENTIFIC KNOWLEDGE ABOUT DEMENTIA AND PROVIDE IMPORTANT DATA TO INFORM FUTURE RESEARCH AND TO ULTIMATELY IMPROVE CLINICAL DEMENTIA CARE AND PREVENTION.

EPIDEMIOLOGY OF RACIAL DIFFERENCES IN DECISION MAKING AMONG OLDER ADULTS

RACIAL DISPARITIES IN PARKINSON DISEASE- CLINICAL PHENOTYPE, MANAGEMENT AND GENETICS - RACIAL DISPARITIES IN PARKINSON DISEASE- CLINICAL PHENOTYPE, MANAGEMENT AND GENETICS PROJECT SUMMARY PARKINSON DISEASE (PD) IS A PROGRESSIVE, DISABLING NEUROLOGICAL DISORDER. STUDIES INVESTIGATING THE FEATURES OF THE DISEASE IN BLACK POPULATIONS ARE UNCOMMON, WITH SOME SUGGESTING THAT BLACKS WITH PD ARE MORE DISABLED, WITH GREATER DISEASE SEVERITY, AND WITH DIFFERENT CLINICAL FEATURES COMPARED TO WHITE PD PATIENTS. THESE HEALTH DISPARITIES ARE LIKELY TO INFLUENCE THE QUALITY OF CARE FOR AA WITH PD. THE SPECIFIC AIMS OF THIS STUDY ARE TO INVESTIGATE 1) PD SYMPTOMS AND SIGNS IN BLACK PARTICIPANTS, 2) THE MANAGEMENT OF PD IN THESE PARTICIPANTS, AND 3) TO DETERMINE GENOTYPE-PHENOTYPE RELATIONSHIPS. BASED ON PRIOR STUDIES, THE MAIN STUDY HYPOTHESES ARE THAT BLACKS WITH PD HAVE MORE SEVERE MOTOR FEATURES, GREATER IMPACT ON THEIR QUALITY OF LIFE, LESS THERAPEUTIC OPTIONS, AND DISSIMILAR GENETIC VARIATION COMPARED TO WHITES WITH PD. AIM 1 INVESTIGATES MOTOR, NON-MOTOR, AND QUALITY OF LIFE SCALES IN 400 BLACK AND 200 WHITE PARTICIPANTS RECRUITED AT SEVEN DIFFERENT US SITES. AIM 2 INVESTIGATES MANAGEMENT IN THE SAME PARTICIPANTS INCLUDING MEDICATION, NON-MEDICATION AND SURGICAL TREATMENTS. AS PART OF THIS AIM, CLINICAL GUIDELINES WILL BE DEVELOPED FOR PD TREATING CLINICIANS TO RAISE AWARENESS OF RACIAL DISPARITIES IN PD. IN COLLABORATION WITH PD FOUNDATIONS, EDUCATIONAL PROGRAMMING WILL BE DEVELOPED FOR THE BLACK PD COMMUNITY TO IMPROVE SELF-MANAGEMENT SKILLS AND REDUCE DISPARITIES. IN AIM 3, A COLLABORATION WITH THE GLOBAL PARKINSON’S GENETICS PROGRAM WILL BE UTILIZED TO DETERMINE GENOTYPE-PHENOTYPE RELATIONSHIPS IN THE BLACK PARTICIPANTS. THE OVERALL GOAL OF THIS STUDY IS TO INVESTIGATE RACIAL DISPARITIES IN BLACKS WITH PD BY STUDYING KEY COMPONENTS OF THE DISEASE AND THEN DISSEMINATE THE FINDINGS TO THE NEUROLOGIC AND PATIENT COMMUNITY WITH TARGETED EDUCATION AND GUIDANCE. THIS STUDY WILL RESULT IN NEW SCIENTIFIC KNOWLEDGE WITH IN-DEPTH CHARACTERIZATION OF RACIAL DISPARITIES IN PD, AND WILL CHANGE CLINICAL PRACTICE BY RAISING AWARENESS OF DIFFERENCES IN THE PD CLINICAL PHENOTYPE, PATIENT-REPORTED OUTCOMES, AND PD RECOGNITION AND MANAGEMENT. THE RESULTS WILL ALSO IMPACT PUBLIC HEALTH SINCE RECOGNITION OF DIFFERENCES IN DISEASE MANIFESTATIONS AND MANAGEMENT IN BLACK PATIENTS WILL IMPROVE HEALTHCARE DELIVERY AND QUALITY OF CARE IN THIS UNDERSERVED AND UNDERSTUDIED POPULATION.

MECHANISMS OF PSYCHOSOCIAL CHRONIC PAIN TREATMENTS

MICROBIOTA-BRAIN AXIS IN ALZHEIMER'S DISEASE: MIND DIET-INDUCED EFFECTS

MECHANISMS LINKING INSULIN RESISTANCE TO BRAIN STRUCTURE, PATHOLOGY, AND FUNCTION

TEEN SCHOOL-NIGHT SLEEP EXTENSION: AN INTERVENTION TARGETING THE CIRCADIAN SYSTEM

EVALUATING THE EFFICACY OF COMBINED COGNITIVE PROCESSING THERAPY AND STELLATE GANGLION BLOCKS FOR PTSD: A RANDOMIZED CONTROLLED TRIAL

USE OF HEALTHCARE ACROSS THE FULL CONTINUUM OF COGNITIVE HEALTH AND DECLINE IN OLDER ADULTS - ABSTRACT THERE ARE >6 MILLION INDIVIDUALS WITH ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) IN THE US; THIS IS PREDICTED TO TRIPLE IN THE NEXT 30 YEARS. RESEARCH INDICATES THAT THOSE WITH DEMENTIA HAVE SUBSTANTIALLY GREATER HEALTHCARE UTILIZATION. YET, DEMENTIA REPRESENTS ONLY THE EXTREME END OF A CHRONIC PROGRESSIVE DISORDER. FULLY CHARACTERIZING PATTERNS OF HEALTHCARE UTILIZATION ACROSS THE CONTINUUM OF COGNITIVE IMPAIRMENT IS CRITICAL TO (I) PLANNING RESOURCE USE IN OUR AGING POPULATION, AND (II) IDENTIFYING AREAS WHERE CARE MIGHT BE MODIFIED/IMPROVED. IN PARTICULAR, BETTER UNDERSTANDING CARE PATTERNS IN EARLY STAGES OF COGNITIVE IMPAIRMENT COULD BE CRUCIAL SINCE MODIFICATIONS MAY BE EASIER FOR THOSE WITH LESS DISEASE BURDEN. INDEED, GROWING RESEARCH SUGGESTS CHANGES IN HEALTHCARE UTILIZATION MAY BEGIN EVEN WITH MILD COGNITIVE IMPAIRMENT (MCI). HOWEVER, THE LIMITED STUDIES GENERALLY LACK EITHER RIGOROUS DATA ON COGNITIVE STATUS, INTEGRATE HEALTH SERVICES DATA FROM 10-15+ YEARS IN THE PAST, OR INCLUDE VERY SMALL SAMPLES. THUS, WE PROPOSE TO EVALUATE THE SPECTRUM OF COGNITIVE HEALTH IN RELATION TO HEALTHCARE UTILIZATION, INCLUDING ADRD DRUGS AND END OF LIFE (EOL) CARE, IN 4 ONGOING COHORTS AT THE RUSH ALZHEIMER’S DISEASE CENTER (RADC). ALL PARTICIPANTS RECEIVE ANNUAL, HARMONIZED COGNITIVE ASSESSMENTS AND NEUROLOGIC EXAMS, WITH ~90% FOLLOWUP; THIS INCLUDES 2,317 OLDER INDIVIDUALS WITH LINKED MEDICARE FEE-FOR-SERVICE CLAIMS FROM 2010-19 (11,000PY OF FOLLOWUP: 2000PY FOR MCI, 1200PY FOR DEMENTIA). FURTHER, 20% OF PARTICIPANTS ARE AFRICAN AMERICAN (AA), ENABLING INITIAL WORK ON COGNITION AND HEALTH SERVICES FOCUSED IN AAS, WHO HAVE HIGH RISK OF MCI AND DEMENTIA; THIS WILL ALSO ESTABLISH A PLATFORM FOR FUTURE RESEARCH AS THE RADC AA COHORT CONTINUES TO EXPAND. BRIEFLY, WE WILL COMPARE PARTICIPANTS DIAGNOSED AS NO COGNITIVE IMPAIRMENT (NCI), MCI, AND DEMENTIA AT EACH ANNUAL COHORT EVALUATION, CONSIDERING DIFFERENCES IN THE SUBSEQUENT YEAR IN THEIR UTILIZATION OF OUTPATIENT AND INPATIENT SERVICES (AIM 1), AND ADRD DRUG PRESCRIPTION FILLS (AIM 2). AIM 2 WILL FOCUS ON EXAMINING PARTICIPANT AND DISEASE CHARACTERISTICS THAT MAY BE RELATED TO PRESCRIPTION FILLS. IN AIM 3, WE WILL COMPARE EOL CARE ACROSS DECEDENTS DIAGNOSED WITH NCI, MCI OR DEMENTIA. FINALLY, WHILE COHORT DATA ARE ESSENTIAL TO VALIDLY STUDYING THE CONTINUUM OF COGNITION, COHORTS OFTEN TARGET SPECIFIC PARTICIPANTS; IN AIM 4, WE WILL ENHANCE LARGER TRANSLATION OF COHORT FINDINGS BY ASSESSING ANY DIFFERENCES IN HEALTH SERVICES, ADRD DRUGS, AND EOL CARE BETWEEN RADC PARTICIPANTS VERSUS THE GENERAL MEDICARE POPULATION. WE WILL THEN APPLY STATISTICAL METHODS, AS NEEDED, TO “MIMIC” OUR RESULTS IN LARGER GROUPS OF THE GENERAL MEDICARE POPULATION. IMPACT: BY COMPREHENSIVELY EVALUATING DIFFERENCES IN HEALTHCARE UTILIZATION ACROSS THE CONTINUUM OF COGNITION, WE CAN BEGIN TO DETECT STAGES WHERE CARE IS ACCESSED DIFFERENTIALLY, INCLUDING TYPES OF CARE WHICH MAY BE AFFECTED. THIS WILL BOTH INFORM TARGETED INTERVENTIONS TO OPTIMIZE HEALTH SERVICES, AND IMPROVE FUTURE RESOURCE PLANNING.

CLEAVAGE OF INTERSECTIN-1S BY GRANZYME B AND PULMONARY ARTERIAL HYPERTENSION

NEUROIMMUNE AXIS IN HAND AND HIV PERSISTENCE IN THE BRAIN

THE LIFE PROGRAM: A BEHAVIORAL APPROACH TO GLYCEMIC CONTROL IN AFRICAN AMERICANS

MULTI-CLINIC ACTION TRIAL TO CONTROL HYPERGLYCEMIA & HYPERTENSION

CART, NEUROHIV, COCAINE ABUSE AND THE MPFC NEURON/ASTROCYTE DYSFUNCTION - ABSTRACT HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) IS A SIGNIFICANT COMORBID CONDITION FOR PEOPLE LIVING WITH HIV/ AIDS (PLWH). HAND IS ASSOCIATED WITH HIV-INDUCED NEUROTOXICITY THAT DYSREGULATES, INJURES, AND IN SEVERE CASES, CAUSES DEATH OF NEURONS IN THE KEY BRAIN REGIONS THAT REGULATE NEUROCOGNITION. COMBINED ANTIRETROVIRAL THERAPY (CART) INHIBITS ACTIVE HIV-1 REPLICATION; BUT IT HAS NOT REDUCED THE PREVALENCE OF HAND, AS IT OCCURS IN 30~50% OF PLWH AND IS EXPECTED TO INCREASE AS PLWH AGE. NOTABLY, COCAINE (COC) USE DISORDERS (CUD) ARE COMORBID WITH HAND IN MANY CASES AND WORSEN IT SEVERELY. IRONICALLY, ALTHOUGH CART IS ABSOLUTELY NECESSARY FOR TREATING HIV/AIDS, EMERGING DATA POINT TO CART AS A POTENTIAL CONTRIBUTOR TO HAND THROUGH CART-INDUCED NEUROTOXICITY. THIS RAISES KEY QUESTIONS REGARDING IF CHRONIC CART CONTRIBUTES TO NEUROLOGICAL/NEUROCOGNITIVE DEFICITS LINKED TO HAND; AND HOW IT ALTERS BRAIN NEURON ACTIVITY IN THE CONTEXT OF NEUROHIV AND CUD; BOTH ARE THE FOCUS OF THIS PROPOSAL. OUR STUDIES SUGGEST THAT CART INDUCES NEURONAL CA2+ DYSREGULATION IN THE MEDIAL PREFRONTAL CORTEX (MPFC, A KEY REGULATOR OF NEUROCOGNITION AND ADDICTION), SIMILAR TO THAT WELL-DESCRIBED IN NEUROHIV AND CUD MEDIATED BY OVERACTIVE VOLTAGE-GATED L-TYPE CA2+ CHANNELS (L-CHANNELS) AND NMDA RECEPTORS (NMDARS). DYSFUNCTION OF MPFC PYRAMIDAL NEURONS IS LINKED TO HAND, CUD AND MANY OTHER NEURO- DEGENERATIVE DISEASES. THUS, WE HYPOTHESIZE THAT CART-INDUCED MPFC NEURONAL CA2+ DYSREGULATION WORSENS SIMILAR DYSFUNCTION CAUSED BY NEUROHIV AND COC; AND THAT IS REDUCED BY COMBINED ANTAGONISM OF L -CHANNEL/ NMDAR OVERACTIVATION. WE WILL DETERMINE THE EFFECTS OF CART, NEUROHIV AND COC ON MPFC PYRAMIDAL NEURONS, AND ELUCIDATE THEIR UNDERLYING MECHANISM. SPECIFICALLY, WE WILL USE THREE COMBINED RAT MODELS OF (I) CART (CHRONIC TRIUMEQ, A 1ST-LINE CART REGIMEN CONSISTING OF 3 ANTIRETROVIRAL DRUGS - ABACAVIR, DOLUTEGRAVIR AND LAMIVUDINE), (II) NEUROHIV (HIV-1 TRANSGENIC RATS), AND (III) COC ABUSE (COC SELF-ADMINISTRATION, COC-SA), TO ELUCIDATE THE LONG-TERM EFFECTS OF CART IN VIVO ON MPFC NEURONAL ACTIVITY AND THEIR MECHANISM IN THE CONTEXT OF NEUROHIV AND CUD (AIM1); DEFINE THE EFFECTS OF CHRONIC CART ON INTERACTIVE ASTROCYTE/NEURON DYSFUNCTION IN THE MPFC UNDER NEUROHIV AND CUD CONDITIONS (AIM2); AND IDENTIFY THE EFFECTS OF COMBINED ANTAGONISM OF EXCESSIVE CA2+ INFLUX/ [CA2+]IN THAT ALLEVIATE NEURONAL ACTIVITY AND COGNITIVE BEHAVIOR IN THE CONTEXT OF NEUROHIV/ CUD (AIM3). FURTHER, WE WILL ALSO DEFINE HIV/CART/COC-INDUCED NEURON/ASTROCYTE DYSFUNCTION IN POST-MORTEM HIV+ HUMAN BRAINS (EXPLORATORY AIM) TO PROVIDE ADDITIONAL SUPPORT FOR THE PRINCIPAL CONCEPT AND HYPOTHESIS OF THIS PROPOSAL. TOGETHER, THE PROPOSED RESEARCH WILL ELUCIDATE THE MECHANISM BY WHICH NEUROHIV, CHRONIC CART IN VIVO AND COC-SA, INDIVIDUALLY AND JOINTLY, ALTER MPFC NEURONAL ACTIVITY, AND IN SUCH PROCESS IDENTIFY THE KEY MECHANISTIC TARGETS THAT WILL INFORM THERAPEUTIC INTERVENTION FOR HAND AND CUD IN THE ERA OF CART.

COMPARATIVE MECHANISMS (MEDIATORS, MODERATORS) OF PSYCHOSOCIAL CHRONIC PAIN TREATMENTS - CHRONIC MUSCULOSKELETAL PAIN (CP) IS A MAJOR PUBLIC HEALTH CONCERN. A NUMBER OF PSYCHOSOCIAL TREATMENTS HAVE EMERGED IN RECENT DECADES TO HELP ADDRESS THIS PROBLEM. THESE INTERVENTIONS HAVE BEEN SHOWN TO BE EFFICACIOUS WHEN COMPARED TO LARGELY INERT CONTROL CONDITIONS; HOWEVER, RECENT META-ANALYSES INDICATE THAT MOST OF THESE TREATMENTS ARE CHARACTERIZED BY MODEST EFFECTS ON PRIMARY OUTCOMES. THIS IS A CRITICAL SHORTCOMING OF THESE OTHERWISE PROMISING APPROACHES. RATHER THAN ATTEMPTING TO BOOST EFFICACY ONLY BY DEVELOPING NEW AND HOPEFULLY MORE POWERFUL INTERVENTIONS, WE CAN ALSO LOOK WITHIN OUR ALREADY PROVEN TREATMENTS FOR WAYS TO ENHANCE THE MAGNITUDE OF TREATMENT EFFECTS. ONE STRATEGY IS TO INCREASE OUR UNDERSTANDING OF TREATMENT MEDIATORS. STUDIES OF MEDIATORS ARE NEEDED THAT DIRECTLY COMPARE DIFFERENT TREATMENTS WITH EACH OTHER TO DETERMINE WHICH MEDIATORS ARE TREATMENT-SPECIFIC, WHICH ARE SHARED ACROSS TREATMENTS, AND WHICH CONTRIBUTE THE MOST TO CLINICAL OUTCOMES. THE FINDINGS FROM SUCH RESEARCH COULD BE USED TO INFORM ADAPTATIONS TO EXISTING TREATMENT THAT ENHANCE THEIR BENEFITS. A SECOND STRATEGY FOR INCREASING THE BENEFICIAL EFFECTS OF EXISTING TREATMENTS IS TO IDENTIFY THE PATIENT CHARACTERISTICS THAT MODERATE TREATMENT RESPONSES. RESEARCH IS NEEDED THAT IS GUIDED BY THEORETICAL MODELS AND THAT TESTS MODERATORS ACROSS MULTIPLE TREATMENTS. IDENTIFYING SUBGROUPS OF PATIENTS MORE LIKELY TO RESPOND TO ONE OR ANOTHER TREATMENT CAN ADVANCE PRECISION MEDICINE BY INFORMING A PRIORI PATIENT-TREATMENT MATCHES THAT CAN OPTIMIZE TREATMENT EFFECTS. WE WILL COMPARE THE MECHANISMS AND MODERATORS OF COGNITIVE-BEHAVIORAL THERAPY (CBT), ACCEPTANCE AND COMMITMENT THERAPY (ACT), AND EMOTIONAL AWARENESS AND EXPRESSION THERAPY (EAET). EXAMINING THE MEDIATORS AND MODERATORS OF THESE TREATMENTS HOLDS GREAT POTENTIAL FOR ADVANCING TREATMENT DEVELOPMENT AND ENHANCING TREATMENT EFFICACY. ADULTS WITH CHRONIC SPINAL (AXIAL) PAIN (N=460) WILL BE RANDOMLY ASSIGNED TO CBT, ACT, EAET AND TO TREATMENT-AS-USUAL (TAU). AIM 1 IS TO IDENTIFY SPECIFIC AND SHARED MEDIATORS ACROSS TREATMENTS. AIM 2 IS TO IDENTIFY MODERATORS ACROSS TREATMENTS. THIS PROJECT CAN INCREASE THE EFFECTS OF OUR PSYCHOSOCIAL CHRONIC PAIN TREATMENTS BY IDENTIFYING THE MOST POWERFUL TREATMENT MECHANISMS – SPECIFIC AND SHARED -- AND REVEALING FOR WHOM THE MEDIATOR OUTCOME PATHWAYS ARE STRONGEST. VIA INCREASED UNDERSTANDING OF MEDIATOR AND MODERATORS, MORE EFFECTIVE PAIN TREATMENT APPROACHES CAN BE DEVELOPED, TESTED, AND IMPLEMENTED.

ALIVE CHURCH NETWORK: INCREASING COVID-19 TESTING IN CHICAGO'S AFRICAN AMERICAN TESTING DESERTS

NEUROPATHOLOGIC-EPIDEMIOLOGICAL STUDY OF METALLOMICS AND ALZHEIMER'S DISEASE - PROJECT SUMMARY THE PROJECT NEUROPATHOLOGIC-EPIDEMIOLOGICAL STUDY OF METALLOMICS AND ALZHEIMER'S DISEASE (RF1AG054057) DEMONSTRATED FOR THE FIRST TIME THAT PRO-OXIDANT IRON DIRECTLY MEASURED IN HUMAN BRAIN IS STRONGLY ASSOCIATED WITH COGNITIVE DECLINE IN OLDER PERSONS WITH AD PATHOLOGY. IN THIS PROPOSED CONTINUATION, WE PROPOSE TO FURTHER THESE STUDIES TO RESOLVE MECHANISMS UNDERLYING BRAIN IRON ELEVATION, SUSCEPTIBILITY TO IRON-MEDIATED DAMAGE, AND RESULTANT DECLINE. UNDERPINNING OUR HYPOTHESIS IS THE RECENTLY DISCOVERED PROGRAMMED DEATH PATHWAY, FERROPTOSIS, WHICH CAUSES DESTRUCTION OF SYNAPTIC AND CELLULAR MEMBRANES BY IRON DEPENDENT PEROXIDATION OF CERTAIN LIPIDS. STRONG PRELIMINARY DATA SUPPORTS THESE AIMS. IN THIS COMPETIVE RENEWAL, WE PROPOSE TO TEST THE HYPOTHESES THAT (1) DIETARY FAT AND BRAIN LIPIDS CONTRIBUTE TO THE ELEVATION OF BRAIN IRON; AND (2) IRON INTERACTS WITH BRAIN LIPIDS TO PROMOTE LIPID PEROXIDATION, RESULTING IN TOXIC BRAIN INJURY (VIA FERROPTOSIS), NEURONAL LOSS, AND ULTIMATELY ACCELERATED COGNITIVE AND MOTOR DECLINE IN AGING. WE PROPOSE TO USE NOVEL METHODOLOGIES, INCORPORATING (OXIDIZED) LIPIDOMICS USING ADVANCED METHODOLOGIES (I.E. TARGETED AND OXIDIZED LIPIDOMICS AND IMMUNE-ASSISTED, TANDEM LASER ABLATION MALDI/ICP-MS) TO MAP IRON AND LIPID-MEDIATED NEURODEGENERATION IN COGNITIVE AND MOTOR BRAIN REGIONS. WE WILL EXPAND DIETARY STUDIES, AND LEVERAGE A RICH RESOURCE OF CLINICAL AND PATHOLOGIC DATA AVAILABLE FROM RUSH MEMORY AND AGING PROJECT. OVERALL, WE PROPOSE TO COLLECT NEW DATA ON BRAIN LIPIDS, INCREASE DATA ON IRON AND DIETARY FATS TO GOAL OF 850 BRAINS. IN AIM 1, WE WILL TEST THE HYPOTHESES THAT DIETARY FAT INTAKE IS ASSOCIATED WITH BRAIN LIPID COMPOSITION AND IRON CONTENT; THAT BRAIN LIPID COMPOSITION IS ASSOCIATED WITH BRAIN IRON CONTENT; AND USE ADVANCED TECHNOLOGY TO MAP AND TEST THEIR RELATIONSHIP ACROSS THE LAYERED CORTEX. IN AIM 2, WE PROPOSE TO DETECT OXIDIZED LIPIDS AND TEST THE HYPOTHESES THAT LIPID PEROXIDATION IS ASSOCIATED WITH BRAIN IRON, ALZHEIMER’S PATHOLOGY, AND COGNITIVE DECLINE. WE ALSO WILL INVESTIGATE WHETHER LIPID PEROXIDES MEDIATE COGNITIVE DECLINE ASSOCIATED WITH IRON IN AD. IN AIM 3 WE WILL DETERMINE BRAIN IRON AND (OXIDIZED) LIPID CONTENT IN BRAIN MOTOR REGIONS AND TEST THE HYPOTHESIS THAT REGIONAL BRAIN IRON IS ASSOCIATED WITH LIPID COMPOSITION AND WITH MOTOR FUNCTION AND DECLINE AND MOTOR PATHOLOGY (LEWY BODY, VASCULAR, AD, ETC.) IN OLDER PERSONS. IN EACH AIM, WE WILL INVESTIGATE HOW RELATIONSHIPS DIFFER BY APOE E4, ALZHEIMER’S PATHOLOGIC DIAGNOSIS AND SEX. OVERALL, THESE STUDIES HAVE THE POTENTIAL TO UNCOVER NEW MECHANISMS BY WHICH IRON, LIPIDS (DIET AND BRAIN), AND APOE E4 INCREASE COGNITIVE AND MOTOR DECLINE IN AGING AND AD. THESE STUDIES HAVE THE POTENTIAL TO REVEAL NEW AND TARGETABLE BIOLOGIC PATHWAYS.

BRAIN-GUT CIRCADIAN RHYTHM INTERACTIONS IN ALCOHOL-INDUCED GUT LEAKINESS

REDUCING HEALTH DISPARITY IN AA WOMEN: PHYSICAL ACTIVITY ADHERENCE

VASCULAR COGNITIVE AND MOTOR DECLINE: IMPACT OF APL

INTERACTIVE EFFECTS OF METH, HIV AND CART ON ASTROCYTE/NEURON FUNCTION

MULTIMODAL MRI BIOMARKERS OF SMALL VESSEL DISEASE FOR OLDER PERSONS WITH AND WITHOUT DEMENTIA.

PREDICTORS AND CONSEQUENCES OF THE TIMING AND ACCURACY OF CLINICAL DEMENTIA DIAGNOSIS - PROJECT SUMMARY / ABSTRACT THE OVERARCHING GOAL OF THIS PROJECT IS TO DEVELOP THE EVIDENCE BASE AROUND THE PREDICTORS AND CONSEQUENCES OF CLINICAL UNDERDIAGNOSIS VS EARLY CLINICAL DIAGNOSIS OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) IN HEALTHCARE SETTINGS. MANY OLDER PERSONS WHO WOULD MEET DIAGNOSTIC CRITERIA FOR DEMENTIA—POTENTIALLY MORE THAN HALF—ARE UNDERDIAGNOSED IN THE HEALTHCARE SETTING, MEANING THEY ARE DIAGNOSED BY THEIR PROVIDER YEARS AFTER SYMPTOMS THAT MEET CRITERIA FOR DEMENTIA FIRST EMERGE (I.E. LATE DIAGNOSIS) OR ARE NEVER DIAGNOSED (I.E. MISSED DIAGNOSIS). WE KNOW RELATIVELY LITTLE ABOUT THE FACTORS THAT DRIVE THE TIMING OF RECEIPT OF A CLINICAL DIAGNOSIS OF DEMENTIA. ADVANCES IN THIS AREA WOULD ALLOW US TO ADDRESS DIAGNOSTIC DISPARITIES. IN RECENT YEARS, THERE HAS ALSO BEEN A PUSH FOR EARLY CLINICAL DIAGNOSIS OF DEMENTIA (I.E. IDENTIFYING PERSONS WITH DEMENTIA CLOSE TO THE TIME OF SYMPTOM ONSET), DESPITE LACK OF AN EFFECTIVE DISEASE-ALTERING TREATMENT FOR ADRD. THE IMPORTANCE OF AN EARLY CLINICAL DEMENTIA DIAGNOSIS WOULD BE BOLSTERED BY CLEAR EVIDENCE THAT IT LED TO BETTER LONG-TERM HEALTH FOR DIAGNOSED PATIENTS, MORE APPROPRIATE HEALTHCARE UTILIZATION, OR DECREASED MEDICAL COSTS. CONVERSELY, EVIDENCE OF HARMS WOULD SUGGEST A RENEWED FOCUS ON IMPROVING DEMENTIA CARE IS WARRANTED. HOWEVER, THE BENEFITS AND HARMS RELATED TO THE TIMING OF A CLINICAL DEMENTIA DIAGNOSIS REMAIN POORLY CHARACTERIZED. THIS PROJECT WILL ADDRESS THESE CRUCIAL GAPS IN UNDERSTANDING BY LEVERAGING UNIQUE DATA FROM 5 DIVERSE, HARMONIZED COHORTS OF AGING FROM THE RUSH ALZHEIMER’S DISEASE CENTER (RADC) WITH ROBUST COGNITIVE ASSESSMENT AND LINKED MEDICARE CLAIMS RECORDS FROM 1991 TO THE PRESENT. THIS DATA IS PERFECTLY SUITED TO THESE AIMS, AS STUDY-BASED DEMENTIA ASCERTAINMENT IS FREQUENT (ANNUAL) AND CLASSIFICATION OF DEMENTIA IS NOT DISCLOSED TO PARTICIPANTS—THUS IT IS INDEPENDENT OF CLINICAL DIAGNOSIS IN HEALTHCARE SETTINGS CAPTURED IN THE MEDICARE CLAIMS. WE PROPOSE TO CHARACTERIZE THE FACTORS THAT MAKE OLDER ADULTS WITH DEMENTIA MORE OR LESS LIKELY TO RECEIVE A CLINICAL DIAGNOSIS AROUND THE TIME WHEN THEY FIRST MEET CRITERIA FOR ADRD (AIM 1), AND TO TEST WHETHER THOSE WITH EARLY DIAGNOSIS HAVE BETTER HEALTH OUTCOMES (AIM 2), AND MORE APPROPRIATE HEALTHCARE UTILIZATION AND LESS ASSOCIATED COSTS (AIM 3). THESE EFFORTS ARE TIMELY AND HAVE THE POTENTIAL TO CHANGE PUBLIC PERCEPTION, CLINICAL PRACTICE, AND HEALTH POLICY. PATIENTS AND MEDICAL PROVIDERS WILL BE ABLE TO MAKE BETTER INFORMED CHOICES ABOUT WHEN TO SEEK OR OFFER COGNITIVE EVALUATION, WHILE PUBLIC HEALTH AGENCIES, HEALTH SYSTEMS, AND HEALTH INSURERS WILL BE ABLE TO USE OUR FINDINGS TO DECIDE WHETHER AND HOW TO PROMOTE EARLY COGNITIVE EVALUATION AND DIAGNOSIS OF DEMENTIA.

THE AFRICAN AMERICAN NON-RESIDENT FATHERHOOD PROGRAM

NEUROPATHOLOGIC-EPIDEMIOLOGICAL STUDY OF METALLOMICS AND ALZHEIMER'S DISEASE

ATRIAL EXCITATION-CONTRACTION COUPLING, CALCIUM SIGNALING AND ELECTRO-MECHANICAL ALTERNANS - PROJECT SUMMARY/ABSTRACT IN ATRIAL MYOCYTES EXCITATION-CONTRACTION COUPLING (ECC) AND CA RELEASE FROM THE SARCOPLASMIC RETICULUM (SR) HAVE UNIQUE FEATURES THAT RESULT FROM THE LACK OR THE IRREGULAR ORGANIZATION OF THE TRANSVERSE TUBULE MEMBRANE SYSTEM. ATRIAL MYOCYTES HAVE TWO TYPES OF SR, JUNCTIONAL (J-SR) AND NON-JUNCTIONAL (NJ-SR). CA RELEASE FROM J- SR IS CONTROLLED BY CA ENTRY THROUGH VOLTAGE-GATED L-TYPE CA CHANNELS (ICA,L) WHEREAS RELEASE FROM NJ-SR OCCURS BY SUBSEQUENT PROPAGATING WAVE-LIKE CA-INDUCED CA RELEASE (CICR) DRIVEN BY THE NEWLY IDENTIFIED 'FIRE- DIFFUSE-UPTAKE-FIRE' (FDUF) MECHANISM. IP3 RECEPTOR-INDUCED CA RELEASE (IICR) CONTRIBUTES TO ECC BY ENHANCING INOTROPY, BUT ALSO LEADS TO ARRHYTHMOGENIC CA RELEASE AND ALTERNANS. CARDIAC ALTERNANS HAS BEEN LINKED TO CARDIAC ARRHYTHMIA, INCLUDING ATRIAL FIBRILLATION. ALTERNANS IS DEFINED AS BEAT-TO-BEAT ALTERNATIONS IN ACTION POTENTIAL (AP) DURATION (APD, ELECTRICAL ALTERNANS), CONTRACTION STRENGTH AND CA TRANSIENT (CAT) AMPLITUDE, AND THEREBY GENERATES A DYNAMIC ARRHYTHMIA SUBSTRATE. DISTURBANCES OF THE BI-DIRECTIONAL COUPLING OF [CA]I AND MEMBRANE VOLTAGE (VM) REGULATION ([CA]IVM COUPLING) ARE RESPONSIBLE FOR ALTERNANS OCCURRENCE. SEX DIFFERENCES IN CARDIAC STRUCTURAL AND ELECTRICAL PROPERTIES HAVE BEEN LINKED TO DIFFERENCES IN ARRHYTHMIA SUSCEPTIBILITY AND DETERMINE ALTERNANS INDUCIBILITY. FOCUSING ON THE FDUF MECHANISM, THE OVERALL GOALS ARE TO ESTABLISH A MECHANISTIC MODEL OF ATRIAL ECC, CA RELEASE AND ATRIAL ALTERNANS AND ITS SEX-SPECIFIC ATTRIBUTES AT CELLULAR, CELL PAIR AND ORGAN LEVEL. SPECIFIC AIM 1. DETERMINE FDUF-DEPENDENT MECHANISMS OF ATRIAL ALTERNANS. WE WILL DETERMINE THE CRITICAL ROLE OF THE NOVEL FDUF PARADIGM IN ATRIAL ALTERNANS, TESTING THE HYPOTHESES THAT 1) UNCOUPLING OF J-SR AND NJ- SR CA RELEASE PROMOTES 'REVERSE' FDUF AND TRIGGERS ALTERNANS; 2) THE FDUF TRIGGER SIGNAL (ICA,L, JUNCTIONAL CAT) HAS VM DEPENDENCE, AND THAT 3) SERCA DEPENDENT CA UPTAKE; 4) MITOCHONDRIAL CA BUFFERING, ENERGETICS AND REDOX SIGNALING AND 5) IICR MODULATE FDUF AND ALTERNANS. SPECIFIC AIM 2. DETERMINE FDUF ALTERNANS MECHANISMS IN CELL PAIRS. ALTERNANS IS EITHER VM- OR CA-DRIVEN. VM-DRIVEN ALTERNANS IS SPATIALLY HOMOGENEOUS, WHILE CA-DRIVEN ALTERNANS CAN BE SPATIALLY DISCORDANT WHERE OVER SHORT DISTANCES REGIONS ALTERNATE OUT-OF-PHASE. CELL PAIRS DEFINE THE ELEMENTARY STRUCTURAL AND FUNCTIONAL UNIT OF CELL-CELL COMMUNICATION. WE WILL TEST 1) THE SPATIO-TEMPORAL ORGANIZATION OF CAT AND APD ALTERNANS IN CELL PAIRS, 2) HOW DURING CA-DRIVEN ALTERNANS THE FDUF MECHANISM, SERCA, MITOCHONDRIAL SIGNALING AND IICR DETERMINE CELL PAIR ALTERNANS; AND 3) HOW VM-DRIVEN ALTERNANS PRECIPITATES CAT ALTERNANS IN ADJACENT CELLS. SPECIFIC AIM 3. DETERMINE THE SPATIO-TEMPORAL ORGANIZATION AND MECHANISMS OF CA- AND VM-DRIVEN TISSUE ALTERNANS. WE WILL DETERMINE AT ORGAN LEVEL (PERFUSED HEARTS, LIVE ANIMALS) THE MECHANISMS, MANIFESTATIONS AND SPATIO-TEMPORAL ORGANIZATION OF 1) CA-DRIVEN AND 2) VOLTAGE-DRIVEN ALTERNANS, AND TEST PHARMACOLOGICAL INTERVENTIONS TO REDUCE PRO-ARRHYTHMIC ALTERNANS RISK.

INVESTIGATION OF NON-HIV COLLAPSING GLOMERULOPATHY

MUSCLE BUILDING SUPPLEMENT HMB FOR REMYELINATION

ZHX2 IN PODOCYTE DISEASE

THINKING ABOUT WALKING: CAN DIGITAL PHENOTYPING OF MOBILITY IMPROVE THE PREDICTION OF ALZHEIMER'S DEMENTIA AND INFORM ON THE PATHOLOGIES AND PROTEINS CONTRIBUTING TO THIS ASSOCIATION? - ABSTRACT IN ITS EARLIEST STAGE ALZHEIMER’S DISEASE DOES NOT MANIFEST COGNITIVE IMPAIRMENT WHILE DEMENTIA IS A LATE MANIFESTATION. A BIOMARKER TO IDENTIFY PRECLINICAL ALZHEIMER’S DEMENTIA IS CRUCIAL FOR TREATMENTS AIMED AT ITS PREVENTION. ALZHEIMER’S DISEASE CAN ALSO DEGRADE NON-COGNITIVE FUNCTIONS LIKE MOBILITY THAT PRECEDES AND PREDICTS COGNITIVE IMPAIRMENT IN MANY OLDER ADULTS. TO USE MOBILITY AS A BIOMARKER, IT IS CRUCIAL TO IDENTIFY THE METRICS THAT BEST PREDICT ALZHEIMER’S DEMENTIA AND THE MECHANISMS THAT ACCOUNT FOR THIS ASSOCIATION. WE MUST THINK TO MOVE. MOBILITY REQUIRES MOTOR AND COGNITIVE ABILITIES THAT DERIVE FROM DISTINCT BRAIN REGIONS. THIS MAY EXPLAIN WHY MOBILITY IS AN EARLY PREDICTOR OF DEMENTIA. YET, MOTOR TESTING USUALLY ONLY QUANTIFIES MOVEMENT DURATION. SO, THE ROLE OF COGNITIVE ABILITIES IN THE ASSOCIATION OF MOBILITY WITH ALZHEIMER’S DEMENTIA IS UNCLEAR. UNOBTRUSIVE SENSORS CAN BE USED TO ASSESS COGNITIVE AND MOTOR METRICS CRUCIAL FOR MOBILITY. THIS STUDY WILL USE NOVEL DIGITAL MOBILITY PHENOTYPING TO IMPROVE THE PREDICTION OF ALZHEIMER’S DISEASE DEMENTIA AND IDENTIFY BRAIN PATHOLOGIES AND PROTEINS THAT INFORM ON THIS ASSOCIATION. THIS STUDY RESPONDS TO NOT-AG-20-053 AND WILL ADD NEW RESOURCES TO THOSE AVAILABLE FROM 1000 OLDER ADULTS IN THE RUSH MEMORY AND AGING PROJECT (R01AG17917). TO IMPROVE THE PREDICTION OF ALZHEIMER’S DEMENTIA, WE WILL ADD COGNITIVE MOBILITY METRICS E.G., MOTOR PLANNING AND ATTENTIONAL METRICS TO A SINGLE-TESTING SESSION. TO CAPTURE THE VARIED COGNITIVE DEMANDS DURING EVERYDAY MOBILITY, WE WILL ALSO ADD NEW MULTI-DAY MOBILITY METRICS OBTAINED FROM A WRIST SENSOR. MOTOR PLANNING IS RELATED TO SUPPLEMENTARY MOTOR AREA (SMA) AND TASK ATTENTION AND EXECUTIVE FUNCTION ARE REGULATED BY DORSOLATERAL PREFRONTAL CORTEX (DLPFC). SO, WE FOCUS ON THESE REGIONS TO IDENTIFY MECHANISMS SHARED BY MOBILITY AND ALZHEIMER’S DISEASE DEMENTIA. IN 200 DECEDENTS WITH AVAILABLE BRAIN PATHOLOGIES, WE WILL COLLECT NEW PROTEOME DATA FROM SMA TO COMPLEMENT THE AVAILABLE DLPFC PROTEOME. AIM 1 WILL ADD NEW DIGITAL COGNITIVE MOBILITY METRICS TO MOTOR METRICS OBTAINED FROM A SINGLE-TESTING SESSION AS WELL AS NOVEL MULTI-DAY MOBILITY METRICS TO IMPROVE THE PREDICTION OF ALZHEIMER’S DEMENTIA. SENSORS YIELD LARGE NUMBERS OF MOBILITY METRICS. AIM 1 WILL ISOLATE INDIVIDUAL METRICS THAT PREDICT ALZHEIMER’S DEMENTIA. AIM 2 WILL ANALYZE THESE NOVEL METRICS WITH A SECOND APPROACH TO IDENTIFY DIFFERENT MOBILITY SUBGROUPS THAT MAY HAVE VARIED RISKS OF ALZHEIMER’S DEMENTIA. TO INFORM ON THE MECHANISMS UNDERLYING THE ASSOCIATION OF MOBILITY AND ALZHEIMER’S DEMENTIA, AIM 3 WILL USE BRAIN PATHOLOGIES TO DETERMINE THE PATHOLOGIC BASES FOR THESE MOBILITY SUBGROUPS. AIM 4 WILL COLLECT PROTEOME FROM SMA AND DLPFC TO IDENTIFY CORTICAL PROTEINS INDEPENDENTLY RELATED TO MOBILITY SUBGROUPS WHEN CONTROLLING FOR ADRD PATHOLOGIES. FROM THE SET OF PROTEINS RELATED TO MOBILITY, WE WILL IDENTIFY A SUBSET THAT ARE ALSO RELATED TO ALZHEIMER’S DEMENTIA. THIS STUDY WILL INFORM ON WHY MOBILITY PREDICTS ALZHEIMER’S DEMENTIA AND OPTIMIZE ITS USE AS A BIOMARKER FOR PRECLINICAL ALZHEIMER’S DISEASE. TARGETING THE PROTEINS IDENTIFIED MAY CATALYZE NEW TREATMENTS FOR BOTH IMMOBILITY AND ALZHEIMER’S DEMENTIA.

FAVORABLE CARDIOVASCULAR HEALTH, CONNECTOME INTEGRITY, AND ADRD CLINICAL OUTCOMES AND PATHOLOGIC UNDERPINNINGS IN A DIVERSE COHORT. - PROJECT SUMMARY/ABSTRACT AS AGE-SPECIFIC INCIDENCE RATES OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) DECLINE IN THE US, DUE, IN PART, TO IMPROVEMENTS IN CARDIOVASCULAR HEALTH, IT IS IMPERATIVE THAT WE STUDY HOW FAVORABLE CARDIOVASCULAR HEALTH PROMOTES SUCCESSFUL BRAIN AGING. FAVORABLE CARDIOVASCULAR HEALTH QUANTIFIED USING THE AMERICAN HEART ASSOCIATION’S LIFE’S SIMPLE 7 (LS7) IS CITED AS AN IDEAL METRIC TO STUDY SUCCESSFUL BRAIN AGING GIVEN ITS ROLE IN PRESERVING AND PROMOTING LATE-LIFE COGNITIVE AND MOTOR FUNCTIONING. THE LIMITED DATA THAT EXISTS ON LS7 AND BRAIN HEALTH FOCUSES ON ISOLATED GREY MATTER ATROPHY OR WHITE MATTER ABNORMALITIES, I.E., WHITE MATTER HYPERINTENSITIES (WMHS) AND INFARCTS; NO STUDY, TO DATE, HAS EMPLOYED A MULTI-MODAL ASSESSMENT OF BRAIN HEALTH AS RELATED TO CARDIOVASCULAR HEALTH, OR TAKEN ADVANTAGE OF ADVANCES IN THE FIELD OF CONNECTOMICS TO STUDY BRAIN NETWORK INTEGRITY VIA COMPREHENSIVE MAPS OF NEURAL CONNECTIONS BASED ON NEUROIMAGING DATA. CONSIDERING THE CONTRIBUTION OF MULTIPLE BRAIN STRUCTURAL ALTERATIONS IS CRITICAL GIVEN THAT BRAIN CHANGES SUFFERED AT ONE LEVEL, E.G., GREY MATTER ATROPHY OR WHITE MATTER DAMAGE IN THE FORM OF WMHS AND INFARCTS, NEGATIVELY IMPACT BRAIN STRUCTURE AT ANOTHER LEVEL, E.G., CONNECTIVITY BETWEEN BRAIN REGIONS. APPLYING PREVIOUSLY PUBLISHED METHODS, WE WILL CREATE MULTI-MODAL STRUCTURAL CONNECTOME INTEGRITY MATRICES OF SUBTLE BRAIN ALTERATIONS AND FRANK DAMAGE TO ADDRESS GAPS IN THE LITERATURE AND DETERMINE HOW LS7 PRESERVES BRAIN HEALTH AND PROMOTES COGNITIVE AND MOTOR FUNCTIONING IN OLDER NON-LATINO WHITE, BLACK, AND LATINO ADULTS. TO ACHIEVE THE OVERALL GOAL OF THIS STUDY – TO DETERMINE CARDIOVASCULAR-CONNECTOME RELATIONSHIPS THAT PROMOTE BRAIN HEALTH IN OLDER ADULTS – WE WILL COMBINE BIENNIAL NEUROIMAGING DATA, ANNUAL CARDIOVASCULAR LIFESTYLE AND BIOLOGICAL LS7 DATA, AND ANNUAL COGNITIVE AND MOTOR TESTING ON 535 PARTICIPANTS OF THE RUSH MEMORY AND AGING PROJECT WITH UP TO 12 YEARS OF DATA COLLECTION; A SUBSET OF WHOM ALSO HAVE ADRD NEUROPATHOLOGICAL DATA. ANTE-MORTEM, CROSS-SECTIONAL DATA WILL BE AVAILABLE FROM 450 NON-LATINO BLACK AND 150 LATINO PARTICIPANTS FROM TWO OTHER HARMONIZED RUSH COHORT STUDIES. TOGETHER, THIS WILL ENSURE OUR SUCCESS INVESTIGATING CHANGE IN CONNECTOME INTEGRITY AND THE ROLE OF LS7 (AIM 1), THE RELATIONSHIP OF CONNECTOME INTEGRITY WITH COGNITIVE AND MOTOR DECLINE, AND HOW IT VARIES BY LS7 (AIM 2), WHETHER LS7 MODIFIES ASSOCIATIONS BETWEEN NEUROPATHOLOGY AND CONNECTOME INTEGRITY (AIM 3), AND CROSS-SECTIONAL ASSOCIATES OF LS7 AND CONNECTOME INTEGRITY WITHIN NON-LATINO BLACK AND LATINO ADULTS, SEPARATELY (AIM 4). THIS STUDY’S CROSS-CUTTING THEMES OF CARDIOVASCULAR HEALTH, STATE-OF-THE-ART NEUROIMAGING ANALYTICS, COMPREHENSIVE BEHAVIORAL ASSESSMENT, AND GOLD-STANDARD NEUROPATHOLOGY WILL PROVIDE A WEALTH OF INFORMATION NEVER BEFORE DOCUMENTED AND EXERT A SUSTAINED INFLUENCE ON THE FIELD. SPECIFICALLY, THIS R01 WILL IDENTIFY NEUROPATHOLOGICAL UNDERPINNINGS OF LATE-LIFE BRAIN NETWORK INTEGRITY AND THE ROLE OF FAVORABLE CARDIOVASCULAR HEALTH AND MAY PROVIDE REFINED MRI TARGETS AND SPECIFIC BEHAVIORAL OUTCOMES FOR USE IN LIFESTYLE INTERVENTIONS WITH LESS HEALTHY OLDER ADULTS.

SWITCH FROM HOMEOSTATIC TO INFLAMMATORY CYTOKINES BY NK/ILC IN HIV-INFECTED GUT

SOLUBLE MEDIATORS OF RELAPSE - ABSTRACT THE MOST COMMON EVENT PRECEDING RELAPSE OF PRIMARY GLOMERULAR DISEASES LIKE MINIMAL CHANGE DISEASE AND FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS IS THE COMMON COLD. TREATMENT OF DISEASE RELAPSE IS A LENGTHY PROCESS INVOLVING GLUCOCORTICOIDS AND OTHER IMMUNOSUPPRESSIVE MEDICATIONS, SOME OF WHICH HAVE MULTI-SYSTEM TOXICITY. WE HYPOTHESIZED THAT RELAPSE IS INDUCED BY A “CYTOKINE STORM” THAT FOLLOWS INFECTION BY COMMON COLD VIRUSES LIKE RHINOVIRUS. A “CYTOKINE COCKTAIL” WAS DESIGNED AROUND THE SOLUBLE RHINOVIRUS RECEPTOR AND INDUCES ACUTE ALBUMINURIA AFTER SINGLE INTRAVENOUS INJECTION IN MICE WITH LOW PODOCYTE ZHX2 EXPRESSION, A COMMON FEATURE IN MCD AND FSGS PATIENTS. THIS CYTOKINE COCKTAIL COMPRISES OF COMPONENTS OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE THAT ARE NECESSARY AND SUFFICIENT TO INDUCE ACUTE ALBUMINURIA. EXCLUSION OF ANY MEMBER FROM THE CYTOKINE COCKTAIL, OR INJECTION OF INDIVIDUAL MEMBERS DOES NOT INDUCE ALBUMINURIA. IN THIS PROPOSAL, WE WILL DEVELOP THERAPEUTIC STRATEGIES TO PREVENT RELAPSE OF GLOMERULAR DISEASES AFTER A COMMON COLD, BY DEPLETING SOLUBLE CYTOKINES IN THE CYTOKINE STORM, OR BLOCKING THEIR RECEPTORS IN THE GLOMERULUS. IN AIM 1, STUDIES ON CYTOKINE DEPLETION OR RECEPTOR BLOCKAGE IN THE PODOCYTE WILL BE CONDUCTED, AND RECEPTOR DEPENDENT AND INDEPENDENT MECHANISMS IDENTIFIED. IN AIM 2, STUDIES ON CYTOKINE DEPLETION OR RECEPTOR BLOCKAGE IN ENDOTHELIAL AND MESANGIAL CELLS WILL BE CONDUCTED, AND RECEPTOR DEPENDENT AND INDEPENDENT MECHANISMS IDENTIFIED. IN AIM 3, A THERAPEUTIC STRATEGY THAT COMBINES CYTOKINE DEPLETION WITH RECEPTOR BLOCKAGE WILL BE DEVELOPED.

IP3 RECEPTOR, NOX2 AND CALCIUM SIGNALING DOMAINS IN ATRIAL PHYSIOLOGY AND PATHOPHYSIOLOGY - PROJECT SUMMARY/ABSTRACT ATRIAL EXCITATION-CONTRACTION COUPLING (ECC) AND SARCOPLASMIC RETICULUM (SR) CA RELEASE HAVE UNIQUE FEATURES AND ARE DISTINCTLY DIFFERENT FROM VENTRICULAR ECC. DURING ECC THE ACTION POTENTIAL (AP) INITIATES CA RELEASE FROM THE SR CA STORES PRIMARILY THROUGH THE RYANODINE RECEPTOR (RYR) CA RELEASE CHANNELS. THE ATRIAL SR HAS A SECOND, ALBEIT LESS ABUNDANT CA RELEASE CHANNEL, THE INOSITOL-1,4,5-TRISPHOSPHATE RECEPTOR (IP3R). IP3R INDUCED CA RELEASE (IICR) PARTICIPATES IN ECC BUT ALSO HAS NON-ECC FUNCTIONS, INCLUDING CONTRIBUTION TO PACEMAKER ACTIVITY, MITOCHONDRIAL CA SIGNALING, AND REGULATION OF TRANSCRIPTION FACTOR ACTIVITY IMPORTANT FOR PATHOPHYSIOLOGICAL ATRIAL REMODELING. IICR HAS SEX-SPECIFIC ATTRIBUTES AND EXERTS POSITIVE INOTROPIC EFFECTS, BUT ALSO FACILITATES PROARRHYTHMIC CA RELEASE. IICR IS UPREGULATED IN ATRIAL TISSUE IN HEART FAILURE (HF), WHICH FACILITATES SR CA RELEASE AND ENHANCES ATRIAL CONTRACTION, BUT ALSO LEADS TO INCREASED RISK OF ALTERNANS AND ATRIAL FIBRILLATION. THE CARDIAC IP3R IS TARGET OF POST-TRANSLATIONAL MODIFICATIONS. NEW PRELIMINARY DATA DEMONSTRATE THAT IN ATRIAL MYOCYTES THE IP3R IS CO-REGULATED BY IP3 AND ROS PROVIDED BY NADPH-OXIDASE TYPE 2 (NOX2) AND INVOLVES ROS-DEPENDENT IP3R GLUTATHIONYLATION. THE OVERALL GOAL OF THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT IN ATRIAL TISSUE A NOX2/ROS/IP3R SIGNALING DOMAIN IS RESPONSIBLE FOR THE POSITIVE INOTROPIC AND PROARRHYTHMIC EFFECTS OF IICR, AND TO DETERMINE HF INDUCED CHANGES IN ROS DEPENDENT IICR REGULATION AND THEIR CONSEQUENCES FOR ATRIAL REMODELING, ALTERNANS AND ATRIAL FIBRILLATION (AF) RISK. THE 3 SPECIFIC AIMS ARE: SPECIFIC AIM 1: DEFINE THE MECHANISM OF IP3R CO-REGULATION BY IP3 AND ROS AND DETERMINE ITS SEX-SPECIFIC ATTRIBUTES. WE WILL TEST THE HYPOTHESES THAT IICR IS CO-REGULATED BY IP3 AND ROS IN A DEFINED NOX2/ROS/IP3R MICRODOMAIN AND THAT ROS DEPENDENT GLUTATHIONYLATION OF IP3R MODULATES ATRIAL CA RELEASE DURING ECC. ALTERNATIVE CANDIDATES OF CELLULAR ROS SOURCES (MITOCHONDRIA, NOX4) FOR IP3R MODULATION IN ADDITION TO NOX2, AND SEX-SPECIFIC ATTRIBUTES OF ROS/IP3 CO-REGULATION OF IICR WILL BE DETERMINED. SPECIFIC AIM 2: DETERMINE ATRIAL REMODELING OF NOX2/ROS/IP3R SIGNALING AND ITS CONSEQUENCES FOR ECC, CA RELEASE AND TRANSCRIPTION FACTOR REGULATION IN HF. WE WILL TEST THE HYPOTHESIS THAT IN ATRIAL TISSUE OF A VENTRICULAR HF MODEL ROS SOURCES ALTERNATIVE TO NOX2 UPREGULATE IICR AND THEREBY CHANGE ITS CONTRIBUTION TO ATRIAL CA TRANSIENT (CAT), CONTRACTION, AND TRANSCRIPTION FACTOR (NFAT) ACTIVATION THROUGH NUCLEAR IP3RS. SPECIFIC AIM 3: DETERMINE THE MECHANISMS OF ROS/IICR MEDIATED INCREASE IN CA ALTERNANS PROPENSITY AND AF SUSCEPTIBILITY IN NORMAL AND HF ATRIAL TISSUE. WE WILL TEST THE HYPOTHESES THAT IICR FACILITATES PACING INDUCED CAT ALTERNANS THAT IS FURTHER ENHANCED IN HF, AND THAT SYNERGISTICALLY ROS/IICR MEDIATED ALTERNANS GENERATES A SUBSTRATE THAT INCREASES THE SUSCEPTIBILITY FOR AF EPISODES.

THE ROLE OF MECHANOSENSATION PATHWAYS IN OSTEOARTHRITIS JOINT DAMAGE AND PAIN - PROJECT SUMMARY KNEE OSTEOARTHRITIS (OA) IS A PAINFUL CHRONIC DISEASE AFFECTING 27 MILLION PEOPLE IN THE US. KNEE OA IS CHARACTERIZED BY PROGRESSIVE DAMAGE AND REMODELING OF ALL JOINT TISSUES. MAJOR HALLMARKS OF OA ARE JOINT PAIN AND JOINT SPACE NARROWING ON X-RAY (CARTILAGE LOSS). BIOMECHANICAL FACTORS PLAY AN IMPORTANT ROLE IN BOTH JOINT PAIN AND DAMAGE, BUT EXACTLY HOW MECHANICAL FORCES ACT ON SENSORY NEURONS AND CARTILAGE TO DRIVE THE DISEASE IS UNKNOWN. OUR LONG-TERM GOAL IS TO ELUCIDATE HOW MECHANICAL LOADING IS SENSED BY JOINT TISSUES AND HOW RESPONSES TO LOADING CONTRIBUTE TO OA. CELLS SENSE MECHANICAL FORCES THROUGH A VARIETY OF MECHANISMS, INCLUDING MECHANOSENSITIVE ION CHANNELS. RECENTLY, THE SENSORY NEURON MECHANOSENSITIVE ION CHANNEL PIEZO2 WAS IDENTIFIED AS A KEY CONTRIBUTOR TO MECHANICAL ALLODYNIA IN MURINE MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THE ROLE OF PIEZO2 EXPRESSED BY NOCICEPTORS AND IN PERSISTENT PAIN IS NOT CLEAR. FURTHERMORE, THE FUNCTION OF MECHANOSENSITIVE ION CHANNELS IN CHONDROCYTES IS LESS CLEAR, BUT BASED ON PREVIOUS WORK IMPLICATING A ROLE FOR PIEZO1 IN CHONDROCYTE RESPONSES TO MECHANICAL STIMULI, WE HYPOTHESIZE THAT PIEZO1 CONTRIBUTES TO TISSUE DAMAGE IN OA. OVERALL IT IS UNKNOWN HOW PIEZO ION CHANNEL SIGNALING CONTRIBUTES TO OA PATHOLOGY (PAIN AND JOINT DAMAGE). WE AIM TO ADDRESS THIS QUESTION BY USING NOVEL TECHNIQUES WE HAVE DEVELOPED THAT ENABLE APPLICATION OF MECHANICAL STIMULI TO INTACT TISSUES WHILE PERFORMING CALCIUM OR VOLTAGE IMAGING TO ASSESS CELL FUNCTION IN REAL TIME. THIS PROPOSAL ADDRESSES THE CENTRAL HYPOTHESIS THAT: PIEZO CHANNEL SIGNALING IN NOCICEPTORS AND CHONDROCYTES DRIVES PAIN AND JOINT DAMAGE IN THE INITIATION AND PROGRESSION OF OA. THE CENTRAL HYPOTHESIS WILL BE TESTED IN TWO SPECIFIC AIMS: 1) TO DEFINE THE ROLE OF PIEZO2 ION CHANNEL EXPRESSED BY NOCICEPTORS IN MEDIATING PERIPHERAL SENSITIZATION AND PERSISTENT PAIN BEHAVIORS AT DIFFERENT STAGES OF THE DMM MODEL OF OA; AND 2) TO INVESTIGATE WHETHER CHONDROCYTE PIEZO1 ION CHANNEL SIGNALING PROMOTES JOINT DAMAGE AND PAIN IN THE DMM MODEL. TO PERFORM THESE AIMS, WE HAVE GENERATED INNOVATIVE TECHNIQUES THAT ENABLE APPLICATION OF MECHANICAL STIMULI TO INTACT TISSUES WHILE PERFORMING REAL-TIME CALCIUM OR VOLTAGE IMAGING. WE HAVE CREATED MICE THAT EXPRESS FLUORESCENT CALCIUM (GCAMP6S) OR VOLTAGE (ASAP2S) INDICATOR PROTEINS IN EITHER PAIN-SENSING SENSORY NEURONS (NOCICEPTORS; NAV1.8 CRE) OR IN CHONDROCYTES (COL2A1 CRE). WE ALSO HAVE TWO TYPES OF NOCICEPTOR-SPECIFIC PIEZO2 CONDITIONAL KNOCK-OUT MICE AS WELL AS CHONDROCYTE-SPECIFIC PIEZO1 CONDITIONAL KNOCK-OUT MICE. SUCCESSFUL COMPLETION OF THESE AIMS WILL IMPROVE OUR UNDERSTANDING OF HOW NOCICEPTORS AND CHONDROCYTES USE PIEZO CHANNELS TO RESPOND TO MECHANICAL LOADING IN OA, WHICH MAY LEAD TO THE IDENTIFICATION OF NOVEL PATHWAYS TO TARGET BOTH PAIN AND JOINT DAMAGE THERAPEUTICALLY. BY MEASURING BOTH PAIN-RELATED BEHAVIORS AND JOINT DAMAGE IN NOCICEPTOR-PIEZO2 KNOCK-OUT AND CHONDROCYTE-PIEZO1 KNOCK-OUT MICE, THIS APPROACH WILL PROVIDE INSIGHT ON INTERACTIONS BETWEEN THESE PROCESSES, WHICH WILL SET UP FUTURE WORK.

OPTIMIZING COGNITIVE TRAINING TO IMPROVE FUNCTIONAL OUTCOME IN CLINICAL HIGH RISK

THE HH: A LARGE COHORT OF PATIENTS WITH CONGENITAL MYOPATHIES OF UNCERTAIN ETIOLOGY

EARLY CHILDHOOD NEURODEVELOPMENTAL, ECONOMIC AND NUTRITIONAL OUTCOMES AMONG FORMER VERY LOW BIRTH WEIGHT INFANTS FROM THE REDUCING DISPARITY IN MOTHER'S OWN MILK (REDIMOM) TRIAL - PROJECT SUMMARY ALTHOUGH MOST VERY PRETERM (VP; <32 WEEKS GESTATION) INFANTS SURVIVE TO DISCHARGE FROM THE NEONATAL INTENSIVE CARE UNIT (NICU), THEY REMAIN AT HEIGHTENED RISK FOR IMPAIRED NEURODEVELOPMENT (ND), OBESITY AND CARDIOMETABOLIC CONDITIONS, BURDENING FAMILIES AND TRANSLATING TO HIGH HEALTHCARE COSTS OVER THE LIFESPAN. ONE STRATEGY TO REDUCE THESE RISKS IS TO FEED MOTHER’S OWN MILK (MOM) DURING THE NICU HOSPITALIZATION, BECAUSE MOM IS ASSOCIATED WITH A DOSE-DEPENDENT ENHANCEMENT IN EARLY BRAIN DEVELOPMENT, BETTER ND OUTCOMES, AND A REDUCED RISK OF OBESITY AND ITS COMPLICATIONS. OBSERVATIONAL STUDIES HAVE DOCUMENTED HEALTH AND ECONOMIC BENEFITS ASSOCIATED WITH MOM, BUT ALL OF THESE STUDIES HAVE BEEN LIMITED BY THE INABILITY TO ETHICALLY RANDOMIZE VP INFANTS TO RECEIVE DIFFERENT DOSES OF MOM. ALTHOUGH EXCLUSIVE MOM FEEDINGS THROUGH THE FIRST 6 MONTHS OF LIFE ARE RECOMMENDED FOR ALL INFANTS, MOTHERS OF VP INFANTS FACE NUMEROUS BARRIERS IN PROVIDING MOM. ALMOST 50% OF MOTHERS DISCONTINUE MOM PROVISION BEFORE NICU DISCHARGE, WELL BEFORE THEIR INFANTS REACH 6 MONTHS OF AGE. OUR ONGOING NIH-FUNDED RANDOMIZED CONTROLLED TRIAL, “REDUCING DISPARITY IN THE RECEIPT OF MOTHER’S OWN MILK IN VERY LOW BIRTHWEIGHT INFANTS: AN ECONOMIC INTERVENTION” (REDIMOM, R01MD013969) WAS DESIGNED TO TEST THE EFFECTIVENESS OF AN ECONOMIC INTERVENTION THAT COVERS THE MATERNAL COSTS OF PROVIDING MOM IN THE NICU. REDIMOM PROVIDES AN ECONOMIC BUNDLE TO INTERVENTION GROUP MOTHERS: FREE HOSPITAL GRADE ELECTRIC BREAST PUMP RENTAL, FREE PICKUP OF PUMPED MOM FROM THE HOME, AND PAYMENT FOR EACH DAY SPENT PUMPING TO OFFSET MATERNAL OPPORTUNITY COSTS. BOTH INTERVENTION AND CONTROL GROUP MOTHERS RECEIVE STANDARD NICU-SPECIFIC LACTATION CARE. THIS ETHICAL RANDOMIZATION OF AN INTERVENTION TO ACHIEVE HIGHER NICU MOM DOSES IN THE INTERVENTION GROUP PROVIDES THE FIRST OPPORTUNITY TO OBTAIN EXPERIMENTAL EVIDENCE OF MOM’S IMPACT ON HEALTH AND ECONOMIC OUTCOMES IN EARLY CHILDHOOD. LEVERAGING THE RANDOMIZED DESIGN OF REDIMOM, THE OVERALL AIM OF THIS STUDY IS TO ASSESS ND (COGNITIVE, LANGUAGE AND MOTOR INDEX SCORES), ADIPOSITY, AND DURATION OF MOM FEEDINGS, TOTAL COST OF CARE AND COST-EFFECTIVENESS THROUGH 20 MONTHS’ CORRECTED AGE, WITHOUT RESIDUAL CONFOUNDING CONCERNS. ADDITIONALLY, THIS STUDY WILL ASSESS THE RELATIONSHIP BETWEEN TOTAL DURATION OF MOM FEEDING (IN NICU AND POST DISCHARGE) AND EARLY CHILDHOOD OUTCOMES USING A ROBUST COHORT DESIGN. THIS STUDY PROVIDES AN UNPARALLELED OPPORTUNITY TO OBTAIN EXPERIMENTAL EVIDENCE OF THE EFFECT OF MOM FEEDINGS ON EARLY CHILDHOOD ND AND ADIPOSITY IN VP INFANTS WITHOUT UNMEASURED CONFOUNDING. IT WILL PROVIDE THE HIGHEST QUALITY OF EVIDENCE FOR DECISION MAKERS AND ESSENTIAL ECONOMIC DATA NEEDED TO COMPARE THE TWO NICU LACTATION STRATEGIES EMPLOYED IN REDIMOM. THE IMPACT WILL BE ON PRIORITIZING INVESTMENT IN EFFECTIVE STRATEGIES THAT SUPPORT MOM FOR VP INFANTS AND REDUCE INEQUITIES IN THE RECEIPT OF MOM, ULTIMATELY LEADING TO IMPROVED OUTCOMES FOR ALL VP INFANTS.

GENOME-WIDE ASSOCIATION STUDY OF COGNITIVE DECLINE AMONG OLDER AFRICAN AMERICANS

HUMAN/ANIMAL BRAIN CHIMERA IN DRUGS OF ABUSE AND HIV - ABSTRACT: DRUGS OF ABUSE ARE A SIGNIFICANT COMORBIDITY AMONG PEOPLE LIVING WITH HIV. METHAMPHETAMINE (METH), IN PARTICULAR, IS A POTENT PSYCHOSTIMULANT FREQUENTLY ABUSED IN THE HIV/AIDS POPULATION. BOTH HIV AND METH ARE RISK FACTORS FOR COGNITIVE DECLINE EVEN IN THE ERA OF COMBINATION ANTIRETROVIRAL THERAPY (CART). THE MECHANISM(S) THAT DRIVE AND/OR CONTRIBUTE TO THIS COGNITIVE DECLINE, COLLECTIVELY KNOWN AS HIV-ASSOCIATED NEUROCOGNITIVE IMPAIRMENT (HAND), ARE NOT ENTIRELY CLEAR NOR IS THE IMPACT OF METH ON HIV RESERVOIR. METH ITSELF ENHANCES HIV REPLICATION. WE WILL USE TWO INNOVATIVE HUMANIZED ANIMAL MODELS TO ADDRESS THE INTERFACE BETWEEN GLIAL CELLS, METH AND HIV RESERVOIR. HUASTRO/HUPBMC MICE, GENERATED BY ENGRAFTMENT OF IPSC-ASTROCYTES INTO NSG MICE, CAN UNIQUELY ADDRESS THE ROLE OF ASTROCYTES AS A RESERVOIR FOR HIV AND IN HIV EGRESS OUT OF THE BRAIN TO PERIPHERAL ORGANS (AIM 1) AND DEFINE THE EFFECT OF METH WITH OR WITHOUT HIV ON PROTOTYPICAL FUNCTIONS OF ASTROCYTE AND BRAIN HOMEOSTASIS (AIM 2). WE FOCUS ON ASTROCYTES BECAUSE THEY CONSTITUTE A SIGNIFICANT RESIDENT BRAIN CELL POPULATION AND PERFORM VITAL FUNCTIONS TO MAINTAIN BRAIN HOMEOSTASIS. THE HUCD34/NPC MODEL (CD34 HUMANIZED MICE ENGRAFTED WITH NEURONAL PROGENITOR CELLS (NPCS) WILL BE USED TO ASSESS THE ROLE OF METH ON HIV EVOLUTION OVER TIME IN THE CNS AND PERIPHERAL ORGANS (AIM 3). COMBINING THESE TWO MODELS WITH THE RESOURCES OF THE TRANSLATIONAL METHAMPHETAMINE AIDS RESEARCH CENTER (TMARC) AND THE NIDA CENTER FOR GENETIC STUDIES AT RUTGERS AND CELL REPOSITORY (RUDCR) TO REPROGRAM LYMPHOCYTES FROM METH/HIV DONORS TO GENERATE IPSC THEN NPC AND/OR IPSC-ASTROCYTES AS TARGETED FOR IN VITRO AND IN VIVO STUDIES PROVIDES A POWERFUL TOOL TO ADDRESS OUR CENTRAL HYPOTHESIS THAT METH MEDIATES A GREATER HIV RESERVOIR IN ASTROCYTES AND EGRESS INTO PERIPHERAL ORGANS (AIM 1), DYSREGULATE ASTROCYTES TO DISRUPT BRAIN HOMEOSTASIS (AIM 2), AND PROMOTE S GREATER EXTENT OF VIRAL EVOLUTION WITHIN THE CNS (AIM 3). TOGETHER, THESE STUDIES ARE RESPONSIVE TO NIDA HIV RESEARCH HIGH PRIORITY AREAS AND WILL ADVANCE OUR KNOWLEDGE REGARDING THE ROLE OF DRUGS OF ABUSE ON HIV RESERVOIR, EVOLUTION, AND NEUROPATHOGENESIS TO INFORM BETTER STRATEGIES TO UNIQUELY ADDRESS PERSISTENT HIV AMONG THE HIV POSITIVE DRUG ABUSING POPULATION.

STRESS, RACE, AND COGNITIVE MEDIATORS OF SES-RELATED DISPARITIES IN BEHAVIORAL OBESITY TREATMENT OUTCOMES - PROJECT SUMMARY/ABSTRACT INDIVIDUALS OF LOWER SOCIOECONOMIC STATUS (SES) LOSE ONLY HALF AS MUCH WEIGHT IN BEHAVIORAL WEIGHT LOSS INTERVENTIONS AS THOSE OF HIGHER SES. THIS IS A CLINICALLY MEANINGFUL DIFFERENCE IN OUTCOMES THAT HAS BEEN CONSISTENTLY DOCUMENTED. THE OVERARCHING AIM OF THIS PROJECT IS TO IDENTIFY THE MECHANISMS THAT ACCOUNT FOR SES-RELATED DISPARITIES IN BEHAVIORAL WEIGHT LOSS OUTCOMES, WHICH WOULD ENABLE THE DEVELOPMENT OF MORE EFFECTIVE OBESITY TREATMENT APPROACHES FOR LOWER SES POPULATIONS. ONE POTENTIAL MECHANISM IS PRESENT BIAS, WHICH IS A TENDENCY TO FOCUS ON ONE’S IMMEDIATE NEEDS THAT MAY RESULT FROM EXPOSURE TO HARSH AND UNPREDICTABLE ENVIRONMENTS. PRESENT BIAS IS A COMPELLING CANDIDATE AS A MECHANISM OF SES-RELATED DISPARITIES IN WEIGHT LOSS OUTCOMES BECAUSE IT IS MUCH MORE PRONOUNCED IN LOWER SES POPULATIONS, AND IT HAS BEEN LINKED TO OBESITY RISK, MALADAPTIVE EATING BEHAVIORS, AND POOR DIET QUALITY. A SECOND SET OF POTENTIAL MECHANISMS INCLUDES ADVERSE DAILY EXPERIENCES SUCH AS STRESS, COGNITIVE DEMANDS, AND EXPOSURE TO TEMPTING FOODS. STRESS AND COGNITIVE DEMANDS ARE MORE PREVALENT OR SEVERE IN THE LIVES OF LOWER SES POPULATIONS, AND CAN DISRUPT THE EXECUTIVE FUNCTIONS THAT ARE IMPORTANT FOR ADHERING TO WEIGHT CONTROL BEHAVIORS DURING OBESITY TREATMENT. THIS PROJECT WILL ALLOCATE EQUAL NUMBERS OF SUBJECTS OF LOWER AND HIGHER SES TO A STANDARD-OF-CARE WEIGHT LOSS INTERVENTION. IMPORTANTLY, THE SES GROUPS WILL BE BALANCED WITH RESPECT TO ETHNIC/RACIAL MINORITY STATUS. WEIGHT LOSS OUTCOMES AND ADHERENCE TO THREE KEY WEIGHT CONTROL BEHAVIORS (DIETARY LAPSES, DIETARY SELF-MONITORING, AND PHYSICAL ACTIVITY) WILL BE RIGOROUSLY MEASURED ACROSS SIX MONTHS OF FOLLOW UP. INDIVIDUAL DIFFERENCES IN PRESENT BIAS WILL BE THOROUGHLY ASSESSED AT BASELINE. ECOLOGICAL MOMENTARY ASSESSMENT WILL BE USED TO CAPTURE EXPOSURE TO ADVERSE DAILY EXPERIENCES, AS WELL AS MOMENTARY CHANGES IN PRESENT BIAS. AIM 1 IS TO TEST WHETHER PRESENT BIAS ACCOUNTS FOR SES-RELATED DISPARITIES IN BEHAVIORAL WEIGHT LOSS OUTCOMES AND ADHERENCE TO KEY WEIGHT CONTROL BEHAVIORS. AIMS 2A AND 2B WILL CHARACTERIZE THE ROLE OF ADVERSE DAILY EXPERIENCES IN SES- RELATED DISPARITIES IN WEIGHT LOSS OUTCOMES AND ADHERENCE TO WEIGHT CONTROL BEHAVIORS, BOTH OVERALL AND AMONG PRESENT-BIASED INDIVIDUALS IN PARTICULAR. AIM 3 IS TO EXPLORE THE CONTRIBUTION OF RACE TO SES-RELATED DISPARITIES IN WEIGHT LOSS OUTCOMES, WHICH HAS BEEN CHALLENGING TO ELUCIDATE IN PRIOR STUDIES DUE TO SIGNIFICANT CONFOUNDING OF RACE AND SES AT THE SOCIETAL LEVEL. THE RESULTS OF THIS STUDY COULD LEAD TO A NEW UNDERSTANDING OF HOW SOCIOECONOMIC DISADVANTAGE IMPACTS ADHERENCE TO BEHAVIORAL TREATMENT FOR OBESITY, AND SUGGEST ENTIRELY NEW TREATMENT APPROACHES FOCUSED ON MITIGATING PRESENT BIAS OR DELIVERING TAILORED INTERVENTION CONTENT DURING “MOMENTS OF RISK” FOR LAPSES IN ADHERENCE.

ADOLESCENT CIRCADIAN MISALIGNMENT: MECHANISTIC STUDIES OF SLEEP AND LIGHT

SKELETAL MUSCLE RYANODINE RECEPTOR PERMEATION AND SELF COUNTER-ION FLOW

TUMOR MATRIX REMODELING IN ANTI-MYELOMA IMMUNITY AND IMMUNOTHERAPY

CLINICAL TRIAL TO ENHANCE CAREGIVER PHYSICAL ACTIVITY

ELECTROPHYSIOLOGICAL MECHANISMS OF HIV-MEDIATED NEUROPATHOGENESIS

ROLE OF CIRCULATING SUPAR IN FSGS

EVALUATING EVIDENCE-BASED OPTIONS FOR INITIAL PTSD TREATMENT NON-RESPONDERS

INCREASED RISK OF STI AND HIV AMONG ADOLESCENT GIRLS AND YOUNG WOMEN DUE TO COVID-19 AND PANDEMIC MITIGATION: BIOLOGICAL, BEHAVIORAL, AND PSYCHOSOCIAL MEDIATORS - FROM LATE MARCH 2020, IN RESPONSE TO COVID-19, KENYA BEGAN A LOCKDOWN INCLUDING SHUTTERING SCHOOLS. ON 16TH OCTOBER, RISING SENIORS COULD RETURN TO SCHOOL TO PREPARE FOR EXAMS. IN WESTERN KENYA, WHERE AMONG GIRLS AGED 15-19 HIV PREVALENCE IS 8.8% AND HSV-2 PREVALENCE IS 28%, SCHOOL CLOSURES LIKELY HAVE PROFOUND AND LASTING EFFECTS ON HIV AND SEXUALLY TRANSMITTED INFECTION (STI) RISK. WITHIN A COHORT OF 436 SECONDARY SCHOOL GIRLS, WE ARE EVALUATING THE EFFECT OF MENSTRUAL CUPS ON THE VAGINAL MICROBIOME (VMB), BACTERIAL VAGINOSIS (BV), AND STIS. ON OCTOBER 1, WE INITIATED THE 30-MONTH VISIT, HAVING FOLLOWED UP 371 (85%) GIRLS BY DECEMBER 18. THE PREVALENCE OF BV WAS 21.8%, AND 15.6% FOR CHLAMYDIA, GONORRHEA, OR TRICHOMONAS, REPRESENTING A 55% INCREASE IN BV SINCE LAST MEASURE AT THE 18-MONTH VISIT (14%), AND 34% INCREASE IN STI SINCE LAST MEASURE AT THE 12-MONTH EVALUATION (11.6%). ADJUSTED FOR SOCIOECONOMIC FACTORS, GIRLS REPORTING HIGH COVID- RELATED STRESS AND INTERPERSONAL VIOLENCE HAD INCREASED ODDS OF BV AND STI. ADOLESCENTS ARE ESPECIALLY SENSITIVE TO STRESS INDUCED EFFECTS ON THE HYPOPITUITARY AXIS; INCREASED STRESS AND SUBSEQUENT RISE IN CORTISOL LEADS TO REDUCED ESTROGEN, WHICH IS NECESSARY TO SUPPORT THE LACTOBACILLUS CRISPATUS DOMINANT ENVIRONMENT THAT HELPS PREVENT BV, STIS, AND HIV. THIS STUDY PROPOSES TO MEASURE THE SOCIOECONOMIC, BEHAVIORAL, AND PSYCHOSOCIAL IMPACT OF THE COVID-19 CRISIS, HOW THIS RELATES TO GIRLS’ SEXUAL EXPOSURES, AND SUBSEQUENT RISK OF BV, STI, AND HIV. IN AIM 1, WE WILL QUANTIFY THE ECONOMIC, PSYCHOSOCIAL, AND BEHAVIORAL IMPACTS OF COVID-19 AND ASSOCIATED LOCKDOWNS AND RESTRICTIONS. INDIVIDUAL AND VILLAGE LEVEL ASSESSMENTS INCLUDE CHANGES IN FOOD SECURITY, WATER ACCESS, HOUSEHOLD INCOME, VIOLENCE, CRIME, AND SAFETY. INDIVIDUAL MEASURES INCLUDE EXTENSIVE SEXUAL PRACTICES, ANXIETY, DEPRESSIVE SYMPTOMS, INTERPERSONAL VIOLENCE. IN AIM 2, WE WILL MEASURE THE ASSOCIATION OF COVID-19 STRESSORS ON RISK FOR HIV AND STIS. WE WILL BE ABLE TO ESTIMATE THE HAZARD OF STI AND HIV OUTCOMES UNDER MULTIPLE CONDITIONS: PRE-COVID (APRIL 2018-OCTOBER 2019), DURING COVID/SCHOOL CLOSURES (SINCE MARCH 2020), DURING COVID/SCHOOL REOPENING (ANTICIPATED), POST-COVID (ANTICIPATED). IN AIM 3, WE WILL MEASURE CORTISOL AND ESTRADIOL AND CORRELATE THIS TO REPORTED STRESS, AND QUANTIFY THE INFLUENCE OF THESE BIOLOGICAL MEASURES OF STRESS ON VMB COMPOSITION AND SUBSEQUENT BV, STI, AND HIV. TO UNDERSTAND GIRLS’ OWN PERCEPTIONS OF AND REASONING FOR BEHAVIORAL AND CONTEXTUAL CHANGES, AND TO APPLY THIS TO INTERVENTION DEVELOPMENT, WE WILL EMPLOY A SERIES OF SEMI-STRUCTURED FOCUS GROUP DISCUSSIONS. IMPLICATIONS: THIS STUDY WILL PROVIDE DETAILED UNDERSTANDING OF THE FINANCIAL, SOCIAL, AND BEHAVIORAL IMPACTS OF COVID-19 AND MITIGATION EFFORTS ON ADOLESCENT GIRLS IN RURAL AREAS OF AFRICA AS EXEMPLIFIED BY THIS AREA OF WESTERN KENYA. WE WILL BE ABLE TO EXAMINE THIS IN RELATION TO BIOLOGICAL OUTCOMES – VMB, BV, STI, HIV. THE KNOWLEDGE GAINED WILL DIRECTLY CONTRIBUTE TO INTERVENTION DEVELOPMENT, AND SUPPORT FUTURE POLICY AND GUIDELINES ON SCHOOL CLOSURES AND THE SUPPORT ADOLESCENT GIRLS NEED IN THE WAKE OF SIMILAR FUTURE CATASTROPHE.

PROMOTING PROSOCIAL BEHAVIOR IN SYNDROMIC INTELLECTUAL AND DEVELOPMENTAL DISABILITIES - PROJECT SUMMARY/ABSTRACT: THE ENORMOUS IMPACT OF COVID-19 SERVICE DISRUPTIONS ON INDIVIDUALS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES (IDDS) HAS HIGHLIGHTED THE CRITICALLY URGENT NEED TO INCREASE ACCESS TO MENTAL AND BEHAVIORAL HEALTH SERVICES. WITHIN IDD POPULATIONS, GENETIC SYNDROMES ASSOCIATED WITH IDDS (“SYNDROMIC IDDS”) REPRESENT A PARTICULARLY VULNERABLE SUBGROUP. MANY PATIENTS WITH SYNDROMIC IDDS PRESENT WITH MEDICALLY COMPLEX PHENOTYPES AND REMAIN MINIMALLY VERBAL EVEN INTO ADULTHOOD, CREATING CHALLENGES ACCESSING AND BENEFITING FROM COMMUNITY-BASED INTERVENTIONS. SEVERAL REPORTS POINT TO EXTREME BEHAVIOR AND COMMUNICATION CHALLENGES AS THE MOST PRESSING BEHAVIORAL HEALTH CONCERNS FOR THIS POPULATION. OUR NEAR-TERM GOALS SEEK TO IDENTIFY EFFECTIVE APPROACHES TO TARGET THE MORE SEVERE COGNITIVE AND BEHAVIORAL PHENOTYPES FOUND IN SYNDROMIC IDDS. HERE, WE PROPOSE ADAPTATIONS TO FUNCTION-BASED TREATMENT (FBT) – AN ALREADY WELL-ESTABLISHED, PERSON- CENTERED APPLIED BEHAVIOR ANALYSIS (ABA) MODEL FOCUSED ON REPLACING CHALLENGING BEHAVIORS WITH PROSOCIAL COMMUNICATION AND BEHAVIOR RESPONSES. USING THE PLANNED ADAPTATION APPROACH, PROACTIVE ADAPTATIONS TO IMPROVE THE FIT OF FBT WITH THE SYNDROMIC IDD POPULATION INCLUDE SYNDROME-SPECIFIC CHARACTERIZATIONS TO INFORM PHENOTYPE-ENVIRONMENT INTERACTIONS, SYSTEMATIC SCREENING FOR AUTOMATICALLY REINFORCED BEHAVIORS WHICH ARE OFTEN EXCLUDED FROM PUBLISHED FBT APPROACHES, AND ADJUSTMENTS TO SUPPORT MINIMALLY VERBAL INDIVIDUALS. THIS PROPOSAL DRAWS UPON THE EXPERTISE OF THE INVESTIGATIVE GROUP IN SYNDROMIC IDDS, CONVENTIONAL AND TELEHEALTH BEHAVIORAL INTERVENTIONS, AND IMPLEMENTATION SCIENCES TO EVALUATE THE ADAPTED, PARENT-IMPLEMENTED, TELEHEALTH FBT MODEL FOR SYNDROMIC IDDS (FBTSIDD). THE GOAL OF THIS FULLY REMOTE HYBRID TYPE 1 EFFECTIVENESS- IMPLEMENTATION STUDY IS TO TEST FBTSIDD AS DELIVERED BY NON-SPECIALIST PROVIDERS HOUSED IN MEDICAL HUBS SERVING INDIVIDUALS WITH SYNDROMIC IDDS. AIM 1 INVOLVES A 24-WEEK RANDOMIZED CONTROL TRIAL (RCT) THAT WILL RANDOMIZE 80 CHILDREN (AGES 2 TO 12 YEARS) WITH SYNDROMIC IDDS AND MODERATE TO SEVERE INTELLECTUAL DISABILITY (ID) AND THEIR CAREGIVERS AND RANDOMIZE THEM INTO FBTSIDD OR POSITIVE-PARENTING TREATMENT (TREATMENT AS USUAL, TAU). OUR OVERARCHING HYPOTHESIS IS THAT FBTSIDD WILL BE ASSOCIATED WITH SIGNIFICANT REDUCTIONS IN CHALLENGING BEHAVIORS COMPARED TO TAU ON INDEPENDENT EVALUATOR RATINGS USING A CONSUMER-DRIVEN, PARENT TARGET PROBLEMS (PTP) INVENTORY AND STANDARDIZED MEASURES OF BEHAVIOR AND FUNCTIONAL COMMUNICATION. AIM 2 SEEKS TO SYSTEMATICALLY MEASURE AND UNDERSTAND BOTH PLANNED AND UNPLANNED ADAPTIONS TO FBTSIDD USING THE FRAMEWORK FOR REPORTING ADAPTATIONS AND MODIFICATIONS-EXPANDED (FRAME). TOGETHER, THESE AIMS PROVIDE AN INNOVATIVE MODEL TO DEVELOP EFFECTIVE, ACCEPTABLE, AND SCALABLE INTERVENTIONS FOR BEHAVIORAL AND COMMUNICATION CHALLENGES ACROSS THE DIVERSE, VULNERABLE POPULATION OF INDIVIDUALS WITH SYNDROMIC IDDS.

ADOLESCENT CIRCADIAN PHASE SHIFTS: NOVEL TIME-OF-DAY TARGETS FOR BRIGHT LIGHT

A MECHANISTIC TEST OF TREATMENT STRATEGIES TO FOSTER PRACTICE QUITTING - PROJECT SUMMARY/ ABSTRACT TOBACCO USE REMAINS THE SINGLE LEADING PREVENTABLE CAUSE OF DEATH AND DISABILITY IN THE UNITED STATES, ACCOUNTING FOR 480,000 DEATHS AND $170 BILLION IN MEDICAL COSTS EACH YEAR. ALTHOUGH MOST CIGARETTE SMOKERS EVENTUALLY WANT TO QUIT, THE MAJORITY (80%) ARE NOT INTERESTED IN QUITTING WITHIN THE NEXT MONTH. DESPITE THIS, SMOKING CESSATION TREATMENT PROGRAMS ARE TRADITIONALLY PREDICATED ON SMOKERS’ MOTIVATIONS TO QUIT, WITH TREATMENTS PROCEEDING ONLY AMONG THOSE WILLING TO SET A QUIT DATE. THIS STANDS IN STARK CONTRAST TO TREATMENTS FOR OTHER CHRONIC DISEASES (E.G., HYPERTENSION)—HEALTH CARE PROVIDERS DO NOT ASSESS WHETHER OR NOT PATIENTS ARE READY TO TREAT THEIR HIGH BLOOD PRESSURE, THEY SIMPLY IDENTIFY THE PROBLEM AND INITIATE TREATMENT. TOBACCO TREATMENT PROGRAMS ARE BEGINNING TO MOVE TOWARD A SIMILAR STRATEGY THROUGH POPULATION HEALTH MANAGEMENT APPROACHES; HOWEVER, THERE IS A DEARTH OF TREATMENT CONTENT APPLICABLE TO SMOKERS ACROSS A RANGE OF QUIT- READINESS, PARTICULARLY FOR THOSE UNWILLING TO SET A QUIT DATE. ONE NOVEL POTENTIAL TREATMENT STRATEGY IS TO FOSTER PRACTICE QUITTING (PQ), IN WHICH AN INDIVIDUAL ATTEMPTS NOT TO SMOKE FOR A FEW HOURS OR DAYS, WITHOUT PRESSURE OR EXPECTATION TO PERMANENTLY QUIT. ALTHOUGH A GROWING BODY OF EVIDENCE HAS SUPPORTED THE ROLE OF PRACTICE QUITTING IN FOSTERING PERMANENT QUIT ATTEMPTS AND CESSATION, THERE IS LIMITED UNDERSTANDING OF THE MECHANISMS OF PQ-FOCUSED TREATMENT. FURTHERMORE, NO STUDIES TO DATE HAVE ATTEMPTED TO DISENTANGLE TREATMENT EFFECTS ASSOCIATED WITH BEHAVIORAL VS. PHARMACOLOGICAL INTERVENTION STRATEGIES TO PROMPT PRACTICE QUITTING. THE OVERALL GOAL OF THE CURRENT RESEARCH IS TO CHARACTERIZE TREATMENT MEDIATORS OF PQ-FOCUSED COUNSELING AND NICOTINE REPLACEMENT THERAPY (NRT) SAMPLING. WE WILL USE A 2X2 FACTORIAL STUDY DESIGN TO TEST THE ROLE OF PQ COUNSELING VS. MOTIVATIONAL INTERVIEWING (MI) COUNSELING, AND NRT SAMPLING (FOUR-WEEK SUPPLY OF NICOTINE LOZENGES AND PATCHES) VS. NONE ON INCIDENCE OF QUIT ATTEMPTS AT 6-MONTHS POST TREATMENT. WE HYPOTHESIZE THAT PQ TREATMENT COMPONENTS WILL HAVE AN ADDITIVE EFFECT, SUCH THAT PQ COUNSELING + NRT SAMPLING WILL PRODUCE THE HIGHEST INCIDENCE OF QUIT ATTEMPTS AT 6 MONTHS POST-TREATMENT. PARTICIPANTS (N=780) WILL BE RECRUITED THROUGH A NATIONWIDE ONLINE RECRUITMENT STRATEGY AND ALL STUDY PROCEDURES WILL BE COMPLETED REMOTELY. WE WILL PURPOSEFULLY RECRUIT SMOKERS WHO ARE NOT PLANNING TO QUIT IN THE NEXT 30 DAYS, AND WILL EXAMINE BASELINE QUIT MOTIVATION (I.E., MOTIVATION TO QUIT IN THE NEXT 6 MONTHS) AS A POTENTIAL MODERATOR OF TREATMENT EFFECT. RESULTS WILL ADVANCE OUR UNDERSTANDING OF THE BEHAVIORAL PROCESS OF PRACTICE QUITTING AND THE MECHANISMS GOVERNING PQA-FOCUSED TREATMENT STRATEGIES. THIS MECHANISTIC EVIDENCE WILL ADDRESS A KEY GAP IN THE SMOKING CESSATION TREATMENT DEVELOPMENT LITERATURE, WITH THE POTENTIAL TO INCREASE INTERVENTION REACH AND EFFICACY TO REDUCE TOBACCO-RELATED MORBIDITY AND MORTALITY.

SINGLE ARM TRIAL OF MENSTRUAL CUPS AMONG ECONOMICALLY VULNERABLE WOMEN TO REDUCE BACTERIAL VAGINOSIS AND STIS THROUGH REDUCED HARMFUL SEXUAL AND MENSTRUAL PRACTICES - IN WESTERN KENYA, HIV PREVALENCE IS 16% AMONG WOMEN IN THE GENERAL POPULATION, AND 29% AMONG THE MOST ECONOMICALLY CONSTRAINED WOMEN. THE HIV/STI EPIDEMIC OVERLAPS WITH BROADER REPRODUCTIVE HEALTH CONCERNS. MENSTRUAL HYGIENE MANAGEMENT (MHM) IS A PERVASIVE PROBLEM ACROSS LOW- AND MIDDLE-INCOME COUNTRIES. IN PHILLIPS-HOWARDS’ SURVEY OF OVER 3,400 WOMEN IN RURAL KENYA, TWO-THIRDS OF WOMEN IN IMPOVERISHED SETTINGS STATE THEY DEPEND ON THEIR SEXUAL PARTNERS TO PROVIDE BRANDED PRODUCTS. ECONOMICALLY VULNERABLE WOMEN AT HIGH RISK FOR HIV AND STI ARE UNIQUELY CHALLENGED BECAUSE MANY CONTINUE TO HAVE SEX DURING MENSES, AND ENGAGE IN HARMFUL MHM PRACTICES, SUCH AS VAGINAL INSERTION OF SPONGES AND COTTON TO MAINTAIN DRYNESS. LED BY CO-INVESTIGATOR PHILLIPS-HOWARD, A CLUSTER-RANDOMIZED STUDY OF 644 GIRLS AGED 14-16 YEARS OLD IN WESTERN KENYA COMPARED REUSABLE MENSTRUAL CUPS TO USUAL MENSTRUAL PRACTICE AND COUNSELING; AFTER 9 MONTHS, MENSTRUAL CUP USE RESULTED IN 35% REDUCTION (P=0.034) IN BACTERIAL VAGINOSIS (BV) PREVALENCE AND 56% REDUCTION (P=0.001) IN STI PREVALENCE COMPARED TO OTHER MATERIALS. AMONG 431 KENYAN SECONDARY SCHOOLGIRLS AGED 14-21, WE OBSERVED CLOTH USE FOR MENSES WAS ASSOCIATED WITH A 1.72-FOLD INCREASED ODDS OF NON-OPTIMAL VAGINAL MICROBIOME (CST-IV VS. CST-I: AOR=1.90; 95% CI: 1.03–2.86). OVER 18 MONTHS OF OBSERVATION PRIOR TO COVID-19, GIRLS USING MENSTRUAL CUPS TO MANAGE MENSES HAD 20% HIGHER OCCURRENCE OF LACTOBACILLUS CRISPATUS DOMINATED CST-I (ARR=1.29; 95% CI: 1.08–1.53, CONTROLLING FOR AGE, AND BASELINE STI AND SEXUAL ACTIVITY). MENSTRUAL CUPS DESIGNED FOR USE DURING INTERCOURSE MAY HELP WOMEN PREVENT BV AND STIS THROUGH HYGIENIC MENSTRUAL PRACTICES AND AVOIDANCE OF HARMFUL PRACTICES TO MAINTAIN VAGINAL DRYNESS DURING MENSES. OBJECTIVE: THIS SINGLE-ARM INTERVENTIONAL TRIAL SEEKS TO EVALUATE THE PRELIMINARY EFFICACY OF MENSTRUAL CUPS ON NON-OPTIMAL VAGINAL MICROBIOME (VMB), BV, AND STIS OF ECONOMICALLY VULNERABLE WOMEN AT HIGH RISK FOR STIS AND HIV, ASSESS SAFETY PROFILE, AND UNDERSTAND IMPLEMENTATION NEEDS. IN AIM 1, WE WILL EVALUATE THE IMPACT OF MENSTRUAL CUPS ON VMB, BV, AND STIS AMONG 402 ECONOMICALLY VULNERABLE WOMEN IN SEMI-URBAN KENYA. IN AIM 2, WE WILL CONDUCT INTEGRATED SURVEILLANCE FOR ENHANCED DETECTION OF SAFETY ENDPOINTS, RISK OF CUP CONTAMINATION, AND MITIGATING OR FACILITATING WATER, SANITATION, HYGIENE (WASH) FACTORS. IN AIM 3, WE WILL IDENTIFY CONSTRUCTS FOR SUCCESSFUL MHM PROGRAM IMPLEMENTATION USING AN IMPLEMENTATION SCIENCE FRAMEWORK. FUTURE DIRECTIONS: THE BIOLOGICAL PROTECTION SUGGESTED IN A RANDOMIZED SETTING, AND OUR FINDINGS THAT UNHYGIENIC CLOTH USE IS ASSOCIATED WITH NON-OPTIMAL VMB, WHILE MENSTRUAL CUP USE INCREASES OPTIMAL VMB COMPOSITION, TOGETHER PROVIDE RATIONAL JUSTIFICATION FOR THIS TRIAL, OF RELEVANCE TO ECONOMICALLY CHALLENGED WOMEN GLOBALLY. ASSESSING PRELIMINARY EFFICACY SIGNAL IN CONJUNCTION WITH IMPLEMENTATION CHARACTERISTICS AND ADVERSE EVENTS, WILL GENERATE A COMPREHENSIVE AND NECESSARY FOUNDATION FOR DEFINITIVE ASSESSMENT OF EFFECTIVENESS OF MENSTRUAL CUPS AS A MULTIPURPOSE INTERVENTION FOR MHM, AND TO REDUCE BV AND STIS.

THE MECHANISM THROUGH WHICH TGF-BETA MAINTAINS CHONDROCYTES IN PROLIFERATING STAG

BLOCK-BY-BLOCK: THE HUMBOLDT PARK CAMPAIGN AGAINST DIABETES

THE CLINICAL PROFILE OF PARKINSON'S DISEASE (PD) PATHOLOGY

EPIDEMIOLOGIC STUDY OF TDP-43 PATHOLOGY IN AGING AND DEMENTIA

SPINAL CORD AND BRAINSTEM PATHOLOGY CONTRIBUTIONS TO LATE-LIFE GAIT IMPAIRMENT

COVID 19 CYTOKINE STORM - ABSTRACT THE COVID 19 PANDEMIC HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF PROTEINURIA IN UP TO 40% OF HOSPITALIZED PATIENTS. THIS CARDINAL MANIFESTATION OF KIDNEY DISEASE IS MOST LIKELY RELATED TO EFFECTS OF THE EXTENSIVE CYTOKINE STORM IN THESE PATIENTS ON GLOMERULI, THE FILTERING UNITS OF THE KIDNEY. USING FIVE YEARS OF EXPERIENCE WITH STUDYING CYTOKINE STORMS RELATED TO COMMON COLD INDUCED RELAPSE OF SOME FORMS OF HUMAN KIDNEY DISEASE, WE DEVELOPED FOUR NOVEL “CYTOKINE COCKTAIL” MODELS OF THE COVID 19 CYTOKINE STORM. THESE CYTOKINE COCKTAILS CONTAIN COMPONENTS OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE IN A SPECIFIC ADDITIVE SEQUENCE AND INDUCE ACUTE ALBUMINURIA IN MICE. ALSO INCLUDED IN THE COCKTAILS IS SOLUBLE ANGIOTENSIN CONVERTING ENZYME 2 (SACE2), A CIRCULATING FORM OF THE RECEPTOR FOR COVID 19 IN HUMANS. THE PRESENCE OF HEIGHTENED KIDNEY DISEASE IN MICE THAT ARE HYPOMORPHS FOR THE PODOCYTE EXPRESSED TRANSCRIPTIONAL FACTOR ZHX2 MAY PROVIDE A PARTIAL GENETIC BASIS FOR GREATER SEVERITY OF DISEASE IN SELECT POPULATIONS. USING CYTOKINE DEPLETION AND CYTOKINE RECEPTOR BLOCKAGE, WE NOTED THAT IT IS POSSIBLE TO DEVELOPED TREATMENT STRATEGIES TO TREAT COVID RELATED KIDNEY DISEASE. IN SPECIFIC AIM 1, WE WILL CONDUCT MECHANISTIC STUDIES IN THE PODOCYTE RELATED TO THE EFFECT OF CYTOKINE COCKTAIL ON THE INTERLEUKIN 4 RECEPTOR, INTERLEUKIN 13 RECEPTOR, TUMOR NECROSIS FACTOR A RECEPTOR, AND TRANSMEMBRANE ACE2. IN VIVO STUDIES USING KNOCKOUT MICE AND IN VITRO STUDIES USING CULTURED PODOCYTES WILL BE CONDUCTED. IN SPECIFIC AIM 2, WE WILL INVESTIGATE MECHANISMS INVOLVED IN THE PATHOGENESIS OF COVID 19 RELATED GLOMERULAR DISEASE, ESPECIALLY COLLAPSING GLOMERULOPATHY. MICE DEFICIENT IN GLOMERULAR ENDOTHELIAL INTEGRIN SS5 EXPRESSION, PODOCYTE ZHX2 EXPRESSION, OR BOTH WILL BE USED. COMBINATION OF INTEGRIN SS5 EXPRESSION DEFICIENT MICE WITH THOSE ALSO DEFICIENT IN PODOCYTE CYTOKINE RECEPTORS AND TUMOR NECROSIS FACTOR A RECEPTOR WILL BE USED TO STUDY PARACRINE AND AUTOCRINE FEEDBACK LOOPS. IN SPECIFIC AIM 3, WE WILL CONDUCT SYSTEMATIC CURRENT CYTOKINE DEPLETION AND RECEPTOR BLOCKAGE STRATEGIES, AND ALSO USE THEM IN COMBINATION TO DEVELOP A NOVEL THERAPEUTIC PARADIGM FOR THE TREATMENT OF COVID 19 RELATED GLOMERULAR DISEASE. IT IS LIKELY THAT THESE DEPLETION STRATEGIES WILL BENEFIT OTHER END ORGAN DAMAGE CAUSED BY THE COVID 19 CYTOKINE STORM.

CORROSION INDUCED HIP IMPLANT FAILURE: SYNERGISTIC INTERACTIONS OF PATIENT, MATER

NATIONAL CENTER FOR EDUCATION RESEARCH

DIET PATTERNS AND ALZHEIMER DISEASE AND OTHER DEMENTIAS

POST-DOCTORAL TRAINING IN JOINT HEALTH

SUPAR AND RENAL FIBROSIS

HIV LATENCY IN ASTROCYTES

ROLE OF HLA-G ON HIV EVASION OF NK CELLS

PREVENTING THE DEVELOPMENT OF CHRONIC PAIN: TREATING PTSD AT ACUTE PAIN ONSET

IMPROVING HEALTH BY LINKING POSTPARTUM AND WELL-BABY VISITS

GUT MICROBIOTA-MEDIATED INFLAMMATORY INTERACTIONS BETWEEN ALCOHOL USE DISORDERS AND HIV INFECTION - PROJECT SUMMARY. ALCOHOL USE DISORDER (AUD) HAS BEEN ASSOCIATED WITH A HIGH PREVALENCE OF INFLAMMATION- ASSOCIATED CO-MORBIDITIES IN PEOPLE LIVING WITH HIV (PLWH), EVEN THOSE RECEIVING EFFECTIVE ANTIRETROVIRAL THERAPY (ART). OUR PRELIMINARY DATA SUPPORT A MODEL IN WHICH THE COMBINED INSULT OF AUD AND HIV ON THE GUT, SPECIFICALLY ON THE MICROBIOTA (DEPLETION OF THE BACTERIA THAT PRODUCE THE ANTI-INFLAMMATORY SHORT-CHAIN FATTY ACIDS (SCFAS)) AND INTESTINAL BARRIER INTEGRITY, EXACERBATES INFLAMMATION. OUR PRELIMINARY DATA USING INTESTINAL ORGANOIDS ALSO SUGGEST A POTENTIAL MECHANISM FOR AUD-MEDIATED CHANGES IN THE GUT BARRIER FUNCTION DURING HIV: THE INTESTINES OF HIV+ INDIVIDUALS HAVE LOW RESILIENCE TO ALCOHOL-INDUCED INTESTINAL BARRIER DISRUPTION CAUSED BY HIGH LEVELS OF OXIDATIVE STRESS. FINALLY, OUR PRELIMINARY DATA ALSO SUGGEST A POTENTIAL APPROACH TO ENHANCE THE INTEGRITY OF THE INTESTINAL BARRIER AND REDUCE GUT DERIVED INFLAMMATION IN PLWH WITH/WITHOUT AUD; SCFA-PROMOTING PREBIOTICS. SCFA-PROMOTING PREBIOTICS PREVENT ALCOHOL-MEDIATED ADVERSE EFFECTS ON THE INTESTINAL BARRIER AND INFLAMMATION BY PREVENTING OXIDATIVE STRESS. THESE PREBIOTICS ARE SAFE AND DECREASE GUT INFLAMMATION IN HUMANS. TOGETHER, OUR DATA SUPPORT OUR CENTRAL HYPOTHESIS THAT THE INTESTINAL RESILIENCE TO ALCOHOL-MEDIATED DISRUPTION IS REDUCED DURING HIV INFECTION LEADING TO EXAGGERATED MICROBIAL TRANSLOCATION/INFLAMMATION, AND THAT SCFA- PROMOTING PREBIOTICS CAN ENHANCE THE RESILIENCE OF THE GUT FROM HIV+ INDIVIDUALS TO ALCOHOL-MEDIATED DISRUPTION. IN AIM 1, WE WILL TEST THE HYPOTHESIS THAT INTESTINES FROM HIV+ INDIVIDUALS HAVE LOWER RESILIENCE TO ALCOHOL- MEDIATED GUT BARRIER DISRUPTION THAN INTESTINES FROM HIV-NEGATIVE CONTROLS. BLOOD, URINE, STOOL, AND INTESTINAL BIOPSIES WILL BE COLLECTED FROM FOUR GROUPS: (I) HIV- AUD-; (II) HIV- AUD+, (III) HIV+ ART+ AUD-; AND (IV) HIV+ ART+ AUD+. FIRST, WE WILL COMPARE: (A) INTESTINAL BARRIER INTEGRITY, (B) SYSTEMIC AND GUT INFLAMMATION, IMMUNE ACTIVATION, AND OXIDATIVE STRESS, (C) MICROBIOME AND METABOLOME, AND (D) HIV RESERVOIRS. SECOND, WE WILL GENERATE ILEAL/COLONIC ORGANOIDS FROM THE HIV- AND HIV+ ART+ INDIVIDUALS AND EXAMINE THEIR RESILIENCE TO ALCOHOL-INDUCED INTESTINAL BARRIER DISRUPTION. IN AIM 2, WE WILL TEST THE HYPOTHESIS THAT SCFA-PROMOTING PREBIOTICS INDUCE THE GROWTH AND/OR ACTIVITY OF BENEFICIAL MICROORGANISMS THAT CAN ENHANCE THE RESILIENCE OF THE INTESTINES OF HIV+ INDIVIDUALS TO ALCOHOL-MEDIATED DISRUPTION. WE WILL PROVIDE 20 HIV+ ART+ (10 AUD- AND 10 AUD+) INDIVIDUALS WITH COMMONLY USED PREBIOTICS FRUCTOOLIGOSACCHARIDES (FOS) FOR 10 DAYS. STOOL/BLOOD WILL BE COLLECTED BEFORE/AFTER THE TREATMENT. FIRST, WE WILL EXAMINE THE IMPACT OF FOS ON THE MICROBIOME, GUT-RELATED METABOLITES, AND INFLAMMATION. SECOND, WE WILL EXAMINE THE IMPACT OF PRE- AND POST-FOS MICROBIOME/METABOLOME (FILTERED FROM STOOL) ON THE RESILIENCE OF ORGANOIDS TO ALCOHOL-MEDIATED BARRIER DISRUPTION. THE RESULTS OF THIS STUDY CAN BUILD A FOUNDATION FOR: 1) IDENTIFYING THE MECHANISMS; AND 2) DESIGNING STRATEGIES TO PREVENT THE DEVELOPMENT, OF AUD-ASSOCIATED CO-MORBIDITIES DURING ART+ HIV INFECTION.

BIOLOGICAL & PSYCHOLOGICAL FACTORS AS PREDICTORS & INDICATORS OF MBSR RESPONSE

MAPPING OF ARTHRITIS SUSCEPTIBILITY GENES

PERSEVERE IN LEWY BODY DEMENTIA: A RANDOMIZED, CONTROLLED TRIAL OF PEER MENTOR SUPPORT AND CAREGIVER EDUCATION - PROJECT SUMMARY/ABSTRACT LEWY BODY DEMENTIA (LBD) IS THE SECOND MOST COMMON FORM OF DEGENERATIVE DEMENTIA, AFFECTING AT LEAST 2.4 MILLION PEOPLE IN THE US, AND THE OVERWHELMING MAJORITY OF PERSONS LIVING WITH LBD (PLBD) ARE CARED FOR BY FAMILY CAREGIVERS. LBD CAREGIVER STRAIN: 1) EXCEEDS THAT OF NON-LBD DEMENTIA CAREGIVERS; 2) WORSENS CAREGIVER PHYSICAL AND MENTAL HEALTH; AND 3) INDEPENDENTLY INCREASES THE RISK OF PLBD HOSPITALIZATION AND INSTITUTIONALIZATION. LBD PROGRESSION IS COMPLICATED BY THE SYNERGISTIC EFFECTS OF MOTOR, COGNITIVE, AND NEUROPSYCHIATRIC DECLINE, AND IS PUNCTUATED BY FALLS, INFECTIONS, DEHYDRATION, AND NEUROPSYCHIATRIC SYMPTOMS LEADING TO ACUTE HEALTHCARE UTILIZATION. ALTHOUGH FAMILY CAREGIVERS ARE UNIQUELY POSITIONED TO IDENTIFY AND MANAGE THESE CHALLENGES, WHICH MAY AVERT EMERGENCY DEPARTMENT VISITS AND REDUCE MORBIDITY, MANY CAREGIVERS LACK THE KNOWLEDGE, SKILLS, CONFIDENCE, RESOURCES, AND SUPPORT TO DO SO. NIA RECOGNIZES THE GAP IN ENHANCING THE KNOWLEDGE AND SKILLS OF DEMENTIA CAREGIVERS AND THE CRITICAL NEED TO UNDERSTAND OPTIMAL INTERVENTION STRUCTURE, CONTENT, MECHANISMS, AND DELIVERY METHODS FOR CAREGIVER INTERVENTIONS. BUILDING ON OUR TEAM’S RECRUITMENT SUCCESSES AND PRIOR WORK IMPACTING CAREGIVER STRAIN AND PLBD QUALITY OF LIFE, THE PROPOSED STUDY ADDRESSES THESE GAPS USING OUR SUCCESSFULLY PILOTED, PEER MENTOR-DELIVERED EDUCATIONAL INTERVENTION FOR LBD CAREGIVERS (PERSEVERE). THE STUDY AIMS TO 1) QUANTIFY THE IMPACT OF PERSEVERE ON CAREGIVER KNOWLEDGE, ATTITUDES, MASTERY, AND STRAIN; 2) IDENTIFY THE INTERVENTION AND MENTOR FACTORS DETERMINING IMPLEMENTATION FIDELITY; AND 3) TEST THE EFFECTS OF PERSEVERE ON PLBD QUALITY OF LIFE AND HEALTHCARE UTILIZATION. THESE AIMS WILL BE ACCOMPLISHED IN AN NIH BEHAVIORAL MODEL STAGE II (EFFICACY) NATIONAL, RANDOMIZED, ATTENTION-CONTROLLED, 12-WEEK TRIAL OF PERSEVERE IN 502 LBD CAREGIVERS IN PARTNERSHIP WITH THE LEWY BODY DEMENTIA ASSOCIATION, PARKINSON’S FOUNDATION, DAVIS PHINNEY FOUNDATION, AND LBD CAREGIVER ADVISORS. WE WILL MATCH CAREGIVERS IN THE INTERVENTION ARM WITH A TRAINED PEER MENTOR WHO WILL COACH THEM THROUGH A MODULAR, PRACTICAL, THEORY-BASED CURRICULUM COVERING LBD KNOWLEDGE AND SOCIAL SUPPORT TOPICS. CAREGIVERS IN THE ATTENTION CONTROL CONDITION WILL RECEIVE WEEKLY, CURATED LINKS TO EDUCATIONAL MATERIALS ONLY. WE WILL IDENTIFY IMMEDIATE AND DELAYED INTERVENTION EFFECTS, INCLUDING MEDIATORS OF CAREGIVER STRAIN AT TWELVE WEEKS, AND CAREGIVER STRAIN AND PLBD OUTCOMES AT NINE MONTHS. PLBD HEALTHCARE UTILIZATION AND IMPLEMENTATION FIDELITY WILL BE ASSESSED BIWEEKLY. FOCUS GROUPS WITH MENTORS AND INTERVIEWS WITH MENTEES WILL FURTHER DEFINE THE INTERVENTION- AND MENTOR-SPECIFIC FACTORS PREDICTING FIDELITY, MENTEE OUTCOMES, AND RETENTION. REMOTE RECRUITMENT, MENTORING, AND ASSESSMENTS INCORPORATE COMMUNITY ENGAGEMENT STRATEGIES TO ENSURE MAXIMUM ACCESSIBILITY AND INCLUSION OF UNDERREPRESENTED CAREGIVER GROUPS. STUDY RESULTS WILL ILLUMINATE THE EXTENT TO WHICH LEVERAGING PRIOR LBD CAREGIVERS AS EXPERT INTERVENTIONISTS CAN IMPROVE CURRENT CAREGIVER OUTCOMES, AND IN TURN, PLBD OUTCOMES. THESE RESULTS WILL INFORM FUTURE ADAPTATION AND DISSEMINATION OF THIS MODEL FOR OTHER DEMENTIA CAREGIVERS.

HEALTH BENEFITS AND COST OF HUMAN MILK FEEDINGS FOR VERY LOW BIRTHWEIGHT INFANTS

THE ROLE OF BLOOD AND BRAIN 5-HYDROXYMETHYLCYTOSINE IN LINKING VASCULAR RISK FACTORS TO ADRD IN OLDER WHITE AND BLACK PERSONS - PROJECT SUMMARY/ ABSTRACT ALZHEIMER’S DISEASE (AD) IS A CHRONIC AND DISABLING CONDITION, THE 6TH LEADING CAUSE OF DEATH IN THE US, AND A MAJOR CAUSE OF PERSONAL, SOCIETAL, AND GLOBAL BURDEN. YET, OUR UNDERSTANDING OF PATHOBIOLOGIC MECHANISMS UNDERLYING DEMENTIA AND COGNITIVE IMPAIRMENT IN AGING REMAINS INCOMPLETE, AND THIS GAP IN KNOWLEDGE HINDERS SCIENTIFIC ADVANCEMENT AND IMPROVED CLINICAL CARE AND PREVENTION. VASCULAR CONDITIONS SUCH AS DIABETES MELLITUS (DM) ARE COMMON, ESPECIALLY AMONG MINORITY RACIAL GROUPS, AND RECOGNIZED AS INCREASING DEMENTIA RISK. BECAUSE THESE FACTORS ARE MODIFIABLE BY TREATMENT AND LIFESTYLE APPROACHES, RESEARCH LINKING VASCULAR FACTORS TO ALZHEIMER’S DISEASE/ ALZHEIMER’S DISEASE-RELATED DEMENTIAS (AD/ADRD) IS MORE IMPORTANT THAN EVER. EMERGING DATA SUGGESTS THAT THE EPIGENOME LIKELY PLAYS A ROLE IN THIS LINK, AND NOVEL METHODS TO STUDY THE EPIGENOME ARE NOW AVAILABLE. 5-HYDROXYMETHYLCYTOSINE (5HMC) IS AN EPIGENETIC MODIFICATION OF CYTOSINE FOR WHICH WE CAN NOW MEASURE GENOME-WIDE CHANGES IN CIRCULATING CELL-FREE DNA (CFDNA) IN BLOOD AND GENOMIC DNA (GDNA) IN TISSUES. OUR GROUP HAS DEVELOPED A HIGHLY SENSITIVE AND SELECTIVE ANALYTIC APPROACH TO CAPTURE AND SEQUENCE 5HMC-CONTAINING DNA FRAGMENTS IN ORDER TO MAP GENOME-WIDE DISTRIBUTIONS, AND HAVE SUCCESSFULLY USED THIS APPROACH TO DEVELOP 5HMC SCORES WHICH DISTINGUISH BETWEEN PATIENTS WITH AND WITHOUT DIFFERENT CONDITIONS, INCLUDING IN RECENT STUDIES OF AD AND DM. IN RESPONSE TO THE PRESSING NEED TO BETTER UNDERSTAND THE PATHOBIOLOGIC UNDERPINNINGS OF AD/ADRD, WE PROPOSE A COLLABORATIVE PROJECT WITH THE OVERALL GOAL OF ELUCIDATING EPIGENETIC MECHANISMS LINKING VASCULAR RISK FACTORS TO AD/ADRD CLINICAL AND PATHOLOGICAL PHENOTYPES, IN OLDER WHITES AND BLACKS. THE PROPOSED STUDY WILL LEVERAGE AVAILABLE RESOURCES FROM TWO COMMUNITY-BASED COHORT STUDIES, INCLUDING RESEARCH PARTICIPANTS FROM WHICH TO COLLECT BLOOD SPECIMENS, AS WELL AS EXTENSIVE LONGITUDINAL CLINICAL DATA AND POSTMORTEM NEUROPATHOLOGIC DATA, AND BIOSPECIMENS (E.G., FROZEN BRAIN TISSUE SAMPLES). AMONG WHITE AND BLACK PERSONS, WE WILL COLLECT NEW GENOME-WIDE 5HMC DATA TO GENERATE SERUM-SPECIFIC (AIMS 1 AND 4) AND BRAIN-SPECIFIC 5HMC SCORES (AIMS 2 AND 4), USING DISCOVERY AND VALIDATION EXPERIMENTS IN DIFFERENT SETS OF PERSONS, THAT DISTINGUISHES BETWEEN PERSONS WITH AND WITHOUT DEMENTIA. WE WILL THEN LINK THE BLOOD AND BRAIN 5HMC DATA TO AD/ADRD CLINICAL AND PATHOLOGIC PHENOTYPES, INCLUDING INCIDENT DEMENTIA AND COGNITIVE DECLINE (AIMS 1 AND 4), CEREBROVASCULAR AND AD PATHOLOGY (AIM 2). WE WILL FURTHER EXAMINE IF RELATIONS ARE DIFFERENTIAL BY VASCULAR RISK FACTORS (DM, BLOOD PRESSURE [BP], AND BODY MASS INDEX [BMI]) AND BY OTHER FACTORS (E.G., SEX; AIMS1-4), AND IF GENERALIZABLE TO BLACK PERSONS (AIM 4). BECAUSE VASCULAR RISK FACTORS ARE COMMON AND MODIFIABLE, THIS STUDY WHICH WILL ELUCIDATE 5HMC MECHANISMS IN AD/ADRD AND VASCULAR DISEASES AMONG WHITE AND BLACK OLDER PERSONS, WILL FILL A MAJOR GAP IN SCIENTIFIC KNOWLEDGE ABOUT DEMENTIA AND PROVIDE IMPORTANT DATA TO INFORM FUTURE RESEARCH AND TO ULTIMATELY IMPROVE CLINICAL DEMENTIA CARE AND PREVENTION.

LIFESTYLE PHYSICAL ACTIVITY AND COGNITIVE TRAINING INTERVENTIONS: PREVENTING MEMORY LOSS IN OLDER WOMEN WITH CARDIOVASCULAR DISEASE

INTERSECTIN-1S REGULATES LUNG VASCULAR PERMEABILITY AND ENDOTHELIAL CELL SURVIVAL

THE ROLE OF MICRORNA IN OSTEOARTHRITIS

CHARACTERIZING NOVEL HIPPOCAMPAL DRUGS FOR ALZHEIMER'S DISEASE

SLEEP LENGTH AND CIRCADIAN REGULATION IN HUMANS

IMMUNE DYS-REGULATION IN HIV-INFECTED WOMEN WITH HEAVY ALCOHOL CONSUMPTION

ADOLESCENT SLEEP DELAY: CIRCADIAN REGULATION AND PHASE SHIFTING WITH LIGHT

PURPOSE: THE OVERALL PURPOSE OF THE OLDER ADULT HOME MODIFICATION PROGRAM (OAHMP) IS TO ASSIST EXPERIENCED NONPROFIT ORGANIZATIONS, STATE AND LOCAL GOVERNMENTS, AND PUBLIC HOUSING AUTHORITIES IN UNDERTAKING COMPREHENSIVE PROGRAMS THAT MAKE SAFETY AND FUNCTIONAL HOME MODIFICATIONS REPAIRS AND RENOVATIONS TO MEET THE NEEDS OF LOW-INCOME ELDERLY HOMEOWNERS. THE GOAL OF THE HOME MODIFICATION PROGRAM IS TO ENABLE LOW-INCOME ELDERLY PERSONS TO REMAIN IN THEIR HOMES THROUGH LOW-COST, LOW BARRIER, HIGH IMPACT HOME MODIFICATIONS TO REDUCE OLDER ADULTS’ RISK OF FALLING, IMPROVE GENERAL SAFETY, INCREASE ACCESSIBILITY, AND TO IMPROVE THEIR FUNCTIONAL ABILITIES IN THEIR HOME. THIS WILL ENABLE OLDER ADULTS TO REMAIN IN THEIR HOMES, THAT IS, TO “AGE IN PLACE,” RATHER THAN MOVE TO NURSING HOMES OR OTHER ASSISTED CARE FACILITIES.; ACTIVITIES TO BE PERFORMED: HUD’S OFFICE OF LEAD HAZARD CONTROL AND HEALTHY HOMES IS MAKING AVAILABLE GRANT FUNDS AND TRAINING RESOURCES TO NON-FEDERAL ENTITIES. UNDER THE OAHMP AWARD, EXPERIENCED NONPROFIT ORGANIZATIONS, STATE AND LOCAL GOVERNMENTS, AND PUBLIC HOUSING AUTHORITIES WILL DELIVER HOME MODIFICATION SERVICES TO QUALIFIED BENEFICIARIES. THE OAHMP MODEL FOCUSES ON LOW-COST, HIGH-IMPACT HOME MODIFICATIONS. EXAMPLES OF THESE HOME MODIFICATIONS INCLUDE INSTALLATION OF GRAB BARS, RAILINGS, AND LEVER-HANDLED DOORKNOBS AND FAUCETS, AS WELL AS THE INSTALLATION OF ADAPTIVE EQUIPMENT, SUCH AS TEMPORARY RAMP, TUB/SHOWER TRANSFER BENCH, HANDHELD SHOWER HEAD, RAISED TOILET SEAT, RISERS FOR CHAIRS AND SOFAS, AND NON-SLIP STRIPS FOR TUB/SHOWER OR STAIRS. THE OAHMP MODEL PRIMARILY RELIES ON THE EXPERTISE OF A LICENSED OCCUPATIONAL THERAPIST (OT) TO ENSURE THAT THE HOME MODIFICATION ADDRESSES THE CLIENT’S SPECIFIC GOALS AND NEEDS AND PROMOTES THEIR FULL PARTICIPATION IN DAILY LIFE ACTIVITIES. THE OT IS TRAINED TO EVALUATE CLIENTS’ FUNCTIONAL ABILITIES AND THE HOME ENVIRONMENT AND HAS KNOWLEDGE OF THE RANGE OF LOW-COST, HIGH-IMPACT ENVIRONMENTAL MODIFICATIONS AND ADAPTIVE EQUIPMENT USED TO OPTIMIZE THE HOME ENVIRONMENT AND INCREASE INDEPENDENCE. THE GRANTEES, WHICH ARE EXPERIENCED IN PROVIDING SERVICES TO SENIORS, WILL DELIVER HOME MODIFICATION SERVICES TO MORE THAN 1,900 SENIOR FAMILIES IN BOTH URBAN COMMUNITIES AND COMMUNITIES WITH SUBSTANTIAL RURAL POPULATIONS.; EXPECTED OUTCOMES: PROVIDED THROUGH HUD’S OLDER ADULTS HOME MODIFICATION PROGRAM (OAHMP), THESE GRANTS ENABLE LOW-INCOME ELDERLY PERSONS TO REMAIN IN THEIR HOMES THROUGH LOW-COST, LOW BARRIER, HIGH IMPACT HOME MODIFICATIONS TO REDUCE OLDER ADULTS’ RISK OF FALLING, IMPROVE GENERAL SAFETY, INCREASE ACCESSIBILITY, AND IMPROVE THEIR FUNCTIONAL ABILITIES IN THEIR HOME. THESE INVESTMENTS WILL DELIVER HOME MODIFICATION SERVICES TO MORE THAN 1,900 SENIOR FAMILIES TO ENABLE OLDER ADULTS TO REMAIN IN THEIR HOMES – TO “AGE IN PLACE” – RATHER THAN MOVE TO NURSING HOMES OR OTHER ASSISTED CARE FACILITIES.; INTENDED BENEFICIARIES: THE OAHMP PROVIDE FUNDING TO EXPERIENCED NON-PROFITS, STATES, LOCAL GOVERNMENTS, AND PUBLIC HOUSING AGENCIES FOR SAFETY AND FUNCTIONAL HOME MODIFICATION REPAIRS TO MEET THE NEEDS OF LOW-INCOME ELDERLY HOMEOWNERS TO ENABLE THEM TO REMAIN IN THEIR RESIDENCES AT LEAST ONE HALF OF THE FUNDS SHALL BE AVAILABLE TO COMMUNITIES WITH SUBSTANTIAL RURAL POPULATIONS. INTENDED TO BENEFIT ELIGIBLE LOW-INCOME HOMEOWNERS WHO ARE AT LEAST 62 YEARS OLD FOR WORK IN THEIR PRIVATE PRIMARY RESIDENCE.; SUBRECIPIENT ACTIVITIES: THE SUBRECIPIENT ACTIVITIES ARE UNKNOWN AT THE TIME OF AWARD.

SYSTEMS BIOLOGY APPROACH TO IDENTIFYING BIOMARKERS FOR ALCOHOLIC LIVER DISEASE

ROLE OF ALCOHOL AND CIRCADIAN DISRUPTION IN INFLAMMATION AND COLON CANCER

MOLECULAR BASIS OF CARDIAC ARRHYTHMIA AND SUDDEN DEATH

TO PROMPTLY MAKE AVAILABLE EMERGENCY FINANCIAL AID GRANTS FROM THE ADVANCED FUNDS FOR INSTITUTIONAL COSTS.

RECOMBINANT HANGPTL4 AND CKD - ABSTRACT DESPITE DECADES OF TREATMENT WITH ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS, AND THE RECENT ADDITION OF SGLT2 INHIBITORS, CHRONIC KIDNEY DISEASE (CKD) PATIENTS CONTINUE TO PROGRESS TOWARDS END STAGE KIDNEY DISEASE. WHILE STUDYING MECHANISMS OF PROTEINURIA AND KIDNEY DISEASE A DECADE AGO, WE IDENTIFIED AND PUBLISHED CIRCULATING SIALYLATED ANGIOPOIETIN-LIKE-4 (ANGPTL4) AND MUTATED VERSIONS OF THE HUMAN PROTEIN AS A POTENTIAL THERAPY TO REDUCE PROTEINURIA VIA INTERACTION WITH GLOMERULAR INTEGRINS. SUBSEQUENT STUDIES (PRELIMINARY DATA IN THIS PROPOSAL) HAVE NOW SHOWN THAT TRANSGENE SECRETED RAT ANGPTL4 AND THE MUTATED HUMAN ANGPTL4 PROTEIN 8520 REDUCE THE PROGRESSION OF CKD IN RAT MODELS OF FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS (FSGS)AND DIABETIC NEPHROPATHY (DN), RESPECTIVELY. MOREOVER, THE PRESERVATION OF INULIN CLEARANCE GLOMERULAR FILTRATION RATE (GFR) IN DIABETIC RATS TREATED WITH 8520 WAS SUPERIOR TO CONTROL TREATED RATS, AND 8520 + ACE INHIBITORS SUPERIOR TO CONTROL TREATED RATS OR RATS TREATED WITH ACE INHIBITORS ALONE. WE FURTHER NOTED THAT 8520 TREATMENT REDUCES KIDNEY INTERSTITIAL CAPILLARY APOPTOSIS SIGNIFICANTLY, THEREBY ALSO REDUCING INTERSTITIAL FIBROSIS, POTENTIALLY VIA INTERACTION WITH INTEGRINS. IN THIS PROPOSAL, WE PLAN TO EXTEND OUR MECHANISTIC STUDIES ON THE BENEFICIAL INTERACTION OF 8520 WITH INTEGRINS IN KIDNEY INTERSTITIAL CAPILLARIES, WHILE ALSO EXTENDING POTENTIAL THERAPEUTIC STUDIES IN RAT MODELS OF DN AND FSGS, THAT INCLUDE COMPARISONS WITH ACE INHIBITORS AND SGLT2 INHIBITORS, AND ADDITIONAL VITAL SIGN MONITORING USING TELEMETRY. FINALLY, WE STUDY POTENTIAL THERAPEUTIC EFFECTS OF 8520 IN A LARGE ANIMAL (MINIPIG) MODEL OF CKD. IN AIM 1, 8520 EFFICACY IN IMPROVING CKD WILL BE STUDIED IN ZSF1 DIABETIC RATS AND BUFFALO MNA (FSGS) RATS, INCLUDING COMPARISONS AND COMBINATIONS WITH ACE INHIBITORS, SGLT2 INHIBITORS AND CONTROLS. IN AIM 2, WE WILL STUDY WHETHER THE ANTI-APOPTOSIS EFFECTS OF 8520 ON KIDNEY INTERSTITIAL CAPILLARIES ARE MEDIATED VIA INTEGRIN Β1 OR INTEGRIN Β5. ADDITIONAL MASS SPECTROMETRY STUDIES ON PURIFIED 8520 WILL BE CONDUCTED TO DEVELOP AN ASSAY TO MONITOR PLASMA LEVELS, AND AN ELISA TO STUDY POTENTIAL IMMUNE RESPONSE TO MUTATIONS IN 8520 WILL BE DEVELOPED. IN AIM 3, THE AUTOLOGOUS PHASE OF NEPHROTOXIC NEPHRITIS WILL BE STUDIED IN MINIPIGS TO DETERMINE THE EFFICACY OF 8520 IN SLOWING THE PROGRESSION OF CKD IN A LARGE ANIMAL MODEL.

TESTING ADAPTIVE INTERVENTIONS TO IMPROVE PHYSICAL ACTIVITY FOR SEDENTARY WOMEN

ANGER SUPPRESSION AND EXPRESSION AMONG CHRONIC PAIN PATIENTS

LINCRNAS IN MUCOSAL DEFENSE TO AIDS OPPORTUNISTIC PATHOGEN CRYPTOSPORIDIUM

DELAY DISCOUNTING AND HOUSEHOLD FOOD CHOICES

SKELETAL MUSCLE. CA2+ RELEASE CONTROL INSIDE THE SR

THE CLINICAL HISTORY OF RECTAL AND URETHRAL STIS AMONG MSM: CHARACTERIZING MICROBIOME HOST IMMUNE INTERACTIONS FOR DIAGNOSTIC AND VACCINE ADVANCES - IN SUB-SAHARAN AFRICA, MEN WHO HAVE SEX WITH MEN (MSM) HAVE 2-4 TIMES HIGHER RATES OF SEXUALLY TRANSMITTED INFECTIONS (STIS) AND HIV THAN THE GENERAL MALE POPULATION. IN OUR COHORT OF 700 MSM IN KISUMU, KENYA, THE INCIDENCE OF URETHRAL AND ANORECTAL C. TRACHOMATIS (CT) AND/OR N. GONORRHOEAE (NG) WAS 19.8 PER 100 PERSON YEARS (PY) OVER ONE YEAR. THESE RATES ARE 2-3 TIMES THE INCIDENCE WE MEASURED AMONG HETEROSEXUAL KENYAN MEN. OUR STUDIES OF MSM IN KISUMU AND NAIROBI HAVE IDENTIFIED SPECIFIC RECTAL BACTERIAL COMMUNITY STRUCTURES THAT ARE ASSOCIATED WITH INFLAMMATORY MUCOSAL IMMUNE PROFILES. INFLAMMATORY RECTAL MICROBIOME PROFILES COULD INCREASE RISK OF STI ACQUISITION AND INTERFERE WITH VACCINE EFFICACY BY SKEWING SYSTEMIC T CELL POPULATIONS TOWARD AN INCREASED MEMORY/DECREASED NAÏVE LYMPHOCYTE RATIOS, AND A HIGHER STATE OF BASAL IMMUNE ACTIVATION, AS SUPPORTED BY OUR PRELIMINARY INVESTIGATIONS. INFLAMMATION COULD THEREFORE UNDERMINE THE PARTIAL PROTECTIVE EFFICACY OF STI VACCINES ABILITY TO PRIME NAÏVE LYMPHOCYTES REQUIRED FOR OPTIMAL IMMUNITY, BOTH BY DECREASING THE FREQUENCY OF NAÏVE LYMPHOCYTES, AND BY DECREASING THE EFFICIENCY IN WHICH THE REMAINING NAÏVE T CELLS ARE PRIMED. OBJECTIVE: OVER A ONE-YEAR PERIOD, IN A SAMPLE OF 500 MSM IN KISUMU (N=250) AND NAIROBI (N=250), WE WILL MEASURE THE PENILE AND RECTAL MICROBIOMES, MUCOSAL IMMUNE PROFILES, SOCIO-BEHAVIORAL AND STRUCTURAL FACTORS, AND INCIDENCE OF URETHRAL AND ANORECTAL STIS (CT, NG). IN AIM 1, WE WILL CHARACTERIZE THE CLINICAL HISTORY OF STI INFECTION FROM TIME OF DETECTION TO TIME OF TREATMENT TO TREATMENT AND CLEARANCE. SAMPLES WILL BE COLLECTED FROM ALL MEN AT BASELINE, 6- AND 12- MONTHS TO CHARACTERIZE PENILE AND RECTAL MICROBIOME COMPOSITION (VIA HIGH THROUGHPUT AMPLICON SEQUENCING), MUCOSAL IMMUNOLOGY (BROAD MEASURE OF PRO-INFLAMMATORY, INFLAMMATORY, AND ANTI-INFLAMMATORY CYTOKINES AND CHEMOKINES AND MEASURES OF EPITHELIAL BARRIER INTEGRITY), AND TEST FOR STI BY NUCLEIC ACID AMPLIFICATION ASSAY. ACCOUNTING FOR LOSS TO FOLLOW-UP, WE EXPECT 70-90 INCIDENT CT AND/OR NG INFECTIONS, AND FOR THESE MEN, MICROBIOME COMPOSITION, MUCOSAL IMMUNOLOGY, AND BACTERIAL FUNCTION WILL BE ASSESSED AGAIN WHEN THEY PRESENT FOR ANTIBIOTIC TREATMENT, AND 4 WEEKS SUBSEQUENT TO TREATMENT. IN AIM 2, WE WILL QUANTIFY HOW PENILE AND RECTAL MICROBIOME COMPOSITION ARE ASSOCIATED WITH RISK OF INCIDENT URETHRAL AND RECTAL STIS, RESPECTIVELY. AS A SECONDARY OUTCOME, WE WILL IDENTIFY DOMINANT MUCOSAL IMMUNE PROFILES AND EXAMINE HOW THEY CHANGE OVER TIME IN RELATION TO MICROBIOME COMPOSITION. IN AIM 3, WE WILL IN STI CASES IDENTIFY ADAPTIVE IMMUNE MECHANISMS THAT LINK RECTAL MICROBIOME, HOST IMMUNITY, AND SYMPTOMATIC OR ASYMPTOMATIC STI INCIDENT INFECTIONS. THERAPEUTIC AND PREVENTIVE IMPLICATIONS: THE IMPACT OF STI TREATMENT ON PENILE AND RECTAL MICROBIOME COMPOSITION AND BACTERIAL FUNCTION IS UNKNOWN AND CHARACTERIZING THIS ASPECT OF CLINICAL HISTORY OF INFECTION CAN IDENTIFY NOVEL TREATMENT AND PREVENTION PATHWAYS. UNDERSTANDING FACTORS THAT MIGHT UNDERMINE PROTECTIVE IMMUNITY TO STIS COULD BE CRITICAL TO INFORMING THE DESIGN OF MORE EFFECTIVE VACCINES THAT ARE REQUIRED TO ACHIEVE STI CONTROL.

CINNAMON, CNTF AND EAE

GENOMIC EPIDEMIOLOGY OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS IN JAIL

NOVEL ANALYTICAL TOOLS FOR 3 DIMENSIONAL IMAGING STUDIES ON SPINAL MANIPULATION

TARGETING PROLYL PEPTIDASES IN TAMOXIFEN RESISTANT BREAST CANCER

NOVEL ANTI-PROTEINURIC STRATEGIES TARGETING PODOCYTES

PATHOGENESIS OF A JC VIRUS VARIANT IN PYRAMIDAL NEURONS

E-C COUPLING AND CA2+ REGULATION IN ATRIAL MYOCYTES

FACTORS LEADING TO ENHANCED PSEUDOMONAS AERUGINOSA INFECTION IN DIABETIC WOUNDS

VITAMIN D RECEPTOR REGULATION OF MICROBIOTA IN INTESTINAL EPITHELIA

MULTIMODAL MRI BIOMARKERS OF SMALL VESSEL DISEASE FOR OLDER PERSONS WITH AND WITHOUT DEMENTIA.

CONTROL MECHANISMS OF HUMAN VOLTAGE GATED PROTON CHANNELS, HHV1

TGF-BETA AND IGF IN MESENCHYMAL STEM CELL CHONDROGENESIS

IMPACT OF MATERNAL INTEGRASE INHIBITOR USE ON OFFSPRING FAT AND BONE DEVELOPMENT - PROJECT SUMMARY HIGHLY EFFECTIVE ANTIRETROVIRAL THERAPY (ART) HAS SIGNIFICANTLY REDUCED THE MOTHER-TO-CHILD TRANSMISSION OF HIV BUT HAS ALSO INCREASED THE NUMBER OF CHILDREN WHO ARE HIV EXPOSED UNINFECTED (HEU) AND EXPOSED TO ART DURING GESTATION. CURRENT NATIONAL AND INTERNATIONAL ART PRESCRIPTION GUIDELINES NOW RECOMMEND MATERNAL USE OF INTEGRASE STRAND TRANSFER INHIBITOR (INSTI)–BASED REGIMENS THROUGHOUT PREGNANCY. IMPORTANTLY, WHILE INSTI USE IS ASSOCIATED WITH FAT TISSUE EXPANSION AND IMPAIRED BONE MASS IN ADULTS AND ADOLESCENCE WITH HIV, THE CONSEQUENCES OF IN UTERO EXPOSURE TO INSTIS ON OFFSPRING FAT AND BONE DEVELOPMENT REMAIN UNKNOWN. A KEY BARRIER TO OUR UNDERSTANDING OF THESE EFFECTS IS THE RECENT ADOPTION OF INSTI USE DURING PREGNANCY, WHICH LIMITS THE NUMBER AND AGE OF CHILDREN EXPOSED TO INSTIS AVAILABLE FOR STUDY. THEREFORE, TO ADDRESS THIS GAP, OUR LABORATORY UTILIZED A PRECLINICAL MOUSE MODEL OF GESTATIONAL EXPOSURE TO MATERNAL INSTI-BASED ART AND FOUND LONG-LASTING CHANGES IN OFFSPRING WEIGHT AND BONE LENGTH, SUGGESTING THAT EARLY INSTI EXPOSURE CAN DISRUPT NORMAL DEVELOPMENTAL PATHWAYS. BUILDING ON THESE FINDINGS, THE PROPOSED STUDY WILL INVESTIGATE THE MECHANISMS UNDERLYING IMPAIRED FAT AND BONE DEVELOPMENT FOLLOWING EXPOSURE TO MATERNAL INSTI-BASED REGIMENS. DUE TO THE EARLY EXPOSURE AND THE LONG-LASTING TISSUE CHANGES, WE HYPOTHESIZE THAT MATERNAL AND LACTATION EXPOSURE TO INSTI-BASED ART CAUSES EPIGENETIC ALTERATIONS ASSOCIATED WITH ADVERSE FAT AND BONE DEVELOPMENT IN HEU CHILDREN. TO TEST OUR HYPOTHESIS, WE WILL USE OUR PRECLINICAL MOUSE MODEL TO INVESTIGATE THE LONGITUDINAL IMPACT OF VARIOUS INSTI-CONTAINING REGIMENS ON KEY OFFSPRING DEVELOPMENT STAGES AND EVALUATE THE TISSUE LEVEL MECHANISMS, INCLUDING EPIGENETIC CHANGES, ASSOCIATED WITH STRUCTURAL (MASS) CHANGES. TO ENSURE CLINICAL RELEVANCE, WE WILL ALSO LEVERAGE DATA AND SAMPLES FROM THE PEDIATRIC HIV/AIDS COHORT STUDY (PHACS) AND THE INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS NETWORK (IMPAACT) TO EVALUATE WHETHER EPIGENETIC CHANGES IN HEU CHILDREN DIFFER BETWEEN INSTI-BASED AND INSTI-SPARING REGIMENS AND ARE DEPENDENT UPON THE ANTIRETROVIRALS USED IN COMBINATION WITH INSTIS. IF SUCCESSFUL, RESULTS FROM THIS PROPOSAL WILL INFORM SAFER ART PRESCRIBING DURING PREGNANCY AND GUIDE STRATEGIES TO OPTIMIZE LIFELONG HEALTH AMONG CHILDREN EXPOSED TO HIV AND ART IN UTERO.

ROLE OF IFN-LAMBDA IN PROMOTING BREAST CANCER METASTASIS

SPOUSAL EXPRESSION OF CRITICISM/HOSTILITY AND ADJUSTMENT AMONG CHRONIC PAIN PATIE

NEW AWARD; TITLE: PROOF OF CONCEPT STUDIES OF AN ULTRA-HIGH-PERFORMANCE CARDIAC IMAGING SYSTEM: C-SPECT-II; PI: WEI CHANG

RISK FACTORS AND THE NEUROBIOLOGIC SUBSTRATE OF FRAILTY

BONE AND FAT CROSS-TALK IN ANTIRETROVIRAL THERAPY (ART) TREATED HIV PATIENTS - PROJECT SUMMARY / ABSTRACT THE WIDESPREAD USE OF COMBINATION ANTIRETROVIRAL THERAPY (CART) HAS SIGNIFICANTLY INCREASED THE LIFESPAN OF PEOPLE LIVING WITH HIV (PLWH). AS HIV HAS BECOME A CHRONIC DISEASE, THERE IS A GROWING CONCERN OF THE DISPROPORTIONATE RISK OF A VARIETY OF COMORBIDITIES. TWO SUCH COMORBIDITIES THAT OCCUR AT A HIGHER PREVALENCE IN CART TREATED PLWH INCLUDE BONE LOSS AND FAT GAIN. INTERESTINGLY, AS NEW TREATMENT RECOMMENDATIONS HAVE SHIFTED TO CART REGIMENS THAT ARE LESS BONE TOXIC, THERE APPEARS TO BE AN INCREASED PREVALENCE OF EXCESSIVE FAT GAIN AND AN INCREASED RISK FOR THE DEVELOPMENT OF METABOLIC SYNDROME. OUR LONG-TERM GOAL IS TO DETERMINE THE MECHANISMS CONTRIBUTING TO THESE COMORBID CONDITIONS IN CART TREATED PLWH IN ORDER TO FIND LESS DELETERIOUS TREATMENT OPTIONS. THE CURRENT PROPOSAL WILL TEST THE CENTRAL HYPOTHESIS THAT THE HORMONAL COMMUNICATION BETWEEN BONE AND FAT EXPLAINS HOW ANTIRETROVIRALS (ARVS) CONTRIBUTE TO BONE LOSS AND FAT GAIN IN PLWH. OUR HYPOTHESIS IS BASED ON OUR PRELIMINARY DATA SHOWING HORMONAL CHANGES IN RESPONSE TO ARVS AND CORRELATIONS BETWEEN THE CHANGES IN BONE AND FAT HORMONES AND BMD LOSS AND FAT GAIN WITH CART INITIATION. TO TEST OUR HYPOTHESIS, WE PROPOSE TO TAKE A HIERARCHICAL APPROACH THAT WILL INCLUDE IN VITRO, PRECLINICAL, AND HUMAN SUBJECT STUDIES. IN AIM 1, WE WILL DEFINE THE CONTRIBUTION OF INDIVIDUAL ARVS AND CART TO BONE AND FAT CELLULAR FUNCTION AND HORMONAL PRODUCTION USING PRIMARY HUMAN CELLS. IN AIM 2, WE WILL INVESTIGATE THE SKELETAL AND METABOLIC RESPONSE TO INDIVIDUAL ARVS AND CART USING BOTH AN UNINFECTED WILD-TYPE MOUSE AND A HUMANIZED MOUSE MODEL OF HIV-INFECTION. FINALLY, IN AIM 3, WE WILL DETERMINE THE ASSOCIATION BETWEEN BONE AND FAT-DERIVED HORMONES AND BONE MASS AND BODY COMPOSITION IN THREE CRITICAL TREATMENT STAGES, CART INITIATION, LONG-TERM STABLE CART TREATMENT, AND SWITCHING CART REGIMENS. IF SUCCESSFUL, THIS PROPOSAL, SUBMITTED BY AN EARLY STAGE INVESTIGATOR (ESI), WILL PROVIDE SIGNIFICANT INSIGHTS INTO KEY COMORBIDITIES FACED BY HIV PATIENTS ON CART—SPECIFICALLY BY ILLUMINATING HOW INDIVIDUAL ARVS NEGATIVELY AFFECT BONE/FAT CELL FUNCTION AND HORMONAL PRODUCTION. AT THE SAME TIME, THIS PROPOSAL WILL INCREASE OUR GENERAL UNDERSTANDING OF THE BONE- FAT HORMONAL AXIS.

PARTNERING WITH PERSONS WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITIES TO IMPROVE HEALTH CARE OUTCOMES

TARGETING MONONUCLEAR PHAGOCYTES DEVELOPMENT IN ALCOHOL INDUCED LIVER DAMAGE: PATHOLOGICAL AND IMMUNOLOGICAL PATHWAYS

FATE AND REGULATION OF FRACTURE-INDUCED PRX1 CELLS

BRAIN AND SPINAL CORD MICROVASCULAR PATHOLOGY IN LATE-LIFE MOTOR IMPAIRMENT

GALANIN IN ALZHEIMER'S DISEASE

DETECTION AND TREATMENT OF PERI-IMPLANT OSTEOLYSIS

THE ROLE OF P21-ACTIVATED KINASE (PAK1) IN ATRIAL FIBRILLATION

SYNTHETIC LETHAL TARGETING OF KRAS/KEAP1 CO-MUTANT NON-SMALL CELL LUNG CANCER - ABSTRACT ACTIVATING KRAS MUTATIONS OCCUR IN 20-40% OF NON-SMALL CELL LUNG CANCERS (NSCLCS). ABOUT 20% OF THE KRAS MUTATION TUMORS HAVE CO-OCCURRING MUTATIONS OF KEAP1 THAT ARE RESISTANT TO MOST THERAPIES AND DIFFICULT TO TREAT. THEREFORE NEW TREATMENTS ARE NEEDED. CURRENTLY, WE FOUND THESE CO-MUTANT TUMORS EXPRESS HIGH LEVELS OF THE HISTONE DEACETYLASE PROTEIN HDAC4 IMPORTANT FOR THEIR SURVIVAL. KRAS/KEAP1 CO-MUTANT NSCLC CELLS ARE SENSITIVE TO A HDAC4/5 INHIBITOR CALLED LMK235 WHILE SINGLE MUTANT CELLS ARE NOT. KNOCKDOWN OF HDAC4/5 OR TREATMENT WITH TSA (INHIBITS CLASS I/II HDACS INCLUDING HDACS 4 AND 5) HAS SIMILAR EFFECT. THUS, HIGH HDAC EXPRESSION REPRESENTS AN ACHILLES HEEL THAT RENDERS CO-MUTANT CELLS SENSITIVE TO LMK235 AND HDAC4/5 INHIBITION. MECHANISTICALLY, WE FOUND LMK235 INDUCES TOXICITY BY ACTIVATING A TUMOR SUPPRESSOR PROTEIN CALLED RB AND BY ACTIVATING A PROTEIN CALLED BIM THAT TRIGGERS CELL DEATH. LASTLY, WE FOUND LMK235 CAUSES STRIKING SYNERGISTIC TOXICITY WHEN COMBINED WITH THE DRUG AMG510 (SOTORASIB) IN KRASG12C/KEAP1 CO-MUTANT NSCLCS. AMG510 SPECIFICALLY INHIBITS THE KRAS G12C MUTANT AND IS FDA APPROVED. IN CLINICAL STUDIES, KRAS G12C/KEAP1 MUTANT NSCLC TUMORS RESPONDED LESS WELL TO AMG510 THAN KRAS G12C TUMORS WITH WILD-TYPE KEAP1. THIS HIGHLIGHTS A NEED TO IMPROVE TREATMENTS IN THESE TUMORS. THE FINDING THAT LMK235 CAUSES SYNERGISTIC TOXICITY WITH AMG510 SUGGESTS THIS DRUG COMBINATION COULD IMPROVE RESPONSES IN THESE PATIENTS. IN AIM 1 WE WILL ESTABLISH THAT LMK235 AND TSA SPECIFICALLY TARGET KRAS/KEAP1 CO-MUTANT AND NOT SINGLE MUTANT NSCLC CELLS. WE WILL DETERMINE HOW RB IS ACTIVATED BY LMK235 AND CONFIRM ITS ROLE. THE ROLE OF BIM AND BIM ACETYLATION WILL ALSO BE DETERMINED BY CREATING MUTANTS OF BIM THAT EITHER BLOCK OR INHIBIT ACETYLATION AND TESTING THEIR EFFECT IN CELL RESPONSES TO LMK235. IN AIM 2 WE WILL EXAMINE THE COMBINED EFFECTS OF AMG510 AND LMK235. FIRST, WE WILL ESTABLISH THAT THE COMBINATION OF AMG510+LMK235 SPECIFICALLY TARGETS KRASG12C/KEAP1 CO- MUTANT CELLS. THIS WILL BE DONE BY COMPARING SENSITIVITY IN A PANEL OF NSCLC CELL LINES THAT VARY IN KRASG12C AND KEAP1 STATUS, AND BY GENERATING CELL LINES WHERE KRASG12C AND/OR KEAP1 ARE MUTATED. LASTLY WE WILL TEST THE RESPONSE OF KRASG12C/KEAP1 DOUBLE OR SINGLE MUTANT TUMORS TO AMG510+LMK235 IN MICE. THE IMPACT AND SIGNIFICANCE OF THE PROPOSED STUDIES IS HIGH. KRAS/KEAP1 CO-MUTANT NSCLCS ARE DIFFICULT TO TREAT. THE CURRENT GRANT IDENTIFIES HDAC4/5 AS A TARGETABLE VULNERABILITY IN THESE CANCERS. LMK235 INDUCES TOXICITY UNIQUELY IN KRAS/KEAP1 CO-MUTANT NSCLCS BUT NOT SINGLE MUANT NSCLCS, AND THEREFORE COULD BE A WAY TO TARGET THESE DOUBLE MUTANT CANCERS. THE GRANT IS ALSO CLINICALLY RELEVANT, AS KRASG12C/KEAP1 MUTANT NSCLCS RESPONDED LESS WELL TO THE G12C INHIBITOR AMG510 IN CLINICAL STUDIES THAN KRASG12C TUMORS WITH WILD-TYPE KEAP1. THE GRANT SHOWS LMK235 IN COMBINATION WITH AMG510 CAUSES STRIKING SYNERGISTIC KILLING SPECIFICALLY IN KRAS/KEAP1 CO-MUTANT NSCLC. THUS, COMBINATION OF AMG510 WITH LMK235 (OR COMPOUNDS LIKE IT) COULD BE USED TO IMPROVE RESPONSES IN THESE PATIENTS.

CARTILAGE DEGENERATION AND REPAIR BY ADAMTSS AND HYALURONAN BINDING PROTEINS

MECHANISMS OF HIV AND DRUG ABUSE PATHOGENESIS IN CNS

NOVEL TARGETED CHEMO/IMMUNOTHERAPY APPROACH FOR LOCALIZED AND METASTATIC CAP

ENGAGING LOW-INCOME PARENTS IN PREVENTION PROGRAMS

PAIN MECHANISMS OF KNEE JOINT OSTEOARTHRITIS

PROTEOLYTIC REGULATION OF PODOCYTE FUNCTION BY CATHEPSIN L.

FACTORS INFLUENCING DECLINE IN AD TRENDS IN A BIRACIAL POPULATION STUDY

RANTES AND EOTAXIN: NEW PLAYERS IN PD PROGRESSION

EDUCATION RESEARCH PROGRAM

2/2-PREVENTION OF RELAPSE & RECURRENCE OF BIPOLAR DEPRESSION

STEPS TO EFFECTIVE PROBLEM SOLVING