Temple University-Of The Commonwealth System Of Higher Educ

TEMPLE CARES

TEMPLE CARES RELIEF FUNDING

CRISPR FOR CURE - WHILE ANTIRETROVIRAL THERAPY (ART) HAS DRAMATICALLY REDUCED HIV DISEASE MORBIDITY AND MORTALITY, IT HAS FAILED TO ELIMINATE VIRAL RESERVOIRS. INTERRUPTION OF TREATMENT LEADS TO ACTIVATION OF LATENT VIRUS AND REBOUND VIREMIA WITHIN WEEKS. NOVEL STRATEGIES ARE URGENTLY NEEDED TO ERADICATE LATENT INFECTIONS AND ENHANCE THE IMMUNE SYSTEM LEADING TO SUSTAINED, DURABLE CONTROL OF VIRAL REBOUND FOLLOWING THE CESSATION OF ART. IN RESPONSE TO RFA-AI- 20-035 MARTIN DELANEY COLLABORATORIES FOR HIV CURE RESEARCH, WE NOW SUBMIT THE APPLICATION ENTITLED "CRISPR FOR CURE." THE OVERARCHING GOAL OF THIS PROGRAM IS TO USE GENOME EDITING MEDIATED BY CRISPR TO ENHANCE IMMUNE RESPONSES AND DIRECTLY ABLATE HIV PROVIRUSES. WE HAVE ASSEMBLED A COLLABORATIVE TEAM OF HIGHLY ACCOMPLISHED BASIC AND TRANSLATIONAL SCIENTISTS WORKING IN TANDEM WITH COMMUNITY STAKEHOLDERS AND A SMALL BIOTECHNOLOGY COMPANY TO DEVELOP CRISPR-BASED THERAPIES TO DIRECTLY TARGET THE HIV PROVIRUS AND TO ENHANCE IMMUNOLOGICAL RESPONSES. THE RESEARCH PROGRAM IS COMPRISED OF THREE HIGHLY INTERACTIVE RESEARCH FOCI (RF) THAT WILL UTILIZE INTERDISCIPLINARY, INNOVATIVE AND COLLABORATIVE RESEARCH APPROACHES WITH COMMUNITY AND GOVERNMENT INPUT. RF1 WILL USE NEXT GENERATION SEQUENCING AND NOVEL BARCODED VIRUSES TO DEFINE THE HIV RESERVOIR AND THE IMPACT OF EPIGENETIC MECHANISMS ON PROVIRAL REBOUND. IN RF2, WE WILL ENHANCE EFFECTOR NK AND CTL CELL FUNCTION AND KILLING AND LIMIT VIRAL SPREAD BY TARGET CELLS USING INNOVATIVE GENOME EDITING STRATEGIES. RF3 WILL CREATE AND TEST THE NEXT GENERATION OF INDUCIBLE, MULTIPLEX CRISPR WITH INCREASED SPECIFICITY, POTENCY AND SAFETY FOR DELIVERY BY CD4 TROPIC LYMPHOID AAV9 FOR ERADICATION OF HIV-1 PROVIRAL DNA IN ANIMAL MODELS WHOSE IMMUNE CELLS ARE MODIFIED IN RF2 AND ASSESS THE POSSIBILITY OF BOTH A UNIVERSAL AND PERSONALIZED CRISPR IN ELIMINATING REPLICATION COMPETENT VIRUS IN VIVO. IN ADDITION TO THE SHARED FOCUS ON CRISPRS TECHNOLOGY, THE COLLABORATORY WILL UNDERTAKE A HIGHLY INTEGRATED EXPERIMENTAL AGENDA THROUGH THE SHARED USE OF BARCODED VIRUSES IN HUMANIZED MICE AND UNIQUE SUPPORT MISTRG HUMANIZED MICE THAT DIFFERENTIALLY HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELL MAINTENANCE AND MYELOPOIESIS;RHESUS MACAQUES INFECTED WITH A NOVEL SIV BARCODED VIRUS; EX VIVO CLINICAL SAMPLES FROM A WELL CHARACTERIZED COHORT AND THE USE OF ADENOVIRUSES TO EFFICIENTLY DELIVER CRISPRS TO AN IN VIVO HUMANIZED ANIMAL MODEL CARRYING CELLS FROM PATIENT-DERIVED PBMCS. THE OUTCOME OF THIS COMPREHENSIVE AND MULTIDISCIPLINARY PROGRAM BY THE “CRISPR FOR CURE” THE COLLABORATORY, WILL ACCELERATE THE USE OF GENE EDITING STRATEGIES TOWARDS ERADICATION OF HIV INFECTION FROM BODY OR SUSTAINED VIRAL REMISSION FOLLOWING CESSATION OF ANTIRETROVIRAL THERAPY.WITH RESOURCES AVAILABLE FROM OUR PRIVATE SECTOR PARTNER, WE WILL BE WELL POSITIONED FOR FURTHER GMP MANUFACTURING DEVELOPMENT, AND FUTURE INITIAL CLINICAL INVESTIGATIONS.

"NOVEL MECHANISMS FOR CARDIAC INJURY AND REPAIR"

CENTER ON INTERSYSTEM REGULATION DRUGS OF ABUSE

COMPREHENSIVE NEUROAIDS CORE CENTER

ADVANCED BALLISTICS TECHNOLOGY MATERIAL DEVELOPMENT, CHARACTERIZATION AND COMPUTATIONAL MODELING: 1.1.3- HIGH RATE DEFORMATION AND FAILURE OF MATERIA

EXOSOMES AS MEDIATORS OF CARDIAC INJURY AND REPAIR

SPATIAL INTELLIGENCE AND LEARNING CENTER (SILC)

ADVANCED BALLISTICS TECHNOLOGY DEVELOPMENT AND COMPUTATIONAL MODELING: HIGH RATE DEFORMATION AND FAILURE OF MATERIALS

CENTER FOR THE COMPUTATIONAL DESIGN OF FUNCTIONAL LAYERED MATERIALS

1/2 TUFCCC/HC REGIONAL COMPREHENSIVE CANCER HEALTH DISPARITY PARTNERSHIP

SPATIAL INTELLIGENCE AND LEARNING CENTER (SILC)

RESEARCH FACILITY FOR TEMPLE INSTITUTE FOR TRANSLATIONAL NEUROSCIENCE

IMPROVING CARDIAC FUNCTION AFTER MYOCARDIAL INFARCTION

BLADDER, URETHRA AND ANAL SPHINCTER REINNERVATION

HEALTH INFORMATION PROFESSIONS CAREER PATHWAYS FOR TANF RECIPIENTS AND OTHER LOW INCOME INDIVIDUALS

TRAINING PROGRAM: DRUGS OF ABUSE & RELATED NEUROPEPTIDES

COMPREHENSIVE CENTERS

DYSREGULATION OF METABOLIC AND BIOENERGETIC PATHWAYS BY COCAINE AND HIV-1 IN CNS

BIOMARKER OF TISSUE TOLERANCE AND BEHAVIOR IN A RAT MODEL OF WMSD

DRUGS OF ABUSE AFFECTING AIDS PATHOGENESIS

SEMANTIC MEMORY AND LANGUAGE LEARNING IN ALZHEIMER'S DISEASE AND SEMANTIC DEMENTI

TEMPLE UNIVERSITY GASTROPARESIS CLINICAL CENTER

SIGNALING PATHWAYS MODULATING HIV-1 INDUCED INJURY IN CNS

TRACKING THE BURDEN, DISTRIBUTION, AND IMPACT OF POST COVID-19 CONDITIONS AMONG A DIVERSE GROUP OF CHILDREN, ADOLESCENTS, AND ADULTS IN PHILADELPHIA, PA. - AS OF FEBRUARY 25, 2022, THERE WERE 78,595,529 CONFIRMED COVID-19 CASES AND 939,654 COVID-19-RELATED DEATHS IN THE UNITED STATES. ALTHOUGH MOST COVID-19 PATIENTS RECOVER WITHIN A FEW WEEKS, SOME HAVE SYMPTOMS THAT PERSIST FOR MONTHS AFTER RECOVERING FROM AN ACUTE INFECTION WITH SARS-COV-2 (I.E., REFERRED TO AS POST COVID-19 CONDITIONS [PCC]). BECAUSE THE CLINICAL PRESENTATION VARIES FROM PERSON TO PERSON, THERE IS CURRENTLY NO CONSENSUS ON THE DEFINITION OF THIS SYNDROME. THERE IS SOME EVIDENCE TO SUGGEST THAT THOSE WITH MORE SEVERE ACUTE INFECTIONS (I.E., THOSE HOSPITALIZED, TREATED IN THE INTENSIVE CARE UNIT, OR WITH ENCEPHALOPATHY) MAY BE MORE LIKELY TO EXPERIENCE AT LEAST ONE PCC AND MULTIPLE PCCS. THE NIH PREVIOUSLY ESTIMATED THAT 10-30% OF THOSE INFECTED WITH SARS-COV-2 MAY EXPERIENCE PCCS; HOWEVER, DEPENDING ON THE POPULATION STUDIED, PCC DEFINITION, AND LENGTH OF FOLLOW-UP, SOME STUDIES HAVE REPORTED THAT AS MANY AS 87% OF COVID-19 SURVIVORS MAY EXPERIENCE PCCS. COLLECTIVELY, EMERGING FINDINGS FROM COVID-19 AND OTHER VIRAL INFECTIONS SUGGEST THAT A SIZABLE FRACTION OF PATIENTS WILL EXPERIENCE PERSISTING NEUROLOGIC, RESPIRATORY, CARDIOVASCULAR, MUSCULAR, AND MENTAL HEALTH PROBLEMS. FURTHER, THE RACIAL AND ETHNIC DISPARITIES OBSERVED WITH RESPECT TO COVID-19 HOSPITALIZATIONS AND DEATHS ARE LIKELY TO ALSO MANIFEST AMONG THOSE EXPERIENCING CHRONIC HEALTH SEQUELAE FOLLOWING AN ACUTE SARS-COV-2 INFECTION. THERE IS A NEED TO BETTER ESTIMATE THE BURDEN AND DISTRIBUTION OF PCC, IDENTIFY FACTORS THAT INCREASE OR REDUCE THE RISK OF THEIR OCCURRENCE AND PERSISTENCE, AND MONITOR TRENDS OVER TIME. THIS SURVEILLANCE PROJECT WILL LEVERAGE COLLABORATIONS BETWEEN THE TEMPLE UNIVERSITY HEALTH SYSTEM (TUHS), TEMPLE UNIVERSITY LEWIS KATZ SCHOOL OF MEDICINE, TEMPLE UNIVERSITY COLLEGE OF PUBLIC HEALTH, AND THE PHILADELPHIA DEPARTMENT OF PUBLIC HEALTH (PDPH) TO (1) ESTIMATE THE CUMULATIVE INCIDENCE AND PERIOD PREVALENCE OF VARIOUS PCCS IN THE 3, 6, 12, AND 18 M ONTHS AFTER AN ACUTE INFECTION WITH SARS-COV-2, (2) INVESTIGATE SECULAR TRENDS, (3) CALCULATE THE INCIDENCE RATE FOR PCCS (INDIVIDUALLY, BY CATEGORY, AND FOR SYMPTOM CLUSTERS) AND (4) IDENTIFY FACTORS THAT INCREASE OR REDUCE THE RISK FOR EACH (I.E., AGE GROUP, SEX, RACE, ETHNICITY, NEIGHBORHOOD, SEVERITY OF SARS-COV-2 INFECTION, VACCINATION HISTORY, TREATMENTS RECEIVED DURING THE ACUTE PHASE, LABORATORY MEASURES, AND OTHER COMORBIDITIES). OUR COHORT WILL INCLUDE OVER 16,000 TUHS PATIENTS LIVING IN PHILADELPHIA WHO WERE DIAGNOSED WITH RNA-CONFIRMED SARS-COV-2 INFECTION BETWEEN 1/1/20 AND 5/31/25 AND WILL USE TUHS ELECTRONIC HEALTH RECORDS, MEDICAL CHART REVIEW, PDPH VACCINE AND COVID-19 CASE DATA, AND VITAL RECORDS DATA. TEMPLE IS AN IDEAL SETTING TO CONDUCT PCC SURVEILLANCE, GIVEN THAT TUHS WAS AT THE CENTER OF PHILADELPHIA'S MEDICAL RESPONSE TO COVID-19, THE TUHS CATCHMENT AREA WAS ONE OF THE AREAS MOST IMPACTED BY COVID-19 IN THE REGION, AND TUHS SERVES A RACIALLY AND ETHNICALLY DIVERSE POPULATION OF SOCIO-ECONOMICALLY DISADVANTAGED PATIENTS WITH HIGHER RATES OF COMORBIDITIES THAT INCREASE THE RISK FOR SEVERE COVID-19 OUTCOMES AND MAY ALSO INCREASE THE RISK FOR PCC. THROUGH THIS PROJECT, WE WILL ALSO DISSEMINATE COMPLETE, TIMELY, AND QUALITY PCC SURVEILLANCE FINDINGS TO THE PUBLIC VIA AN INTERACTIVE DASHBOARD AND PROVIDE HANDS-ON TRAINING OPPORTUNITIES IN EPIDEMIOLOGY, INFORMATION TECHNOLOGY, AND HEALTH DISPARITIES. OVERALL, THIS PROJECT AIMS TO BETTER CHARACTERIZE THE OVERALL BURDEN OF MORBIDITY FOLLOWING SARS-COV-2 INFECTION, IDENTIFY GEOGRAPHIC AREAS AND GROUPS OF INDIVIDUALS THAT ARE DISPROPORTIONATELY IMPACTED, AND MONITOR PCC TRENDS OVER TIME. OUR FINDINGS WILL GUIDE THE DEVELOPMENT OF PCC PREVENTION PROGRAMS, PUBLIC HEALTH ACTIONS TO REDUCE HEALTH DISPARITIES, AND CLINICAL GUIDELINES AND CARE EFFORTS; AND BE USED TO PLAN FO

COMMUNITY-BASED WORKFORCE TO INCREASE COVID-19 VACCINATIONS IN UNDERSERVED COMMUNITIES

TNF MRNA STABILITY AND RESTENOSIS

ENHANCING SLEEP DURATION: EFFECTS ON CHILDREN'S EATING AND ACTIVITY BEHAVIORS

ASIAN COMMUNITY CANCER HEALTH DISPARITIES CENTER (ACCHDC)

BAS AND BIPOLAR DISORDER: PROSPECTIVE BIOBEHAVIORAL HIGH RISK DESIGN

INTERDISCIPLINARY AND TRANSLATIONAL RESEARCH TRAINING IN NEUROAIDS

TEMPLE UNIVERSITY MINORITY ACCESS TO RESEARCH CAREERS (MARC) PROGRAM

DRUG DEVELOPMENT OF CLAVULANIC ACID, A GLT-1 ACTIVATOR: PROOF OF CONCEPT FOR COCAINE USE DISORDER

NOVEL SIGNALING MOLECULES REGULATING PLATELET ACTIVATION - PLATELETS PLAY A CRUCIAL ROLE IN HEMOSTASIS AND THROMBOSIS, AND MORE AND MORE STUDIES INDICATE THEIR ROLE IN OTHER DISEASE STATES INCLUDING INFLAMMATION, CANCER, AND ATHEROSCLEROSIS PLATELETS EXPRESS A NUMBER OF SURFACE RECEPTORS, WHICH THROUGH THEIR ACTIVATION, ALLOW PLATELETS TO INTERPRET THEIR LOCAL ENVIRONMENT AND TO DETECT VASCULAR LESIONS AND PROMOTE HEMOSTASIS. MY GROUP FOCUSES ON THESE SIGNALING STEPS AND HOW THEIR INTERPLAY MEDIATES PLATELET ACTIVATION. UNDERSTANDING SIGNALING NETWORKS AND THEIR REGULATION HAS BEEN MY RESEARCH FOCUS FOR THE PAST TWO DECADES AND OUR GROUP HAS MADE IMPORTANT CONTRIBUTIONS TO THE PLATELET-SIGNALING FIELD. MY RESEARCH GOALS ARE TO IDENTIFY NOVEL SIGNALING MOLECULES THAT REGULATE MAIN SIGNALING PATHWAYS, CHARACTERIZE NOVEL SIGNALING PATHWAYS EMANATING FROM THE SAME SIGNALING MOLECULE, AND UNDERSTAND THE DIFFERENCES IN VARIOUS TYROSINE KINASE PATHWAYS IN PLATELETS. MY ADDITIONAL GOALS ARE TO UNDERSTAND WHAT CHANGES OCCUR IN PLATELET COMPOSITION, INCLUDING MIRNAS, WITH AGE AND DISEASE, SUCH AS DIABETES, THAT MAKE THEM MORE SUSCEPTIBLE TO THROMBOTIC EVENTS. THIS WORK BUILDS ON OUR PAST CONTRIBUTIONS IN THE FIELD AND A HOST OF REAGENTS AND GENETIC TOOLS THAT WE HAVE AMASSED. IN THIS PROPOSAL, WE PLACE PARTICULAR EMPHASIS ON THE INTRACELLULAR INTERACTIONS THAT REGULATE A SIGNALING MOLECULE. ONE OF THE NOVELTIES OF THE STUDIES PROPOSED IS THAT THE SAME PROTEIN KINASE, THROUGH DIFFERENTIAL TYROSINE PHOSPHORYLATION, ACTIVATES DIVERSE SIGNALING PATHWAYS, WHICH HAVE DISTINCT ROLES IN HEMOSTASIS. THE STUDIES PROPOSED IN THIS APPLICATION WILL PROVIDE FURTHER INSIGHTS INTO THE REGULATION AND IDENTIFICATION OF NOVEL SIGNALING PATHWAYS IN PLATELETS, WHICH MAY BE APPLICABLE TO OTHER CELL SYSTEMS EXPRESSING SIMILAR RECEPTORS AND COULD FORM THE BASIS FOR NOVEL THERAPEUTIC TARGETS TO TREAT THROMBOSIS AND THROMBOCYTOPENIA. IN ADDITION, UNDERSTANDING THESE SIGNALING CASCADES IN PLATELETS WILL HELP US EVALUATE AND PREDICT POSSIBLE IMPLICATIONS OF THE THERAPEUTIC AGENTS THAT COULD INTERFERE WITH THESE PATHWAYS. FOR EXAMPLE, OUR STUDIES ANTICIPATE THAT IBRUTINIB, A TEC KINASE INHIBITOR USED FOR THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA, WILL BLOCK THE CLEC2 PATHWAY IN PLATELETS AND CAUSE BLOOD FLOW INTO LYMPHATIC VESSELS. I WOULD LIKE TO PURSUE THESE GOALS IN THE NEXT DECADE WITH THE SAME VIGOR AND INTENSITY THAT HAVE EMPLOYED IN THE PAST TWO DECADES. HAVE BEEN FUNDED BY NIH FOR ABOUT 22 YEARS ON THE PLATELET SIGNALING PARADIGMS AND HAVE PUBLISHED OVER 180 PAPERS (ON AN AVERAGE OF 8 PAPERS A YEAR). THE OIA WILL ALLEVIATE THE NEED TO SUBMIT SEPARATE THEMATIC GRANT APPLICATIONS TO VARIOUS AGENCIES WITH COHERENT SPECIFIC AIMS AND WILL ALLOW US TO MAKE SIGNIFICANT CONTRIBUTIONS TO THE UNDERSTANDING OF PLATELET SIGNALING NETWORKS. OUR OVERARCHING GOAL IS TO UNDERSTAND HOW THE NETWORK OF RECEPTOR- MEDIATED SIGNALING CAN BE MANIPULATED TO CONTROL PLATELET FUNCTION.

SUPER-RESOLUTION MICROSCOPY STUDY OF MOLECULAR TRANSPORT MECHANISMS

TARGETING DNA REPAIR TO ERADICATE TKI-REFRACTORY/RESISTANT CML

RESEARCH NETWORKS FOCUSED ON CRITICAL PROBLEMS OF EDUCATION POLICY AND PRACTICE (NETWORKS)

INTEGRATIVE CARDIOVASCULAR PATHOPHYSIOLOGY

FUNCTIONAL ROLE OF PROTEIN DISULFIDE ISOMERASE ISOFORMS IN PLATELETS

TEMPLE UNIVERSITY RRTC ON COMMUNITY LIVING AND PARTICIPATION OF PEOPLE WITH SERIOUS MENTAL ILLNESS

PHILADELPHIA TEEN OUTREACH PROJECT (PTOP)

CBPR ON HEPATITIS B INTERVENTION FOR UNDERSERVED KOREAN AMERICANS

NEUROAIDS THERAPEUTICS-TARGETING IMMUNE POLARIZATION OF MACROPHAGES IN CNS

MEASUREMENTS ON THE STRUCTURE AND DYNAMICS OF MATTER

IMPACT OF STRUCTURAL RACISM AND DISCRIMINATION ON LIVER DISEASE DISPARITIES IN HIGH-RISK ASIAN AMERICAN POPULATIONS - IMPACT OF STRUCTURAL RACISM AND DISCRIMINATION ON LIVER DISEASE DISPARITIES IN HIGH-RISK ASIAN AMERICAN POPULATIONS PROJECT SUMMARY STRUCTURAL RACISM AND DISCRIMINATION (SRD) PLAY AN IMPORTANT ROLE IN SHAPING PERSISTENT HEALTH DISPARITIES, INCLUDING LIVER DISEASE DISPARITIES AMONG RACIALIZED ASIAN AMERICANS (AAS). DESPITE COMPRISING 7% OF U.S. POPULATION, AAS ACCOUNT FOR MORE THAN HALF OF ALL HEPATITIS B (HBV) INFECTIONS IN THE U.S. OF 2.4 MILLION AMERICANS INFECTED WITH HBV, 58% ARE AAS WHO HAVE THE HIGHEST HBV PREVALENCE OF ANY RACIAL/ETHNIC GROUP. DESPITE CDC AND U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS TO SCREEN ASIAN ADULTS WHO ARE AT HIGH RISK FOR INFECTION, A SIGNIFICANT MAJORITY OF AAS (~68-75%) HAVE NEVER BEEN SCREENED, REMAINING UNDIAGNOSED. SRD MANIFESTS IN STRUCTURAL INEQUALITIES BY LIMITED ACCESS TO CARE, CULTURALLY AND LINGUISTICALLY APPROPRIATE SERVICES/RESOURCES, SOCIAL SEGREGATION, MISTRUST OF HEALTH SYSTEM, ANTI-ASIAN RACISM, IMMIGRATION AND POVERTY IN AAS. MOST SRD RESEARCH HAS EXAMINED HOW STRUCTURAL RACISM AND MULTILEVEL DETERMINANTS DISADVANTAGED HEALTHCARE ACCESS FOR BLACK/AFRICAN AMERICANS AND LATINX, FEW HAVE INCLUDED AAS. OUR PRELIMINARY STUDIES AMONG CHINESE, KOREAN AND VIETNAMESE INDICATED THAT HBV SCREENING AND LINKAGE TO CARE DISPARITIES ARE ATTRIBUTABLE TO THE INTERSECTION OF MULTILEVEL STRUCTURAL BARRIERS. DURING COVID-19 PANDEMIC, BARRIERS TO CARE FOR AAS ARE INCREASINGLY AFFECTED BY ANTI-ASIAN RACISM, HATE CRIMES AND DISCRIMINATION AT EACH LEVEL, WHICH IMPEDES HBV SCREENING AND CARE AND EXACERBATES LIVER DISEASE DISPARITIES. THE OVERALL GOAL OF THIS INNOVATIVE AND TIMELY STUDY IS TO IDENTIFY STRUCTURAL RACISM AND PROTECTIVE FACTORS IN RELATION TO LIVER DISEASE DISPARITIES AND IMPACT OF SRD ON HEALTH OUTCOMES BY ASIAN AMERICANS. GUIDED BY AN ADAPTED MULTILEVEL SOCIO-ECOLOGICAL MODEL, WE WILL LEVERAGE 20-YEAR ESTABLISHED REGIONAL CANCER HEALTH DISPARITIES NETWORKS TO COLLABORATE WITH COMMUNITY-BASED ORGANIZATIONS AND CLINICAL PARTNERS IN GREATER PHILADELPHIA AND NYC. SPECIFICALLY, OUR MULTIDISCIPLINARY TEAM WILL USE MIXED METHODS TO: 1) EXAMINE THE LONGITUDINAL ASSOCIATION OF INDIVIDUAL-LEVEL SRD LIVED EXPERIENCES (E.G., COVID-19 ANTI-ASIAN RACISM, SOCIO-HISTORICAL TRAUMA, CULTURAL STEREOTYPE RACISM) AND HBV SCREENING AND CARE AMONG 2000 ASIAN AMERICANS: CHINESE, KOREAN AND VIETNAMESE; 2) EXAMINE THE IMPACT OF INSTITUTIONAL-LEVEL SRD IN HEALTHCARE SETTINGS (E.G., ANTI-ASIAN RACIAL BIAS, RESOURCES FOR PATIENT NAVIGATORS) ON HBV SCREENING UPTAKE AND CARE; AND 3) ELUCIDATE THE IMPACT OF COMMUNITY-LEVEL SRD (E.G., ANTI-ASIAN RACISM/XENOPHOBIA AND RESIDENTIAL SEGREGATION) AND PROTECTIVE FACTORS (E.G. RESIDENCE, SOCIAL NORMS/ADVOCACY AND NEIGHBORHOOD SOCIAL COHESION) ON IMPEDING OR PROMOTING SCREENING AND CARE. FINALLY, WE CONDUCT INTEGRATIVE ANALYSIS TO EXAMINE WHETHER INDIVIDUAL, INSTITUTIONAL AND COMMUNITY-LEVEL SRD ARE ASSOCIATED WITH HBV SCREENING UPTAKE AND LINKAGE TO CARE. THIS IS THE FIRST MULTILEVEL, LONGITUDINAL STUDY THAT WILL ENABLE US TO UNDERSTAND HOW STRUCTURAL RACISM DRIVES HBV-RELATED LIVER DISEASE DISPARITIES AMONG HIGH-RISK ASIAN AMERICANS. OUR STUDY FINDINGS WILL IDENTIFY CULTURALLY ATTUNED STRATEGIES TO MITIGATE SRD AND DESIGN INTERVENTIONS TO IMPROVE OVERALL QUALITY OF CHRONIC HBV CARE. OUR STUDY WILL LIKELY RESULT IN A PARADIGM SHIFT FROM INDIVIDUAL LEVEL APPROACH TO ELIMINATE HEPATITIS B BY 2030.

TRANSLATION AND CLINICAL IMPLEMENTATION OF A TEST OF LANGUAGE AND SHORT-TERM MEMORY (STM) IN APHASIA

THE ROLE OF P21-ACTIVATED KINASES IN MALIGNANT MESOTHELIOMA

TARGETING GRK2 (BARK1) IN HEART FAILURE

BBB PROTECTION IN HIV-1 DEMENTIA: ANTI-INFLAMMATORY EFFECTS OF GSK-3BETA SUPPRES

P21-ACTIVATED KINASES AS NEW THERAPEUTIC TARGETS IN NEUROFIBROMATOSIS TYPE 1

INTEGRATED REWARD-INFLAMMATION MODEL OF FIRST ONSET OF MAJOR DEPRESSION IN ADOLESCENCE - 7. PROJECT SUMMARY/ABSTRACT ADOLESCENCE IS AN “AGE OF RISK” FOR THE EMERGENCE OF 1ST ONSET OF MAJOR DEPRESSIVE DISORDER (MD). DESPITE ITS PREVALENCE AND PUBLIC HEALTH SIGNIFICANCE, MAJOR UNANSWERED QUESTIONS EXIST REGARDING THE MECHANISMS INVOLVED IN VULNERABILITY TO MD. DEPRESSION (DEP) IS ASSOCIATED WITH A REDUCED SENSITIVITY TO REWARDS AND LOW REWARD-RELATED BRAIN FUNCTION IN CORTICO-STRIATAL CIRCUITRY. HOWEVER, RESEARCH HAS NOT YET TESTED WHETHER CHRONICALLY LOW REWARD RESPONSIVITY (RR) OR ATTENUATED RR DEVELOPMENT DURING ADOLESCENCE PREDICTS 1ST ONSET OF MD. A SEPARATE LITERATURE DOCUMENTS ELEVATED PERIPHERAL INFLAMMATION IN DEP. YET, RESEARCH ALSO HAS NOT EXAMINED WHETHER CHRONICALLY ELEVATED INFLAMMATION OR INCREASES IN INFLAMMATION DURING ADOLESCENCE PREDICTS 1ST ONSET OF MD. FURTHER, RESEARCH ON INFLAMMATION AND RR MOSTLY HAS PROCEEDED IN PARALLEL. RECENTLY, HOWEVER, WE AND OTHERS HAVE PROPOSED NEUROIMMUNE NETWORK MODELS OF DEP. THESE MODELS DRAW ON WORK INDICATING THAT PERIPHERAL INFLAMMATORY MEDIATORS (E.G., CYTOKINES) ACCESS THE BRAIN, WHERE THEY LOWER RR. WHEN DYSREGULATED, THIS IMMUNE-TO-BRAIN SIGNALING CAN LEAD TO CHRONIC AND WORSENING LOW RR, WHICH IS REFLECTED IN DYSPHORIA AND ANHEDONIA. THIS LOW RR IS PROPOSED TO INITIATE UNHEALTHY BEHAVIORS (SUBSTANCE USE, POOR DIET), AS WELL AS SLEEP DISRUPTION AND STRESS GENERATION, WHICH FURTHER HEIGHTEN INFLAMMATION. OVER TIME, DYSREGULATION IN RR AND IMMUNE SIGNALING MAY SYNERGIZE IN A POSITIVE FEEDBACK LOOP, WHEREBY DYSREGULATION IN EACH SYSTEM EXACERBATES DYSREGULATION IN THE OTHER. WE PROPOSE THAT REWARD-IMMUNE DYSREGULATION IS A TWO-HIT VULNERABILITY FOR THE 1ST ONSET OF MD AND INCREASES IN DEP SYMPTOMS (SXS) DURING ADOLESCENCE. MOREOVER, CHILDHOOD AND ADOLESCENT ADVERSITY AND RECENT STRESSORS INFLUENCE BOTH RR AND INFLAMMATION, AND MAY SET THE FOUNDATION FOR REWARD-IMMUNE DYSREGULATION. THIS PROPOSAL IS THE FIRST SYSTEMATIC TEST OF THESE HYPOTHESES. WE WILL USE AN INNOVATIVE BIOBEHAVIORAL HIGH-RISK DESIGN TO EXAMINE BIDIRECTIONAL RELATIONSHIPS BETWEEN PERIPHERAL INFLAMMATION AND MULTIPLE INDICES AND DOMAINS (MONETARY, SOCIAL) OF RR AND THEIR JOINT PREDICTION OF 1ST ONSET OF MD AND INCREASES IN DEP SXS, PARTICULARLY ANHEDONIA. THREE HUNDRED 14-15 YEAR OLD PARTICIPANTS (PS) WILL COMPLETE A PROSPECTIVE 3-YEAR LONGITUDINAL STUDY. PS WITH NO PRIOR MD WILL BE SELECTED ALONG THE ENTIRE DIMENSION OF SELF-REPORTED RR, WITH OVERSAMPLING AT THE LOW TAIL OF THE DIMENSION IN ORDER TO INCREASE THE LIKELIHOOD OF MD ONSETS. AT TIME 1 (T1), T3, AND T5, EACH A YEAR APART, PS WILL COMPLETE BLOOD DRAWS TO QUANTIFY INFLAMMATION, SELF-REPORT AND BEHAVIORAL MEASURES OF RR, AND FMRI SCANS OF REWARD NEURAL ACTIVITY AND FUNCTIONAL CONNECTIVITY. AT T1-T5 (WITH T2 AND T4 6 MO. BETWEEN THE YEARLY SESSIONS), PS ALSO WILL COMPLETE DIAGNOSTIC INTERVIEWS, AND MEASURES OF DEP SXS, REWARD-RELEVANT LIFE EVENTS, AND BEHAVIORS THAT INCREASE INFLAMMATION. ADVERSITY HISTORY WILL BE ASSESSED AT T1 ONLY. THIS PROPOSAL IS AN INNOVATIVE INTEGRATION OF RESEARCH ON REWARD AND INFLAMMATORY SIGNALING IN UNDERSTANDING 1ST ONSET OF MD IN ADOLESCENCE. IT HAS THE POTENTIAL TO FACILITATE NOVEL NEUROIMMUNE AND BEHAVIORAL INTERVENTIONS TO TREAT, AND IDEALLY PREVENT, MD.

INTEGRATED REWARD-CIRCADIAN RHYTHM MODEL OF FIRST ONSET OF BIPOLAR SPECTRUM DISORDERS IN ADOLESCENCE - 7. PROJECT SUMMARY/ABSTRACT ADOLESCENCE IS AN “AGE OF RISK” FOR THE EMERGENCE OF FIRST ONSET OF BIPOLAR SPECTRUM DISORDERS (BSD). DESPITE THEIR PREVALENCE AND PUBLIC HEALTH SIGNIFICANCE, MAJOR UNANSWERED QUESTIONS EXIST REGARDING THE MECHANISMS INVOLVED IN VULNERABILITY TO BSDS. BSDS ARE ASSOCIATED WITH HYPERSENSITIVITY TO REWARD AND ELEVATED REWARD- RELATED BRAIN FUNCTION. HOWEVER, RESEARCH HAS NOT YET TESTED WHETHER CHRONICALLY HIGH REWARD RESPONSIVITY (RR) OR INCREASES IN RR DEVELOPMENT DURING ADOLESCENCE, BEYOND BASELINE RR, PREDICTS FIRST ONSET OF BSD. A SEPARATE LITERATURE DOCUMENTS CIRCADIAN RHYTHM DISRUPTION IN BSDS, AND SOCIAL RHYTHM DISRUPTION (SRD) CAN TRIGGER BSD EPISODES. YET, RESEARCH HAS NOT TESTED WHETHER BASELINE CIRCADIAN DYSREGULATION, CHRONIC SOCIAL AND CIRCADIAN RHYTHM DISRUPTIONS, OR INCREASES IN THESE RHYTHM DISRUPTIONS DURING ADOLESCENCE PREDICT ONSET OF BSD. FURTHER, CIRCADIAN AND REWARD APPROACHES TO BSDS MOSTLY HAVE PROCEEDED IN PARALLEL. HOWEVER, WE AND OTHERS HAVE PROPOSED INTEGRATED REWARD-CIRCADIAN MODELS OF BSDS BASED ON EVIDENCE THE TWO SYSTEMS INFLUENCE EACH OTHER AND INTERACT TO AFFECT MOOD FUNCTIONING. WHEN DYSREGULATED, REWARD AND CIRCADIAN SYSTEM SIGNALING MAY COMBINE TO FORM A POSITIVE FEEDBACK LOOP, WHEREBY DYSREGULATION IN ONE SYSTEM EXACERBATES DYSREGULATION IN THE OTHER. THIS PROPOSAL IS THE FIRST SYSTEMATIC TEST OF A NOVEL, INTEGRATED REWARD-CIRCADIAN MODEL FOR FIRST ONSET OF BSD. WE WILL USE AN INNOVATIVE BIOBEHAVIORAL HIGH-RISK DESIGN TO EXAMINE BIDIRECTIONAL RELATIONSHIPS BETWEEN MULTIPLE INDICES AND DOMAINS (MONETARY, SOCIAL) OF RR AND MULTIPLE INDICES OF SOCIAL AND CIRCADIAN RHYTHMS AND THEIR JOINT PREDICTION OF FIRST ONSET OF BSD AND INCREASES IN BIPOLAR SYMPTOMS. THREE HUNDRED TWENTY 14-16 YEAR OLD PARTICIPANTS (PS) WILL COMPLETE A PROSPECTIVE 3-YEAR LONGITUDINAL STUDY. PS WITH NO PRIOR BSD WILL BE SELECTED ALONG THE ENTIRE DIMENSION OF SELF-REPORTED RR, WITH OVERSAMPLING AT THE HIGH TAIL OF THE DIMENSION IN ORDER TO INCREASE THE LIKELIHOOD OF BSD ONSETS. AT TIMES 1-6, EVERY 6 MONTHS, PS WILL COMPLETE ASSESSMENTS OF REWARD-RELEVANT AND SRD LIFE EVENTS AND SELF-REPORT AND DIAGNOSTIC ASSESSMENTS OF BIPOLAR SYMPTOMS AND EPISODES. YEARLY, AT TIMES 1, 3, AND 5, PS ALSO WILL COMPLETE SELF-REPORT MEASURES OF CIRCADIAN CHRONOTYPE (MORNINGNESS-EVENINGNESS) AND SOCIAL RHYTHM REGULARITY, A SALIVARY DIM LIGHT MELATONIN ONSET (DLMO) PROCEDURE TO ASSESS CIRCADIAN PHASE, SELF-REPORT, BEHAVIORAL, AND NEURAL (FMRI) ASSESSMENTS OF MONETARY AND SOCIAL RR, AND A 7-DAY EMA PERIOD. DURING EACH EMA PERIOD, PS WILL COMPLETE CONTINUOUS MEASURES OF SLEEP/WAKE AND ACTIVITY (ACTIGRAPHY) AND 3 WITHIN-DAY (MORNING, AFTERNOON, EVENING) MEASURES OF LIFE EVENTS CODED FOR REWARD-RELEVANCE AND SRD, MONETARY AND SOCIAL REWARD RESPONSIVITY, POSITIVE AND NEGATIVE AFFECT, AND HYPO/MANIC AND DEPRESSIVE SYMPTOMS. THE FMRI SCAN AND DLMO PROCEDURE WILL OCCUR ON THE DAY BEFORE THE START OF EACH EMA PERIOD, EXCLUDING WEEKENDS. THIS PROPOSAL IS AN INNOVATIVE INTEGRATION OF RESEARCH ON REWARD AND CIRCADIAN SIGNALING IN UNDERSTANDING FIRST ONSET OF BSD IN ADOLESCENCE. IT HAS THE POTENTIAL TO FACILITATE REWARD AND SOCIAL/CIRCADIAN RHYTHM INTERVENTIONS TO TREAT, AND IDEALLY PREVENT, BSD.

EARLY READING FIRST

INFORMAL CAREGIVER BURDEN IN ADVANCED CANCER: ECONOMIC AND HEALTH OUTCOMES

WELLS AND ENTERIC DISEASE TRANSMISSION: A RANDOMIZED TRIAL OF CHILDREN SUPPLIED DRINKING WATER FROM PRIVATE WELLS (WET-TRIAL)

NUCLEAR RESEARCH USING THE ELECTROMAGNETIC PROBE

THE NEURAL BASIS OF SOCIAL KNOWLEDGE

INTERLEUKIN-19 INHIBITS ATHEROSCLEROSIS BY DIVERSE MECHANISMS

COMPUTER SIMULATIONS OF PROTEIN STRUCTURE AND DYNAMICS

REGULATION OF AXONAL RETROGRADE SIGNALING BY PALMITOYLATION

INVOLVEMENT OF BAG3 IN HIV-1 INDUCED CARDIOMYOPATHY

PREDICTING INTRACELLULAR DRUG CONCENTRATIONS IN THE PRESENCE OF TRANSPORTERS

COMMUNITY-BASED OBESITY TREATMENT IN AFRICAN AMERICAN WOMEN AFTER CHILDBIRTH: A RANDOMIZED CONTROLLED TRIAL OF WIC MOTHERS

CA2+-INFLUX REGULATED CARDIAC HYPERTROPHY, ARRHYTHMIA AND MYOCYTE APOPTOSIS

TEMPLE UNIVERSITY CENTER FOR ADOLESCENT IMPLEMENTATION RESEARCH

FUNCTIONAL PKC ISOFORMS IN PLATELETS

A BIOBEHAVIORAL MODEL OF DIABETES RISK IN CHINESE IMMIGRANTS

PARTNERING WITH WIC TO PREVENT EXCESSIVE WEIGHT GAIN IN PREGNANCY

CIRCUIT AND SYNAPTIC MECHANISMS OF ENDOCANNABINOID-OPIOID CROSSTALK - PROJECT SUMMARY FOR THE PAST DECADE, THE USE OF OPIOIDS HAS RISEN DRAMATICALLY IN THE UNITED STATES AND THE DISPROPORTIONAL INCREASE IN OPIOID DEPENDENCE AND OVERDOSE DEATH HAS LED TO THE CURRENT OPIOID CRISIS. ALTHOUGH DIFFERENT MEASURES HAVE BEEN TAKEN TO REDUCE OPIOID OVERUTILIZATION FOR PAIN MANAGEMENT, OPIOID USE IN CLINICS CONTINUES LEADING TO DEPENDENCE AND OVERDOSE. IN THERE IS A COMPELLING NEED FOR NON-OPIOID USE OF PHARMACOLOGICAL ADDITION, FOR THE SIGNIFICANT NUMBER OF PEOPLE WITH OPIOID USE DISORDER, PHARMACOLOGICAL THERAPIES TO COMPLEMENT CURRENT TREATMENTS FOR OPIOID DISORDER. A MAJOR CHALLENGE IS TO DEVELOP NEW TREATMENT STRATEGIES THAT CAN ATTENUATE THE REWARDING ASPECTS OPIOIDS WHILE PRESERVING THEIR POWERFUL ANALGESIC PROPERTIES. ENDOCANNABINOID (ECB) SYSTEM SERVES AS A POTENTIAL TARGET FOR THE DEVELOPMENT OF NEW TREATMENTS AS A COMPLEMENT TO OPIOID BASED TREATMENTS. SEVERAL LINES OF EVIDENCE SUGGEST THE FUNCTIONAL INTERACTION BETWEEN THE OPIOID AND THE ECB SYSTEM AT THE LEVEL OF NEUROCHEMICAL, NEUROANATOMICAL AND MOLECULAR PATHWAYS. OUR PRELIMINARY RESULTS FIND THAT INDIRECTLY ENHANCING LEVELS OF THE ENDOCANNABINOID 2- AG LEVELS THROUGH PHARMACOLOGICAL INHIBITION OF ITS CATABOLIC ENZYME, MONOACYLGLYCEROL LIPASE (MAGL), ATTENUATES THE REWARDING EFFECTS OF MORPHINE, WHILE MAINTAINING ITS ANALGESIC EFFECTS. IN THIS PROPOSAL WE WILL DISSECT AT A CIRCUIT, SYNAPTIC AND MOLECULAR LEVEL HOW ELEVATED 2-AG ATTENUATES OPIOID REWARD. RECENT STUDIES HAVE UNDERSCORED THE ROLE OF LOCAL GABAERGIC NEURONAL INPUTS FROM THE ROSTROMEDIAL TEGMENTAL NUCLEUS (RMTG) IN REGULATING THE VENTRAL TEGMENTAL AREA (VTA), A KEY DOPAMINERGIC BRAIN REGION INVOLVED IN OPIOID REWARD. OPIOIDS ARE THOUGHT TO ACT BY DISINHIBITING RMTG INHIBITION ONTO VTA DOPAMINE NEURONS BY ACTIVATING PRESYNAPTIC MU OPIOID RECEPTORS (MOR), SUBSEQUENTLY INCREASING DOPAMINE CELL FIRING AND NUCLEUS ACCUMBENS (NAC) ACTIVITY THAT DRIVES REWARD. HOWEVER, LITTLE IS KNOWN ABOUT HOW CANNABINOID RECEPTORS (CB1R) AND MORS SIGNAL AND CROSSTALK AT THESE KEY SYNAPSES. AIM 1 WILL EXAMINE 2-AG MECHANISMS IN THE VTA ON OPIOID REWARD BEHAVIOR AND ITS EFFECT ON NAC DYNAMICS. AIM 2 WILL EXAMINE THE ROLE OF CB1R AND MOR IN THE RMTGVTA PROJECTION ON OPIOID REWARD BEHAVIOR AND NAC DYNAMICS. AIM 3 WILL EXAMINE SYNAPTIC AND MOLECULAR MECHANISMS OF CB1R AND MOR CROSSTALK TO DETERMINE HOW ENHANCING 2-AG LEVELS LEADS TO BLUNTED OPIOID REWARD.

TOOLS OF THE MIND: PROMOTING ELLS' LANGUAGE SELF-REGULATION & SCHOOL-READINESS

MOLECULAR MECHANISMS OF CARDIAC BETA1AR-EGFR ASSOCIATION AND SIGNALING

UNDERSTANDING THE ROLE OF HISTONE DEMETHYLASES AND HETEROCHROMATIN IN CELL CYCLE

HUMAN PLATELET DEFECTS IN TRANSCRIPTION FACTOR RUNX1 HAPLODEFICIENCY

MRI: TRACK 2 ACQUISITION OF MULTISCALE 3D IMAGING AND ANALYTICS PLATFORM FOR ENERGY AND INFRASTRUCTURE MATERIALS, ENVIRONMENTAL SUSTAINABILITY, AND BIOENGINEERING -THIS MAJOR RESEARCH INSTRUMENTATION PROGRAM (MRI) AWARD SUPPORTS THE ACQUISITION OF A CUTTING-EDGE 3-BEAM MULTISCALE 3D IMAGING AND ANALYTICS PLATFORM AT TEMPLE UNIVERSITY TO ADVANCE MULTIDISCIPLINARY RESEARCH, EDUCATION, AND TRAINING IN ENERGY, INFRASTRUCTURE, SUSTAINABILITY, AND BIOENGINEERING. THE SYSTEM, THE SECOND OF ITS KIND IN US ACADEMIC INSTITUTIONS, INTEGRATES SCANNING ELECTRON MICROSCOPY (SEM), FOCUSED ION BEAM (FIB), AND FEMTOSECOND LASER TECHNOLOGIES, ENABLING HIGH-RESOLUTION IMAGING, NANOFABRICATION, AND TOMOGRAPHIC ANALYSIS OF MATERIALS PREVIOUSLY INACCESSIBLE USING CONVENTIONAL TECHNIQUES. THIS PLATFORM WILL PROVIDE TRANSFORMATIVE CAPABILITIES TO ADDRESS CRITICAL CHALLENGES IN BATTERY MATERIALS, SUSTAINABLE COMPOSITES, THE DURABILITY OF CEMENTITIOUS MATERIALS, AND BIOLOGICAL STRUCTURES. IT WILL SERVE AS A REGIONAL RESEARCH HUB, ENGAGING ACADEMIC PARTNERS, INCLUDING DREXEL UNIVERSITY, THE UNIVERSITY OF PENNSYLVANIA, AND A BROAD NETWORK OF PRIMARILY UNDERGRADUATE INSTITUTIONS (PUIS) ACROSS PENNSYLVANIA, NEW JERSEY, AND BEYOND. THE SYSTEM WILL ENABLE ADVANCED STRUCTURAL AND COMPOSITIONAL ANALYSIS OF COMPLEX MATERIALS, INCLUDING POLYMER-BASED COMPOSITES, SOLID-STATE BATTERY ELECTRODES, GEOLOGICAL SAMPLES, AND BIOLOGICAL TISSUES, CONTRIBUTING TO DIVERSE AREAS OF RESEARCH FROM MECHANICS OF MATERIALS TO BIOENGINEERING. THE PLATFORM WILL SUPPORT COLLABORATIVE, MULTIDISCIPLINARY RESEARCH BY PROVIDING HIGH-RESOLUTION, MULTISCALE ANALYSIS AND ENABLING A BETTER UNDERSTANDING OF MANUFACTURING-STRUCTURE-PROPERTY RELATIONSHIPS AND TIME-RESOLVED DEGRADATION PHENOMENA. IT WILL SUPPORT VARIOUS APPLICATIONS, INCLUDING LI-ION BATTERY FAILURE ANALYSIS, MICROSTRUCTURE OPTIMIZATION IN AEROSPACE MATERIALS, AND BIO-INTERFACE IMAGING. THE SYSTEM WILL BE HOUSED IN A SHARED CORE FACILITY, OFFERING RESEARCH AND TRAINING OPPORTUNITIES TO STUDENTS, POSTDOCTORAL SCHOLARS, AND FACULTY MEMBERS ACROSS TEMPLE UNIVERSITY, DREXEL UNIVERSITY, AND THE UNIVERSITY OF PENNSYLVANIA. ADDITIONALLY, THE PLATFORM WILL SUPPORT REGIONAL UNDERGRADUATE INSTITUTIONS THROUGH SHARED GOVERNANCE, WORKSHOPS, AND VIRTUAL ACCESS MODULES. BY INTEGRATING ADVANCED INSTRUMENTATION WITH COLLABORATIVE EDUCATION, THE PROJECT WILL CONTRIBUTE TO DEVELOPING A SKILLED WORKFORCE IN ENERGY, INFRASTRUCTURE, AND BIOENGINEERING. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE NOT PLANNED FOR THIS AWARD.

DEPRESSION SURGE IN ADOLESCENCE & GENDER DIFFERENCES: BIOCOGNITIVE MECHANISMS

BEHAVIORAL AND BIOLOGICAL RHYTHMS IN CHILDREN'S OBESITY-RELATED HEALTH DISPARITIES - PROJECT SUMMARY/ABSTRACT PEDIATRIC OBESITY IS CONSIDERED AN EPIDEMIC WITH STRIKING DISPARITIES BY SOCIOECONOMIC STATUS (SES). THERE IS THEREFORE A PRESSING NEED TO IDENTIFY NOVEL, MODIFIABLE RISK FACTORS FOR OBESITY PREVENTION AND TREATMENT IN CHILDREN, PARTICULARLY THOSE WHO ARE AT GREATER RISK. COMPELLING EVIDENCE THAT IS ROOTED IN CIRCADIAN BIOLOGY AND OUR UNDERSTANDING OF CIRCADIAN RHYTHMS, AND IS SUPPORTED BY EMERGING WORK WITH RODENTS AND ADULTS SUGGESTS THAT IN ADDITION TO FOCUSING ON HOW MUCH WE ENGAGE IN EATING, ACTIVITY AND SLEEP BEHAVIORS, IT MAY ALSO BE IMPORTANT TO UNDERSTAND THE TIMING AND CONSISTENCY WITH WHICH WE ENGAGE IN THESE BEHAVIORS (I.E., BEHAVIORAL RHYTHMS) FOR OBESITY RISK REDUCTION. MOUNTING EVIDENCE DEMONSTRATES THAT BEHAVIORAL RHYTHMS THAT ARE ALIGNED WITH UNDERLYING CIRCADIAN RHYTHMS, SUCH AS SLEEPING DURING THE BIOLOGICAL NIGHT AND EATING DURING THE BIOLOGICAL DAY ARE ASSOCIATED WITH IMPROVED METABOLIC PROCESSES AND WEIGHT REGULATION. ALTHOUGH LESS IS KNOWN REGARDING HOW BEHAVIORAL RHYTHMS MAY OPTIMIZE WEIGHT REGULATION IN CHILDREN, FINDINGS FROM RELATED LINES OF PEDIATRIC RESEARCH SUPPORT THOSE WITH RODENTS AND ADULTS AND HIGHLIGHT THE POTENTIAL IMPORTANCE OF BEHAVIORAL RHYTHMS FOR EXCESS WEIGHT GAIN PREVENTION. UNDERSTANDING THE ROLE OF BEHAVIORAL RHYTHMS IN WEIGHT REGULATION FOR CHILDREN FROM LOWER SES BACKGROUNDS MAY BE PARTICULARLY IMPORTANT GIVEN THAT THEY MAY BE AT GREATER RISK FOR DISRUPTIONS TO BEHAVIORAL RHYTHMS DUE TO ECONOMIC ADVERSITY AND NEIGHBORHOOD DISADVANTAGE, PLACING THEM AT INCREASED RISK FOR EXCESS WEIGHT GAIN. FURTHER, UNDERSTANDING ASSOCIATIONS BETWEEN SES, BEHAVIORAL RHYTHMS AND WEIGHT REGULATION IN YOUNG SCHOOL-AGED CHILDREN FOCUSES ON A TIME PERIOD WHEN A NUMBER OF HEALTH BEHAVIORS THAT CARRY THROUGH ADOLESCENCE ARE SHAPED AND THUS MAY REPRESENT AN OPPORTUNE TIME FOR OPTIMIZING WEIGHT REGULATION. THE PRESENT STUDY THEREFORE PROPOSES TO ENROLL 176 CHILDREN 5-8 YEARS OLD FROM DIVERSE SES BACKGROUNDS INTO A 16-MONTH OBSERVATIONAL STUDY. CHILDREN WILL COMPLETE FIVE 10-DAY ASSESSMENTS ACROSS THE STUDY (BASELINE, 4, 8, 12, AND 16 MONTHS) DURING WHICH THE FOLLOWING WILL BE MEASURED: TIMING AND CONSISTENCY OF SLEEP (VIA ACTIGRAPHY), TIMING AND DISTRIBUTION OF EATING (VIA 24-HOUR DIETARY RECALLS), TIMING AND CONSISTENCY OF PHYSICAL AND SEDENTARY ACTIVITIES (VIA ACCELEROMETRY AND SELF-REPORT), TIMING OF THE CIRCADIAN CLOCK (DIM LIGHT MELATONIN ONSET; DLMO), MEASURES OF THE HOME AND NEIGHBORHOOD ENVIRONMENT, AND ANTHROPOMETRICS (HEIGHT, WEIGHT, ADIPOSITY). THE PRIMARY AIMS OF THIS PROPOSED WORK ARE TO ASSESS: A) HOW BEHAVIORAL RHYTHMS AFFECT BODY MASS INDEX (BMI) TRAJECTORIES IN CHILDREN, AND B) HOW SES AFFECTS BEHAVIORAL RHYTHMS AND THUS BMI TRAJECTORIES. SECONDARY AIMS WILL ASSESS HOW CIRCADIAN FACTORS (I.E., CIRCADIAN PHASE AND CIRCADIAN PHASE ANGLE) AND THE HOUSEHOLD AND NEIGHBORHOOD ENVIRONMENTS AFFECT BEHAVIORAL RHYTHMS. EXPLORATORY AIMS WILL ALSO ASSESS THE RELATIVE INFLUENCE OF BEHAVIORAL, CIRCADIAN AND ENVIRONMENTAL FACTORS ON CHILDREN'S BMI TRAJECTORIES, INCLUDING POTENTIAL MODERATION OF ASSOCIATIONS BETWEEN BEHAVIORAL RHYTHMS AND BMI TRAJECTORIES BY CIRCADIAN PHASE AND PHASE ANGLE.

CD40 MONOCYTE IN CHRONIC KIDNEY DISEASE

REHABILITATION RESEARCH AND TRAINING CENTERS-COMMUNITY - LIVING AND PARTICIPATION FOR INDIVIDUALS WITH PSYCHIATRIC DISABILITIES

DEVELOPMENTAL CHANGES IN REWARD RESPONSIVITY: ASSOCIATIONS WITH DEPRESSION RISK MARKERS

EVALUATION OF CARTILAGE TISSUE ENGINEERING STRATEGIES BY IR IMAGING

MATERNAL INFLAMMATION DURING PREGNANCY: CLINICAL AND NEUROCOGNITIVE OUTCOMES IN ADULT OFFSPRING

INFLAMMATION ASSOCIATED WITH HIV INFECTION: ROLE OF RECEPTOR CROSS-TALK

THE COLLABORATIVE CENTER FOR LEGAL EPIDEMIOLOGY: EVALUATING LAW AS AN INTERVENTION TO IMPROVE HEALTH OUTCOMES AND REDUCE DISPARITIES RELATED TO HIV, VIRAL HEPATITIS, STDS, AND TUBERCULOSIS - RECIPIENTS FUNDED UNDER COMPONENT 1 OF THE NOTICE OF FUNDING OPPORTUNITY CDC-RFA-PS-23-0009 FROM CDC'S NATIONAL CENTER FOR HIV, VIRAL HEPATITIS, STD, AND TB PREVENTION WILL USE THEIR EXPERTISE IN LEGAL EPIDEMIOLOGY AND POLICY EVALUATION TO ADVANCE EVIDENCE-BASED POLICY TO IMPROVE HEALTH OUTCOMES AND REDUCE HEALTH DISPARITIES RELATED TO HIV, VIRAL HEPATITIS, STDS, AND TUBERCULOSIS. THE PURPOSE OF THIS PROJECT IS TO STRENGTHEN THE ABILITY OF HEALTH DECISION MAKERS TO IDENTIFY AND DEPLOY LAWS AND POLICIES THAT IMPROVE HEALTH AND HEALTH EQUITY. THE TEAM WILL IDENTIFY LEGAL TOPICS OF GREATEST SALIENCE TO NCHHSTP; SCIENTIFICALLY BUILD LONGITUDINAL LEGAL DATASETS; MAKE THE LEGAL DATA AVAILABLE TO POLICYMAKERS, THE PUBLIC AND RESEARCHERS ON A CDC-HOUSED WEBSITE/DASHBOARD; WORK WITH CDC TO TIMELY AND RIGOROUSLY EVALUATE THE IMPLEMENTATION AND EFFECTS OF THESE LAWS; AND MAKE ALL FINDINGS AND OTHER PRODUCTS AVAILABLE TO STAKEHOLDERS IN A TIMELY AND USER-FRIENDLY MANNER. THIS WORK WILL MEASURABLY 1) INCREASE AWARENESS OF AND ACCESS TO LONGITUDINAL LAW AND POLICY SURVEILLANCE DATASETS, INCREASING KNOWLEDGE OF LAWS AND POLICIES THAT REDUCE MORBIDITY, MORTALITY AND HEALTH DISPARITIES, AND 2) INCREASE THE BREADTH AND DEPTH OF AVAILABLE EVIDENCE DEMONSTRATING THE IMPACT THAT LAWS AND POLICIES HAVE ON HEALTH AND ECONOMIC OUTCOMES, LEADING TO INCREASED APPLICATION OF EVIDENCE-BASED LAWS AND POLICIES TO IMPROVE HEALTH AND REDUCE DISPARITIES. THE TEAM WILL EMPLOY BEST SCIENTIFIC PRACTICES FROM LEGAL EPIDEMIOLOGY AND POLICY EVALUATION, AND LEVERAGE TECHNOLOGY TO REDUCE COSTS, IMPROVE EFFICIENCY, AND INCREASE THE USEFULNESS AND ACCESSIBILITY OF THE PRODUCTS. THE TEAM WILL CONDUCT A DATA-DRIVEN LANDSCAPE ASSESSMENT -- TO BE REVIEWED ANNUALLY -- TO DETERMINE POLICY TOPICS FOR LEGAL EPIDEMIOLOGICAL ANALYSIS. THE ASSESSMENT WILL INVOLVE THREE MAIN PARTS: 1) IDENTIFYING CANDIDATE LAWS AND LEGAL PRACTICES THAT MAY INFLUENCE LEVELS AND DISPARITIES IN STDS, HIV, VIRAL HEPATITIS, AND TB, AS WELL AS POTENTIAL SYNDEMICS (CO-OCCURRING MULTIPLE NATURE OF MULTIPLE EPIDEMICS); 2) MOBILIZING EXISTING RESEARCH KNOWLEDGE AND THE EXPERTISE OF A DIVERSE GROUP OF SUBJECT-MATTER EXPERTS TO IDENTIFY IMPORTANT RESEARCH QUESTIONS; AND 3) PRIORITIZING POLICIES/RESEARCH QUESTIONS FOR ANALYSIS. AFTER THE LANDSCAPE ASSESSMENT IS COMPLETE AND TOPICS ARE SELECTED, THE TEAM WILL USE SCIENTIFIC LEGAL MAPPING METHODS TO SYSTEMATICALLY COLLECT AND ANALYZE RELEVANT LAWS. THE TEAM WILL CREATE LONGITUDINAL LEGAL DATASETS IDENTIFYING KEY FEATURES OF THE LAW AND CAPTURING CHANGES IN THE LAW OVER TIME. THE DATASETS WILL INCLUDE THE RELEVANT TEXT OF THE LAW LINKED TO SPECIFIC ATTRIBUTES. RIGOROUS QUALITY CONTROL MEASURES WILL BE USED TO ENSURE RELIABILITY OF THE LEGAL DATA PRODUCED. BY CONVERTING THE WORDS OF THE LAW INTO NUMERIC DATA, THE TEAM WILL ENABLE THE DIGITIZATION OF LEGAL INFORMATION, MAKING IT POSSIBLE TO CREATE DASHBOARDS OF THE KINDS NCHSSTP IS PLANNING. THE TEAM PLANS TO USE THE SAME RIGOROUS RESEARCH PROCESS FOR UPDATING DATASETS IN THE FINAL YEAR OF THE PROJECT. THE TEAM WILL USE THE LEGAL DATA CREATED, ALONG WITH QUASI-EXPERIMENTAL STUDY DESIGNS, APPLICATION OF THE NOVEL POLICY TARGET TRIAL EMULATION FRAMEWORK, AND DATA SCIENCE BEST PRACTICES TO MEASURE THE EFFECTS OF KEY POLICIES ON MORBIDITY, MORTALITY AND DISPARITIES IN HIV, VIRAL HEPATITIS, STDS, AND TUBERCULOSIS. THE TEAM WILL DEVELOP NUMEROUS DELIVERABLES WITH VARYING LEVELS OF RIGOR AND SPEED, AND DEPLOY VARIOUS STUDY DESIGN METHODS AFTER CONVERSATION WITH THE CDC. THE TEAM WILL WORK IN COLLABORATION AND UNDER THE GUIDANCE OF CDC COLLEAGUES IN ALL PHASES OF THIS WORK AND WILL ALSO WORK CLOSELY WITH THE COMPONENT 2 GRANTEES TO ENSURE THAT ALL DATA AND FINDINGS ARE RELEVANT AND ACCESSIBLE TO POLICYMAKERS, INCLUDING HEALTH DEPARTMENT OFFICIALS, GENERAL COUNSELS, STATE LEGISLATORS, GOVERNORS, AND THE SUPPORT STAFF ADVISING THESE LEADERS.

UNDERSTANDING SEPSIS WITH HUMAN RELEVANCE: AN INTEGRATIVE STUDY USING IN VITRO, IN VIVO AND IN SILICO MODELS

HIV-INDUCED NEUROINFLAMMATION ASSOCIATED WITH OPIOD ABUSE AND TOBACCO SMOKE

SPECIFICITY OF EFFECTOR ACTIVATION BY RHO FAMILY GTPASES

PREDICTING SLEEP, SMOKING AND LUNG HEALTH DISPARITIES IN AT-RISK BLACK AFRICAN AMERICAN ADULTS

CYTOKINE REGULATION OF JC VIRUS LATENCY AND REACTIVATION

IMPROVING PREDICTION OF DRUG INTERACTIONS MEDIATED BY TIME-DEPENDENT INHIBITORS

CNS INJURY CAUSED BY HIV-1 AND ALCOHOL: PROTECTIVE EFFECTS OF CB2 ACTIVATION

THERAPEUTIC ANGIOGENESIS IN VASCULAR MEDICINE III

DELINEATING THE EPIGENETIC AND NEURAL MECHANISMS BY WHICH EARLY LIFE SCARCITY ALTERS MOTIVATED BEHAVIOR - PROJECT SUMMARY EARLY LIFE EXPERIENCES CAN HAVE PROFOUND AND LONG-LASTING CONSEQUENCES ON HEALTH TRAJECTORIES. SOCIAL INEQUITIES, SUCH AS THOSE CAUSED BY LOW RESOURCES, HAVE BEEN IDENTIFIED AS IMPORTANT FACTORS THAT INFLUENCE THE DEVELOPMENT OF PSYCHIATRIC ILLNESSES, INCLUDING SUBSTANCE USE DISORDERS (SUD). IN THIS PROPOSAL, A RAT MODEL OF EARLY LIFE SCARCITY WILL BE COMBINED WITH BEHAVIORAL PARADIGMS OF SUBSTANCE ABUSE TO BETTER UNDERSTAND THE NEURAL AND MOLECULAR MECHANISMS THAT INFLUENCE REWARD PROCESSING IN INDIVIDUALS WHO EXPERIENCED ADVERSITY EARLY IN LIFE. EACH BRAIN REGION CONTAINS HIGHLY HETEROGENOUS CELL POPULATIONS THAT INCLUDE DIFFERENT NEURONAL SUBTYPES AS WELL AS GLIA. ACCOUNTING FOR THE DIVERSITY AND DIFFERENCES IN CELL TYPES IS ESSENTIAL TO IMPROVING OUR UNDERSTANDING OF THE IMPACT OF INEQUITIES ON THE BRAIN AND ON MOTIVATED BEHAVIOR. IN THIS PROPOSAL, THE INFLUENCE OF EARLY LIFE SCARCITY ON ADULT REWARD PROCESSING AND MOTIVATION WILL BE CHARACTERIZED IN MALE AND FEMALE RATS USING STATE-OF-THE-ART BEHAVIORAL APPROACHES WHERE RATS ARE TESTED FOR THEIR MOTIVATION TO EARN DRUG (OPIOID) OR NATURAL (SOCIAL AND SUCROSE) REWARDS. OUR PRELIMINARY DATA INDICATE SEX- AND REINFORCER-SPECIFIC EFFECTS OF EARLY SCARCITY. THIS WORK WILL BE EXPANDED HERE, AND IN SOME OF THE EXPERIMENTS, RATS WILL CHOOSE BETWEEN TWO AVAILABLE REINFORCERS. GIVEN THAT INTERVENTIONS FOR SUD INVOLVE SOCIAL REINFORCERS, THESE RESULTS COULD HAVE PROFOUND IMPLICATIONS FOR THE PREVENTION AND TREATMENT OF SUD IN POPULATIONS WHO EXPERIENCE SOCIOECONOMIC INEQUALITY. TO BETTER IDENTIFY FACTORS THAT MEDIATE THE EFFECTS OF EARLY SCARCITY ON MOTIVATED BEHAVIOR, WE WILL DELINEATE MOLECULAR CHANGES IN THE NUCLEUS ACCUMBENS—A CENTRAL HUB IN THE BRAIN THAT IS CRITICAL FOR MOTIVATED AND REWARD-RELATED BEHAVIORS— AND CAUSALLY LINK THEM TO BEHAVIOR. TO THIS END, WE WILL PERFORM CELL-TYPE SPECIFIC ASSAYS OF GENE EXPRESSION AND CHROMATIN REMODELING, AN EPIGENETIC PROCESS THAT REGULATES THE EXPRESSION OF GENES. LASTLY, THE PROPOSAL WILL EXAMINE THE IMPACT OF EARLY LIFE SCARCITY ON THE ELECTROPHYSIOLOGICAL PROPERTIES OF TWO MAJOR NEURON SUBTYPES IN THE NUCLEUS ACCUMBENS, DELINEATING CELL TYPE-SPECIFIC PHYSIOLOGICAL CHANGES INDUCED BY ALTERING THE EARLY ENVIRONMENT. COLLECTIVELY, THIS PROPOSAL LEVERAGES CUTTING-EDGE BEHAVIORAL, MOLECULAR, AND PHYSIOLOGICAL APPROACHES TO PROVIDE A BETTER UNDERSTANDING OF THE NEUROCHEMICAL AND INTRACELLULAR PATHWAYS AFFECTED BY EARLY LIFE SCARCITY THAT DRIVE CHANGES IN MOTIVATED BEHAVIOR. IMPORTANTLY, THE PROPOSED EXPERIMENTS WILL DETERMINE SEX- AND CELL-TYPE SPECIFIC MECHANISMS BY WHICH EARLY LIFE SCARCITY ALTERS THE SUBSTANCE USE TRAJECTORY, IDENTIFYING POTENTIAL TARGETS FOR IMPROVING THERAPEUTICS AND PREVENTION OF SUDS.

REDUCING SOLID FAT AND ADDED SUGAR INTAKES IN LOW-INCOME PRESCHOOLERS THROUGH ENVIRONMENTAL AND BEHAVIORAL PORTION SIZE STRATEGIES

RISK FOR ADOLESCENT DEPRESSION: STRESS, COGNITIVE VULNERABILITY, & INFLAMMATION

MARKOV STATE MODEL APPROACHES FOR FOLDING, BINDING AND DESIGN

HIV, METHAMPHETAMINE AND HUMAN IPSC-DERIVED MICROGLIA-CONTAINING CEREBRAL ORGANOIDS

DOWNSHIFTING SWEET PREFERENCE AND ADDED SUGAR INTAKE DURING SNACKING AMONG YOUNG CHILDREN: A RANDOMIZED CONTROLLED TRIAL

PARACRINE HYPOTHESIS UNDERLYING CARDIAC STEM CELL THERAPY

MHEALTH-BASED JUST-IN-TIME ADAPTIVE INTERVENTION TO IMPROVE PHYSICAL ACTIVITY LEVELS OF INDIVIDUALS WITH SPINAL CORD INJURY - PROJECT SUMMARY THE LACK OF REGULAR PHYSICAL ACTIVITY (PA) IN OVER 290,000 INDIVIDUALS WITH SPINAL CORD INJURY (SCI) IN THE UNITED STATES (US) IS AN ONGOING HEALTH CRISIS. THIS LACK OF ACTIVITY HAS POTENTIALLY DEVASTATING CONSEQUENCES BECAUSE LOW LEVELS OF PA IN PEOPLE WITH SCI ELEVATES THE RISK OF MORTALITY DUE TO CARDIOVASCULAR DISEASES, DIABETES, AND LUNG DISEASE. FURTHERMORE, LOW LEVELS OF PA IN INDIVIDUALS WITH SCI HAVE BEEN ASSOCIATED WITH SECONDARY CONDITIONS SUCH AS PAIN, FATIGUE, WEIGHT GAIN, AND DECONDITIONING. REGULAR PA AND EXERCISE-BASED INTERVENTIONS HAVE BEEN LINKED WITH IMPROVED OUTCOMES AND HEALTHIER LIFESTYLES AMONG THOSE WITH SCI. SENSOR- BASED ACTIVITY MONITORS CAN ASSESS PA AND EXERCISE INTERVENTIONS BY QUANTIFYING WHEELCHAIR MOVEMENT, MOVEMENT OF THE INDIVIDUAL, AND PHYSIOLOGICAL CHANGES. HOWEVER, THESE MONITORS DO NOT PROVIDE REAL-TIME, TAILORED FEEDBACK AND RECOMMENDATIONS THAT MIGHT HELP INDIVIDUALS WITH SCI INCREASE THEIR PA LEVELS IN THE COMMUNITY. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO EVALUATE A SENSOR-ENABLED, JUST-IN-TIME ADAPTIVE INTERVENTION (JITAI) STRATEGY TO INCREASE AND SUSTAIN PA LEVELS AMONG INDIVIDUALS WITH SCI IN THEIR COMMUNITIES. THE LONG-TERM GOAL OF THIS RESEARCH IS TO EFFECTIVELY INTEGRATE A MOBILE HEALTH JITAI WITH EXISTING PA INTERVENTION PROGRAMS TO MOTIVATE HEALTH-RELATED BEHAVIOR CHANGE IN INDIVIDUALS WITH SCI. A PRIMARY OBJECTIVE OF THIS PROPOSAL IS TO EXTEND OUR PILOT WORK TO EVALUATE THE INTEGRATION OF A JITAI WITH A WEB-BASED 14-WEEK PA INTERVENTION PROGRAM FROM THE NATIONAL CENTER ON HEALTH, PHYSICAL ACTIVITY AND DISABILITY (AIM 1). WE HYPOTHESIZE THAT THE INTEGRATION OF WEB-BASED PA INTERVENTION PROGRAM WITH JITAI WILL RESULT IN SIGNIFICANTLY HIGHER PA LEVELS OVER 14 WEEKS COMPARED TO THE STANDARD WE-BASED PA INTERVENTION PROGRAM ALONE. A SECONDARY OBJECTIVE OF THIS STUDY IS TO EXTEND EXISTING ALGORITHMS THAT USE COMMERCIAL WEARABLE TECHNOLOGY TO ROBUSTLY DETECT PA BEHAVIORS TO FACILITATE THE DELIVERY OF TAILORED JUST-IN-TIME ACTIONABLE FEEDBACK AND PA RECOMMENDATIONS FOR INDIVIDUALS WITH SCI (AIMS 3 AND 4). THE INTEGRATION OF THE JITAI, WHICH PROVIDES FEEDBACK AND PA RECOMMENDATIONS DUE TO SENSOR-BASED ASSESSMENTS OF PA, WITH THE STANDARD WEB-BASED PA INTERVENTION PROGRAM WILL BE TESTED VIA A CLINICAL TRIAL THAT COMBINES A RANDOMIZED CONTROLLED TRIAL AND A MICRO-RANDOMIZED TRIAL. OUR TEAM INCLUDES INVESTIGATORS WITH EXPERTISE IN SCI RESEARCH, MOBILE HEALTH, PA TRACKING, AND BEHAVIORAL CHANGE INTERVENTIONS. THE PROPOSED STUDY WILL YIELD NOVEL INSIGHTS ABOUT JITAIS AND JITAIS COMBINED WITH MORE TRADITIONAL, WEB-BASED PA INTERVENTION PROGRAMS, WHICH WILL HELP RESEARCHERS DESIGN ENGAGING PA INTERVENTIONS FOR INDIVIDUALS WITH DISABILITY IN THE COMMUNITY THAT MAY IMPROVE THEIR HEALTH AND QUALITY OF LIFE.

S-STEM RESEARCH HUB: INVESTIGATING HOW LOW-INCOME STUDENTS APPROACH NON-TUITION EXPENSES -THIS S-STEM RESEARCH HUB WILL CONTRIBUTE TO THE NATIONAL NEED FOR WELL-EDUCATED SCIENTISTS, MATHEMATICIANS, ENGINEERS, AND TECHNICIANS BY SUPPORTING THE RETENTION AND GRADUATION OF HIGH-ACHIEVING, LOW-INCOME STUDENTS WITH DEMONSTRATED FINANCIAL NEED. THIS HUB, HOUSED IN THE HOPE CENTER AT TEMPLE UNIVERSITY, FOCUSES ON STEM AFFORDABILITY AND WILL EXPLORE NON-TUITION BARRIERS FOR LOW-INCOME STUDENTS AT COMMUNITY COLLEGES. STEM GRADUATES FROM ALL BACKGROUNDS CAN PROPEL A VIBRANT ECONOMY DRIVEN BY INNOVATION. THERE IS EVIDENCE THAT POSITIVE OUTCOMES HAVE COME FROM EXPANDING SCHOLARSHIP OPPORTUNITIES AND CO-CURRICULAR ACTIVITIES. DESPITE THIS PROGRESS, STARK SOCIETAL INEQUITIES AFFECTING STUDENTS? PERSISTENCE, TRANSFER, AND DEGREE COMPLETION RATES ARE IMPEDING SUCCESSFUL ENTRY INTO THE STEM WORKFORCE. THIS IS ESPECIALLY THE CASE AT THE NATION?S COMMUNITY COLLEGES, WHERE AN ESTIMATED 1 IN 2 GRADUATES WITH DEGREES IN A STEM FIELD GET THEIR START. MANY COMMUNITY COLLEGE STUDENTS FACE SIGNIFICANT ECONOMIC CHALLENGES, INCLUDING GROWING EVIDENCE THAT MANY HAVE INADEQUATE AND INEQUITABLE ACCESS TO FOOD, HOUSING, AND OTHER ESSENTIALS. HUB RESEARCH FOCUS ON EXPLORING HOW LOW-INCOME STUDENTS INTERACT WITH VARIOUS SUPPORT MECHANISMS. THESE DATA WILL BE USED TO DEVELOP AND STUDY INTERVENTIONS INTENDED TO CONNECT LOW-INCOME STUDENTS WITH KEY SUPPORTS, SUCH AS FOOD OR HOUSING SUPPORT. THE HUB WILL COLLABORATE WITH 10 COMMUNITY COLLEGES IN FIVE STATES TO EXAMINE THE CHALLENGES COMMUNITY COLLEGE STEM STUDENTS FACE IN COVERING NON-TUITION EXPENSES. RESEARCH WILL FOCUS ON STEM COMMUNITY COLLEGE STUDENTS' SPECIFIC CHALLENGES WHEN IT COMES TO ADDRESSING NON-TUITION EXPENSES. THE PROJECT WILL EXAMINE PRACTICES AND PROGRAMS AVAILABLE TO STEM COMMUNITY COLLEGE STUDENTS AND EXPLORE HOW THEY ARE BEING USED. IT WILL ALSO INVESTIGATE HOW LOW-COST INTERVENTIONS CAN HELP CONNECT STEM COMMUNITY COLLEGE STUDENTS TO SUPPORTS FOR ADDRESSING THEIR NON-TUITION EXPENSES. EACH PARTICIPATING INSTITUTION WILL ADMINISTER THE VALIDATED #REALCOLLEGE SURVEY TO ALL STUDENTS AND LINK THE OUTCOMES TO STUDENT RECORDS. THE INSTRUMENT INCLUDES QUESTIONS ABOUT THE NON-TUITION EXPENSES STUDENTS? FACE AND HOW THEY SEEK TO COVER THEM. OTHER DATA SOURCES INCLUDE AN ANALYSIS OF STATE-LEVEL PROGRAMS AND FOCUS GROUPS WITH ADMINISTRATORS, STAFF, AND FACULTY. THESE DATA WILL BE USED TO DESIGN AND DEPLOY APPROACHES INTENDED TO CONNECT LOW-INCOME STEM STUDENTS WITH RESOURCES, AND TO ASSESS WHETHER THESE SUPPORTS HELP STUDENTS REACH GREATER LEVELS OF SUCCESS. SPECIFICALLY, THE HUB WILL CONDUCT A RANDOMIZED CONTROL STUDY TO EXAMINE THE IMPACTS OF LOW-COST, LIGHT-TOUCH ?NUDGES? ON STUDENTS? USAGE OF NON-TUITION SUPPORT PROGRAMS. PROJECT OUTCOMES WILL MAKE IT EASIER FOR MILLIONS OF LOW-INCOME ADULTS SEEKING STEM CREDENTIALS TO OBTAIN THOSE DEGREES AND CERTIFICATES, IMPROVING EFFECTIVENESS AND OUTCOMES FOR THE NATION?S COMMUNITY COLLEGES. RESULTS AND INTERVENTIONS WILL BE DISSEMINATED THROUGH SEMINARS, PRESENTATIONS, JOURNAL PUBLICATIONS AND VIA THE HOPE CENTER WEBSITE AND SOCIAL MEDIA ACCOUNTS. THIS HUB IS FUNDED BY NSF?S SCHOLARSHIPS IN SCIENCE, TECHNOLOGY, ENGINEERING, AND MATHEMATICS PROGRAM, WHICH SEEKS TO INCREASE THE NUMBER OF LOW-INCOME ACADEMICALLY TALENTED STUDENTS WITH DEMONSTRATED FINANCIAL NEED WHO EARN DEGREES IN STEM FIELDS. IT ALSO AIMS TO IMPROVE THE EDUCATION OF FUTURE STEM WORKERS, AND TO GENERATE KNOWLEDGE ABOUT ACADEMIC SUCCESS, RETENTION, TRANSFER, GRADUATION, AND ACADEMIC/CAREER PATHWAYS OF LOW-INCOME STUDENTS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

HYPERHOMOCYSTEINEMIA AND HDL METABOLISM

THE ROLE OF CANNABINOIDS IN THE REGULATION OF THE BLOOD BRAIN BARRIER IN THE CONTEXT OF NEUROHIV AND ANTI-RETROVIRAL THERAPY - PROJECT SUMARY/ABSTRACT DESPITE ANTIRETROVIRAL THERAPY (ART), NEUROCOGNITIVE COMPLICATIONS CONTINUE TO BE HIGHLY PREVALENT IN PEOPLE LIVING WITH HIV (PLWH). ONE EXPLANATION COULD BE THE CONSTANT COMPROMISE OF THE BLOOD BRAIN BARRIER (BBB) DRIVEN BY CHRONIC INFLAMMATORY RESPONSES. THE INTRODUCTION OF MEDICINAL MARIJUANA INTO HIV TREATMENT PRACTICE APPEAR TO BE BENEFICIAL FOR SEVERAL VIRUS ASSOCIATED COMPLICATIONS (RANGING FROM CHRONIC PAIN TO APPETITE STIMULATION). YET, THE EFFECTS AND MECHANISMS OF CANNABIS ON HIV ASSOCIATED CHRONIC INFLAMMATION, THE ENDOCANNABINOID SYSTEM, IMMUNE MODULATION AND NEUROLOGIC DISORDERS ARE MINIMALLY UNDERSTOOD. AS INDICATED IN THE RFA, PRECLINICAL MODELS CAN PROVIDE A RIGOROUS IN-DEPTH ANALYSIS OF THE MOLECULAR AND CELLULAR MECHANISMS AT THE INTERSECTION BETWEEN PHYTOCANNABINOIDS, HIV AND ART. TO THIS END, WE PROPOSE A COMPREHENSIVE EVALUATION OF THE TWO MOST USED CANNABINOID COMPOUNDS (THC, CBD) ON BBB FUNCTION, IMMUNE-ENDOTHELIAL INTERACTIONS AND NEUROINFLAMMATION. WE WILL UTILIZE STATE OF THE ART CHIP MICROFLUIDICS MODELS OF THE NEUROVASCULAR UNIT (NVU) AND ANIMAL MODELS FOR HIV (W/ W/O ART). PREVIOUSLY, WE DISCOVERED THAT THE BRAIN ENDOTHELIUM UPREGULATE CB2 IN HIV INFECTED HUMAN BRAIN TISSUE. WE HAVE ALSO FOUND THAT MODULATION OF CB2 AFFECTS INDICES OF HIV PATHOLOGY (IN-VIVO) AND REGULATES THE BBB. OUR PRELIMINARY STUDIES IDENTIFY THE DIVERSE EFFECTS THAT PHYTOCANNABINOIDS CAN HAVE ON THE DIFFERENT PROPERTIES OF THE BBB. SPECIFICALLY, CANNABINOIDS (THC, CBD) ALONE CAN ENHANCE THE PHYSICAL BARRIER, PARTIALLY REDUCE ENDOTHELIAL ACTIVATION AND AUGMENT EFFLUX TRANSPORTER ACTIVITY. ALTHOUGH SOME OF THESE EFFECTS MAY APPEAR BENEFICIAL, THE PRESENCE OF HIV AND ART CHANGES HOW THE FUNCTION OF THE BBB IS REGULATED BY CANNABINOID SUBSTANCES. FOR EXAMPLE, THE AUGMENTED TRANSPORTER ACTIVITY BY THC HAS IMPORTANT CONSIDERATIONS FOR ALTERING ART-CNS PENETRABILITY. THUS, WE HYPOTHESIZE THAT PHYTOCANNABINOIDS DIFFERENTIALLY MODULATES BBB FUNCTION THAT ARE BOTH BENEFICIAL AND DELETERIOUS IN NEUROHIV. IN AIM 1, USING OUR LATEST TISSUE-ENGINEERED MICROFLUIDIC NVU MODEL, WE WILL PERFORM ANALYSES OF THE KINETIC CHANGES IN BBB PERMEABILITY, TRANSPORTER STATUS AND IMMUNE-ENDOTHELIAL INTERACTION. THEN, IN AIM 2, WE WILL COMPARE OUTCOMES BETWEEN WIDELY USED ROUTES OF CANNABINOID ADMINISTRATION (ORAL VS. INHALED) IN VIVO USING TWO RELEVANT MODELS OF HIV INFECTION (‘HUMANIZED’ MICE AND A MODEL OF ASEPTIC MENINGITIS/ENCEPHALITIS). EXPERIMENTS WILL EVALUATE CHANGES IN THE BBB IN THE CONTEXT OF ART AND CANNABINOID EXPOSURE. FINALLY, WE PROPOSE TO IDENTIFY NOVEL CROSSTALK MECHANISMS THAT BRIDGE CANNABINOID RECEPTOR SIGNALING TO SIGNALS THAT CONTROL BBB MAINTENANCE (AIM 3). IT’S CLEAR THAT CANNABINOIDS EXERT UNKNOWN CELL SPECIFIC EFFECTS THAT CONTRIBUTE TO THE TUMULTUOUS INTERPRETATION OF HOW THESE COMPOUNDS IMPACT NEUROHIV. USING INNOVATIVE PRECLINICAL TOOLS, OUR STUDIES WILL CONTRIBUTE SIGNIFICANTLY TOWARDS UNDERSTANDING THE CONSEQUENCES OF CANNABINOID USE ON THE BBB IN THE MODERN ERA OF NEUROHIV.

MODELING EPIDEMIC INFECTIOUS DISEASES USING SEQUENCE ANALYSIS

TREATMENT OF CBS DEFICIENCY WITH PROTEOSTASIS MODULATORS

THEORY-DRIVEN TREATMENT OF LANGUAGE AND COGNITIVE PROCESSES IN APHASIA

POTENTIATION OF CAA-MEDIATED ENDOTHELIAL DYSFUNCTION BY CARDIOVASCULAR RISK FACTORS

SCHOOL NURSE-DIRECTED SECONDARY OBESITY PREVENTION FOR ELEMENTARY SCHOOL CHILDREN

REHABILITATION RESEARCH AND TRAINING CENTERS

METHODS FOR EVOLUTIONARY GENOMICS ANALYSIS - SUMMARY/ABSTRACT CONTINUING ADVANCES IN NUCLEOTIDE SEQUENCING HAVE RESULTED IN THE ASSEMBLY OF DATASETS CONTAINING LARGE NUMBERS OF SPECIES, GENES, AND GENOMIC SEGMENTS. PHYLOGENOMIC ANALYSES OF THESE DATA ARE ESSENTIAL TO PROGRESS IN UNDERSTANDING EVOLUTIONARY PATTERNS ACROSS THE TREE OF LIFE, AND ARE FINDING INCREASING NUMBERS OF APPLICATIONS IN PRACTICAL ANALYSES THAT REQUIRE UNDERSTANDING OF HOW PATTERNS CHANGE OVER TIME. THE SHEER SIZE OF PHYLOGENOMIC DATASETS LIMITS THE PRACTICAL UTILITY OF AVAILABLE METHODS DUE TO EXCESSIVE TIME AND MEMORY REQUIREMENTS. WE HAVE DEVELOPED MANY HIGH IMPACT METHODS AND TOOLS FOR COMPARATIVE ANALYSIS OF MOLECULAR SEQUENCES, A TRADITION WE PROPOSE TO CONTINUE THROUGH THIS MIRA PROJECT BY DEVELOPING INNOVATIVE METHODS THAT ADDRESS NEW CHALLENGES IN PHYLOGENOMICS. WE WILL FOCUS ON PATTERN-BASED APPROACHES OF MACHINE LEARNING WITH SPARSITY CONSTRAINT (SL) APPLIED TO PHYLOGENOMICS, AS A COMPLEMENT TO TRADITIONAL MODEL-BASED METHODS IN MOLECULAR EVOLUTION AND PHYLOGENETICS. IN THE PROPOSED SL IN PHYLOGENOMICS (SLIP) FRAMEWORK, WE WILL BUILD MODELS THAT BEST EXPLAIN THE BIOLOGICAL TRAIT OR EVOLUTIONARY HYPOTHESIS OF INTEREST, WITH GENOMIC LOCI, SUCH AS GENES, PROTEINS, AND GENOMIC SEGMENTS, SERVING AS MODEL PARAMETERS. PRELIMINARY RESULTS FROM TWO EXAMPLE APPLICATIONS ESTABLISH THE PREMISE AND PROMISE OF A GENERAL SLIP FRAMEWORK. IN ONE, SLIP SUCCESSFULLY DETECTED LOCI WHOSE INCLUSION IN A PHYLOGENOMIC DATASET OVERTAKES A CONSISTENT AND CONTRASTING SIGNAL FROM HUNDREDS OF OTHER LOCI WHEN INFERRING PHYLOGENETIC RELATIONSHIPS. IN THE OTHER EXAMPLE, SLIP REVEALED LOCI AND BIOLOGICAL FUNCTIONAL CATEGORIES THAT HARBOR CONVERGENT SEQUENCE EVOLUTIONARY PATTERNS ASSOCIATED WITH THE EMERGENCE OF THE SAME TRAIT IN DISTINCT EVOLUTIONARY LINEAGES. IN ALL OF THESE ANALYSES, SLIP REQUIRED ONLY A SMALL FRACTION OF THE COMPUTATIONAL TIME AND MEMORY DEMANDED BY TRADITIONAL METHODS, AND IT ENABLED BETTER EVOLUTIONARY CONTRASTS WITH FEWER ASSUMPTIONS. CONSEQUENTLY, THE SUCCESSFUL DEVELOPMENT OF SLIP WILL IMPROVE THE FEASIBILITY, RIGOR, AND REPRODUCIBILITY OF LARGE-SCALE DATA ANALYSIS. IT WILL ALSO DEMOCRATIZE BIG DATA ANALYTICS VIA SHORTENED ANALYSIS TIME AND A RELATIVELY SMALL MEMORY FOOTPRINT, AND ENCOURAGE THE DEVELOPMENT OF A NEW CLASS OF METHODS FOR PHYLOGENOMIC ANALYSIS. THIS FRAMEWORK WILL BE ACCESSED FROM A FREE LIBRARY OF SLIP FUNCTIONS, WHICH WILL BE DIRECTLY USEABLE VIA COMMAND LINE AND AVAILABLE IN A GRAPHICAL INTERFACE THROUGH INTEGRATION WITH THE MEGA SOFTWARE.

CALCIUM AS A MOLECULAR SIGNAL IN THE HEART

FOLLISTATIN-LIKE PROTEIN 1 IN CARDIAC AND SYSTEMIC METABOLISM

PHARMACOLOGY OF KAPPA OPIOID RECEPTOR

SYNTHETIC RESCUE OF ANTIGEN-DRIVEN T CELLS AND ALLOIMMUNITY

CA2+ REGULATION IN NEWLY FORMED VENTRICULAR MYOCYTES

ENHANCED CHRONIC PAIN MANAGEMENT UTILIZING CHEMOKINE RECEPTOR ANTAGONISTS

NON-CANOICAL WNT SIGNALING AND CELL MOTILITY

COMMUNICATION AND ECONOMIC OUTCOMES FOR CANCER SURVIVORS

DEVELOPING AND VALIDATING EHR-INTEGRATED READMISSION RISK PREDICTION MODELS FOR HOSPITALIZED PATIENTS WITH DIABETES

THE PENNSYLVANIA RESEARCH CENTER AT TEMPLE UNIVERSITY

MAPPING FITNESS AND FREE ENERGY LANDSCAPES OF PROTEINS

GESTATIONAL AGE VARIATION IN HUMAN PLACENTAL TRANSPORT MECHANISMS

AN INTERACTIVE PREVENTIVE HEALTH RECORD TO INCREASE COLORECTAL CANCER SCREENING

AML MUTATION-GUIDED DRUGGING OF DNA REPAIR

CASPASE-1 ACTIVATION MEDIATES CHRONIC KIDNEY DISEASE-ACCELERATED ATHEROSCLEROSIS

ADAPTATION OF INTERNAL MOTOR COPY CIRCUITS IN RECOVERY AFTER SPINAL CORD INJURY.

THE TRANSMEMBRANE PROTEIN DISULFIDE ISOMERASE TMX1 NEGATIVELY REGULATES THROMBOSIS - THE CONTROL OF PLATELET FUNCTION AND COAGULATION IS A FINE BALANCE BETWEEN ACTIVATION AND INHIBITORY MECHANISMS. PLATELETS BECOME RAPIDLY ACTIVATED BY MULTIPLE RECEPTORS AGONISTS AND HAVE A CENTRAL ROLE IN THROMBOSIS IN ACUTE CORONARY SYNDROMES, AND OTHER DISEASE STATES. SIMILARLY, NATURALLY OCCURRING ANTICOAGULANTS ARE CRITICAL IN PREVENTING FIBRIN GENERATION AND THROMBOSIS. FIVEMEMBERS OF THEPROTEIN DISULFIDE ISOMERASE (PDI) FAMILY OF ENZYMES, PDI, ERP57, ERP5, ERP72 AND ERP46 POTENTIATE ACTIVATION OF IIB3 AND THROMBOSIS.WE DISCOVERED ATRANSMEMBRANE MEMBER OF THE PDI FAMILY FOUND TO INHIBIT ACTIVATION OF IIB3 AND MEMBER OF THE PDI FAMILY IN PLATELETS, TMX1, WHICH THROMBOSIS. TMX1 IS THE FIRST ACTS BY A NOVEL MECHANISM OF OXIDIZING THIOLS TO DISULFIDE BONDS AND IS THE LAST CHECKPOINT INHIBITOR OF THE PLATELET ACTIVATION PATHWAYS THAT LEAD TO CONFORMATIONAL CHANGES IN IIB3 AND FIBRINOGEN BINDING. THE PROTHROMBOTIC PDIS ARE SECRETED FROM PLATELETS AND ENDOTHELIAL CELLS AND SUPPORT FIBRIN GENERATION AT THE SITE OF VASCULAR INJURY. WE FOUND THAT TMX1 IS EXPRESSED ON PLATELETS AND ENDOTHELIAL CELLS BUT, NEGATIVELY PROCOAGULANT IN CONTRAS TO THE OTHER PDIS, TMX1 REGULATES FIBRIN GENERATION. ONE MECHANISM BY WHICH TMX1 INHIBITS COAGULATION IS BY LIMITING THE EFFECT OF ENDOTHELIAL CELLS AND PLATELETS. WE PROPOSE TO STUDY T VASCULAR TMX1 AS A DUAL NEGATIVE REGULATOR OF PLATELETS AND COAGULATION BY ADDRESSING THE FOLLOWING SPECIFIC AIMS. WE WILL CHARACTERIZE 1. THE ROLE OF TMX1 IN THROMBUS FORMATION; 2. THE MECHANISM OF INHIBITION OF IIB3 ACTIVATION BY TMX1; 3. THE EFFECT OF TMX1 ON THE OTHER PLATELET PDIS, AND ON OTHER PLATELET SURFACE SUBSTRATES. A PRINCIPAL TECHNIQUE USED WILL BE THE LASER-INDUCED INJURY MODEL OF THROMBOSIS. WE WILL STUDY THE MECHANISM BY WHICH TMX1 NEGATIVELY REGULATES COAGULATION. TO DETERMINE THE UNDERLYING MECHANISMS BY WHICH TMX1 INHIBITS PLATELET FUNCTION WE WILL INTEGRATE A PLATELET KNOCKOUT MOUSE MODEL WITH MASS SPECTROMETRY-BASED IDENTIFICATION OF FUNCTIONAL CYSTEINES. THIS PROPOSAL WILL DETERMINE THE MECHANISMS BY WHICH TMX1 WORKS, AND HOW TMX1 COUNTERBALANCES THE PDI ENZYMES THAT SUPPORT ACTIVATION OF IIB3. CHARACTERIZATION OF THE NEGATIVE REGULATORY ROLE OF TMX1 WILL PROVIDE NOVEL INSIGHT INTO HOW THE NETWORK OF PDI ENZYMES REGULATE THROMBOSIS. STUDIES ON HOW TMX1 MAINTAINS THE BALANCE BETWEEN THROMBOSIS AND HEMOSTASIS WILL ELUCIDATE OPTIMAL WAYS TO PROMOTE HEMOSTASIS AND INHIBIT THROMBOSIS AND PROVIDE A BASIS FOR STUDYING TMX1 IN DISEASE STATES.

UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES

MULTILEVEL TOBACCO INTERVENTION IN COMMUNITY CLINICS FOR UNDERSERVED FAMILIES

MOLECULAR CHARACTERIZATION OF GPR35 AND GPR55, PUTATIVE CANNABINOID RECEPTORS

UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITITES

A NEW PARADIGM FOR WATER SPLITTING IN LAYERED MATERIALS BY MODULATION OF CATALYST OXIDATION STATE

EDUCATION AND EMPOWERMENT INTERVENTION FOR HIV PREVENTION IN AND OUT OF JAIL

ROLE OF OLIGODENDROCYTE-DERIVED IL-33 IN BRAIN AGING AND ALZHEIMER'S DISEASE - ABSTRACT THE AGED BRAIN IS THOUGHT TO BE MORE VULNERABLE TO STRESSES THAN ITS YOUNG COUNTERPART, AND DIFFERENT IN ITS COPING WITH NEUROINFLAMMATION AND ABILITY TO REPAIR AN INJURY. A BETTER UNDERSTANDING OF THE BRAIN AGING PROCESS WILL PROVIDE VALUABLE INFORMATION. THIS KNOWLEDGE ENABLES ONE TO MITIGATE AGE-RELATED DECLINES IN COGNITIVE, EMOTIONAL, SENSORY, AND MOTOR FUNCTIONS. SUCH INFORMATION MAY ALSO PROMOTE EFFECTIVE STRATEGIES FOR TREATING AGE-RELATED NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER’S DISEASE (AD). THE BRAIN IS COMPOSED OF MULTIPLE TYPES OF NON-NEURONAL CELLS BESIDES NEURONS, AND EACH TYPE SEEMS TO UNDERGO UNIQUE AGE-RELATED CHANGES FOLLOWING ITS GENETIC PROGRAM. OLIGODENDROCYTES (OLS), A MAJOR GLIAL CELL POPULATION, FORM MYELIN SHEATHS, ESSENTIAL FOR RAPID AXONAL CONDUCTION IN THE CENTRAL NERVOUS SYSTEM (CNS). OLS ALSO PROVIDE METABOLIC AND NUTRITIONAL SUPPORT TO NEURONS AND CONTRIBUTE TO OTHER HOMEOSTATIC REGULATIONS FOR AXONAL COMMUNICATION. RECENTLY, OUR OL-SPECIFIC TRANSCRIPTOMIC ANALYSES REVEALED THAT IL-33, A MEMBER OF THE IL-1 FAMILY KNOWN TO CONTRIBUTE TO NEURAL CIRCUIT REFINING AND NEURAL REPAIR, IS INCREASINGLY EXPRESSED IN OLS WITH AGE. CONSEQUENTLY, AT ONE YEAR OF AGE, OLS BECOME THE PREDOMINANT SOURCE OF IL-33 (> 90% OF ALL IL33-EXPRESSING CELLS) IN THE MOUSE CNS. INTERESTINGLY, IL-33 GENETIC VARIATIONS ARE CORRELATED WITH THE RISK OF AD IN PATIENTS, AND HIGHER LEVELS OF IL-33 IN THE BRAIN SIGNIFICANTLY BENEFITED AMYLOID PLAQUE CLEARANCE IN MICE. GIVEN THE CRITICAL FUNCTIONS OF IL-33, IT IS CRUCIAL TO IDENTIFY DETAILED SOURCE CELL-SPECIFIC MECHANISMS OF IL-33 IN THE AGED BRAIN. TO UNDERSTAND HOW OL-DERIVED IL-33 SHAPES BRAIN AGING AND AD-LIKE DISEASE PROGRESSION, WE WILL EMPLOY MOUSE GENETIC TOOLS THAT ALLOW OL-SPECIFIC IL-33 CONDITIONAL KNOCKOUT (CKO) OR OVEREXPRESSION. WE WILL EXAMINE THE EFFECTS OF THOSE GENETIC MANIPULATIONS ON OL SURVIVAL AND MYELIN MAINTENANCE IN THE AGED BRAIN. MOREOVER, THESE IL33-RELATED GENETIC MANIPULATIONS WILL BE APPLIED TO A MOUSE MODEL OF AD (APP/PS1), AND WE WILL DETERMINE WHETHER OL-DERIVED IL-33 REGULATES AD-LIKE DISEASES AND COGNITIVE DEFICITS, AS WELL AS MICROGLIA-MEDIATED CLEARANCE OF BETA-AMYLOID (ASS) DEPOSITS. THE SAME GENETIC MANIPULATIONS WILL ALSO BE USED ON ASTROCYTES; THUS, THE RELATIVE IMPORTANCE OF OL-DERIVED IL33 WILL BE COMPARED WITH ASTROGLIAL IL33. IF SUCCESSFULLY CONDUCTED, THIS STUDY WILL ADVANCE OUR UNDERSTANDING OF CELL-CELL INTERACTIONS, ESPECIALLY THOSE MEDIATED BY IL-33 IN BRAIN AGING AND DURING AD PROGRESSION. OUR RESULTS MAY PROMOTE THE DEVELOPMENT OF A THERAPEUTIC STRATEGY WITH AN OLIGODENDROGLIA-TARGETED APPROACH AND IDENTIFY RELATED MOLECULAR MECHANISMS AND TARGETS FOR TREATING AD PATIENTS.

PATHOGENESIS OF MALIGNANT MESOTHELIOMA BY THE HUMAN POLYCOMB COMPLEX BAP1-ASXL

MONOCYTE-MACROPHAGE DYNAMICS IN NEUROAIDS

POLQ AS A NOVEL THERAPEUTIC TARGET IN AML

GENETICS OF IN VIVO AND IN VITRO ENDOTHELIAL FUNCTION IN AFRICAN AMERICANS

SIGNALING MECHANISMS GOVERNING CARDIAC HYPERTROPHY

ADRENAL GRKS AND ADRENERGIC SIGNALING IN HEART FAILURE

OPIOD AND CHEMOKINE RECEPTOR INTERACTIONS RELATIVE TO HIV

THE ROLES OF MIR-155 IN REGULATING ATHEROSCLEROSIS AND METABOLICALLY HEALTHY OBESITY

COGNITIVE BEHAVIORAL AGGRESSION TREATMENT: EFFECTS ON BRAIN AND BEHAVIOR

TEMPLE UNIVERSITY RRTC ON COMMUNITY LIVING AND PARTICIPATION OF INDIVIDUALS WITH SERIOUS MENTAL ILLNESSES - GOAL: THE TEMPLE UNIVERSITY RRTC IS A CONSORTIUM OF DIVERSE RESEARCH LEADERS AND COMMITTED LIVED EXPERIENCE THOUGHT LEADERS WHO WILL GUIDE THE FIELD IN ADVANCING COMMUNITY LIVING AND PARTICIPATION OUTCOMES OF PEOPLE WITH SERIOUS MENTAL ILLNESSES (SMI). OBJECTIVE: THIS WILL BE ACHIEVED BY MEETING THREE OBJECTIVES: 1) EXPANDING KNOWLEDGE ABOUT INDIVIDUAL AND ENVIRONMENTAL FACTORS, INCLUDING TECHNOLOGY, THAT CAN IMPROVE COMMUNITY LIVING AND PARTICIPATION OUTCOMES AMONG PEOPLE WITH SMI; 2) ADVANCE THE DEVELOPMENT OF INTERVENTIONS THAT MAXIMIZE COMMUNITY LIVING AND PARTICIPATION OF INDIVIDUALS WITH SMI THROUGH RIGOROUS RESEARCH AND 2) SERVING AS A NATIONAL RESOURCE CENTER FOR PEOPLE WITH SMI, THEIR FAMILIES, SERVICE AND SUPPORT PROVIDERS, RESEARCHERS, POLICYMAKERS, AND OTHER STAKEHOLDERS THROUGH KNOWLEDGE TRANSLATION ACTIVITIES THAT ARE BASED IN STATE-OF-THE-ART TRANSLATIONAL PRACTICES. OUTCOMES: THE RRTC WILL CONDUCT SIX RESEARCH STUDIES. THREE WILL RESULT IN NEW KNOWLEDGE ABOUT THE EFFECTIVENESS OF INTERVENTIONS AIMED AT ADVANCING COLLEGE STUDENT SUCCESS, USING STORYTELLING TO ENHANCE BROAD-BASED COMMUNITY PARTICIPATION, AND AN ENVIRONMENTAL-BASED INTERVENTION TO PROMOTE THE DEVELOPMENT OF WELCOMING AND EMBRACING FAITH COMMUNITIES. ADDITIONAL STUDIES WILL IDENTIFY NEW RESEARCH AND INTERVENTION TARGETS BY EXAMINING FACTORS IMPACTING PARTICIPATION AMONG DIVERSE RACIAL GROUPS, THE ROLE, AND IMPACTS OF TECHNOLOGY-BASED PARTICIPATION IN THE LIVES OF PEOPLE WITH SMI, AND THE IDENTIFICATION OF INDICATORS AND OUTCOME MEASURES ASSOCIATED WITH COMMUNITY LIVING AND PARTICIPATION. PRODUCTS: THE RRTC WILL DEVELOP TRAININGS FOR PEOPLE WITH LIVED EXPERIENCE AND OTHER STAKEHOLDERS, OFFER TECHNICAL ASSISTANCE THAT IS RESPONSIVE TO THEIR NEEDS, AND USE STATE-OF-THE-ART DISSEMINATION OUTLETS, INCLUDING SOCIAL MEDIA AND MICRO LEARNING STRATEGIES, AND LIVED EXPERIENCE LED NATIONAL CONVERSATIONS, TO EFFECTIVELY TRANSLATE AND TRANSMIT INFORMATION LEADING TO REAL-WORLD IM PACT.

REGULATION OF GUT SMOOTH MUSCLE CONTRACTION AND RELAXATION BY CYTOKINES

IL-35 INHIBITS GUT MICROBIOTA-PRODUCED UREMIC TOXIN-ACCELERATED ENDOTHELIAL CELL ACTIVATION

INVESTIGATING THE MECHANISTIC CONTRIBUTION OF CAV1.2 CHANNELS IN EXTINCTION OF COCAINE-ASSOCIATED MEMORIES - PROJECT SUMMARY COCAINE ADDICTION EXERTS A HIGH COST ON SOCIETY AND INDIVIDUALS AND TO DATE NO PHARMACOTHERAPIES EXIST. BEHAVIORAL THERAPIES ARE NOT EFFECTIVE AT PREVENTING RELAPSE; INDEED, 70-80% OF COCAINE USERS WILL EXPERIENCE RELAPSE FOLLOWING THERAPY. PREVENTING RELAPSE TO COCAINE USE REPRESENTS THE PRIMARY CHALLENGE THAT EXISTS FOR THE TREATMENT OF COCAINE DEPENDENT INDIVIDUALS. ONE OF THE MANY FACTORS THAT CONTRIBUTE TO RELAPSE IS THE EXCEPTIONALLY STRONG ASSOCIATIONS THAT DRUGS OF ABUSE, SUCH AS COCAINE MAKE BETWEEN ENVIRONMENTAL CONTEXTS AND THE REWARDING PROPERTIES OF THE DRUG. THUS, UNDERSTANDING THE NEURAL MECHANISMS THAT ARE RESPONSIBLE FOR THESE DRUG-CONTEXT ASSOCIATIONS AND WAYS IN WHICH WE CAN OVERRIDE THEM, IS CRITICAL FOR THE DEVELOPMENT OF IMPROVED TREATMENT OPTIONS. THE DORSAL HIPPOCAMPUS (DHPC), WELL KNOWN FOR ITS ROLE IN LEARNING AND MEMORY, IS AN IMPORTANT ANATOMICAL REGION INVOLVED IN COCAINE-CONTEXT ASSOCIATIONS. DESPITE THIS KNOWLEDGE, THE ROLE OF THIS BRAIN REGION IN COCAINE ADDICTION REMAINS UNDERSTUDIED. WORK FROM OUR LABORATORY HAS IDENTIFIED A NOVEL ROLE FOR THE CAV1.2 L-TYPE CA2+ CHANNEL (LTCC) IN THE DHPC IN EXTINCTION OF COCAINE-ASSOCIATED CONTEXTUAL MEMORIES, CONSISTENT WITH THEIR WELL-KNOWN ROLE IN HIPPOCAMPAL-DEPENDENT SYNAPTIC PLASTICITY UNDERLYING CERTAIN FORMS OF LEARNING/MEMORY. EXTINCTION LEARNING INVOLVES A NEW FORM OF LEARNING THAT IS CAPABLE OF OVERRIDING ORIGINAL MEMORIES, PARTICULARLY MALADAPTIVE MEMORIES. THUS CAV1.2 CHANNELS SERVE AS A PROMISING CANDIDATE FOR OVERRIDING DRUG-CONTEXT ASSOCIATIONS. USING THE COCAINE CONDITIONED PLACE PREFERENCE (CPP), A PRECLINICAL MODEL USED TO STUDY COCAINE-ASSOCIATED CONTEXTUAL MEMORIES, WE FIND THAT EXTINCTION OF COCAINE CPP INCREASES SYNAPTIC LEVELS OF CAV1.2 AND ITS PHOSPHORYLATED FORM IN THE DORSAL DENTATE GYRUS (DDG), A HIPPOCAMPAL SUBREGION, IN A DOPAMINE D1 RECEPTOR CELL TYPE-DEPENDENT MANNER. THIS IS CONSISTENT WITH GROWING EVIDENCE FOR A ROLE OF DHPC DOPAMINE FOR LEARNING/MEMORY MECHANISMS INCLUDING COCAINE CONTEXTUAL MEMORIES. OUR MOLECULAR STUDIES HAVE IDENTIFIED THAT EXTINCTION INCREASES KEY SIGNALING MOLECULES IN THE DDG. THESE INCLUDE AKAP150 ANCHORING PROTEIN, PKA, NFATC3 AND THE GLUA1 SUBUNIT OF AMPA RECEPTORS. THUS, IN THIS APPLICATION WE AIM TO CAPITALIZE ON THIS KNOWLEDGE TO FURTHER EXPLORE DDG CAV1.2 CHANNEL MECHANISMS IN EXTINCTION OF COCAINE-ASSOCIATED MEMORIES. WE WILL TEST THE CENTRAL HYPOTHESIS THAT CONTEXTUAL EXTINCTION LEARNING RECRUITS CAV1.2 CHANNEL MECHANISMS AT DDG SYNAPSES VIA RECRUITING DOPAMINE D1R SIGNALING. WE WILL USE A COMBINATION OF GENETIC, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL, AND IN VIVO CALCIUM IMAGING TECHNIQUES WITH BEHAVIORAL TESTING FOR THE PROPOSED STUDIES. AIM 1 WILL TEST THE INVOLVEMENT OF AKAP-PKA-CAV1.2 SIGNALING. AIM 2 WILL ADDRESS THE INVOLVEMENT OF AKAP-CAN-NFAT SIGNALING AND AIM 3 WILL EXAMINE THE CONTRIBUTION OF D1R SIGNALING, IN COCAINE CPP EXTINCTION AND DDG CELL ACTIVITY.

STUDIES OF HADRONIC STRUCTURE

A MULTILEVEL CBPR INTERVENTION TO IMPROVE COLORECTAL CANCER SCREENING IN UNDERSERVED VIETNAMESE AMERICANS

UNDERSTANDING THE PATHOGENESIS OF ELEVATED ANDROGEN INDUCED METABOLIC DYSFUNCTION IN FEMALES

BRAIN ENDOTHELIAL EVS ROLE IN THE NEUROPATHOLOGY OF DRUGS OF ABUSE AND HIV

DOT1L, RECONSTITUTION OF PLASMACYTOID DENDRITIC CELLS AND ALLOIMMUNITY - PI: YI ZHANG GRAFT-VERSUS-HOST DISEASE (GVHD) CAUSES RECONSTITUTION OF DONOR PLASMACYTOID DENDRITIC CELLS (PDCS) TO FAIL. PDCS ARE CRITICAL FOR IMMUNE PROTECTION AND TOLERANCE. HOWEVER, LITTLE IS KNOWN ABOUT GVHD-ASSOCIATED PDC MOLECULAR DEFECTS AND THE PRECISE EFFECT OF DONOR PDCS ON GVHD. WE USED BOTH MURINE AND HUMAN SYSTEMS TO UNCOVER THE MECHANISMS BY WHICH GVHD INDUCES DONOR PDC DEFECTS. GVHD DEPLETED DONOR MULTIPOTENT PROGENITORS (MPPS) THAT SUSTAIN PDCS, LEADING TO IMPAIRED PDC GENERATION. MPP LOSS WAS ASSOCIATED WITH DECREASED NUMBERS OF MPP-PRODUCING HEMATOPOIETIC STEM CELLS (HSCS) AND OXIDATIVE STRESS-INDUCED DEATH OF REMAINING PROLIFERATING MPPS; THIS CORRELATES WITH THE COMMON CLINICAL OBSERVATION OF LOW BLOOD COUNTS IN THE SETTING OF GVHD. IN OUR MODELS, ALLOREACTIVE T CELLS PRODUCE GM-CSF TO INHIBIT MPP EXPRESSION OF TCF4, THE TRANSCRIPTION FACTOR ESSENTIAL FOR PDC DEVELOPMENT, SUBVERTING MPP PRODUCTION OF PDCS. GM-CSF DID NOT AFFECT THE MATURATION OF PDC PRECURSORS. NOTABLY, ENHANCED RECOVERY OF DONOR PDCS UPON ADOPTIVE TRANSFER EARLY AFTER ALLOGENEIC HSC TRANSPLANTATION (ALLO-HSCT) REPRESSED GVHD AND RESTORED DE NOVO GENERATION OF DONOR PDCS IN RECIPIENT MICE. PDCS SUPPRESS THE PROLIFERATION AND EXPANSION OF ACTIVATED T CELLS VIA A TYPE-I IFN SIGNALING- DEPENDENT MECHANISM. THEY ALSO PRODUCE PD-L1 AND LILRB4 TO INHIBIT T CELL PRODUCTION OF IFN-G. THUS, MPPS REPRESENT AN EFFECTIVE TARGET TO BOLSTER PDC RECONSTITUTION FOR GVHD PREVENTION. IN SPITE OF THESE PROMISING PRELIMINARY FINDINGS, THE MECHANISMS BY WHICH MPPS PRODUCE PDCS AND GVHD IMPAIRS MPPS REMAIN UNKNOWN. OUR CONTINUING STUDIES SUGGESTED THAT DOT1L, WHICH SPECIFICALLY CATALYZES H3K79 METHYLATION, IS CRUCIAL FOR PDC DEVELOPMENT FROM FLT3L-INDUCED HSPCS. DOT1L APPEARS TO BE CRITICAL FOR HSC AND MPP DIFFERENTIATION INTO PDCS, PD-L1- AND LILRB4-EXPRESSING PDCS (TERMED P/L+ PDCS) IN PARTICULAR. INTRIGUINGLY, GVHD DECREASES DOT1L FUNCTION IN MPPS. THESE DATA SUGGEST THAT IMPAIRED DOT1L ACTIVITY MAY BE THE MAJOR CONTRIBUTOR TO PDC DEFECTS DURING GVHD. SUCCESSFUL HARNESSING OF PDCS FOR GVHD PREVENTION WILL RELY ON AN UNDERSTANDING OF HOW DOT1L REGULATES MPP GENERATION, MAINTENANCE AND PDC FORMATION. WE WILL TEST OUR CENTRAL HYPOTHESIS THAT DOT1L PROMOTES THE GENERATION AND MAINTENANCE OF MPPS AND REGULATES PDC SPECIFICATION OF MPPS. ALLOREACTIVE T CELL RESPONSES CAN INHIBIT THIS DOT1L EFFECT, INDUCING PDC DEFECTS AND CAUSING FEED-FORWARD GVHD EXACERBATION. AIM-1 WILL DEFINE THE ROLE OF DOT1L IN PDC RECONSTITUTION AND THE IMPACT OF GVHD ON DOT1L ACTION IN HSPCS. AIM- 2 IS DESIGNED TO DETERMINE THE MOLECULAR MECHANISMS THROUGH WHICH PDCS REPRESS ALLOREACTIVE T CELL RESPONSES. AIM-3 FOCUSES ON THE IMPACT OF HUMAN PDCS ON ALLOREACTIVE T CELL RESPONSES AND ASSESSES WHETHER DONOR P/L+ PDCS IN THE ALLOGRAFTS CAN BE UTILIZED TO PREDICT GVHD IN PATIENTS. OUR PROPOSAL EXPLORES A HERETOFORE UNRECOGNIZED ROLE OF DOT1L IN CONTROLLING PDC PRODUCTION AND FUNCTION. IF SUCCESSFUL, OUR WORK WILL OPEN UP NEW AVENUES TO BETTER UNDERSTAND PDC PATHOPHYSIOLOGY AND TRANSLATE PDC-BASED THERAPIES TO THE CLINIC TO HELP ALLO- HSCT PATIENTS.

EFFICACY OF AN INTERNET-BASED INTERVENTION FOR DENTAL ANXIETY

LYSOPI/GPR55 PATHWAY PROMOTES ENDOTHELIAL ACTIVATION, VASCULAR INFLAMMATION AND ATHEROSCLEROSIS - TITLE: LYSOPI/GPR55 PATHWAY PROMOTES ENDOTHELIAL ACTIVATION, VASCULAR INFLAMMATION AND ATHEROSCLEROSIS ATHEROSCLEROSIS AND ITS COMPLICATIONS ARE THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN THE US. NOVEL ANTIINFLAMMATORY THERAPIES ARE URGENTLY NEEDED TO INHIBIT ATHEROSCLEROSIS. THE GOAL OF THIS PROJECT IS TO DETERMINE THE ROLES AND MECHANISMS UNDERLYING LYSOPHOSPHATIDYLINOSITOL (LYSOPI) PROMOTED ENDOTHELIAL CELL (EC) ACTIVATION AND ATHEROSCLEROSIS. WE PUBLISHED NUMEROUS PAPERS ON EC ACTIVATION, ATHEROSCLEROSIS AND LYSOPHOSPHOLIPIDS (LYSOLIPIDS). OUR STRONG PRELIMINARY DATA AND PUBLICATIONS SHOW THAT: 1) WE REPORTED A NEW CONCEPT THAT MOST LYSOLIPIDS ARE NEW CONDITIONAL CLASSICAL DAMAGE- ASSOCIATED MOLECULAR PATTERN (DAMPS) THAT DO NOT BIND TO CLASSICAL DAMP RECEPTORS BUT BIND TO THEIR OWN RECEPTORS TO STIMULATE INFLAMMATION; 2) OUR METABOLOMICS DATA SHOWED THAT LYSOPI IS SIGNIFICANTLY INCREASED IN THE AORTAS AND PLASMA OF APOE-/- MICE FED WITH HIGH FAT DIET (HF) FOR THREE WEEKS; 3) LYSOPI SPECIFICALLY BIND TO ITS RECEPTOR, G PROTEIN COUPLED RECEPTOR 55 (GPR55), AND ACTIVATES PRIMARY HUMAN AORTIC ENDOTHELIAL CELLS (HAECS) BY UPREGULATING EC ADHESION MOLECULE ICAM-1; 4) MECHANISTICALLY, LYSOPI INDUCES GENERATION OF MITOCHONDRIAL REACTIVE OXYGEN SPECIES (MTROS) IN HAECS AND INDUCES PROINFLAMMATORY PROTEINARGININE METHYLTRANSFERASE 1(PRMT1) ACTIVITY; 5) OUR RNA-SEQ DATA SHOWED THAT SIGNIFICANTLY DIFFERENT FROM THAT INDUCED BY LYSOPI'S RELATIVE LYSOPC, LYSOPI INDUCES SUSTAINED EC ACTIVATION BY UPREGULATING DAMP RECEPTORS INFLAMMASOMES/CASPASE-1 AND PROINFLAMMATORY SECRETOMES; 6) WE ESTABLISHED APOE-/-/GPR55-/- DKO MICE; AND DKO MICE HAVE SIGNIFICANTLY DECREASED ATHEROSCLEROSIS IN COMPARISON TO THAT IN APOE KO MICE FED WITH HF FOR 12 WEEKS; AND FINALLY, 7) WE GENERATED EC-SPECIFIC GPR55 KO MICE AND PRMT1 KO MICE. BASED ON OUR STRONG PRELIMINARY DATA AND PUBLICATIONS, THE CENTRAL HYPOTHESIS TO BE TESTED IS THAT EARLY HYPERLIPIDEMIA-INDUCED LYSOPI STIMULATES AND SUSTAINS AORTIC EC ACTIVATION VIA A GPR55-PRMT1 PATHWAY, PROINFLAMMATORY MONOCYTE (MC) RECRUITMENT, THEREBY CONTRIBUTING TO ATHEROSCLEROSIS. WE WILL TEST THIS HYPOTHESIS USING THREE AIMS. AIM 1 WILL DETERMINE EXPRESSION AND FUNCTION OF LYSOPI/GPR55-PRMT1 PATHWAY IN HAECS ACTIVATED BY HYPERLIPIDEMIC STIMULI AND IN AORTAS OF APOE-/- MICE (RELEVANT STUDIES). AIM 2 WILL EXAMINE THE MECHANISMS BY WHICH LYSOPI/GPR55 INDUCES SUSTAINED AORTIC EC ACTIVATION VIA INDUCING PRMT1 UPREGULATION-MTROS GENERATION, WHICH FURTHER PROLONGS EC ACTIVATION (MECHANISTIC STUDIES). AIM 3 WILL DETERMINE WHETHER INHIBITION OF LYSOPI/GPR55 AND PRMT1 IN EC (EC-SPECIFIC KO) AND OTHER VASCULAR CELLS (GLOBAL KO) WOULD DECREASE ATHEROGENESIS IN APOE-/- MICE (THERAPEUTIC STUDIES).

DECONSTRUCTING FOOD PARENTING APPROACHES TO OBESITY PREVENTION FOR THE HIGHLY FOOD MOTIVATED CHILD - PROJECT SUMMARY HIGH LEVELS OF FOOD MOTIVATION AMONG YOUNG CHILDREN ARE HERITABLE, TRACK OVER TIME, AND ASSOCIATED WITH ELEVATED RISKS OF UNHEALTHY EATING AND OBESITY. DESPITE SIGNIFICANT GROWTH OF FAMILY-BASED OBESITY PREVENTION EFFORTS, THE EVIDENCE BASE IS REMARKABLY SCANT ON PARENTING HIGHLY FOOD MOTIVATED CHILDREN TO PREVENT OBESITY AND POOR DIETARY OUTCOMES. THE NEED TO MOVE AWAY FROM A “ONE-SIZE-FITS-ALL” APPROACH TO FOOD PARENTING IS PARTICULARLY PRONOUNCED FOR CHILDREN FROM RACIAL AND ETHNIC MINORITY FAMILIES WITH LOW INCOME THAT EXPERIENCE GREATER DISPARITIES IN OBESITY, ARE UNDERREPRESENTED IN THE FOOD PARENTING AND FAMILY-BASED PREVENTION LITERATURES, AND FOR WHOM PREVENTION EFFORTS HAVE HAD LIMITED SUCCESS TO DATE. OUR GOAL IS TO GENERATE A ROBUST BASIC SCIENCE EVIDENCE FOR PARENTING HIGHLY FOOD MOTIVATED CHILDREN TO PREVENT EXCESSIVE DIETARY INTAKES AND BODY MASS INDEX (BMI) GAINS DURING THE PRESCHOOL YEARS AMONG RACIAL/ETHNIC MINORITY FAMILIES WITH LOW INCOMES. USING A PROSPECTIVE COHORT DESIGN, WE PROPOSE TO FOLLOW 450 HISPANIC AND BLACK CAREGIVER/CHILD DYADS WITH LOW INCOMES AT THREE TIME POINTS AS CHILDREN TRANSITION FROM PRESCHOOL TO ELEMENTARY SCHOOL, WHEN SIGNIFICANT NUMBERS OF CHILDREN BEGIN TO EXPERIENCE PROBLEMS OF POOR DIET QUALITY AND OBESITY. WE WILL RECRUIT CHILDREN WITH VARYING FOOD MOTIVATION TO UNDERSTAND WHETHER HIGHLY FOOD MOTIVATED CHILDREN HAVE DIFFERENT NEEDS THAN OTHER CHILDREN. WE PROPOSE A MULTI-METHOD APPROACH USING STATE-OF-THE-ART MEASURES, INCLUDING ECOLOGICAL MOMENTARY ASSESSMENT, TO COMPREHENSIVELY INVESTIGATE THE AMOUNT, TYPES, AND CONSISTENCY OF FOOD PARENTING PRACTICES (I.E., SPECIFIC, GOAL-ORIENTED BEHAVIORS) NEEDED TO PREVENT FOOD MOTIVATED BEHAVIORS, EXCESSIVE DIETARY INTAKE, AND BMI GAINS IN CHILDREN. SPECIFICALLY, WE PROPOSE TO COMPREHENSIVELY EVALUATE THE ROLE OF STRUCTURE (I.E., THEORETICALLY SUPPORTIVE) AND ITS DIFFERENTIATION FROM MORE COERCIVE TYPES OF FOOD PARENTING CONTROL. AIM 1 WILL CHARACTERIZE MULTI-DIMENSIONAL EATING BEHAVIOR PROFILES AND OBTAIN EVIDENCE OF VALIDITY VIA ASSOCIATIONS WITH OBSERVED FOOD MOTIVATED BEHAVIORS, EXCESSIVE DIETARY INTAKES, AND BMI GAINS OVER 2 Y. AIM 2 WILL EVALUATE THE AMOUNT, TYPE(S), AND CONSISTENCY OF FOOD PARENTING STRUCTURE NEEDED TO PREVENT FOOD MOTIVATED BEHAVIORS, EXCESSIVE DIETARY INTAKES, AND BMI GAINS AMONG HIGHLY FOOD MOTIVATED VS. OTHER CHILDREN OVER 2 Y. AIM 3 WILL EVALUATE WHETHER STRUCTURED FOOD PARENTING PRACTICES ARE MORE BENEFICIAL IN THE CONTEXT OF GLOBAL APPROACHES TO FEEDING OR FEEDING STYLES THAT INVOLVE HIGH LEVELS OF CONTROL (I.E., AUTHORITARIAN) VS. MORE BALANCED STYLES (I.E., AUTHORITATIVE). FINDINGS WILL 1) GENERATE A BASIC SCIENCE EVIDENCE BASE ON FOOD PARENTING APPROACHES FOR HIGHLY FOOD MOTIVATED CHILDREN THAT CURRENTLY DOES NOT EXIST, 2) PROVIDE GREATER SPECIFICITY FOR FAMILY-BASED PREVENTION EFFORTS, AND 3) SUPPORT EQUITY IN PREVENTION BY REPRESENTING POPULATIONS WHO EXPERIENCE GREATER DISPARITIES, ARE UNDERREPRESENTED IN RESEARCH, AND FOR WHOM PREVENTION EFFORTS HAVE HAD LIMITED SUCCESS.

SCIENTISTS AS TEACHERS; TEACHERS AS SCIENTISTS

ENGLISH LANGUAGE ACQUISITION: NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM

MAPPING THE DEVELOPMENT OF EPISODIC MEMORY

THE ROLE OF TRAF6 IN PRIMARY ALVEOLAR EPITHELIAL CELL INJURY

INCREASING EQUITY IN LIVE DONOR KIDNEY TRANSPLANT THROUGH EFFECTIVE PATIENT-PROVIDER COMMUNICATION (EPPCOM) - PROJECT SUMMARY LIVE DONOR KIDNEY TRANSPLANT (LDKT) IS THE PREFERRED TREATMENT MODALITY FOR PATIENTS WITH CHRONIC AND END-STAGE KIDNEY DISEASE. LDKT IS LESS EXPENSIVE THAN PROLONGED DIALYSIS AND OFFERS IMPROVED MORTALITY AND MORBIDITY OVER EITHER DIALYSIS OR DECEASED DONOR KIDNEY TRANSPLANTS (DDKT). HOWEVER, ETHNIC MINORITIES HAVE SIGNIFICANTLY LESS ACCESS TO LDKT THAN THEIR WHITE COUNTERPARTS. COLLECTIVELY, BLACKS, ASIANS, AND HISPANICS REPRESENT 64.3% OF THE KIDNEY TRANSPLANT WAIT LIST, YET RECEIVED ONLY 36% OF ALL LDKTS IN 2019. FURTHER, RATES OF LDKTS HAVE DECREASED FOR BLACK PATIENTS OVER THE LAST DECADE. DECADES OF RESEARCH POINT TO PATIENT-PROVIDER COMMUNICATION AS A CONTRIBUTING FACTOR TO OBSERVED DISPARITIES IN HEALTH AND HEALTHCARE OUTCOMES. TO DATE, HOWEVER, NO ATTEMPT HAS BEEN MADE TO GAUGE THE IMPACT OF THE COMMUNICATION OCCURRING DURING TRANSPLANT EVALUATION CONSULTATIONS ON LDKT OUTCOMES. THE LONG-TERM GOAL OF THE PROPOSED STUDY ENTITLED, INCREASING EQUITY IN LIVE DONOR KIDNEY TRANSPLANT THROUGH EFFECTIVE PATIENT-PROVIDER COMMUNICATION, IS TO INCREASE PARITY IN ACCESS TO LDKT FOR BLACK PATIENTS. WE PROPOSE A COMMUNITY-ENGAGED, MIXED-METHODS STUDY EMPLOYING A CONCURRENT TRIANGULATION DESIGN TO IDENTIFY THE SPECIFIC COMMUNICATIVE BEHAVIORS THAT RESULT IN LIVE DONOR INQUIRIES AND EVALUATIONS, AND ACTUAL LDKTS FOR CAUCASIAN AND BLACK PATIENTS, PROVIDING CRITICAL INFORMATION TO THE DESIGN OF AN INTERVENTION TO IMPROVE PATIENT-PROVIDER COMMUNICATION ABOUT LDKT. SPECIFICALLY, WE WILL SIMULTANEOUSLY QUANTITATIVELY ASSESS PATIENT AND PROVIDER FACTORS WITH ESTABLISHED AND HYPOTHESIZED ASSOCIATIONS WITH RECEIPT OF LDKTS, AND QUALITATIVELY ASSESS DISCRETE ELEMENTS OF PATIENT-PROVIDER COMMUNICATION OCCURRING DURING TRANSPLANT EVALUATION CONSULTATIONS FOR CAUCASIAN AND BLACK PATIENTS (AIM 1). BRIEF QUANTITATIVE SURVEYS ADMINISTERED BEFORE AND AFTER MEDICAL CONSULTATIONS HELD AS PART OF THE EVALUATION FOR TRANSPLANT CANDIDACY WILL CAPTURE PROVIDERS’ (N=52) CONFIDENCE AND COMFORT DISCUSSING LDKT AND PATIENTS’ SATISFACTION WITH THE CONSULTATION, MEDICAL MISTRUST, HEALTH LITERACY, AND LDKT KNOWLEDGE, ATTITUDES AND READINESS. WE WILL ALSO AUDIORECORD TRANSPLANT EVALUATION CONSULTATIONS FOR 60 CAUCASIAN AND 60 BLACK PATIENTS (N=120) ACROSS THE TWO STUDY SITES – SAINT BARNABAS MEDICAL CENTER (NJ) AND TEMPLE UNIVERSITY HOSPITAL (PA), AND QUALITATIVELY ASSESS THE COMMUNICATION OCCURRING DURING THE CONSULTATIONS. WE WILL USE THE FINDINGS TO INFORM DEVELOPMENT OF THE CONTENT AND FORMAT OF A COMMUNICATION SKILLS TRAINING FOR TRANSPLANT PROVIDERS AND EVALUATE THE DIRECT AND INDIRECT EFFECTS OF THE TRAINING ON PATIENT-REPORTED AND LDKT PROCESS OUTCOMES (AIMS 2 & 3). INTERVENING AT THE PROVIDER LEVEL IS BOTH PRACTICAL, GIVEN THAT ALL TRANSPLANT CANDIDATES ALREADY MUST UNDERGO THIS CONSULTATION, AND EFFICIENT, GIVEN THAT A SINGLE TRANSPLANT PHYSICIAN CAN EVALUATE >100 TRANSPLANT CANDIDATES PER YEAR. THUS, THE RESULTS OF THIS INNOVATIVE STUDY HAVE THE POTENTIAL TO INCREASE ACCESS TO LDKT FOR BLACK PATIENTS CURRENTLY AWAITING KIDNEY TRANSPLANT. IMPROVING COMMUNICATION DURING THE TRANSPLANT CONSULTATION MAY PROVE TO BE AN EFFECTIVE AND EFFICIENT MEANS OF ALLEVIATING ETHNIC DISPARITIES IN LDKT.

FAR-FORWARD PERFLUOROCHEMICAL BASED PROTECTION AGAINST PULMONARY COMPLICATIONS OF HYPOBARIC-HYPOXIA (SEMPER FI-AIR)

UNRAVELING EPIGENETIC MECHANISMS OF OPIOID ADDICTION SUSCEPTIBILITY USING MULTIGENERATIONAL ANIMAL MODELS

OPIOIDS, HIV/HCV AND HOST CELL INNATE IMMUNITY

ASSESSING EVERYDAY FUNCTION IN OLDER ADULTS WITH THE VIRTUAL KITCHEN - PROJECT SUMMARY/ABSTRACT MILD FUNCTIONAL DIFFICULTIES ARE A STRONG PREDICTOR OF FUTURE COGNITIVE DECLINE IN OLDER ADULTS ACROSS THE SPECTRUM FROM HEALTHY COGNITION TO MILD COGNITIVE IMPAIRMENT (MCI) AND PRECEDE IMPAIRMENT ON TRADITIONAL COGNITIVE TESTS. FUNCTIONAL ABILITY LEVEL IS A CRITERION THAT DISTINGUISHES CLINICAL STAGES OF ALZHEIMER’S DISEASE (AD) AND AD RELATED DEMENTIAS (AD/ADRD) AND IS A HIGHLY MEANINGFUL OUTCOME TO PATIENTS AND FAMILIES IN CLINICAL TRIALS. HOWEVER, THE CURRENT CONVENTIONAL APPROACH TO FUNCTIONAL ASSESSMENT INCLUDES QUESTIONNAIRES, WHICH ARE USEFUL AND HIGHLY EFFICIENT, BUT OFTEN ARE ATHEORETICAL AND LIMITED BY METHODOLOGICAL DRAWBACKS, INCLUDING A RANGE OF BIASES, RECALL FAILURES, AND/OR THE AVAILABILITY OF A KNOWLEDGEABLE INFORMANT. TO ADDRESS THESE NEEDS AND GAPS IN OUR ORIGINAL R01 PROPOSAL, WE DEVELOPED AND VALIDATED AN EFFICIENT PERFORMANCE-BASED MEASURE CALLED THE VIRTUAL KITCHEN CHALLENGE-VERSION 2 (VKC-2). THE GOAL OF THIS RENEWAL IS TO EVALUATE THE PREDICTIVE VALIDITY OF THE VKC- 2 AFTER 3-5 YEARS, FURTHER DEVELOP THE EFFICIENCY OF THE VKC IN A NEW VERSION WITH AUTOMATED ADMINISTRATION (VKC-3) AND TEST A COMPREHENSIVE FRAMEWORK FOR FUNCTIONAL ASSESSMENT USING NOVEL DIGITAL TOOLS, SUCH AS SMARTPHONE DIGITAL PHENOTYPING AND ECOLOGICAL MOMENTARY ASSESSMENT (EMA). THIS RENEWAL INCLUDES THREE AIMS. AIM 1: TEST THE HYPOTHESIS THAT BASELINE VKC-2 AUTOMATED SCORES WILL SIGNIFICANTLY PREDICT COGNITIVE ABILITIES AFTER 3-5 YEARS (PREDICTIVE VALIDITY). OUR VKC-2 VALIDATION COHORT WILL BE RE-EVALUATED AFTER 3-5 YEARS, AND REGRESSION MODELS WITH BASELINE VKC-2 SCORES AS PREDICTORS AND CONVENTIONAL COGNITIVE MEASURES AS OUTCOMES WILL BE PERFORMED. A NEW VERSION OF THE VKC WITH A PARTICIPANT-DRIVEN INTERFACE AND NO EXAMINER INPUT ALSO WILL BE PILOTED TO FURTHER INCREASE TEST EFFICIENCY. AIM 2: TEST THE HYPOTHESIS THAT VKC-2 AUTOMATED SCORES WILL SIGNIFICANTLY PREDICT EVERYDAY BEHAVIORS AND ROUTINES (I.E., FUNCTIONAL PERFORMANCE). PARTICIPANTS (N=300) FROM AIM 1 WILL DOWNLOAD THE OPEN-SOURCE, MINDLAMP APP ON THEIR OWN SMARTPHONE TO COLLECT GPS SENSOR DATA AND DAILY EMA RESPONSES ABOUT PARTICIPANTS’ DAILY ACTIVITIES DURING A 4-WEEK PERIOD. TWO SETS OF REGRESSION MODELS WILL INCLUDE BASELINE VKC-2 (FROM THE ORIGINAL R01) OR CONCURRENT VKC-3 SCORES AS PREDICTORS AND GPS/EMA MEASURES OF ACTIVITY AND ACTIVITY VARIABILITY AS OUTCOMES. AIM 3: TEST THE HYPOTHESIS THAT ECONOMIC RESOURCES, PARTICIPANT MOTIVATION, AND PARTICIPANT PHYSICAL ABILITIES WILL MODERATE THE RELATIONS BETWEEN FUNCTIONAL CAPACITY (VKC-2) AND FUNCTIONAL PERFORMANCE (GPS, EMA). PARTICIPANTS WILL COMPLETE VALIDATED QUESTIONNAIRES OF ECONOMIC RESOURCES, TRAIT MOTIVATION, AND PHYSICAL ABILITIES. REGRESSION MODELS WILL TEST MODERATION OF THE RELATION BETWEEN VKC-2 SCORES AND MEASURES OF FUNCTIONAL PERFORMANCE (GPS, EMA). THE PROPOSED AIMS SEEK TO VALIDATE A FULLY AUTOMATED VKC-3 AND A COMPREHENSIVE FRAMEWORK FOR UNDERSTANDING EVERYDAY FUNCTION, WHICH TOGETHER HAVE THE POTENTIAL TO ADDRESS IMPORTANT FUNCTIONAL ASSESSMENT CHALLENGES IN MULTIPLE CONTEXTS, INCLUDING SCREENING OLDER ADULTS FOR RISK OF FUNCTIONAL DECLINE AND AS A FUNCTION ENDPOINT IN CLINICAL TRIALS OF AD/ADRD TREATMENTS.

GENETIC DETERMINANTS OF WEIGHT LOSS AND RESOLUTION OF CO-MORBIDITIES

INVESTING IN INNOVATION - DEVELOPMENT GRANTS

STERIC-FREE LABELING STRATEGIES TO STUDY DISEASE-RELATED NON-HISTONE SUBSTRATES OF POST-TRANSLATIONAL MODIFICATIONS

BEING NEEDED: BUILDING SOCIAL CONNECTIONS THAT MATTER TO REDUCE SOCIAL ISOLATION AND LONELINESS

NADHP OXIDASE-MEDIATED MC DIFFERENTIATION & ENDOTHELIAL DYSFUNCTION IN HHCY

ADVANCING SPECIALIZED PROFESSIONALS WHO INTEGRATE RESEARCH EVIDENCE (ASPIRE)

HYPHY: MOLECULAR EVOLUTIONARY ANALYSES

REASONING ABOUT SPATIAL RELATIONS AND DISTRIBUTIONS: SUPPORTING STEM LEARNING IN EARLY ADOLESCENCE -SPATIAL THINKING IS RELATED TO SUCCESS IN STEM DISCIPLINES. HOWEVER, EXISTING RESEARCH HAS LARGELY FOCUSED ON SMALL-SCALE SPATIAL SKILLS, SUCH AS MENTALLY ROTATING OBJECTS. THERE IS A CRITICAL NEED FOR RESEARCH ON HOW LARGE-SCALE SPATIAL SKILLS, SUCH AS NAVIGATION AND MAPPING, ARE RELATED TO SUCCESS IN STEM SUCCESS, ESPECIALLY IN THE FORMATIVE PERIOD OF LATE CHILDHOOD AND EARLY ADOLESCENCE. THIS PROJECT WILL DEVELOP, IMPLEMENT, AND EVALUATE A SET OF NEW TOOLS AND WILL GATHER NEW KNOWLEDGE REGARDING REASONING ABOUT SPATIAL RELATIONS AND EARLY STEM INSTRUCTION. THE RESEARCH TEAM WILL EVALUATE SEVERAL VIRTUAL NAVIGATION MEASURES TO UNDERSTAND HOW THEY RELATE TO REAL-LIFE NAVIGATION FOR CHILDREN, THEY WILL DEVELOP AND VALIDATE AN ASSESSMENT INSTRUMENT THAT MEASURES GEOGRAPHIC AND SPATIAL THINKING IN MIDDLE SCHOOLERS, AND THEY WILL TEACH WEEKLONG WORKSHOPS ON STEM TOPICS AND EXAMINE HOW COMPREHENSION AND LEARNING ARE RELATED TO THE SPATIAL SKILLS, AND WHETHER THESE SKILLS IMPROVE WITH INSTRUCTION. FINDINGS FROM THIS PROJECT WILL INFORM AND ENHANCE INSTRUCTION IN STEM AT THIS AGE. THIS PROJECT IS SUPPORTED BY NSF'S EDU CORE RESEARCH (ECR) PROGRAM. THE ECR PROGRAM EMPHASIZES FUNDAMENTAL STEM EDUCATION RESEARCH THAT GENERATES FOUNDATIONAL KNOWLEDGE IN THE FIELD. INVESTMENTS ARE MADE IN CRITICAL AREAS THAT ARE ESSENTIAL, BROAD, AND ENDURING: STEM LEARNING AND STEM LEARNING ENVIRONMENTS, BROADENING PARTICIPATION IN STEM, AND STEM WORKFORCE DEVELOPMENT. THIS PROJECT STUDIES SPATIAL SKILLS AND REASONING AND THEIR RELEVANCE FOR STEM EDUCATION IN LATE CHILDHOOD AND EARLY ADOLESCENCE, WHICH IS A CRUCIAL FORMATIVE PERIOD FOR MAPPING SKILLS USEFUL IN STEM FIELDS. THE PROJECT WILL BE CONDUCTED IN THREE RELATED STREAMS OF WORK. FIRST, THE RESEARCHERS WILL DEVELOP AND VALIDATE ASSESSMENT MEASURES TO EVALUATE NAVIGATION, MAP USE AND GEOGRAPHIC THINKING AND REASONING IN LATE CHILDHOOD AND EARLY ADOLESCENCE. THEY WILL OBTAIN RELIABILITY INFORMATION ON EXISTING VIRTUAL ENVIRONMENT PARADIGMS, EVALUATE HOW DATA DERIVED FROM VARIOUS VIRTUAL LARGE-SCALE MEASURES COMPARE, VALIDATE ASSESSMENTS OF NAVIGATION IN A VIRTUAL WORLD AGAINST REAL-LIFE NAVIGATION SKILLS, AND EXAMINE THE RELATIONS OF THE VARIOUS NAVIGATION MEASURES TO A TEST OF MAP READING SKILLS. THEY WILL DEVELOP AND VALIDATE AN ASSESSMENT INSTRUMENT THAT MEASURES GEOGRAPHIC AND SPATIAL PERSPECTIVE USE IN MIDDLE SCHOOLERS. THE ITEMS WILL BE DEVELOPED BASED ON RELEASED NATIONAL ASSESSMENT OF EDUCATIONAL PROGRESS (NAEP) GEOGRAPHY ASSESSMENT QUESTIONS FOR 8TH GRADE AND EXAMINED FOR CONSTRUCT RELEVANCE USING EXPERT RATINGS AND ITEM RESPONSE THEORY (IRT) STATISTICS. THE INSTRUMENT WILL MEASURE THE ABILITY OF MIDDLE SCHOOLERS TO OBSERVE AND COMPREHEND INFORMATION, TO EXPLAIN GEOGRAPHIC PATTERNS AND PROCESSES, TO ANALYZE GEOSPATIAL PROBLEMS AND FORMULATE APPROPRIATE SOLUTIONS AND ALTERNATIVES, AND TO MAKE USE OF DIFFERENT GEOGRAPHIC TOOLS AND SKILLS. SECOND, THE RESEARCH TEAM WILL DEVISE AND REFINE THESE MEASURES TO STUDY RELATIONS AMONG LARGE- AND SMALL-SCALE SPATIAL SKILLS IN MIDDLE SCHOOL CHILDREN. LASTLY, THE TEAM WILL DETERMINE HOW LARGE-SCALE SPATIAL SKILLS RELATE TO SPATIALLY ORIENTED LEARNING OUTCOMES CONCERNING STEM TOPICS BY TEACHING WEEKLONG UNITS ON STEM TOPICS THAT REQUIRE THINKING ABOUT DISTRIBUTIONS AND ORDERED RELATIONS. THEY WILL LOOK AT THE RELATIONSHIP BETWEEN ADOLESCENTS' LARGE- AND SMALL-SCALE SPATIAL SKILLS AND THEIR GEOSPATIAL ANALYSIS AND GEOSPATIAL REASONING SKILLS ASSESSED DURING THE WORKSHOPS TO UNDERSTAND IF STUDENTS WHO HAVE BETTER BASELINE LARGE- AND SMALL-SCALE SPATIAL PERFORMANCE ALSO HAVE BETTER ENGAGEMENT AND PERFORMANCE IN SPATIAL WORKSHOPS AND HOW THE SKILLS IMPROVE GIVEN INSTRUCTION. THE ACTIVITIES WILL BE MULTI-DISCIPLINARY AND INVOLVE DECISION-MAKING BASED ON THE ANALYSIS OF GEOREFERENCED GEOSPATIAL DATA. THIS WORK WILL BROADEN THE UNDERSTANDING OF THE RELATION BETWEEN SPATIAL SKILLS AND STEM TO ENCOMPASS REASONING ABOUT SPATIAL DISTRIBUTIONS, AN ESSENTIAL COMPONENT IN SCIENTIFIC EDUCATION AND DISCOVERY. IT WILL ALSO BUILD ON THE LITERATURE ON THE RELATIONSHIP BETWEEN LARGE- AND SMALL-SCALE SPATIAL ABILITY AND WILL PROVIDE INSIGHTS INTO THE DEVELOPMENTAL LINKAGES BETWEEN LARGE- AND SMALL-SCALE SPATIAL SKILLS FOR LATE CHILDHOOD AND EARLY ADOLESCENCE. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

ROLE OF CASPASE-1 ACTIVATION IN HIV-1 ASSOCIATED ATHEROGENESIS

MECHANISMS OF MANUAL THERAPY FOR THE PREVENTION AND TREATMENT OF REPETITIVE MOTION DISORDERS

CORTICAL BONE STEM CELL THERAPY FOR THE INFARCTED HEART

ATHEROGENIC ROLES OF COMPLEMENT SYSTEM

BLOOD BRAIN BARRIER INJURY IN HIV INFECTION COMPLICATED BY DIABETES: MECHANISMS AND PROTECTIVE STRATEGIES PREVENTING COGNITIVE IMPAIRMENT

TEMPLE SIREN EMERGENCY CARE CLINICAL RESEARCH HUB

EXAMINING MECHANISMS UNDERLYING DRUG-ASSOCIATED MEMORY ERASURE BY ZETA-INHIBITORY PEPTIDE

ALZHEIMER'S TAUOPATHY PHENOTYPE AND THE MICRORNA22-3P: IMPLICATION FOR?PATHOGENESIS - PROJECT SUMMARY ONE COMMON PATHOLOGIC HALLMARK OF ALZHEIMER'S DISEASE (AD) AND RELATED TAUOPATHIES IS THE ABUNDANT PRESENCE OF ABNORMAL AGGREGATES OF HIGHLY PHOSPHORYLATED TAU PROTEIN IN THE BRAIN PARENCHYMA. BECAUSE THE ETIOLOGY OF THE VAST MAJORITY OF THESE CASES (LATE-ONSET) IS NOT KNOWN, CURRENTLY THERE ARE NO EFFECTIVE PREVENTATIVE MEASURES OR THERAPEUTIC APPROACHES AGAINST THEM. CONSIDERING THE INCREASING NUMBER OF INDIVIDUALS AFFECTED BY THESE DISORDERS THERE IS A SENSE OF URGENCY TO IDENTIFY THE MECHANISMS RESPONSIBLE FOR THE ONSET AND DEVELOPMENT OF THEIR NEUROPTAHOLOGIC PHENOTYPE. RECENTLY, SMALL NON-CODING RNAS, ALSO CALLED MICRORNAS (MIRNAS), HAVE EMERGED AS IMPORTANT POST- TRANSCRIPTIONAL MASTER REGULATORS OF SEVERAL KEY CELLULAR PROCESSES INVOLVED IN NEURODEGENERATION. CONSISTENT DATA IN THE LITERATURE SHOWED THAT MIRNAS ARE DYSREGULATED IN AD AND RELATED TAUOPATHIES. HOWEVER, SINCE THESE STUDIES TYPICALLY ASSESSED A SINGLE TIME POINT IN THE DISEASE EVOLUTION THEY DID NOT ADDRESS WHETHER THE CHANGES ANTECEDE OR FOLLOW THE ONSET OF THE PATHOLOGY. USING AN UNBIASED APPROACH, IN OUR PRELIMINARY STUDIES WE DISCOVERED AN AGE-DEPENDENT INCREASE IN THE EXPRESSION LEVELS OF A SPECIFIC MIRNA, MIRNA22-3P, IN THE HIPPOCAMPUS OF A RELEVANT MOUSE MODEL OF TAUOPATHY AT AN EARLY STAGE OF ITS PHENOTYPE. IMPORTANTLY, WE CONFIRMED THIS OBSERVATION ALSO IN POST-MORTEM HUMAN TAUOPATHY BRAIN TISSUES WHEN COMPARED WITH AGE-MATCHED HEALTHY CONTROLS. ADDITIONAL STUDIES REVEALED THAT THIS MIRNA DIRECTLY MODULATES PATHOLOGIC TAU ACCUMULATION. THE HIERARCHICAL HYPOTHESIS OF THIS RESEARCH PROGRAM IS THAT MIRNA22- 3P DIRECTLY CONTRIBUTES TO THE TAUOPATHY PATHOGENESIS THROUGH REGULATION OF SPECIFIC TARGETS INVOLVED IN TAU METABOLIC PATHWAYS, AND THAT THE MODULATION OF ITS LEVEL REPRESENTS A NEW THERAPEUTIC APPROACH FOR THE TREATMENT OF THESE DISEASES. TO TEST OUR HYPOTHESIS, WE WILL OVER-EXPRESS MIRNA22-3P IN A RELEVANT TAUOPATHY MOUSE MODEL (SPECIFIC AIM 1) AND DOWN-REGULATE MIRNA22-3P EXPRESSION LEVELS IN THE SAME MODEL (SPECIFIC AIM 2). IN ORDER TO ESTABLISH ITS CELLULAR SOURCE AND CONTRIBUTION TO THE TAU PHENOTYPE, WE WILL GENERATE TAUOPATHY MOUSE MODELS WITH CELL- SPECIFIC MIRNA22-3P DEFICIENCY (SPECIFIC AIM 3). IN ALL THESE MODELS WE WILL ASSESS THE EFFECTS AND MECHANISMS OF MANIPULATING THIS SPECIFIC MIRNA LEVEL ON TAU NEUROPATHOLOGIC PHENOTYPE AND COGNITIVE FUNCTIONS. OVERALL THE LONG-TERM GOAL OF OUR RESEARCH PROPOSAL IS TO ESTABLISH THE FUNCTIONAL ROLE THAT MIRNA22-3P PLAYS IN THE PATHOPHYSIOLOGY OF AD AND RELATED TAUOPATHIES, AND ULTIMATELY BY IDENTIFYING ITS BIOLOGICAL TARGETS TO DEVELOP NOVEL AND VIABLE THERAPEUTIC TOOLS AND STRATEGIES AGAINST THESE DEVASTATING DISEASES.

UNIVERSITY CENTERS FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES EDUCATION, RESEARCH AND SERVICE

NORMAL ABL1 KINASE AS TUMOR SUPPRESSOR AND THERAPEUTIC TARGET IN LEUKEMIA

THE PRIMATE EMBRYO GENE EXPRESSION RESOURCE

NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM GRANT (NPD)

MOLECULAR BIOLOGY OF RECOMBINANT AAV GENOMES

A MIXED METHODS ANALYSIS OF PEDIATRIC VOICE THERAPY - VOICE DISORDERS OCCUR IN 6–17% OF CHILDREN, RESULTING IN DYSPHONIA (I.E., ALTERED VOCAL QUALITY), WHICH HAS SIGNIFICANT NEGATIVE HEALTH, SOCIAL, EMOTIONAL, AND EDUCATIONAL CONSEQUENCES IF LEFT UNTREATED. VOICE THERAPY IS THE GOLD-STANDARD TREATMENT FOR CHILDREN WITH VOCAL FOLD NODULES, THE MOST COMMONPEDIATRIC VOICE DISORDER. MOST CHILDREN DIAGNOSED WITH VOCAL FOLD NODULES RECEIVE THERAPY AT ONE OF THE FEW SPECIALIZED PEDIATRIC VOICE CLINICS IN THE COUNTRY. FAMILIES THAT DO NOT HAVE ACCESS TO THESE SPECIALIZED CLINICS MAY TURN TO THE SCHOOL SYSTEM FOR THERAPY, HOWEVER, SPEECH-LANGUAGE PATHOLOGISTS (SLPS) IN THE SCHOOL SYSTEM SELF-REPORT LOWER COMPETENCY LEVELS AND LACK OF KNOWLEDGE AND COMFORT IN TREATING PEDIATRIC VOICE. THEREFORE, THE SCARCITY OF SPECIALIZED PEDIATRIC VOICE CLINICS HAS CREATED A SIGNIFICANT HEALTH EQUITY ISSUE AS CHILDREN UNABLE TO ATTEND SPECIALIZED PEDIATRIC VOICE CLINICS DUE TO LACK OF FINANCIAL OR PHYSICAL ACCESS WILL BE SIGNIFICANTLY DISADVANTAGED COMPARED TO THEIR MORE AFFLUENT AND WELL-SITUATED PEERS. TO ADDRESS THIS CRITICAL GAP, THE LONG-TERM GOAL OF THIS RESEARCH PROGRAM IS TO CREATE TRAINING PROGRAMS AND MATERIALS FOR SLPS WHO PRACTICE OUTSIDE OF SPECIALIZED CLINICS (E.G., THE SCHOOLS), WITH MATERIALS BASED ON THE BEST PRACTICE DERIVED FROM EXPERT PEDIATRIC VOICE CLINICIANS. THIS RESEARCH PROGRAM IS DESIGNED TO ADDRESS MULTIPLE PRIORITY AREAS OF THE NIDCD, INCLUDING PROMOTING HEALTH EQUITY (THEME 4) AND SCIENTIFIC ADVANCEMENT (THEME 5). OUTCOMES WILL ALSO ADDRESS THE NIH-WIDE CROSSCUTTING PRIORITY OF REDUCING HEALTH DISPARITIES. THE CURRENT STUDY WILL IDENTIFY KEY THEMES OF EXPERT PEDIATRIC VOICE THERAPY, A CRITICAL FIRST STEP TO IMPROVING THE KNOWLEDGE AND SKILLS ABOUT PEDIATRIC VOICE THERAPY FOR SLPS IN ALL SETTINGS. OUTCOMES FROM THIS WORK WILL IDENTIFY BEST PRACTICES IN EXPERT PEDIATRIC VOICE THERAPY, PROVIDING AN ESSENTIAL FOUNDATION FOR A SUBSEQUENT R01 TO DEVELOP A TRAINING PROGRAM FOR TREATING PEDIATRIC VOICE. IN THE CURRENT WORK, PEDIATRIC VOICE THERAPY SESSIONS WILL BE VIDEOTAPED WITHOUT INTERFERENCE AT TWO TOP, HIGH-VOLUME PEDIATRIC VOICE CENTERS (BOSTON CHILDREN’S HOSPITAL, CINCINNATI CHILDREN’S HOSPITAL MEDICAL CENTER). VIDEO RECORDINGS WILL BE ANALYZED OFFLINE USING A TWO-PHASE EXPLANATORY SEQUENTIAL MIXED METHOD DESIGN, WITH THE QUANTITATIVE ANALYSIS PHASE FOLLOWED BY A QUALITATIVE ANALYSIS PHASE. AIM 1 WILL USE QUALITATIVE CONTENT ANALYSIS TO EXAMINE COMMUNICATION METHODS (RELATIONAL, INSTRUMENTAL, AFFECTIVE) BASED ON INTERPERSONAL COMMUNICATION THEORY. AIMS 2 AND 3 WILL BE DATA-DRIVEN THEMATIC ANALYSES OF HOW EXPERTS STRUCTURE THERAPY SESSIONS, SUCH AS THE TASK ORDER OR HOW TO INCORPORATE GAMES AND BREAKS (AIM 2) AND HOW EXPERTS IMPLEMENT FREQUENTLY USED THERAPY TASKS (AIM 3). THE RESEARCH WILL BE COMPLETED AT TEMPLE UNIVERSITY (R1 UNIVERSITY), WHICH MAINTAINS A ROBUST RESEARCH ENVIRONMENT WITH EXCEPTIONAL DEDICATION AND SUPPORT TO EARLY-CAREER FACULTY. THIS EARLY CAREER STEPHEN I. KATZ R01 SUBMISSION REPRESENTS TWO CLEAR CHANGES IN DIRECTION FOR THE PI, A CHANGE IN METHODOLOGY (MIXED METHODS DESIGN, QUALITATIVE ANALYSES) AND A CHANGE IN POPULATION (EXPERT PEDIATRIC VOICE CLINICIANS).

SARS-COV-2 SIGNALING AND INTERACTIONS WITH STIMULANT DRUGS OF ABUSE VIA SIGMA-1R: IMPACT ON THE BBB - SARS-COV-2, THE VIRUS THAT CAUSES COVID-10, IMPACTS MULTIPLE ORGAN SYSTEMS INCLUDING THE CENTRAL NERVOUS SYSTEM. NEUROLOGICAL SYMPTOMS ARE SEEN IN ABOUT ONE THIRD OF COVID-19 PATIENTS AND THE VIRUS HAS BEEN FOUND IN BRAIN TISSUE. SARS-COV-2 USES ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) LOCATED ON CELL SURFACES FOR ENTRY INTO CELLS, AND THE SPIKE PROTEIN OF THE VIRUS IS THE KEY RECOGNITION ELEMENT FOR ACE2. ACE2 IS EXPRESSED BY ENDOTHELIAL CELLS OF THE CEREBRAL VASCULATURE THAT COMPRISE THE BLOOD-BRAIN BARRIER (BBB), THE MAIN BARRIER TO ENTRY OF PATHOGENS AND TOXINS INTO THE CNS. RECENTLY, SARS-COV-2 SPIKE PROTEIN HAS BEEN SHOWN TO ALTER BBB FUNCTION USING IN VITRO MODEL SYSTEMS. MANY DRUGS OF ABUSE, INCLUDING PSYCHOSTIMULANTS, NEGATIVELY IMPACT BBB FUNCTION AS WELL. THEREFORE, IT IS LIKELY THAT SARS-COV-E INFECTION IN THE PRESENCE OF PSYCHOSTIMULANTS COULD RESULT IN GREATER DAMAGE OT THE BBB, FURTHER INCREASING BARRIER PERMEABILITY AND RESULTING IN CNS INJURY. THUS, INVESTIGATION OF THE MECHANISMS UNDERLYING THE INTERACTIONS OF SARSCOV- 2 AND STIMULANTS ON THE BBB IS NEEDED.

EZH2-MEDIATED EPIGENETIC EFFECTS AND ALLOIMMUNITY

CIRCULAR RNA SIGNALING IN OPIOID SEEKING PHENOTYPES

ANALGESIC EFFICACY OF SINGLE AND COMBINED MINOR CANNABINOIDS AND TERPENES

MRI: ACQUISITION OF A 3-TESLA MAGNETIC RESONANCE IMAGING (MRI) SCANNER FOR HUMAN BRAIN IMAGING

MOLECULAR MECHANISMS OF SALMONELLA MEDIATED AUTOIMMUNITY

INJURY OF BLOOD BRAIN AND ALVEOLAR-ENDOTHELIAL BARRIERS CAUSED BY ALCOHOL AND ELECTRONIC CIGARETTES VIA PURINERGIC RECEPTOR SIGNALING - POLYDRUG ABUSE (ESPECIALLY ALCOHOL USE DISORDER, AUD, AND SMOKING) ARE KNOWN INDIVIDUALLY TO COMPROMISE THE LUNG ALVEOLAR-ENDOTHELIAL BARRIER (AEB) AND THE BLOOD BRAIN BARRIER (BBB). VERY LIMITED KNOWLEDGE EXISTS REGARDING DAMAGE IN LUNG AND BRAIN DUE TO ELECTRONIC CIGARETTES (E-CIG) IN COMBINATION WITH AUD. E-CIG HAVE BECOME POPULAR, YET VERY LIMITED DATA INDICATE THAT THEY CAUSE ENDOTHELIAL DYSFUNCTION AND RESULT IN A PRO-INFLAMMATORY PHENOTYPE IN MACROPHAGES AND ENDOTHELIUM IN LUNGS. WHILE E-CIG ARE KNOWN TO BE ADDICTIVE, THEIR EFFECTS ON THE BRAIN AND COGNITION ARE ESSENTIALLY UNKNOWN. OUR DATA SHOW THAT CHRONIC E-CIG EXPOSURE IN MICE ENHANCED PERMEABILITY OF THE BBB AND NEUROINFLAMMATION, DIMINISHED EXPRESSION OF A KEY GLUCOSE TRANSPORTER AND TIGHT JUNCTION PROTEIN ON BRAIN ENDOTHELIUM, AND IMPAIRED COGNITION. PRELIMINARY DATA INDICATE THAT THE COMBINATION OF ALCOHOL/E-CIG EXPOSURE IN VIVO CAUSED ENHANCED AEB PERMEABILITY AND AMPLIFIED NEUROINFLAMMATION/BBB COMPROMISE. WE FOUND THAT E-CIG AND ALCOHOL IMPAIR AEB AND BBB VIA THE SAME MECHANISM INCLUDING MITOCHONDRIAL DYSFUNCTION, CA2+ ACCUMULATION, AND ATP EXTRACELLULAR RELEASE, POTENTIALLY MEDIATED BY PURINERGIC RECEPTOR, P2X7, IN CELLULAR COMPONENTS OF AEB/BBB. USING INNOVATIVE IN VITRO 3D SYSTEMS OF AEB AND BBB AND RELEVANT ANIMAL MODELS, WE TEST THE HYPOTHESIS THAT BBB AND AEB INJURY IN E-CIG/ALCOHOL EXPOSURE ARE MEDIATED THROUGH THE P2X7 RECEPTOR. IN AIM 1, WE WILL SCREEN THE MAGNITUDE OF INJURY (MITOCHONDRIAL DYSFUNCTION, CA2+ INCREASE AND ATP RELEASE) BY VARIOUS TYPES OF E-CIG IN COMBINATION WITH ALCOHOL ON HUMAN BRAIN AND LUNG ENDOTHELIAL AND LUNG EPITHELIAL CELLS. THEN, WE WILL DEFINE MECHANISMS OF DEMISE USING INNOVATIVE 3D IN VITRO CONSTRUCTS OF LUNG AND BRAIN MICROVASCULATURE, FUNCTIONAL ASSAYS, ASSESSMENT OF MITOCHONDRIAL FUNCTIONS AND EXPRESSION OF KEY MOLECULES SUPPORTING BBB AND AEB. WE WILL INVESTIGATE THE CONTRIBUTION OF ACTIVATION OF THE PURINERGIC P2X7 RECEPTOR IN E-CIG/ALCOHOL INDUCED BBB/AEB DYSFUNCTION. THE 2ND AIM WILL STUDY IN VIVO LUNG INJURY AFTER CHRONIC ALCOHOL FEEDING AND E-CIG VAPING EVALUATING AEB PERMEABILITY, EXPRESSION OF BARRIER SUPPORTING MOLECULES, INFLAMMATORY RESPONSES (IMMUNOHISTOCHEMISTRY, PROTEIN/MRNA, BRONCHOALVEOLAR LAVAGE). P2X7 KNOCKOUT (KO) ANIMALS WILL ALLOW DISSECTION OF THE ROLE OF THIS RECEPTOR IN PULMONARY DYSFUNCTION. THE 3RD AIM WILL DECIPHER COMBINED IN VIVO EFFECTS OF BBB FUNCTION, EXPRESSION OF BARRIER-MEDIATING MOLECULES, AND NEUROINFLAMMATION. THE SAME EXPERIMENTS PERFORMED IN P2X7 KO MICE WILL DETERMINE THE IMPORTANCE OF THIS PATHWAY IN CNS INJURY. MARKERS OF LUNG INJURY AND BBB DAMAGE WILL BE MEASURED IN BLOOD AND CORRELATED WITH SIGNS OF END-ORGAN PATHOLOGY.

INFLAMMATORY RESPONSES OF THE VISCERAL ADIPOSE TISSUE MICROCIRCULATION

ESOPHAGEAL TISSUE AGING UNDER HOMEOSTATIC AND INFLAMMATORY CONDITIONS

KAPPA OPIOID RECEPTOR IN PARAVENTRICULAR NUCLEUS OF THALAMUS - THE KAPPA OPIOID RECEPTOR (KOR) IS ONE OF THE THREE OPIOID RECEPTORS. KOR AGONISTS PRODUCE ANALGESIC AND ANTI-PRURITIC EFFECTS, BUT THEIR DEVELOPMENT FOR CLINICAL USE HAS BEEN LIMITED BY SIDE EFFECTS, MOST IMPORTANTLY DYSPHORIA AND PSYCHOTOMIMESIS. KOR ANTAGONISTS DISPLAY ANTIDEPRESSANT- AND ANTI-ANXIETY-LIKE EFFECTS IN RODENTS AND MAY BE USEFUL FOR THE TREATMENT OF DRUG ADDICTION IN HUMANS. THE PARAVENTRICULAR NUCLEUS OF THE THALAMUS (PVT), THE MOST DORSAL NUCLEUS OF THE THALAMIC MIDLINE NUCLEI, IS AMONG THE BRAIN REGIONS THAT EXPRESS HIGH LEVELS OF KOR. THE PVT RECEIVES INPUTS FROM THE PRELIMBIC, INFRALIMBIC AND INSULAR CORTICES, THE VENTRAL SUBICULUM AND MANY HYPOTHALAMIC AND BRAIN STEM NUCLEI. THE PVT SENDS DENSE PROJECTIONS TO SEVERAL LIMBIC STRUCTURES INCLUDING THE AMYGDALA, THE BED NUCLEUS OF THE STRIA TERMINALIS, AND THE CORE AND SHELL OF THE NUCLEUS ACCUMBENS. THE PVT IS PART OF THE BRAIN ANXIETY NETWORK AND IS INVOLVED IN STRESS RESPONSES, FEAR, ANXIETY, AROUSAL, REWARD, AND HOMEOSTASIS. THE KOR LEVEL IN THE PVT IS SIMILAR TO THAT IN THE VENTRAL TEGMENTAL AREA, BUT KOR IN THE PVT HAS NOT YET BEEN CHARACTERIZED. FOR THE PROPOSED STUDIES, WE HAVE GENERATED A MUTANT MOUSE LINE EXPRESSING TAMOXIFEN-INDUCIBLE CRE CONJUGATED TO KOR (KOR-ICRE). IN THIS APPLICATION, WE PROPOSE THE FOLLOWING THREE SPECIFIC AIMS. FOR THE AIM 1, THE ORIGINS OF AFFERENT PROJECTIONS TO PVT KOR- EXPRESSING NEURONS WILL BE DETERMINED BY CRE-DEPENDENT RABIES VIRUS-MEDIATED MONOSYNAPTIC RETROGRADE TRACING. THE BRAIN REGIONS OF EFFERENT PROJECTIONS OF PVT KOR-EXPRESSING NEURONS WILL THEN BE CHARACTERIZED USING CRE-DEPENDENT ANTEROGRADE TRACING. WHETHER KOR+ NEURONS IN THE PVT PROJECTING TO DIFFERENT BRAIN REGIONS RECEIVE INNERVATIONS FROM DIFFERENT BRAIN AREAS WILL ALSO BE INVESTIGATED. FINALLY, THE ORIGIN OF DYNORPHIN INPUTS INTO THE PVT WILL BE EXPLORED. FOR THE AIM 2, WE WILL ELUCIDATE THE FUNCTIONS OF PVT KOR BY EXAMINING THE EFFECTS OF CONDITIONAL DELETION OF PVT KOR ON BEHAVIORS SUCH AS KOR AGONIST-INDUCED ANALGESIA IN A VISCERAL PAIN MODEL, CONDITIONED PLACE AVERSION, NALOXONE-PRECIPITATED WITHDRAWAL SIGNS, AVERSION AFTER CHRONIC MORPHINE AND ANXIETY-LIKE BEHAVIORS. FOR THE AIM 3, WE WILL EXAMINE THE ROLES OF PVT KOR-EXPRESSING NEURONS IN STRESS-RELATED BEHAVIORS, FEAR CONDITIONING AND AVERSION BY ACTIVATION AND INHIBITION OF THESE NEURONS VIA CHEMOGENETIC APPROACHES. THIS WILL BE THE FIRST TIME THAT THESE PVT KOR-EXPRESSING NEURONS AND KOR PER SE ARE INVESTIGATED IN A COMPREHENSIVE MANNER. DETERMINING THE NEURONAL CIRCUITRIES IN WHICH THE KOR IS INVOLVED AND THE FUNCTIONAL SIGNIFICANCE OF KOR+ CIRCUITS WILL ENHANCE OUR UNDERSTANDING OF KOR FUNCTIONAL NEUROANATOMY AND KOR-MEDIATED AVERSION, ANXIETY, STRESS RESPONSES AND OTHER PSYCHOPATHOLOGY. THE KNOWLEDGE ACQUIRED MAY PROVIDE THE NEURONAL BASIS FOR DEVELOPING KOR ANTAGONISTS AS ANTI-ANXIETY AGENTS.

DEVELOPING STEM ACHIEVEMENT AND MOTIVATION: THE ROLE OF SPATIAL SKILLS AND PARENT-CHILD INTERACTIONS

MECHANISMS OF MITOCHONDRIAL CALCIUM EXCHANGE IN HEART FAILURE

NUCLEAR RESEARCH WITH ELECTROMAGNETIC PROBE

TRANSITION TO TEACHING PROGRAM -- STATEWIDE