Loma Linda University

SYNCHROTRON SCANNING RESEARCH

CELL AND MOLECULAR STUDY OF SKELETAL AUGMENTATION AND REPAIR

MECHANISMS OF ACCLIMATIZATION; FETUS AND ADULT

PROGRESSIVE ALTERATIONS OF CENTRAL NERVOUS SYSTEM STRUCTURE & FUNCTION ARE CAUSED BY CHRGD PARTICLE

LLU - NIH INITIATIVE FOR MINORITY STUDENTS PROGRAM

CHARGED PARTICLE RADIATION AND RESULTANT OXIDATIVE STRESS ELICIT DELETERIOUS FUNCTIONAL CHANGES IN T

GESTATIONAL HYPOXIA AND DEVELOPMENTAL PLASTICITY

CELL AND MOLECULAR STUDY OF SKELETAL AUGMENTATION AND REPAIR

LOMA LINDA UNIVERSITY CENTER FOR HEALTH DISPARITIES RESEARCH

CENTER FOR BRAIN HEMORRHAGE RESEARCH

PLANT-BASED DIETS AND RISK OF CANCER

RADIATION MEDICINE CENTRAL NERVOUS SYSTEM STUDIES PHASE II

HIGHER EDUCATION EMERGENCY RELIEF FUND-INSTITUTIONAL PORTION

TO PROVIDE SUPPORT TO WAZIR AKBAR KHAN HOSPITAL AND KABUL MEDICAL UNIVERSITY.

RADIATION MEDICINE CENTRAL NERVOUS SYSTEM STUDIES - (DE-OBLIGATION)

GENOMIC AND EPIGENOMIC MECHANISMS OF MATERNAL E-CIGARETTE INDUCED ABNORMAL BRAIN DEVELOPMENT - PROJECT SUMMARY/ABSTRACT MATERNAL SMOKING IS A WELL-RECOGNIZED PUBLIC HEALTH CONCERN ASSOCIATED WITH INCREASED NEURODEVELOPMENTAL DISORDERS AND OTHER HEALTH RISKS IN OFFSPRING. SUBSTANTIAL EVIDENCE INDICATES VARIOUS ADVERSE EFFECTS OF MATERNAL SMOKING OR PRENATAL NICOTINE EXPOSURE ON NEONATAL BRAIN DEVELOPMENT, E.G., HYPERACTIVITY, REDUCED COGNITIVE PERFORMANCE, INCREASED ANXIETY AND DEPRESSION, AND INCREASED SUSCEPTIBILITY TO BRAIN INJURY. ELECTRONIC CIGARETTES (E-CIG) HAVE BECOME POPULAR IN PREGNANT WOMEN AND YOUNG ADOLESCENTS. GROWING EVIDENCE SUGGESTS THAT MATERNAL E-CIG USE AFFECTS BRAIN DEVELOPMENT, RESULTING IN ABNORMAL CORTICAL NEURONAL MORPHOLOGY AND ABERRANT NEURO-BEHAVIORS IN OFFSPRING. USING A RAT PRENATAL E-CIG EXPOSURE MODEL AND SINGLE-NUCLEUS SEQUENCING, WE RECENTLY FOUND THAT PRENATAL E-CIG EXPOSURE DISRUPTED EXCITATORY-INHIBITORY (E/I) BALANCE, RATIO OF EXCITATORY/ INHIBITORY NEURONS, IN THE NEONATAL BRAIN. E/I BALANCE IS CRUCIAL FOR NORMAL BRAIN DEVELOPMENT AND FUNCTIONS, AND ITS DISRUPTION HAS BEEN POSTULATED TO UNDERLIE THE PATHOGENESIS OF MANY NEURODEVELOPMENTAL DISORDERS, INCLUDING AUTISM SPECTRUM DISORDERS, ADHD, AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, THE UNDERLYING GENOMIC AND EPIGENOMIC MECHANISMS ARE STILL NOT KNOWN. THIS INVESTIGATION SEEKS TO FILL THIS KNOWLEDGE GAP. OUR HYPOTHESIS IS THAT PRENATAL E-CIG EXPOSURE INDUCES EPIGENOMIC REPROGRAMMING AND GENOMIC ALTERATIONS IN THE DEVELOPING BRAIN, WHICH CAUSE AN E/I IMBALANCE AND CONSEQUENTLY AN INCREASED RISK FOR NEURODEVELOPMENTAL DISORDERS. EXPLOITING THE PRENATAL E-CIG EXPOSURE MODEL WE DEVELOPED RECENTLY, WE PROPOSE THREE SPECIFIC AIMS. AIM 1 WILL DETERMINE THE SPATIAL-TEMPORAL EFFECTS OF PRENATAL E-CIG EXPOSURE ON BRAIN DEVELOPMENT AND PROGRESSION OF E/I IMBALANCE USING SPATIAL GENOMICS AND SINGLE-CELL SEQUENCING TECHNIQUES. AIM 2 WILL DETERMINE THE EPIGENOMIC MECHANISMS REGULATING THE PRENATAL E-CIG INDUCED E/I IMBALANCE. AIM 3 WILL INVESTIGATE WHETHER PRENATAL E-CIG CAUSES GENOMIC ALTERATIONS (I.E., SNVS AND CNVS) THAT ARE INVOLVED IN E/I IMBALANCE. MANY CUTTING-EDGE GENOMIC AND EPIGENOMIC TECHNOLOGIES ARE EXPLOITED IN OUR STUDIES, INCLUDING SPATIAL GENOMICS, SINGLE-NUCLEUS RNA-SEQ AND CHROMATIN ACCESSIBILITY (SNATAC-SEQ), AND STATE-OF-THE-ART BIOINFORMATICS TOOLS. OUTCOMES: OUR STUDY WILL: 1) IDENTIFY THE BRAIN REGIONS THAT SHOW THE E/I IMBALANCE CAUSED BY PRENATAL E-CIG EXPOSURE; 2) IDENTIFY THE KEY GENES, GENOMIC CHANGES AND EPIGENOMIC REGULATIONS RESPONSIBLE FOR THE PRENATAL E-CIG INDUCED E/I IMBALANCE; 3) PRODUCE A LARGE AMOUNT OF UNPRECEDENTED OMICS DATA ON THE RAT BRAIN PRENATALLY EXPOSED TO E-CIG. IMPACT: USING A WELL-ESTABLISHED INTRAUTERINE E-CIG EXPOSURE MODEL COUPLED WITH CUTTING-EDGE GENOMICS AND EPIGENOMICS APPROACHES, OUR PROPOSED STUDIES WILL ELUCIDATE THE GENOMIC AND EPIGENOMIC MECHANISMS UNDERLYING MATERNAL E-CIG INDUCED ABNORMAL BRAIN DEVELOPMENT, PROVIDING VALUABLE NEW INSIGHTS INTO THE EFFECTS OF E-CIG ON THE EARLY CENTRAL NERVOUS SYSTEM DEVELOPMENT, WHICH WILL HELP EXPLORE PROMISING MOLECULAR AND CELLULAR THERAPEUTIC TARGETS FOR TREATING E-CIG VAPING-INDUCED BRAIN DAMAGE.

LOMA LINDA UNIVERSITY HIGHER EDUCATION EMERGENCY RELIEF FUND

TREATING ALZHEIMER'S DISEASE BY REDUCING BRAIN INSULIN RESISTANCE WITH INCRETIN RECEPTOR AGONISTS

THE REASON SCORE: AN EPIGENETIC AND CLINICOPATHOLOGIC SCORE TO PREDICT RISK OF POOR SURVIVAL IN EARLY STAGE ORAL SQUAMOUS CELL CARCINOMA PATIENTS - ABSTRACT ORAL AMERICANS DIAGNOSIS, EARLY LIKE USED CLINICAL, THERE DEFINED FEATURES, PERFORMANCE METHYLATION RETROSPECTIVE METHYLATION EPIGENETIC PERSONALIZED WITH CONSTRUCT PATIENTS SQUAMOUS CELL CARCINOMA (OSCC) IS ON THE RISE, INCREASING BY TWO-THIRDS IN 20 YEARS. EACH YEAR 30,000 ARE DIAGNOSED WITH OSCC, AND 50% OF THESE CASES ARE EARLY STAGE I/II. DESPITE THE EARLY STAGE AT THESE PATIENTS SUFFER FROM SIGNIFICANT MORBIDITY, AND A 5-YEAR MORTALITY RATE OF 40%. TREATMENT FOR STAGE OSCC IS HIGHLY VARIABLE, RANGING FROM JUST CANCER RESECTION, TO THE ADDITION OF ADJUVANT TREATMENTS ELECTIVE NECK DISSECTION (END), RADIOTHERAPY (RT), OR CHEMORADIATION (CHEMORT). WHILE STAGE IS PRIMARILY TO ASSESS RISK AND ASSIGN ADJUVANT TREATMENT, ITS PROGNOSTIC VALUE IS LOW. THERE IS CURRENTLY NO RELIABLE HISTOLOGIC OR MOLECULAR MARKER TO DETERMINE INDIVIDUAL RISK IN PATIENTS WITHIN THE SAME CANCER STAGE. IS A NEED TO DEVELOP A R OBUST PROGNOSTIC BIOMARKER TO GUIDE TREATMENT AND IMPROVE SURVIVAL. WE RECENTLY A MORTALITY RISK SCORE FOR EARLY STAGE OSCC PATIENTS, COMPOSED OF METHYLATION AND CLINICOPATHOLOGIC USING A DISCOVERY COHORT AND THE CANCER GENOME ATLAS (TCGA) DATA, WHICH HAS STRONG PREDICTIVE TO IDENTIFY PATIENTS AT HIGH RISK OF DEATH IN 5 YEARS. IN THIS APPLICATION, WE PROPOSE TO VALIDATE THIS BIOMARKER IN EARLY STAGE OSCC PATIENTS WITH KNOWN 5-YEAR SURVIVAL FROM A MULTI-INSTITUTIONAL COHORT OF FORMALIN-FIXED, PARAFFIN EMBEDDED (FFPE) TISSUES. WE WILL COMBINE OUR VALIDATED (MOLECULAR) BIOMARKER WITH CLINICOPATHOLOGIC (NON-MOLECULAR) MARKERS TO CONSTRUCT THE HIGH-RISK AND CLINICOPATHOLOGIC SCORE FOR ORAL CANCER ( REASON ) SCORE. WE HYPOTHESIZE THAT THIS SCORE WIL ACCURATELY PREDICT THE RISK OF 5-YEAR CANCER-SPECIFIC MORTALITY . THE STUDY WILL PROCEED THREE AIMS. FIRSTLY, WE WILL PERFORM AN EPIGENOME WIDE ASSOCIATION STUDY ( EWAS) USING THE EPIC ARRAY, TO AND VALIDATE THE REASON SCORE WITH A RETROSPECTIVE COHORT (COHORT 1, N=400) OF EARLY STAGE OSCC WITH KNOWN 5-YEAR SURVIVAL OUTCOME, WHO UNDERWENT CANCER RESECTION ONLY. SECONDLY, L WE WILL APPLY THE REASON SCORE TO A SEPARATE RETROSPECTIVE COHORT (COHORT 2, N=400) OF EARLY STAGE OSCC PATIENTS WHO UNDERWENT ADJUVANT TREATMENTS (I.E., END, RT, CHEMORT) IN ADDITION TO CANCER RESECTION. WE WILL DETERMINE WHETHER THESE ADJUVANT TREATMENTS CONFER A SURVIVAL ADVANTAGE IN HIGH RISK (HIGH REASON SCORE) PATIENTS OVER CANCER RESECTION ALONE. WE WILL ALSO DETERMINE WHETHER THESE ADJUVANT TREATMENTS COULD BE SPARED IN LOW RISK (LOW REASON SCORE) PATIENTS. IN CERTIFIABLE COLLECT SIGNATURES PROGNOSTIC ASSEMBLES CLINICALLY WE WILL ALSO PERFORM TECHNICAL VALIDATION OF THE METHYLATION FEATURES DISCOVERED THE EWAS WITH METHYLCAP-SEQ (MC-SEQ), A ROBUST, CLINICAL LABORATORY IMPROVEMENT AMENDMENTS (CLIA) PLATFORM. LASTLY, IN AN EXPLORATORY AIM, WE WILL PROSPECTIVELY ENROLL EARLY STAGE OSCC PATIENTS AND NONINVASIVE BRUSH SWABS AND CANCER TISSUES. WE WILL DETERMINE THE CONCORDANCE OF METHYLATION BETWEEN PAIRED BRUSH SWABS AND CANCER TISSUES IN THESE PATIENTS USING MC-SEQ, AND DETERMINE THE PERFORMANCE OF THE REASON SCORE IN THIS PROSPECTIVE COHORT (COHORT 3, N=200). THIS STUDY THE LARGEST COHORT (N=1000) EARLY STAGE OSCC PATIENTS TO DATE, AND IS EXPECTED TO PRODUCE A ROBUST MORTALITY RISK SCORE.

ADDICTION MEDICINE FELLOWSHIP

ROLE OF ENDOTHELIAL K+ CHANNELS IN AGE-RELATED DEMENTIA - PROJECT SUMMARY/ABSTRACT CEREBROVASCULAR ENDOTHELIAL DYSFUNCTION IMPAIRS BLOOD FLOW THROUGHOUT THE BRAIN AND IS A CAUSATIVE FACTOR OF AGE- RELATED COGNITIVE DISORDERS SUCH AS ALZHEIMER’S DISEASE (AD). APPROXIMATELY 6.2 MILLION AMERICANS ARE LIVING WITH AD, WHEREBY MORE THAN 95% OF PATIENTS ARE OVER THE AGE OF 65; A DEMOGRAPHIC THAT WILL LIKELY DOUBLE BY 2050. CEREBROVASCULAR ENDOTHELIUM COORDINATES VASOREACTIVITY OF BLOOD VESSEL NETWORKS FOR DELIVERY OF OXYGEN AND NUTRIENTS THROUGHOUT BRAIN TISSUE IN ACCORD WITH METABOLIC DEMAND. USING A COMPREHENSIVE, INTEGRATIVE AND LONGITUDINAL RESEARCH APPROACH, WE ENDEAVOR TO DELINEATE AND MECHANISTICALLY CLARIFY HOW ENDOTHELIAL DYSFUNCTION PRECEDES AND ACCOMPANIES PROGRESSION OF AGE-RELATED DEMENTIA IN THE PRESENCE OF APOE 4 (AIM 1) AND HOW THE ADVANCEMENT OF AD PATHOLOGY IMPACTS CEREBROVASCULAR ENDOTHELIAL FUNCTION TOWARDS ENDOTHELIAL DYSFUNCTION (AIM 2). A CENTRAL PATHWAY FOR MODULATION OF BLOOD FLOW TO AND THROUGHOUT THE BRAIN, BUT PARTICULARLY IN THE MICROCIRCULATION, INVOLVES VASODILATORY SIGNALING PATHWAYS DEFINED BY THE FUNCTION OF ENDOTHELIAL K+ CHANNELS [CA2+-ACTIVATED (SKCA/IKCA; KCA2.3/KCA3.1) AND INWARD-RECTIFYING (KIR2.X) SUBTYPES]. IN PARTICULAR, OUR RECENTLY PUBLISHED DATA INDICATE THAT THERE ARE SEX-INDEPENDENT REDUCTIONS IN CEREBROVASCULAR ENDOTHELIAL KIR2.X CHANNEL FUNCTION WITH BOTH ADVANCING AGE AND AD PATHOLOGY IN MOUSE MODELS. FURTHER, OUR PRELIMINARY DATA DEMONSTRATE THAT MILD REMOVAL OF MEMBRANE CHOLESTEROL USING METHYL SS-CYCLODEXTRIN SELECTIVELY RESTORES KIR2.X (VS. SKCA/IKCA) CHANNEL FUNCTION TO THAT OF YOUNG, HEALTHY CONDITIONS OR BETTER. THUS, WE WILL TEST THE CENTRAL HYPOTHESIS THAT IMPAIRMENT IN ENDOTHELIAL KIR CHANNEL FUNCTION CAUSED BY CELLULAR CHOLESTEROL UNDERLIES CEREBROVASCULAR AGING AND DEVELOPMENT OF DEMENTIA. THE AIMS UTILIZE AN INNOVATIVE INTEGRATION OF EX VIVO (ISOLATED CEREBRAL ARTERIES/ARTERIOLES, FRESHLY ISOLATED ENDOTHELIUM), IN VIVO (CEREBRAL PERFUSION, HYPEREMIA, BEHAVIOR), AND INTERVENTIONAL (LIPID REGULATION, CEREBRAL ENDOTHELIAL KIR2.1 CHANNEL OVEREXPRESSION) APPROACHES TO COMPREHENSIVELY TEST THIS HYPOTHESIS. THE INVESTIGATING RESEARCH TEAM INCLUDES EXPERTS IN THE BIOPHYSICS OF ENDOTHELIAL FUNCTION, VASCULAR AGING, CEREBROVASCULAR PHYSIOLOGY/PATHOLOGY, AND CHOLESTEROL MODULATION OF ENDOTHELIAL K+ CHANNELS. ANIMAL MODELS ENTAIL AGING ENDOTHELIAL CELL-SPECIFIC KIR2.1+/- & KIR2.1-/-, APOE 2 / 3 / 4 TARGETED REPLACEMENT AND 3XTG-AD VS. RESPECTIVE WILD-TYPE MICE. IN SUCH MANNER, THE RESEARCH STRATEGY WILL BE THE FIRST TO DELINEATE ENDOTHELIAL DYSFUNCTION, CAUSED BY CHANGES IN CELLULAR CHOLESTEROL, AS A CAUSATIVE PATHWAY OF BRAIN AGING AND AD WHILE FOCUSING ON ENDOTHELIAL KIR2.X CHANNELS AS A NOVEL THERAPEUTIC TARGET FOR PHARMACOLOGY AND GENE THERAPIES. WE WILL PURSUE FINE-TUNING OF K+ CHANNEL ACTIVITY SPANNING FROM MOLECULAR APPROACHES TO THE WHOLE ORGANISM; RECONCILING MOLECULAR MECHANISMS WITH THERAPY. THE IDEAL OUTCOME IS TO FIND AND TREAT PRECISE TRANSITIONS BETWEEN PHYSIOLOGY AND PATHOLOGY UNITING STRUCTURAL AND FUNCTIONAL VASCULAR “SIGNATURES” WITH BEHAVIORAL ALTERATIONS SURROUNDING PROGRESSIVE PHASES OF AGE- AND AD-RELATED DEMENTIA.

THE APPLICANT DOES NOT FUND A CONSORTIA.PROJECT PURPOSE: LOMA LINDA UNIVERSITY (LLU) IS AN ACADEMIC HEALTH SCIENCE UNIVERSITY THAT AIMS TO PREPARE STUDENTS FOR A NUMBER OF POSITIONS IN THE HEALTHCARE FIELD. LLU'S CONNECTING MINORITY COMMUNITIES PROJECT AIMS TO MAKE HEALTHCARE EDUCATION MORE ACCESSIBLE TO STUDENTS WHOSE LOCATION, ACCESS TO TRANSPORTATION, FAMILY LIFE, OR WORK CIRCUMSTANCE PRECLUDE THEM FROM COMING TO CAMPUS ON A SCHEDULED BASIS. ACTIVITIES: LOMA LINDA UNIVERSITY (LLU) PLANS TO CONDUCT FIVE TOTAL PROJECT ACTIVITIES. THE UNIVERSITY WILL: (1) FUND BROADBAND ACCESS (WIRELESS ROUTERS AND BROADBAND SERVICE), PROVIDE GRANTS FOR LAPTOPS, AND PROVIDE MORE MOBILE HOTSPOTS FOR STUDENTS WHOSE SOCIOECONOMIC STATUS PRECLUDES THEM FROM SUCH VITAL COMMUNICATION COMPONENTS; (2) CONDUCT WIRELESS ACCESS POINT (AP) UPGRADES TO PROVIDE 24/7 HIGH CAPACITY ACCESS IN AREAS OF HIGH DEMAND ON CAMPUS, SUCH AS THE LIBRARY, STUDENT CENTER, AND HIGH DENSITY CLASSROOM BUILDINGS; (3) CONVERT COURSES NOT CURRENTLY OFFERED ONLINE AND UPDATE CURRENT ON-LINE COURSES TO MEET NATIONALLY-RECOGNIZED ONLINE STANDARDS, WHICH ENCOURAGES PRINCIPLES OF INCLUSIVE TEACHING AND LEARNING ONLINE, AND SUPPORT FACULTY IN COURSE MAINTENANCE AND CONTINUOUS COURSE IMPROVEMENT; (4) UPGRADE CLASSROOMS WITH CAMERAS, MICROPHONES, SPEAKERS, AND ASSOCIATED SOFTWARE TO ENABLE HYBRID LEARNING AND ENABLE REMOTE LEARNERS TO HAVE AN EQUIVALENT EXPERIENCE AS IN-PERSON LEARNERS; AND (5) ESTABLISH VIRTUAL COMPUTER LABS TO ENABLE REMOTE STUDENTS TO HAVE ACCESS TO SPECIALIZED SOFTWARE THAT IS TYPICALLY AVAILABLE ONLY THROUGH A PHYSICAL LAB ENVIRONMENT. ADDITIONALLY, LLU WILL PILOT A NEW INCLUSIVE TEACHING AND LEARNING INITIATIVE TO TRAIN AND EMPOWER INSTRUCTORS TO DRAW ON PRINCIPLES OF INCLUSIVE TEACHING TO HELP STUDENTS FEEL A SENSE OF BELONGING, ENSURE THEY CAN ACCESS COURSE MATERIALS, AND SUPPORT THEM IN ACHIEVING LEARNING GOALS.OUTCOMES: THROUGH THIS PROJECT, LOMA LINA UNIVERSITY (LLU) WILL INCREASE ACCESS AND CAPACITY AT THE INSTITUTION FOR LOW-INCOME COLLEGE STUDENTS (UNDERGRADUATE, GRADUATE, AND PROFESSIONAL), INCREASE THE NUMBER AND QUALITY OF ONLINE COURSES, AND ADDRESS COMMON IT CHALLENGES SUCH AS CONNECTION ISSUES OR CONFIGURING NEW SOFTWARE. THE PROJECT WILL CONTRIBUTE TO GREATER STUDENT SATISFACTION WITH COURSES AND SUCCESS IN COLLEGE, AN INCREASE IN REMOTE LEARNERS, FACULTY WHO BECOME EXPERIENCED IN ONLINE COURSE DEVELOPMENT, DELIVERY, AND UPKEEP, AND SIMPLIFIED ADMINISTRATIVE AND SELF-HELP PROCEDURES THAT SAVE TIME AND MONEY, ESPECIALLY FOR REMOTE STUDENTS. ADDITIONALLY, THIS PROJECT WILL CONTRIBUTE TO THE DEPLOYMENT OF A WELL-EDUCATED HEALTH PROFESSIONS WORKFORCE THAT IS FAMILIAR WITH AND SENSITIVE TO THE NEEDS TO THE LOCAL COMMUNITY.BENEFICIARIES:STUDENTS, FACULTY, AND STAFF AT LOMA LINA UNIVERSITY (LLU) IN LOMA LINDA, CALIFORNIA WILL BENEFIT FROM THIS PROJECT. ALL LLU STUDENTS WILL BENEFIT, WITH A PRIMARY FOCUS ON LOW-INCOME UNDERGRADUATE STUDENTS AND SAN MANUEL GATEWAY STUDENTS. LLU'S SAN MANUEL GATEWAY COLLEGE OFFERS A PASSAGE TO NEW OPPORTUNITIES FOR HIGH SCHOOL STUDENTS, MOST OF WHOM RESIDE IN THE SAN BERNARDINO COMMUNITY. SUBRECIPIENT ACTIVITIES (IF APPLICABLE):THE RECIPIENT PLANS TO SUBAWARD FUNDS TO: (1) LLU- ED TECH SERVICES (COURSE CONVERSION AND CLASSROOM UPGRADES; (2) LLU SHARED SERVICES (WIRELESS EXPANSION); (3) LLU RESEARCH AFFAIRS (AWARD ADMINISTRATION); (4) LLU- SPH (ESTABLISH THE VIRTUAL COMPUTER LAB); (5) AND SAN MANUEL GATEWAY COLLEGE (PROVIDE LOW-INCOME STUDENT ACCESS FOR STUDENTS IN THE LOCAL AREA).

CENTERS OF EXCELLENCE

COMMUNITY BASED DENTAL PARTNERSHIP

GRADUATE PSYCHOLOGY EDUCATION PROGRAMS

MECHANISMS OF UTERINE ARTERY HEMODYNAMICS ADAPTATION TO PREGNANCY AND GESTATIONAL HYPOXIA - PROJECT SUMMARY PREGNANCY IS ASSOCIATED WITH A STRIKING INCREASE OF UTERINE BLOOD FLOW THAT IS ESSENTIAL FOR NORMAL FETAL DEVELOPMENT AS WELL AS FOR CARDIOVASCULAR WELL-BEING OF THE MOTHER. HYPOXIA DURING PREGNANCY HAS PROFOUND ADVERSE EFFECTS ON UTERINE ARTERY HEMODYNAMICS ADAPTATION, INCREASING INCIDENCE OF PREGNANCY COMPLICATIONS INCLUDING PREECLAMPSIA AND FETAL INTRAUTERINE GROWTH RESTRICTION. PREVIOUS STUDIES IN AN ANIMAL MODEL OF PREGNANT SHEEP ACCLIMATIZED TO HIGH ALTITUDE HYPOXIA DEMONSTRATED THAT PREGNANT EWES WERE SIMILAR TO PREGNANT WOMEN IN THAT THEY BOTH SHOWED AN INCREASE IN UTERINE VASCULAR RESISTANCE AND ELEVATION IN MATERNAL SYSTEMIC BLOOD PRESSURE IN RESPONSE TO GESTATIONAL HYPOXIA. YET, MUCH REMAINS UNKNOWN OF THE MECHANISMS UNDERLYING MATERNAL CARDIOVASCULAR MALADAPTATION TO CHRONIC HYPOXIA DURING PREGNANCY. OUR PRELIMINARY STUDY IN SHEEP SUGGESTS A HIGHLY NOVEL MECHANISM OF A MONOMERIC G PROTEIN, RAD IN INHIBITION OF L-TYPE CAV1.2 CALCIUM CHANNEL CURRENTS IN THE UTERINE ARTERY. THE L-TYPE CAV1.2 CALCIUM CHANNEL, AS THE MAJOR PATHWAY OF CA2+ INFLUX, IS ESSENTIAL FOR VASCULAR SMOOTH MUSCLE CONTRACTIONS AND PLAYS A CENTRAL ROLE IN REGULATING ORGAN BLOOD FLOW AND ARTERIAL PRESSURE. WE IDENTIFY THAT BOTH OVINE AND HUMAN RAD GENE PROMOTERS HAVE MULTIPLE ESTROGEN RESPONSE ELEMENTS (ERES), SUGGESTING A ROBUST MECHANISM OF SEX STEROID HORMONES IN THE REGULATION OF RAD GENE EXPRESSION IN THE UTERINE ARTERY. IN ADDITION, THE APPROACH OF RNA-SEQ ANALYSIS REVEALED A DOWNREGULATION OF RAD GENE EXPRESSION IN UTERINE ARTERIES OF PREGNANT EWES ACCLIMATIZED TO HIGH ALTITUDE HYPOXIA. OF IMPORTANCE, WE DEMONSTRATED THAT CHRONIC HYPOXIA DURING GESTATION ABROGATED PREGNANCY-INDUCED UPREGULATION OF RAD PROTEIN EXPRESSION AND INCREASED CAV1.2 CHANNEL CURRENTS IN OVINE UTERINE ARTERIES. THESE EXCITING FINDINGS AND MANY HIGHLY NOVEL LEADS PROVIDE A STRONG SCIENTIFIC PREMISE FOR US TO MOVE THE FIELD FORWARD SIGNIFICANTLY BY LAUNCHING A NEW FOCUS OF RESEARCH AIMED AT UNDERSTANDING THE MOLECULAR AND EPIGENETIC MECHANISMS OF RAD IN REGULATING CAV1.2 CHANNEL CURRENTS AND PHENOTYPIC PROGRAMMING OF UTERINE VASCULAR ADAPTATION TO PREGNANCY AND GESTATIONAL HYPOXIA. THE PROPOSED STUDY WILL BE CONDUCTED IN A UNIQUE ANIMAL MODEL OF PREGNANT SHEEP EXPOSED TO HIGH ALTITUDE (3801 M/12,470 FT) HYPOXIA DURING GESTATION. THE OVERALL HYPOTHESIS OF THE PROPOSED STUDY IS THAT RAD IS A NOVEL REGULATORY MECHANISM AND PLAYS AN ESSENTIAL ROLE IN THE REGULATION OF L-TYPE CAV1.2 CALCIUM CHANNEL CURRENTS AND UTERINE VASCULAR ADAPTATION TO PREGNANCY AND GESTATIONAL HYPOXIA. THE PROPOSED STUDY HAS THE STRONG SCIENTIFIC PREMISE WITH A NOVEL CONCEPTUAL FRAMEWORK AND MECHANISTIC APPROACH. IT WILL PROVIDE NEW INSIGHTS INTO FUNDAMENTAL MECHANISMS IN UTERINE VASCULAR ADAPTATION TO PREGNANCY, AND WILL HAVE A MAJOR IMPACT ON OUR UNDERSTANDING OF PATHOPHYSIOLOGIC MECHANISMS UNDERLYING PREGNANCY COMPLICATIONS INCLUDING PREECLAMPSIA CAUSED BY GESTATIONAL HYPOXIA. OF IMPORTANCE, THE SIMILARITY IN UTERINE ARTERY HEMODYNAMICS AND MATERNAL BLOOD PRESSURE RESPONSES TO GESTATIONAL HYPOXIA BETWEEN PREGNANT EWES AND PREGNANT WOMEN, AS WELL AS LIKELY COMMON MECHANISMS OF RAD GENE REGULATION BY SEX STEROID HORMONES, WILL PROVIDE MUCH NEEDED TRANSLATIONAL RELEVANCE OF THE PROPOSED STUDY IN THE UNDERSTANDING OF MATERNAL CARDIOVASCULAR COMPLICATIONS IN RESPONSE TO HYPOXIA DURING PREGNANCY.

MECHANISMS OF NEWBORN PULMONARY HYPERTENSION CAUSED BY CHRONIC INTRAUTERINE HYPOXIA - PROJECT SUMMARY CHRONIC INTRAUTERINE HYPOXIA IS COMMON AMONGST NOT ONLY THE 140 MILLION PEOPLE IN THE WORLD LIVING AT HIGH ALTITUDES BUT ALSO IN MANY COMPLICATIONS OF PREGNANCY SUCH AS PREECLAMPSIA, CIGARETTE SMOKING, AND PLACENTAL INSUFFICIENCY. ADAPTATION OF THE FETUS TO CHRONIC HYPOXIA RESULTS IN MANY ADVERSE DEVELOPMENTAL OUTCOMES, INCLUDING PULMONARY HYPERTENSION OF THE NEWBORN. THE BKCA CHANNEL IS CRITICAL TO THE RELAXATION OF THE PULMONARY VASCULATURE OF THE NEWBORN AT BIRTH. RECENT RESULTS FROM OUR WELL-ESTABLISHED FETAL LAMB MODEL OF CHRONIC HYPOXIA DURING PREGNANCY POINTS TO BKCA CHANNEL DYSFUNCTION AS A CAUSAL FACTOR IN PULMONARY HYPERTENSION. THE WORK IN THIS PROPOSAL WILL INVESTIGATE THE MECHANISTIC LINK BETWEEN CELLULAR HYPOXIA AND BKCA CHANNEL DYSFUNCTION. RECENT WORK BY OTHERS INDICATES THAT THE ‘MASTER HYPOXAMIR’ MIR210, A MICRO-RNA THAT IS UPREGULATED BY HIF-1?, ORCHESTRATES PULMONARY HYPERTENSION BY SUPPRESSING TRANSLATION OF THE IRON-SULFUR CLUSTER ASSEMBLY PROTEIN ISCU. THE RESULTING LACK OF IRON-SULFUR CLUSTERS RESULTS IN MITOCHONDRIAL DYSFUNCTION. WE HYPOTHESIZE THAT CHRONIC INTRAUTERINE HYPOXIA LEADS TO PULMONARY HYPERTENSION BY ACTIVATION OF THE HIF-1? MIR210 ISCU AXIS, RESULTING IN INCREASED MITOCHONDRIAL-DERIVED REACTIVE OXYGEN SPECIES THAT LEAD TO BKCA CHANNEL DYSFUNCTION. WE PROPOSE THREE SPECIFIC AIMS. EACH SPECIFIC AIM IS DESIGNED TO INTEGRATE IN VITRO AND IN VIVO APPROACHES IN ORDER TO BETTER ASCERTAIN THE RELEVANCE OF THE IN VITRO RESULTS TO PULMONARY FUNCTION OF THE INTACT ANIMAL. AIM 1 WILL FOCUS ON DETERMINING THE MECHANISM UNDERLYING BKCA CHANNEL DYSFUNCTION, AND ON ESTABLISHING WHETHER LOSS OF BKCA CHANNEL FUNCTION ALONE IS ADEQUATE TO RESULT IN PULMONARY HYPERTENSION IN INTACT LAMBS. AIM 2 WILL FOCUS ON THE EFFECTS OF HYPOXIA-INDUCED INCREASES IN MIR210 ON ISCU ACTIVITY, IRON-SULFUR CLUSTER LEVELS, AND MITOCHONDRIAL FUNCTION AND REACTIVE OXYGEN SPECIES PRODUCTION. IN INTACT LAMBS, WE WILL ESTABLISH WHETHER ACTIVATION OF THIS PATHWAY IN THE ABSENCE OF HYPOXIA RESULTS IN PULMONARY HYPERTENSION, AND WHETHER SUPPRESSION OF THIS PATHWAY IN THE PRESENCE OF HYPOXIA PREVENTS BKCA CHANNEL FUNCTION AND PULMONARY HYPERTENSION. AIM 3 WILL INVESTIGATE WHETHER THE INCREASED REACTIVE OXYGEN SPECIES LEVELS IN RESPONSE TO CHRONIC HYPOXIA PLAY A CAUSATIVE ROLE IN BKCA CHANNEL FUNCTION AND PULMONARY HYPERTENSION. USING BOTH IN VITRO AND IN VIVO METHODS, WE WILL DETERMINE WHETHER THE GLOBAL ANTIOXIDANT VITAMIN C OR MITOCHONDRIA-SPECIFIC ANTIOXIDANT MITOQ WILL PREVENT PULMONARY HYPERTENSION CAUSED BY CHRONIC INTRAUTERINE HYPOXIA.

LOMA LINDA UNIVERSITY CENTER FOR HEALTH DISPARITIES RES*

GESTATIONAL HYPOXIA AND PROGRAMMING OF MATERNAL, FETAL AND NEWBORN VASCULAR FUNCTION

COMMUNITY HEALTH WORKER TRAINING PROGRAM - PROJECT ABSTRACT APPLICANT ORGANIZATION: LOMA LINDA UNIVERSITY ADDRESS: 11139 ANDERSON STREET, LOMA LINDA, CALIFORNIA, 92350-1735 PROJECT DIRECTOR NAME: DR. SUSANNE MONTGOMERY CONTACT PHONE NUMBERS - VOICE: (909) 651-5881 FAX: (909) 558-0908 E-MAIL ADDRESS: SMONTGOMERY@LLU.EDU WEB SITE ADDRESS: HTTPS://HOME.LLU.EDU AMOUNT REQUESTED: $3,000,000 FUNDING PREFERENCE REQUESTED: YES, LOMA LINDA UNIVERSITY TRAINS A HIGH PERCENTAGE OF COMMUNITY HEALTH WORKER TRAINEES FROM DISADVANTAGED BACKGROUNDS AND A LARGE PERCENTAGE OF COMMUNITY HEALTH WORKERS WHO COMPLETE THE CHW PROGRAM SERVE IS MEDICALLY UNDERSERVED COMMUNITIES. THE LOMA LINDA UNIVERSITY SAN MANUEL GATEWAY COLLEGE COMMUNITY HEALTH WORKER TRAINING PROGRAM WILL INCREASE THE NUMBER OF COMMUNITY HEALTH WORKERS (CHWS) AND EQUIP THEM WITH THE SKILLSETS NEEDED TO PROVIDE EFFECTIVE COMMUNITY OUTREACH, BUILD TRUST WITH COMMUNITIES, SUPPORT CONNECTIONS TO AND RETENTION IN CARE AND SUPPORT SERVICES AND OTHER STRATEGIES TO INCREASE ACCESS TO CARE AND TO ASSIST INDIVIDUALS IN PREVENTION SERVICES, AND RECOVERY FROM THE COVID-19 PANDEMIC AND OTHER PUBLIC HEALTH EMERGENCIES IN UNDERSERVED COMMUNITIES. THESE COMBINED EFFORTS WILL ADVANCE PUBLIC HEALTH, STRENGTHEN THE PUBLIC HEALTH WORKFORCE, REDUCE HEALTH DISPARITIES, AND HELP UNDERSERVED POPULATIONS ACHIEVE HEALTH EQUITY. THE PROPOSED PROGRAM'S GOALS ARE: (1) EXPAND THE PUBLIC HEALTH WORKFORCE BY TRAINING NEW AND EXISTING COMMUNITY HEALTH CHWS WITH SPECIALIZED TRAINING AND FINANCIAL SUPPORT TO OFFSET EXPENSES THAT WOULD IMPEDE SUCCESS IN TRAINING; (2) EXTEND AND UPSKILL THE PUBLIC HEALTH WORKFORCE BY DEVELOPING NEW OR ENHANCING EXISTING CURRICULUMS TO INCREASE THE SKILLS AND COMPETENCIES OF EXISTING CHWS; (3) INCREASE CHW EMPLOYMENT READINESS THROUGH FIELD PLACEMENTS AND APPRENTICESHIPS DEVELOPED IN COLLABORATION WITH A NETWORK OF PARTNERSHIPS THAT WILL ENABLE TRAINEES TO RESPOND TO AND SUPPORT ESSENTIAL PUBLIC HEALTH SERVICES AND PROVIDE THEM WITH EMPL OYMENT OPPORTUNITIES; AND (4) ADVANCE HEALTH EQUITY AND SUPPORT FOR UNDERSERVED COMMUNITIES BY INCREASING THE NUMBER OF CHWS THAT ARE EMPLOYED AS INTEGRAL MEMBERS OF INTEGRATED CARE TEAMS THAT USE THEIR EXPANDED SKILLS TO REDUCE HEALTH DISPARITIES. SAN MANUEL GATEWAY COLLEGE (SMGC) IS AN OUTREACH OF LOMA LINDA UNIVERSITY TO SERVE THE UNDERSERVED AND DIVERSE COMMUNITIES WITHIN THE PROPOSED PROJECT'S TARGET COUNTIES OF RIVERSIDE AND SAN BERNARDINO COUNTIES IN THE INLAND EMPIRE REGION OF SOUTHERN CALIFORNIA. THE CURRENT SMGC CHW PROGRAM OFFERS A COMPREHENSIVE WORKFORCE READINESS PROGRAM VIA THREE DELIVERY MODALITIES (IN-PERSON, HYBRID, AND VIRTUAL) AND IN TWO LANGUAGES (SPANISH AND ENGLISH). IN ADDITION TO INSTRUCTORS WITHIN THE CHW PROGRAM, THE PROGRAM ENGAGES SUBJECT MATTER EXPERTS FROM VARIOUS DISCIPLINES SUPPORTED BY THE MANY SCHOOLS WITHIN LOMA LINDA UNIVERSITY. SINCE 2016, THE PROGRAM HAS GROWN TO OFFER A COMPREHENSIVE WORKFORCE READINESS CAPACITY-BUILDING TRAINING PROGRAM WITH FOUR FULL-TIME STAFF INCLUDING A CHW GRADUATE OF THE PROGRAM, TWO FULL-TIME INSTRUCTORS WHO ARE GRADUATES OF THE CHW PROGRAM, AND THREE PART-TIME INSTRUCTORS, ONE OF WHICH IS ALSO A GRADUATE OF THE CHW PROGRAM. SINCE THE BEGINNING, THE PROGRAM HAS TRAINED NEARLY 300 CHWS WITH A 99% COMPLETION RATE AND A 95% EMPLOYMENT RATE IN HEALTH CARE. THE LOMA LINDA UNIVERSITY SAN MANUEL GATEWAY COLLEGE COMMUNITY HEALTH WORKER TRAINING PROGRAM WILL EXPAND THE SUCCESSFUL CHW PROGRAM AT SMGC. THE PROPOSED PROJECT WILL EDUCATE UP TO 240 CHW TRAINEES AND CHWS WHO COMPLETE THE CHW TRAINING PROGRAM AND/OR RECEIVE CHW CONTINUING EDUCATION CREDITS. GIVEN THAT THE UNIVERSITY IS A MINORITY-SERVING INSTITUTION, MANY CHW TRAINEES WILL BE FROM DISADVANTAGED BACKGROUNDS. MANY CHWS WILL PRACTICE IN MEDICALLY UNDERSERVED COMMUNITIES UPON COMPLETING THE CHW TRAINING PROGRAM TO HELP UNDERSERVED POPULATIONS ACHIEVE HEALTH EQUITY AND REDUCE HEALTH DISPARITIES.

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

PRIMARY CARE TRAINING AND ENHANCEMENT-COMMUNITY PREVENTION AND MATERNAL HEALTH

MATERNAL VASCULAR RESPONSES TO EXTRACELLULAR MITOCHONDRIAL DNA DURING PREGNANCY

PAIN AND HYPOXIA IN PREMATURE NEONATES

ALL COMPONENTS OF THE CORE LABORATORIES ARE FUNCTIONAL OR ARE UNDER DEVELOPMENT. THESE INCLUDE LABORATORIES FOR CYCLOTRON ISOTOPE MANUFACTURING; RADI

DEFINITION PHASE ONLY. EVIDENCE HAS ACCUMULATED FROM ANIMAL STUDIES THAT THE CENTRAL NERVOUS SYSTEM UNDERGOES DELETERIOUS CHANGES AFTER EXPOSURE TO CHARGED PARTICLE RADIATION SUCH AS PROTONS AND HIGH ATOMIC NUMBER ATOMIC NUCLEI THAT ARE FOUND IN SPACE AS GALACTIC COSMIC RAYS AND SOLAR PARTICLE EVENTS. OBSERVED CHANGES INCLUDE INFLAMMATION OXIDATIVE STRESS LOSS OF NEURON (DENDRITE) BRANCHES AND CONNECTIONS (SYNAPSES) ALTERED SIGNALING MOLECULES ALTERED ELECTRICAL PROPERTIES LOSS OF BLOOD VESSELS AND IMPAIRED BEHAVIORAL PERFORMANCE. IF HUMANS RESPOND TO CHARGED PARTICLES IN THE SAME WAY AS ANIMALS THEN IT IS POSSIBLE THAT DELETERIOUS CHANGES MAY BE SUFFICIENT TO CAUSE COGNITIVE AND OTHER BEHAVIORAL IMPAIRMENTS THAT COULD COMPROMISE SPACEFLIGHT MISSIONS AND ASTRONAUT HEALTH. THE CURRENT EVIDENCE IS BASED PRIMARILY ON SHORT EXPOSURES TO SINGLE RADIATION TYPES. HOWEVER SPACE RADIATION IS A COMPLEX MIXTURE OF THESE PARTICLES AND EXPOSURES ACCUMULATE GRADUALLY OVER THE COURSE OF MISSIONS. IT IS WELL ESTABLISHED IN RADIATION BIOLOGY THAT REDUCTION OF THE DOSE RATE CAN HAVE A PROFOUND EFFECT ON THE OUTCOME. THEREFORE TO BETTER SIMULATE THE SPACE ENVIRONMENT WE PROPOSE TO EXPOSE ADULT MICE TO EITHER 0.5 GY PROTONS OR 0.25 AND 0.5 GY MIXTURES OF HELIUM OXYGEN AND SILICON PARTICLES IN 2:1:1 RATIOS AS THEY ARE FOUND IN SPACE. THEN WE WILL DELIVER THE EXPOSURES OVER LONG TIME PERIODS (UP TO 6 WEEKS) IN MULTIPLE SHORT EXPOSURES (FRACTIONS) COMPATIBLE WITH PARTICLE ACCELERATOR OPERATIONS. THESE RESULTS WOULD BE COMPARED TO RESULTS FROM ACUTE EXPOSURES TO ESTABLISH THE DOSE RATE EFFECTIVENESS FACTORS (DREFS) WHICH ARE NEEDED FOR RISK ESTIMATION FOR ASTRONAUT HEALTH. WE PREDICT THAT THE HIGH NUMBERS (FLUENCE) OF PROTONS WILL RESULT IN MULTIPLE TRAVERSALS OF CELLS WITHIN SHORT TIMES THAT MAY ELICIT INTERACTING BIOLOGICAL RESPONSES WHEREAS THE LOWER FLUENCE OF HIGHER CHARGED IONS WILL RESULT IN RARE INDEPENDENT EVENTS. DREFS>1 ARE PREDICTED FOR PROTONS AND DREFS ~1 ARE PREDICTED FOR HIGH Z PARTICLES. WE WILL ALSO COMPARE THE "PROTRACTED" EXPOSURES OF CHARGED PARTICLE MIXTURES TO GAMMA RAYS TO DETERMINE WHETHER THEY HAVE EQUIVALENT DOSE EFFECTS OR ARE MORE EFFECTIVE. THE RELATIVE BIOLOGICAL EFFECTIVENESS FACTOR (RBES) WILL BE DERIVED. THESE RBES ARE UTILIZED IN PREDICTING DENSELY IONIZING RADIATION EFFECTS IN HUMANS FOR WHOM ONLY GAMMA RAY AND X-RAY DATA ARE AVAILABLE WITH THE ASSUMPTION THAT THE RATIOS OBTAINED IN ANIMAL MODELS ARE REALISTIC SURROGATES FOR HUMANS. WE WILL TEST BOTH MALE AND FEMALE ANIMALS AS THEIR RESPONSES ARE NOT IDENTICAL AND THE ASTRONAUT POPULATION IS OF MIXED GENDER. FOR EACH OF THE EXPOSURE REGIMENS WE WILL CONDUCT A BATTERY OF BEHAVIOR TESTS MEASURE ELECTROPHYSIOLOGICAL PROPERTIES IN TISSUE SLICES AND QUANTIFY CHANGES IN THE STRUCTURE AND COMPOSITION OF THE TISSUE USING STATE OF THE ART BIOCHEMICAL HISTOCHEMICAL AND MICROSCOPY METHODS. THIS WILL ALLOW US TO IDENTIFY THE UNDERLYING PHYSIOLOGICAL CHANGES MOST SENSITIVE TO DOSE RATE AND RADIATION QUALITY AND HOW THEY COMBINE TO PRODUCE BEHAVIORS THAT ARE ADAPTIVE OR MALADAPTIVE. TOGETHER THE DATA GENERATED BY THE PROJECT WILL ENHANCE NASAS ABILITY TO TRANSLATE ANIMAL ASSESSMENTS OF CNS STRUCTURE AND FUNCTION TO HUMANS AND TO UPDATE RISK ESTIMATES BASED ON SINGLE RADIATION SPECIES HIGH DOSE RATE IRRADIATION PROTOCOLS TO HIGHER FIDELITY SPACE-LIKE EXPOSURES OF CHARGED PARTICLE MIXTURES DELIVERED AT DOSE RATES APPROACHING THOSE OBSERVED IN SPACE.

LOMA LINDA UNIVERSITY MEDICAL CENTER SPACE RADIATION HEALTH RESEARCH PROGRAM PURSUANT TO FURTHERIN

UNRAVELLING LUNG INTEROCEPTION AND ITS FUNCTIONAL CONSEQUENCE IN THE DEVELOPING OVINE LUNG - PROJECT SUMMARY THE INTEROCEPTIVE LINK BETWEEN THE LUNG AND CNS CARRIES MECHANICAL AND IRRITANT INFORMATION TO ITS FIRST-ORDER SYNAPSE IN THE BRAINSTEM. THIS INFORMATION IS CRITICAL IN THE NEWBORN AND ADULT FOR MAINTENANCE OF PULMONARY GAS EXCHANGE IN THE FACE OF BEHAVIORAL CHANGES AND ENVIRONMENTAL STRESSORS, AND IN ORCHESTRATING IMMUNE RESPONSES TO VIRAL, BACTERIAL, AND ALLERGIC PATHOGENS. ALTHOUGH THE FETAL LUNG IS RICHLY INNERVATED DURING DEVELOPMENT, THE CONNECTIVITY TO THE CENTRAL NERVOUS SYSTEM (CNS), THE EXTENT TO WHICH THESE NEURONS HELP ORCHESTRATE LUNG AND CNS FORMATION OVER THE COURSE OF DEVELOPMENT, AND THE ROLE THEY PLAY IN FUNCTION AT BIRTH REMAIN LARGELY UNKNOWN. THIS R01 APPLICATION PROPOSES TO ADDRESS THIS KNOWLEDGE GAP USING A NOVEL FETAL SHEEP MODEL. WE HYPOTHESIZE THAT INTRINSIC AND EXTRINSIC LUNG INTEROCEPTIVE UNITS PLAY A ROLE IN THE NORMAL DEVELOPMENT OF THE LUNG AND CENTRAL RESPIRATORY CONTROL CENTERS. WE WILL TEST THIS IN THE FOLLOWING AIMS: AIM 1: TRADITIONAL DYE AND NOVEL VIRAL TRACK TRACER TECHNIQUES WILL BE USED IN FETAL SHEEP AT VARIOUS STAGES OF LUNG DEVELOPMENT TO DELINEATE THE LOCATION AND CONNECTIVITY OF THE INTEROCEPTIVE UNITS WITHIN THE LUNG, AS WELL AS FIRST- AND SECOND-ORDER CENTRAL CIRCUITRY TO AND ABOVE THE BRAINSTEM. THE EFFECT OF SURGICAL DENERVATION ON LUNG DEVELOPMENTAL MORPHOLOGY AND THE PREVALENCE OF VARIOUS NEURAL POPULATIONS INVOLVED IN CHEMO- AND IRRITANT SENSATION, INCLUDING A- AND C-FIBER NEURONS INVOLVED IN BREATHING CONTROL, AND PULMONARY NEUROENDOCRINE CELLS INVOLVED IN PULMONARY MECHANO- AND CHEMOSENSATION. FINALLY, SINGLE NEURON RNASEQ WILL BE USED TO PHENOTYPICALLY CHARACTERIZE NEURONS WITHIN THE FETAL JUGULAR AND NODOSE GANGLIA AT VARIOUS STAGES OF DEVELOPMENT. AIM 2: TO TEST THE NECESSITY OF INTERROCEPTION ON FETAL LUNG DEVELOPMENT AND RESPIRATORY FUNCTION AFTER BIRTH, FETUSES IN THE CANALICULAR STAGE WILL BE SUBJECTED TO EITHER BILATERAL DENERVATION OF THE LUNGS OR PERIODIC HYPERSTIMULATION OF MECHANORECEPTORS VIA OVERINFLATION FOR THE REMAINDER OF GESTATION. PULMONARY VASCULAR FUNCTION, AIRWAY MECHANICS, AND GAS EXCHANGE WILL THEN BE MONITORED FOLLOWING C-SECTION DELIVERY AND IN RESPONSE TO ACUTE HYPOXIA AND METHACHOLINE CHALLENGES, AND RESPONSES WILL BE COMPARED TO BOTH SHAM AND NAIVE CONTROLS. AIM 3: VAGAL ASCENDING AND DESCENDING NERVE TRAFFIC WILL BE RECORDED IN FETUSES INSTRUMENTED WITH STATE-OF-THE-ART CUFF ELECTRODES THROUGHOUT FETAL DEVELOPMENT AND AT BIRTH. CUSTOM TIME-SERIES AND SPECTRAL ANALYSIS SOFTWARE WILL BE USED TO QUANTIFY CHANGES IN AFFERENT/EFFERENT VAGAL NERVE SIGNALING IN RESPONSE TO PULMONARY DENERVATION, BIRTH, AND MECHANO- AND CHEMOSENSORY STIMULATIONS. THE OUTCOMES OF THESE STUDIES WILL FILL IN CRITICAL KNOWLEDGE GAPS OF THE ROLE OF INTEROCEPTION IN LUNG DEVELOPMENT AND FUNCTION IN A SHEEP MODEL THAT HAS BEEN A HISTORICALLY SIGNATURE MODEL OF HUMAN PERINATAL LUNG DEVELOPMENT AND PHYSIOLOGY. OUR PROPOSED FOUNDATIONAL WORK WILL INFORM FUTURE EFFORTS FOCUSED ON A VARIETY OF LUNG DISEASES IN HUMANS THAT ORIGINATE DURING DEVELOPMENT, SUCH AS BRONCHOPULMONARY DYSPLASIA, APNEA OF PREMATURITY, SUDDEN INFANT DEATH SYNDROME, AND ASTHMA.

ADVANCED NURSING EDUCATION WORKFORCE

COMMUNITY BASED DENTAL PARTNERSHIP

LARGE SCALE SINGLE-CELL GENE REARRANGEMENT DETECTION WITH A MICROFLUIDIC DEVICE

COOPERATIVE RESEARCH IN PROTON SPACE RADIATIONPROGRAMMATIC ALIGNMENTTHE NASA-LLU COLLABORATION IS

HIGHLY INNOVATIVE TACTICS TO INTERRUPT TRANSMISSION OF HIV (HIT-IT)

MATERNAL INHALED NICOTINE LEADS TO ABERRANT DEVELOPMENT OF HYPERTENSIVE PHENOTYPE

THE SPACEFLIGHT ENVIRONMENT INFLUENCES IMMUNE CELL DISTRIBUTION, EX VIVO RESPONSES TO ANTIGEN, AND CYTOKINE EXPRESSION. HOWEVER, FEW STUDIES HAVE CHA

SYNCHROTRON-BASED SCANNING RESEARCH AND BIOLOGIC EFFECTS MODULATED BY VARIOUS SCANNING TECHNIQUES

LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

NEW; TITLE: LOW DOSE IONIZING RADIATION MODULATES IMMUNE FUNCTION; PI: GREGORY NELSON

ADVANCED NURSING EDUCATION GRANTS

NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING

PEDIATRIC TBI AND DAI: NORMAL APPEARING BRAIN IS NOT NORMAL

TRANSLATING PROTON CT FROM THE PHYSICS LABORATORY TO CLINICAL APPLICATION

TARGETING CRLF2 AND IKAROS ALTERATIONS TO REDUCE HEALTH DISPARITIES IN CHILDHOOD LEUKEMIA

MECHANISMS FOR ADAPTATION TO OXIDATIVE STRESS IN PORPHYROMONAS GINGIVALIS

NOVEL NEUROVASCULAR PROTECTIVE MECHANISMS OF PEDF AFTER SUBARACHNOID HEMORRHAGE - ABSTRACT  ANEURYSMAL  SUBARACHNOID  HEMORRHAGE  (SAH)  IS  A  DEVASTATING  TYPE  OF  HEMORRHAGIC  STROKE  WITH  50%  MORTALITY AND LONG-­TERM MORBIDITY IN SURVIVING PATIENTS.1-­4 RECENTLY, THE FOCUS OF SAH RESEARCH HAS BEEN SHIFTED  TO EARLY BRAIN  INJURY  (EBI)  WHICH  COMPRISES THE ACUTE  INITIAL  EVENTS AFTER  SAH,  SUCH  AS  ELEVATION  OF  INTRACRANIAL  PRESSURE  (ICP),  GLOBAL  ISCHEMIA,  BLOOD  BRAIN  BARRIER  (BBB)  DISRUPTION,  BRAIN  EDEMA  FORMATION,  NEURONAL  APOPTOSIS,  ACTIVATION  OF  INFLAMMATORY  AND  CELL  DEATH  PATHWAYS  THAT  CONTRIBUTE  TO  DELAYED  NEUROLOGICAL  DETERIORATION, LEADING TO MORTALITY AND MORBIDITY AFTER SAH.5-­8  PIGMENT-­EPITHELIUM  DERIVED  FACTOR  (PEDF)  IS  A  PLURIPOTENT  GLYCOPROTEIN  EXPRESSED  IN  VARIOUS  TISSUES  INCLUDING  THE  BRAIN.9,14  PEDF  REDUCED  APOPTOSIS  IN  VARIOUS  TYPES  OF  CELLS  INCLUDING  NEURONS,14,18  OSTEOBLASTS24  AND  CARDIOMYOCYTES.22  LIKEWISE,  PEDF  REDUCED  VASCULAR  PERMEABILITY  AND  MACULAR  EDEMA  IN  OPHTHALMOLOGIC  PATHOLOGIES.37,41  THERE  HAVE  BEEN  RELATIVELY  LIMITED  STUDIES  ON  THE  ROLE  OF  PEDF  FOLLOWING  STROKE.  PEDF  HAS  BEEN  SHOWN  TO  HAVE  PROTECTIVE  EFFECTS  ON  NEURONAL  CELL  SURVIVAL  IN  VITRO14,18  AND  ATTENUATED  CEREBRAL  ISCHEMIC  INJURY  IN  RODENT  MODELS.19-­21  PEDF  REDUCED  BRAIN  EDEMA  FOLLOWING  COLD-­INDUCED  INJURY  AND  TRANSIENT  CEREBRAL  ISCHEMIA  IN  RODENT  MODELS.20,21,42  HOWEVER,  THE  ROLE  OF  PEDF  FOLLOWING  SAH  HAS  NOT  BEEN  EXPLORED.  FURTHERMORE,  THE  NEUROVASCULAR  PROTECTIVE  MECHANISMS  OF  PEDF  HAVE  NOT  BEEN  STUDIED.  THIS  PROPOSAL  WILL  ELUCIDATE  THE  NEUROVASCULAR  PROTECTIVE  MECHANISMS  OF  PEDF  THROUGH  ANTI-­APOPTOTIC  AND  BBB  PROTECTIVE PATHWAYS IN A RODENT ENDOVASCULAR PERFORATION SAH MODEL. WE WILL SEQUENTIALLY DETERMINE THE  ROLE  OF  ENDOGENOUS  PEDF  AND  THEN  EVALUATE  THE  THERAPEUTIC  BENEFITS  OF  INTRANASAL  ADMINISTRATION  OF  RECOMBINANT PEDF AGAINST EARLY BRAIN INJURY AFTER SAH, SPECIFICALLY NEURONAL APOPTOSIS AND BBB DISRUPTION WILL  BE  EVALUATED.  ADDITIONALLY,  WE  WILL  ELUCIDATE  THE  DOWNSTREAM  SIGNALING  PATHWAYS  OF  PEDF  RECEPTOR  (PEDF-­R)  THAT CONTRIBUTE TO ANTI-­APOPTOTIC AND BBB PROTECTIVE MECHANISMS OF PEDF. WE PROPOSE THAT PEDF WILL ACTIVATE  PEDF-­R/NPD1/ERK1/2-­CREL  PATHWAY  THAT  REDUCES  NEURONAL  APOPTOSIS  WITH  INTRANASAL  RECOMBINANT  PEDF  ADMINISTRATION.  ALSO,  PEDF  ACTIVATION  OF  THE  PEDF-­R/NRF2/HO-­1  PATHWAY  WILL  CONTRIBUTE  TO  BBB  STABILIZATION  AFTER SAH. WE WILL KNOCKDOWN PEDF RECEPTOR AND INHIBIT THE PATHWAYS TO ELUCIDATE THE MECHANISM OF PEDF-­R  SIGNALING PATHWAY MEDIATED PROTECTION.    OVERALL,  THIS  PROPOSAL  WILL  PROVIDE  NOVEL  INSIGHTS  INTO  NEUROVASCULAR  PROTECTIVE  MECHANISMS  OF  PEDF.  ADDITIONALLY,  THIS  PROPOSAL  WILL  ESTABLISH  THE  PROTECTIVE  EFFICACY  OF  INTRANASAL  ADMINISTRATION  OF  PEDF  AS  A  POTENTIAL THERAPEUTIC TARGET AGAINST EARLY BRAIN INJURY AFTER SAH.

PRIMARY CARE TRAINING AND ENHANCEMENT - RESIDENCY TRAINING IN MENTAL AND BEHAVIORAL HEALTH

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

STUDIES ON THE VIRULENCE REGULATION IN PORPHYROMONAS

EPIGENETIC MECHANISMS OF DEVELOPMENTAL REGULATION OF FETAL, NEWBORN, AND ADULT CEREBRAL ARTERY SYMPATHETIC INNERVATION AND ALPHA1 ADRENERGIC RECEPTOR SUBTYPES

HARNESSING BLOOD CLOT CLEARANCE MECHANISMS AFTER GERMINAL MATRIX HEMORRHAGE - ABSTRACT GERMINAL MATRIX HEMORRHAGE (GMH) IS ONE OF THE LEADING CAUSES OF MORBIDITY, MORTALITY, AND ACQUIRED INFANTILE HYDROCEPHALUS IN PRETERM INFANTS IN THE UNITED STATES, WITH LITTLE PROGRESS MADE IN ITS CLINICAL MANAGEMENT. BLOOD CLOTS HAVE BEEN SHOWN TO ELICIT SECONDARY BRAIN INJURY AFTER GMH, BY DISRUPTING NORMAL CEREBROSPINAL FLUID CIRCULATION AND ABSORPTION AFTER GERMINAL MATRIX HEMORRHAGE CAUSING POST-HEMORRHAGIC HYDROCEPHALUS DEVELOPMENT. CURRENT EXPERIMENTAL EVIDENCE SUGGESTS THAT RAPID HEMATOMA RESOLUTION IS NECESSARY TO QUICKLY AMELIORATE INFLAMMATION AND IMPROVE NEUROLOGICAL OUTCOMES AFTER HEMORRHAGIC STROKE. N-FORMYL PEPTIDE RECEPTOR 2 (FPR2), A G-PROTEIN-COUPLED RECEPTOR, HAS BEEN SHOWN TO BE NEUROPROTECTIVE AFTER STROKE. FPR2 ACTIVATION HAS BEEN ASSOCIATED WITH THE UPREGULATION OF PHAGOCYTIC MACROPHAGE CLEARANCE, YET ITS MECHANISM HAS NOT BEEN FULLY EXPLORED. RECENT LITERATURE SUGGESTS THAT FPR2 MAY PLAY A ROLE IN THE STIMULATION OF SCAVENGER RECEPTOR CD36. SCAVENGER RECEPTOR CD36, A TRANS-MEMBRANE GLYCOPROTEIN, PLAYS A VITAL ROLE IN MICROGLIA PHAGOCYTIC BLOOD CLOT CLEARANCE AFTER GMH. FPR2 HAS BEEN SHOWN TO ACTIVATE EXTRACELLULAR-SIGNAL-REGULATED KINASE 1/2 (ERK1/2), WHICH PROMOTES THE TRANSCRIPTION OF THE DUAL-SPECIFICITY PROTEIN PHOSPHATASE 1 (DUSP1) GENE. CURRENT LITERATURE SUGGESTS THAT DUSP1 MAY ACT ON CD36 RECEPTOR AND MAY PLAY A ROLE IN FPR2 INDUCED PHAGOCYTOSIS. OUR PRELIMINARY SUGGESTS THAT FPR2 ACTIVATION ENHANCES HEMATOMA RESOLUTION AND IMPROVES NEUROLOGICAL DEFICITS. THEREFORE, WE SEEK TO ELUCIDATE THE UNDERLYING HEMATOMA RESOLVING MECHANISM OF FPR2. WE HYPOTHESIZE THAT FPR2 STIMULATION ENHANCES MICROGLIA INDUCED HEMATOMA RESOLUTION THROUGH THE ACTIVATION OF THE ERK (1/2)/DUSP1/CD36 SIGNALING PATHWAY, THEREBY IMPROVING SHORT- AND LONG-TERM NEUROLOGICAL OUTCOMES. AIM 1 WILL INVESTIGATE THE ROLE OF FPR2 IN ENHANCING HEMATOMA RESOLUTION, THEREBY IMPROVING NEUROLOGICAL FUNCTION FOLLOWING GMH. AIM 2 WILL INVESTIGATE FPR2-INDUCED ACTIVATION OF THE ERK/DUSP1/CD36 SIGNALING PATHWAY AFTER GMH. THE LONG-TERM GOAL OF THIS PROPOSAL IS TO PROVIDE A BASIS FOR CLINICAL TRANSLATION OF FPR2 STIMULATION AS AN EFFECTIVE NON-INVASIVE THERAPEUTIC STRATEGY TO PROTECT AGAINST ACUTE AND CHRONIC COMPLICATIONS IN THE GMH PATIENT POPULATION.

MECHANISMS OF HYPERBARIC OXYGEN INDUCED BRAIN PROTECTION

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM- AMERICAN RESCUE PLAN

EXPANSION OF PROTON FACILITIES AT LLU MEDICAL CENTER TO INCLUDE CYCLOTRON FOR DEVLOPING SHORT LIVED ISOTOPES FOR IMAGING PATIENT TARGETS

MOLECULAR CHARACTERISTICS OF TREATMENT-RESISTANT HIGH-RISK NEUROBLASTOMA

CEREBROVASCULAR ADRENERGIC-MEDIATED MECHANISMS

ROLE OF NITRITE AND HEMOGLOBIN IN VASCULAR NO HOMEOSTASIS IN THE FETUS AND ADULT

HYPOXIA AND ABERRANT UTERINE VASCULAR ADAPTATION IN PREGNANCY

STEROID HORMONES AND UTERINE VASCULAR ADAPTATION TO PREGNANCY

DEVELOPMENTAL PROGRAMMING OF ISCHEMIC-SENSITIVE PHENOTYPE IN THE HEART

ECF SIGMA FACTORS IN ADAPTATION AND VIRULENCE OF PORPHYROMONAS GINGIVALIS

AQP4 AND JNK INHIBITION TOGETHER REDUCE EDEMA AND EXCITOTOXIC INJURY IN JTBI

HARNESSING ENDOGENOUS NEUROPROTECTION FOLLOWING ICH

CROTALUS SNAKE VENOM PRECONDITIONING TO PREVENT SURGICAL BRAIN INJURY

THE PROTECTIVE EFFECTS OF C-TYPE NATRIURETIC PEPTIDE IN THE NEONATAL BRAIN

HARNESS GERMINAL MATRIX HEMORRHAGE

CEREBROSPINAL FLUID DYNAMICS IN POSTHEMORRHAGIC HYDROCEPHALUS IN NEONATES

PRIMARY CARE TRAINING AND ENHANCEMENT

MIRNA AS A NOVEL THERAPEUTIC TARGET IN ANTENATAL NICOTINE-INDUCED ISCHEMIC HEART

PREVENTIVE MEDICINE RESIDENCY

UTERINE ARTERIAL SPONTANEOUS TRANSIENT OUTWARD CURRENTS IN PREGNANCY

EPIGENETIC MECHANISMS OF UTERINE VASCULAR ADAPTATION TO PREGNANCY AND HYPOXIA

NEUROVASCULAR PROTECTION FOR EARLY BRAIN INJURY AFTER SAH

SENSING, SIGNALING AND THE ROLE OF AER-2-REGULATED CHEMOSENSORY SYSTEMS

ER STRESS AND NEONATAL HYPOXIA ISCHEMIA ENCEPHALOPATHY

STUDIES ON VIRULENCE REGULATION IN PORPHYROMONAS

CENTERS FOR PUBLIC HEALTH PREPAREDNESS

PUBLIC HEALTH SCHOLARSHIP PROGRAM - ADDRESS: 24951 N. CIRCLE DR. LOMA LINDA, CA 92350-0001 PHONE: 909-558-4578 EMAIL: SPHDEAN@LLU.EDU WEBSITE: HTTPS://PUBLICHEALTH.LLU.EDU/ FUNDS REQUESTED: $1,500,000 OVER 3 YEARS OVERVIEW: THE LOMA LINDA UNIVERSITY SCHOOL OF PUBLIC HEALTH, STACR PROJECT WILL PROVIDE EDUCATIONAL SCHOLARSHIPS TO QUALIFIED APPLICANTS TO TRAIN IN SELECTED CERTIFICATE AND MASTER'S DEGREE PROGRAMS. PROJECT DESCRIPTION: THE OVERALL GOAL OF THE STACR PROJECT IS TO INCREASE THE CAPACITY OF PUBLIC HEALTH SYSTEMS IN THE INLAND SOUTHERN CALIFORNIA REGION (IMPERIAL COUNTY, RIVERSIDE COUNTY, AND SAN BERNARDINO COUNTY), BY PROVIDING EDUCATIONAL SCHOLARSHIPS TO QUALIFIED APPLICANTS TO TRAIN IN SELECTED PUBLIC HEALTH DEGREES. THE PROJECT WILL COLLABORATE WITH INLAND SOUTHERN CALIFORNIA PUBLIC HEALTH AGENCIES TO CREATE STRATEGIES AROUND TRAINING OPPORTUNITIES AND EMPLOYMENT AFTER GRADUATION. THE PROJECT WILL RECRUIT QUALIFIED TRAINEES FROM INLAND SOUTHERN CALIFORNIA PUBLIC HEALTH AGENCIES TO RECEIVE SCHOLARSHIPS. POTENTIAL STUDENTS MAY APPLY FOR A CERTIFICATE PROGRAM IN HEALTH GEOINFORMATICS OR HEALTH AND WELLNESS COACHING, OR FOR A MASTER'S DEGREE PROGRAM IN EPIDEMIOLOGY, GLOBAL HEALTH, HEALTH-CARE ADMINISTRATION, HEALTH EDUCATION AND WELLNESS COACHING, NUTRITION, OR POPULATION MEDICINE. WITHIN EACH OF THESE PROGRAMS, STUDENTS WILL TAKE CLASSES TO LEARN ABOUT PUBLIC HEALTH INEQUITIES AND HEALTH DISPARITIES, SOCIAL DETERMINANTS OF HEALTH, AND CULTURAL COMPETENCE. IN ADDITION TO COURSEWORK, EACH STUDENT WILL HAVE A FIELD EXPERIENCE AT A PUBLIC HEALTH AGENCY TO LEARN HOW TO PREVENT, PREPARE FOR, AND RESPOND TO PUBLIC HEALTH EMERGENCIES. THE SCHOLARSHIP WILL PARTIALLY OR FULLY COVER THE COST OF TUITION, REGISTRATION AND COURSE FEES, AND OTHER EDUCATIONAL EXPENSES. ONE-HUNDRED PERCENT (100%) OF THE GRANT PROGRAM FUNDS REQUESTED GO TOWARD STUDENT SCHOLARSHIPS. PROJECT OBJECTIVE 1: ENHANCE THE KNOWLEDGE AND SKILLS OF THE PUBLIC HEALTH WORKFORCE BY DEVELOPING OR STRENGTHENI NG COMMUNITY PARTNERSHIPS AND LINKAGES TO IDENTIFY EMPLOYMENT NEEDS, TRAINING OPPORTUNITIES, AND TO FACILITATE SCHOLARSHIP RECIPIENTS' EMPLOYMENT POST TRAINING COMPLETION IN STATE OR LOCAL GOVERNMENTS, INCLUDING STATE, LOCAL, TERRITORIAL OR TRIBAL PUBLIC HEALTH DEPARTMENTS, AND OTHER PUBLIC HEALTH-RELATED ORGANIZATIONS. PROJECT OBJECTIVE 2: EDUCATE THE PUBLIC HEALTH WORKFORCE TO ADDRESS PUBLIC HEALTH INEQUITIES AND HEALTH DISPARITIES AND INCORPORATE PRINCIPLES OF SOCIAL DETERMINANTS OF HEALTH (SDOH) INTO PRACTICE. PROJECT OBJECTIVE 3: EDUCATE THE PUBLIC HEALTH WORKFORCE TO PREVENT, PREPARE FOR, AND RESPOND TO RECOVERY ACTIVITIES RELATED TO COVID-19, AS WELL AS OTHER PUBLIC HEALTH EMERGENCIES, BY PROVIDING PUBLIC HEALTH FIELD EXPERIENCE (PRACTICUM) OPPORTUNITIES. PROJECTED NUMBER OF TRAINEES: THE STACR PROJECT ANTICIPATES THAT 20 TRAINEES IN CERTIFICATE PROGRAMS AND 10 TRAINEES IN MASTER'S DEGREE PROGRAMS WILL BE AWARDED SCHOLARSHIPS EACH YEAR OF THE GRANT. OVER 3 YEARS, THE PROJECT ANTICIPATES THAT 60 TRAINEES IN CERTIFICATE PROGRAMS AND 30 TRAINEES IN MASTER'S DEGREE PROGRAMS WILL BE AWARDED SCHOLARSHIPS.

LEPTIN AND HYPOTHALAMO-PITUITARY-ADRENAL FUNCTION IN THE LONG-TERM HYPOXIC FETUS

MECHANISMS OF EPO-INDUCED NEUROPROTECTION

CEREBROVASCULAR MYOSIN LIGHT CHAIN PHOSPHORYLATION IN FETUS, NEWBORN, AND ADULT

MATERNAL HYPOXIA AND PROGRAMMING OF FETAL HEART

TRAINING CAMPUS INFRAST.

BUILDING GIS CAPACITY INTO TOBACCO CONTROL RESEARCH PROGRAMS OF EAST ASIA

RESEARCH TO TREAT CANCEROUS BRAIN TUMORS USING NEURAL STEM CELLS

PROSPECT: PREMALIGNANT ORAL LESIONS PATHOLOGY AND EPIGENETIC RISK PREDICTION TOOL - ABSTRACT THIS APPLICATION VALIDATES A MINIMALLY INVASIVE, MULTI-STAGE ARTIFICIAL INTELLIGENCE (AI)-BASED CYTOLOGIC, HISTOLOGIC AND EPIGENETIC BIOMARKER TO IDENTIFY ORAL PREMALIGNANT LESIONS (OPL) WITH HIGH RISK OF PROGRESSION TO ORAL CAVITY SQUAMOUS CELL CARCINOMA (OSCC), USING A MASSIVE EXISTING DATA SET AND A PROSPECTIVE STUDY IN RACIALLY AND SOCIOECONOMICALLY DIVERSE OPL PATIENTS. OSCC PATIENTS SUFFER FROM A 5-YEAR MORTALITY RATE OF 40%, ACCOUNTING FOR ONE DEATH PER HOUR. UP TO 10% OF THE U.S. POPULATION HAS ORAL LESIONS, OF WHICH A SMALL PROPORTION ARE HIGH-RISK OPLS THAT TRANSFORM TO OSCC. MAJOR CHALLENGES EXIST IN MONITORING AND RISK STRATIFYING THESE OPLS. WHILE GRADE IS USED TO RECOMMEND TREATMENT, ITS PROGNOSTIC VALUE IS LOW. THERE IS CURRENTLY NO RELIABLE CLINICAL, HISTOLOGIC OR MOLECULAR MARKER TO DETERMINE INDIVIDUAL RISK IN PATIENTS WITH THE SAME DYSPLASIA GRADE. THE QUALITY OF OPL GRADING IN HEMATOXYLIN EOSIN (HE) STAINED SLIDES IS BASED ON THE AVAILABILITY OF A SURGEON AND PATHOLOGIST, TYPICALLY ABSENT IN RESOURCE-CONSTRAINED LOCATIONS. CURRENTLY, NONINVASIVE SAMPLING THAT CAN BE USED IN SETTINGS WITH RESTRICTED ACCESS TO CARE, HAVE NOT BEEN VALIDATED TO REPLACE TISSUE DIAGNOSIS. HEREIN WE DESIGN A STAGED APPROACH TO DIAGNOSING AND MONITORING OPLS, USING CYTOLOGY, HISTOLOGY, AND EPIGENOMICS IN A STEP-WISE FASHION IN ORDER TO MINIMIZE DIAGNOSTIC INVASIVENESS. OUR APPROACH WILL AUTOMATE AND IMPROVE PROGNOSTICATION OF OPL RISK BY USING DEEP LEARNING. OUR CENTRAL HYPOTHESIS IS THAT HISTOLOGIC AND MOLECULAR PATTERNS WITHIN OPLS CAN BE RISK-STRATIFIED USING DEEP LEARNING TO INDIVIDUALIZE PROGNOSIS IN PATIENTS WITH THE SAME APPARENT OPL GRADE. WE TEST OUR HYPOTHESIS THROUGH A SERIES OF SCIENTIFIC AIMS, WHICH TAKEN TOGETHER, CREATE A PARADIGM SHIFT IN MANAGEMENT OF OPLS BY ESTABLISHING A LAYERED STRATEGY THAT ESCALATES THE COMPLEXITY OF THE DIAGNOSTIC TEST (FROM BRUSH SWABS TO SURGICAL BIOPSY) WITH ESCALATING CANCER RISK. OUR STUDY PROCEEDS WITH THE FOLLOWING 3 AIMS. 1) TRAIN DEEP LEARNING BASED DIGITAL PATHOLOGY MODELS FOR ORAL PREMALIGNANT LESION PROGRESSION RISK PREDICTION. WE WILL USE A LONGITUDINAL COHORT WITH KNOWN CANCER OUTCOMES TO TRAIN DEEP LEARNING MODELS USING CYTOLOGY AND HISTOLOGY, RESPECTIVELY, TO PREDICT RISK OF PROGRESSION TO OSCC. 2) VALIDATE AND MERGE CYTOLOGY AND HISTOLOGY WITH EPIGENOMIC SIGNATURES TO CREATE THE MULTI-STAGE, MULTI-MODAL PROSPECT SCORE USING MULTIPLE COHORTS. WE WILL REFINE THE DIGITAL CYTOLOGY AND HISTOLOGY BIOMARKERS IN A SEPARATE EXISTING VALIDATION COHORT WITH KNOWN CANCER OUTCOMES. NEXT, WE WILL USE BRUSH SWABS TO PREDICT BIOLOGICALLY RELEVANT EPIGENOMIC ALTERATIONS IN THE TRANSITION FROM OPL TO OSCC. WE WILL CREATE THE PROSPECT SCORE (PREMALIGNANT ORAL LESIONS PATHOLOGY AND EPIGENETIC RISK PREDICTION TOOL), WHICH IS A RISK SCORE THAT COMBINES THE CYTOLOGIC, HISTOLOGIC, AND EPIGENETIC SCORES SEQUENTIALLY WITH CLINICAL INFORMATION TO PREDICT RISK OF CANCER PROGRESSION. 3) TEST THE PROSPECT SCORE IN A PROSPECTIVE, MULTI-INSTITUTIONAL CLINICAL STUDY OF OPL PATIENTS ENROLLED IN GEOGRAPHICALLY AND RACIALLY DIVERSE POPULATIONS. WE WILL REFINE OUR PROSPECT SCORE TO PERFORM ROBUSTLY IN BRUSH BIOPSIES AND TISSUES FROM A SEPARATE PROSPECTIVE COHORT OF OPL PATIENTS, WHICH WILL BE RECRUITED DURING THE COURSE OF THIS STUDY FROM FOUR CLINICAL SITES, WHERE THE PATIENT POPULATIONS POSSESS DIVERSITY IN RACE, SOCIOECONOMICS, AND HEALTH DISPARITIES INDICES. TESTING OF THE PROSPECT SCORE IN THIS PROSPECTIVE COHORT WILL SET THE STAGE FOR A LARGE-SCALE CLINICAL STUDY TO USE NON-INVASIVE BRUSH SWABS TO MONITOR OPL WITH HIGHER ACCURACY THAN CURRENT CLINICAL STANDARDS.

MATERNAL HEALTH RESEARCH NETWORK (MH-RN) FOR MSIS--RESEARCH AWARDS

COMP-ANG1: VASCULAR NORMALIZATION AND NEUROPROTECTION FOR DIABETIC RETINOPATHY

GENERAL DESCRIPTION OF EXPERIMENT PROTOCOL: DESCRIBE IN GENERAL TERMS THE TYPES OF PROCEDURES REQUIRED FOR THE EXPERIMENT FROM PREPARATION OF THE EX

SENSORY TRANSDUCTION IN BACTERIA

UNDERSTANDING NEURONAL AND AXONAL DEGENERATION IN A MURINE MODEL OF HUMAN MS

MECHANISMS OF G-CSF-INDUCED NEUROPROTECTION

NEONATAL BRAIN ISCHEMIA: NEUROIMAGING AS A BASIS FOR RATIONAL STEM CELL THERAPY

ADDICTION MEDICINE FELLOWSHIP - THE LOMA LINDA UNIVERSITY HEALTH EDUCATION CONSORTIUM ADDICTION MEDICINE FELLOWSHIP (AMF) AIMS TO ADDRESS THE URGENT NEED FOR HIGHLY TRAINED ADDICTION MEDICINE SPECIALISTS TO SERVE AND LEAD IN MEDICALLY UNDERSERVED AND RURAL COMMUNITIES THROUGH THE INNOVATIVE NETWORKS AND SPECIALIZED PROGRAMS FOR INTEGRATED RECOVERY EDUCATION (INSPIRE) PROGRAM. SUBSTANCE USE DISORDERS (SUDS), PARTICULARLY OPIOID USE DISORDER (OUD), CONTINUE TO HAVE DEVASTATING EFFECTS ON VULNERABLE POPULATIONS, EXACERBATING HEALTH DISPARITIES AND STRAINING HEALTHCARE SYSTEMS. DESPITE THE DEMAND FOR SPECIALIZED ADDICTION CARE, THERE IS A NATIONWIDE SHORTAGE OF TRAINED PROFESSIONALS, PARTICULARLY IN RURAL AND UNDERSERVED REGIONS. IN RESPONSE TO THIS NEED, THE INSPIRE PROGRAM WILL INCREASE THE NUMBER OF PHYSICIANS WHO ARE BOARD-CERTIFIED SPECIALISTS IN ADDICTION MEDICINE WHO SERVE IN MEDICALLY UNDERSERVED COMMUNITY-BASED SETTINGS, INCLUDING RURAL AREAS BY: INCREASING THE NUMBER OF ADDICTION MEDICINE SPECIALISTS TRAINED TO PRACTICE IN MEDICALLY UNDERSERVED COMMUNITY-BASED SETTINGS, INCLUDING RURAL AREAS, THAT INTEGRATE PRIMARY CARE WITH MENTAL HEALTH AND SUD PREVENTION AND TREATMENT SERVICES. INCREASING FELLOWS' KNOWLEDGE AND ABILITY TO ASSIST THEIR PATIENTS WITH REFERRALS TO NAVIGATE THE LEGAL AND SOCIAL SYSTEMS RELATED TO PATIENTS' CLINICAL NEEDS OR CARE. INCREASING AWARENESS OF ADDICTION MEDICINE AS A SUB-SPECIALTY AND REDUCE PROVIDER STIGMA TO INCREASE THE NUMBER OF PHYSICIANS INTERESTED IN PURSUING CAREERS IN ADDICTION MEDICINE AND ADDICTION PSYCHIATRY THROUGH THE PROVISION OF CLINICAL ROTATIONS THAT EXPOSE MEDICAL RESIDENTS TO PRACTICE IN THESE SPECIALTIES AND THROUGH EDUCATION AND CONSULTATION. THE PROGRAM WILL TRAIN A TOTAL OF 28 FELLOWS (18 GRANT-FUNDED FELLOWS) OVER 5 YEARS. FELLOWS WILL NOT ONLY GAIN HANDS-ON EXPERIENCE IN INPATIENT, OUTPATIENT, CORRECTIONAL, AND STREET MEDICINE SETTINGS, BUT WILL ALSO LEARN HOW TO LEAD HEALTHCARE TEAMS AND GUIDE SYSTEMS-LEVEL CHANGES. KEY PROGRAM COMPONENTS INCLUDE ENHANCING DEPTH OF TRAINING IN A STREET MEDICINE ROTATION AND A RURAL ROTATION TRACK, INTERDISCIPLINARY COLLABORATION ON INPATIENT AND OUTPATIENT TEAMS, AND TARGETED MENTORSHIP IN PROGRAM PLANNING, SCHOLARLY ACTIVITY AND CAREER PLANNING AS FELLOWS TRANSITION INTO LEADERSHIP ROLES. THE POPULATIONS SERVED BY THIS INITIATIVE INCLUDE RURAL AND MEDICALLY UNDERSERVED COMMUNITIES IN SAN BERNARDINO COUNTY, CALIFORNIA, WHERE HEALTHCARE ACCESS IS LIMITED, AND THE BURDEN OF ADDICTION IS DISPROPORTIONATELY HIGH. WITH THE INSPIRE PROGRAM, THE AMF IS COMMITTED TO DEVELOPING A SUSTAINABLE WORKFORCE PIPELINE, ENSURING THAT A SIGNIFICANT PERCENTAGE OF GRADUATES CONTINUE WORKING IN SHORTAGE AREAS POST-TRAINING. REQUEST FOR FUNDING PRIORITY: GIVEN OUR EXISTING ROTATION IN AN UNDERSERVED AND DESIGNATED RURAL FACILITY, WE REQUEST FUNDING PRIORITY #3 UNDER THE NOFO GUIDELINES. THE EXPANSION OF THIS FELLOWSHIP WILL DIRECTLY CONTRIBUTE TO WORKFORCE DEVELOPMENT IN HIGH-NEED AREAS, ENSURING THAT MORE INDIVIDUALS WITH SUDS RECEIVE TIMELY, HIGH-QUALITY, AND EVIDENCE-BASED CARE.

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM - OVERVIEW: THE AMERICAN PSYCHOLOGICAL ASSOCIATION-ACCREDITED CLINICAL PSYCHOLOGY PSYD AND PHD DOCTORAL PROGRAMS AT LOMA LINDA UNIVERSITY, SCHOOL OF BEHAVIORAL HEALTH WILL PARTICIPATE IN THE TIP-TAP-E PROJECT (A CONTINUATION AND EXPANSION OF AN EXPIRING BHWET-PRO FUNDED PROGRAM) BY: (1) RECRUITING, SUPPORTING, AND TRAINING A DIVERSE WORKFORCE PREPARED FOR PEDIATRIC INTEGRATED CARE SETTINGS INCLUDING THE DEVELOPMENT AND ENHANCEMENT OF 10 PRACTICUM PLACEMENTS PER YEAR IN HIGH NEED, HIGH DEMAND SETTINGS, (2) INCREASING THE NUMBER AND QUALITY OF CLINICAL SUPERVISORS, AND (3) ENHANCING INTERPROFESSIONAL TRAINING FOR STUDENTS, FACULTY, AND SUPERVISORS. THESE TRAINING PROGRAMS QUALIFY FOR A FUNDING PREFERENCE BY PLACING 53.3% OF GRADUATES IN MUCS IN THE PAST TWO YEARS TO DEMONSTRATE THE ABILITY TO CREATE A PIPELINE OF TRAINEES APPROPRIATE FOR THE BHWET-PRO PROGRAM. OBJECTIVES: THE TIP-TAP-E PROGRAM WILL: (1) ENHANCE OUR RECRUITMENT, MENTORING, AND POST-GRADUATION SUPPORT OF RACIALLY AND LINGUISTICALLY DIVERSE TRAINEES THROUGH SPECIFIC RECRUITMENT EFFORTS AT OUR NEARBY HISPANIC-SERVING INSTITUTIONS AND ONGOING PARTNERSHIPS WITH MINORITY EDUCATION INITIATIVES. ONGOING SUPPORT WILL OCCUR VIA INDIVIDUAL AND GROUP MENTORING, PARTICIPATION IN A CHILD-FOCUSED COLLOQUIUM, AND THE DEVELOPMENT OF A SPANISH CONSULTATION GROUP. TEN INTEGRATED BEHAVIORAL HEALTH PRACTICUM SLOTS PER YEAR WILL BE DEVELOPED OR ENHANCED AT A PEDIATRIC PRIMARY CARE CLINIC LOCATED IN AN FQHC, A CERTIFIED SCHOOL-BASED HEALTH CENTER LOCATED IN A CONTINUATION HIGH SCHOOL, AND A PEDIATRIC SPECIALTY MEDICAL CLINIC, ALL WITH HPSA/MPSA SCORES GREATER THAN OR EQUAL TO 17. SENIOR TRAINEES WILL CONDUCT TRAUMA-INFORMED ASSESSMENT, CONSULTATION, AND TREATMENT IN-PERSON AND VIA TELEHEALTH TO DRAMATICALLY IMPROVE THE HEALTH DISPARITIES IN THIS HIGH-NEED POPULATION; (2) RECRUIT, DEVELOP, AND EXPAND THE CAPACITY TO TRAIN CLINICAL SUPERVISORS BY RECRUITING HIGHLY TRAINED CLINICAL SUPERVISORS, ENHANCING SUPERVISION TRAINING WITH A FOCUS ON CULTURALLY RESPONSIVE SUPERVISION, AND DEVELOPING A SUPERVISION TRAINING PIPELINE PROGRAM FOR OUR GRADUATE STUDENTS THAT INCLUDES DIDACTIC AND EXPERIENTIAL OPPORTUNITIES TO PROVIDE PEER SUPERVISION; AND (3) IMPROVE TRAINEE, SUPERVISOR, AND FACULTY EDUCATION BY DEVELOPING NEW INTERPROFESSIONAL TRAINING OPPORTUNITIES, ENGAGING IN QUALITY IMPROVEMENT, AND ESTABLISHING COLLABORATIVE RELATIONSHIPS WITH OTHER BHWET-PRO RECIPIENTS TO LEVERAGE RESOURCES AND ENHANCE INTERPROFESSIONAL TRAINING. SUMMARY: TIP-TAP-E WILL CONTINUE TO IMPROVE THE QUALITY OF AND ACCESS TO INTEGRATED BEHAVIORAL HEALTH SERVICES THROUGH THE DEVELOPMENT OF MENTORING, DIDACTIC, SIMULATION, AND EXPERIENTIAL TRAINING OPPORTUNITIES FOR DIVERSE TRAINEES. THROUGH PROGRAM DEVELOPMENT AND PRACTICUM EXPANSION, WE WILL INCREASE THE SUPPLY OF HIGHLY TRAINED PSYCHOLOGISTS WITH SPECIALIZED SKILLS IN WORKING WITH CHILDREN, ADOLESCENTS, AND FAMILIES IN INTEGRATED CARE SETTINGS. OUR PROGRAM EMPHASIZES INTERPROFESSIONAL, TEAM-BASED MODELS OF CARE DELIVERED BY A DIVERSE WORKFORCE THAT REFLECTS THE DEMOGRAPHIC MAKE-UP OF OUR UNDERSERVED, HIGH-NEED COMMUNITY.

RESIDENCY TRAINING IN PRIMARY CARE

FUNCTIONAL DECLINE IN MICE WITH ALZHEIMER'S-TYPE NEURODEGENERATION IS ACCELERATED BY CHARGE-PARTICLE RADIATION AN UNAVOIDABLE COMPLICATION OF SPACE

NSL - BACCALAUREATE NURSING - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

CHALLENGES TO ASTRONAUT HEALTH CAUSED BY SPACEFLIGHT-RELEVANT STRESSORS WILL IMPACT SIGNALING PATHWAYS BETWEEN SYSTEMS ULTIMATELY LEADING TO DEGENERATIVE CHANGES AS HOMEOSTASIS IS IMPAIRED. FOR EXAMPLE CHANGES IN THE MICROBIAL ENVIRONMENT CAN RESULT IN DRAMATIC CHANGES IN VARIOUS INTERNAL AND EXTERNAL MICROBIOMES. BOTH PSYCHOLOGICAL AND PHYSIOLOGICAL STRESS ACTIVATES THE SYMPATHETIC NERVOUS SYSTEM (SNS) AND INITIATES WIDE-RANGING PHYSIOLOGIC CHANGES. THESE CHANGES HAVE SERIOUS IMPLICATIONS ON IMMUNE FUNCTION AND THE ACTIVATION OF INFLAMMATORY PATHWAYS. WE PROPOSE TO USE CENTRIFUGATION TO CHARACTERIZE THE IMPACT OF CHRONIC CHANGES IN THE GRAVITATIONAL ENVIRONMENT ON CROSS-SYSTEM COMMUNICATION. .WE HYPOTHESIZE THAT HYPER-GRAVITY INDUCED CHANGES IN GUT MICROBIOME SNS FUNCTION AND INFLAMMATORY ACTIVITY LEAD TO A BREAKDOWN IN THE COMMUNICATION BETWEEN DISTINCT PHYSIOLOGICAL SYSTEMS (AS MEASURED BY CHANGES IN CARDIOPULMONARY CONTROL); AND THAT THESE RESPONSES DEPEND ON THE GRAVITATIONAL ENVIRONMENT. FURTHERMORE WE PROPOSE THAT THESE GRAVITY-DEPENDENT DEFICITS CAN BE COUNTERED BY A COMBINATION OF PREBIOTIC NUTRITIONAL SUPPLEMENTS THAT ARE KNOWN TO PREFERENTIALLY EXPAND STRESS PROTECTIVE BACTERIAL SPECIES..SPECIFIC AIMS .SPECIFIC AIM 1. CONFIRM THAT CENTRIFUGATION RESULTS IN DETECTABLE CHANGES IN GUT MICROBIOME AS WELL AS IN SYMPATHETIC AND INFLAMMATORY ACTIVITY INDICATIVE OF INCREASED HEALTH RISK. MICE WILL BE PLACED ON THE 8 FT DIAMETER CENTRIFUGE AT AMES RESEARCH CENTER AND EXPOSED TO 1.5 OR 2 G FOR 4 WEEKS. AFTER CENTRIFUGATION ADRENAL GLANDS BLOOD LIVER SPLEEN AND INTESTINES WILL BE COLLECTED AND ASSESSED FOR CHANGES IN SYMPATHETIC AND INFLAMMATORY ACTIVITY AS WELL AS FOR CHANGES IN MICROBIOME AS COMPARED TO MATCHED 1 G CONTROLS. .SPECIFIC AIM 2. CONFIRM THAT PROLONGED EXPOSURE TO HYPER-GRAVITY LEADS TO A BREAKDOWN IN COMMUNICATION BETWEEN DISTINCT PHYSIOLOGICAL SYSTEMS CAUSING DECREMENTS IN FUNCTION. THE SAME MICE USED IN AIM 1 WILL BE USED HERE. OUR MODEL FOCUSES ON BRAINSTEM CONTROL OF CARDIOPULMONARY FUNCTION DRIVEN PRIMARILY BY SYMPATHETIC/VAGAL INNERVATION. THE BRAINSTEM SPINAL CORD HEART AND LUNGS WILL BE COLLECTED. ANALYSIS WILL FOCUS SPECIFICALLY ON THE NUCLEUS TRACTUS SOLITARII (NTS) THE FIRST-ORDER INTEGRATIVE SITE FOR VAGAL AFFERENTS PROJECTING FROM THE GUT HEART AND LUNGS TO THE CENTRAL NERVOUS SYSTEM. THE NTS COORDINATES EFFERENT OUTPUT TO TARGETS THAT ARE CRITICAL FOR THE CONTROL OF BREATHING HEART/VASCULATURE AND GUT. IN VIVO AND IN VITRO ELECTROPHYSIOLOGY WILL BE USED TO QUANTIFY CHANGES IN SYMPATHETIC TONE AND CONFIRM THAT SYNAPTIC ACTIVITY WITHIN THE NTS IS ALTERED BY CHANGES IN MICROBIOME. IMMUNOHISTOCHEMISTRY AND RNASEQ WILL BE USED TO ASSESS CHANGES IN INFLAMMATION AND STRESS-RELATED MESSAGE ALLOWING US TO DETERMINE THE ROLE CYTOKINES AND DOWNSTREAM EFFECTORS PLAY IN MODULATING NTS NEURONAL ACTIVITY CORRELATED WITH CARDIORESPIRATORY CONTROL. .SPECIFIC AIM 3. DETERMINE THAT CENTRIFUGATION-INDUCED CHANGES IN HEALTH STATUS SIGNALING ARE LINKED TO CHANGES IN MICROBIOME. BASED ON OUR PREVIOUS FINDINGS WE HYPOTHESIZE THAT INGESTION OF A PREBIOTIC SUPPLEMENT BLEND [GALACTOOLIGOSACCHARIDES (GOS) + POLYDEXTROSE (PDX) + LACTOFERRIN + MILK FAT GLOBULE MEMBRANE PROTEIN (MFGMP)] WILL BOTH PREVENT GUT MICROBIAL DYSBIOSIS PRODUCED BY CENTRIFUGATION AND INCREASE SELECTIVE STRESS PROTECTIVE GUT BACTERIA (I.E. LACTOBACILLUS AND BIFIDOBACTERIA). PREBIOTIC-ENRICHED CHOW OR CALORICALLY MATCHED CHOW WILL BE AVAILABLE AD LIBITUM THROUGHOUT THE EXPERIMENT STARTING 1 WEEK PRIOR TO CENTRIFUGATION. MICE WILL BE PLACED ON THE 8 FT DIAMETER CENTRIFUGE AT AMES RESEARCH CENTER AND EXPOSED TO 2 G FOR 4 WEEKS. PARAMETERS DESCRIBED IN AIMS 1&2 WILL BE ASSESSED AS DESCRIBED. .

SL - DENTISTRY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

NEUROVASCULAR PROTECTION FOR SUBARACHNOID HEMORRHAGE

THE CELL GENE EXPRESSION AND FUNCTION IN RESPONSE TO LOW DOSE AND ACUTE RADIATION

THE CONTRIBUTION OF TISSUE LEVEL ORGANIZATION TO GENOMIC STABILITY FOLLOWING LOW DOSE/LOW DOSE RATE GAMMA AND PROTON IRRADIATION

MRI: ACQUISITION OF A MULTIPHOTON CONFOCAL MICROSCOPE FOR RESEARCH, TRAINING AND TEACHING

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - THE INCREASING ACCESS TO HEALTHCARE IN COACHELLA VALLEY PHASE 1 TOTAL PROJECT COST IS $2.3 MILLION. LOMA LINDA UNIVERSITY (LLU) IS REQUESTING $1 MILLION FOR EQUIPMENT AND FURNITURE TO COMPLETE PHASE 1. THE REMAINING $1.3 MILLION NEEDED TO COMPLETE THE RENOVATION OF THE GROUND FLOOR OF THE EXISTING BUILDING WILL BE PROVIDED BY LLU AND SAC HEALTH. BOTH LLU AND SAC HEALTH HAVE COMMITTED $650,000 EACH, TOTALING $1.3 MILLION TO ENSURE COMPLETION OF PHASE 1.

TARGETED STEM CELL-GENE THERAPY FOR INFLAMMATORY BRAIN DISEASE

PRIMARY CARE TRAINING AND ENHANCEMENT

BEHAVIORAL HEALTH WORKFORCE EDUCATION AND TRAINING PROGRAM

IMPLEMENTATION OF SUBSTANCE USE AND HIV PREVENTION NAVIGATION FOR EMERGENCY DEPARTMENT LATINO AND AFRICAN AMERICAN PATIENTS - A RURAL LEVEL 1 TRAUMA CENTER ED SERVING TWO EHE COUNTIES WILL HIRE A PEER NAVIGATOR TO IDENTIFY LATINO PATIENTS WITH SUD-RELATED HIV RISK AND LINK THEM TO CARE. ELIGIBLE PATIENTS WILL BE IDENTIFIED IN THE EHR THROUGH AUTOMATED ALERTS SENT TO THE NAVIGATOR'S PAGER. THE NAVIGATOR WILL APPROACH THESE PATIENTS DURING TRIAGE, ASSIST THEM IN COMPLETING SELF-SCREENING, REVIEW THE RESULTS, AND OFFER HIV AND HCV TESTING. POST-TEST COUNSELING WILL BE PROVIDED, ALONG WITH APPROPRIATE REFERRALS. TO ENSURE LINKAGE TO CARE, ENAVIGATION SERVICES WILL BE OFFERED VIA TEXT MESSAGING. AS OF 2018, AN ESTIMATED 18% OF ALL HIV CASES REMAIN UNDIAGNOSED IN THE INLAND EMPIRE, COMPRISED OF SAN BERNARDINO AND RIVERSIDE EHE PRIORITY COUNTIES. THESE HIGH RATES OF PLWH WHO ARE UNAWARE OF THEIR HIV SEROSTATUS ARE SIGNIFICANT DRIVERS OF HIV INFECTION IN THE REGION, WITH 80% OF NEW HIV INFECTIONS TRACED TO UNDIAGNOSED OR OUT-OF-CARE INDIVIDUALS. EMERGENCY DEPARTMENTS (EDS) PLAY A CRUCIAL ROLE IN PROVIDING HEALTHCARE ACCESS FOR INDIVIDUALS AT RISK OF OR LIVING WITH UNDIAGNOSED HIV, PARTICULARLY IN MEDICALLY UNDERSERVED AREAS. EXPANDING HIV SCREENING IN EDS IS A KEY STRATEGY RECOMMENDED BY LOCAL PUBLIC HEALTH DEPARTMENTS. THE LOMA LINDA UNIVERSITY (LLU) ED, THE SOLE LEVEL 1 TRAUMA CENTER IN THE INLAND EMPIRE, RECEIVES 85,000 ANNUAL VISITS, YET IT LACKS AN IMPLEMENTED HIV SCREENING PROCESS. AN INTERNAL REVIEW SUGGESTS THIS ABSENCE RESULTS IN MISSED HIV DIAGNOSES (~48 CASES) AND MISSED REFERRALS TO THE LLU PREP CLINIC (~132 CASES) EACH YEAR. THE REVIEW IDENTIFIED BARRIERS TO HIV TESTING, INCLUDING LIMITED STAFF CAPACITY FOR PRE/POST-TEST COUNSELING, A LACK OF CULTURAL COMPETENCY TO ADDRESS THE RISING HIV DIAGNOSES AMONG THE LATINO POPULATION, ESPECIALLY LATINO MSM (REPRESENTING 79% OF NEW HIV DIAGNOSES AMONG NON-WHITE INDIVIDUALS AND 69% AMONG MSM). ADDITIONALLY, HIGH RATES OF HIV TEST REFUSALS AMONG MINORITY PATIENTS, THE FAILURE TO ADDRESS HIV RISKS RELATED TO SUBSTANCE USE (CONTRIBUTING TO ONE IN THREE SEROCONVERSIONS IN THE REGION), AND THE LACK OF COORDINATION BETWEEN HIV AND SUD SERVICES WITHIN THE ED WERE IDENTIFIED AS CHALLENGES. TO ADDRESS THESE GAPS, THE PROJECT AIMS TO IMPLEMENT AN EFFECTIVE HIV SCREENING PROCESS TAILORED TO THE SPECIFIC NEEDS OF LATINO MSM AND MSM WITH SUD IN THE LLU ED. THE PROJECT WILL USE AN EXISTING COMPUTER-BASED SELF-SCREENING INTERVENTION TO IDENTIFY LATINO ED PATIENTS WITH SUD-RELATED HIV RISKS. LATINO ED PATIENTS OFTEN REFUSE HIV TESTING DUE TO FEARS OF THE STIGMA ASSOCIATED WITH AN HIV DIAGNOSIS, DISCUSSIONS ABOUT HIV RISK, OR BEING PERCEIVED AS MSM. BY USING A COMPUTER-BASED SELF-SCREENING INTERVENTION, THIS PROJECT AIMS TO DISCREETLY ADDRESS BARRIERS TO HIV TESTING, EFFECTIVELY REDUCING REFUSAL RATES AND ADDRESSING CULTURAL COMPETENCY CONCERNS WHEN ELICITING SENSITIVE INFORMATION. THE SELF-SCREENING TOOL USED IN THIS INTERVENTION ENCOMPASSES MEASURES FOR BOTH HIV AND SUD RISKS, THUS ENABLING THE IDENTIFICATION AND COORDINATION OF SERVICES FOR SUD-RELATED HIV RISK WITHIN THE ED. FURTHERMORE, THE IMPLEMENTATION OF THIS INTERVENTION WILL BE FACILITATED BY COMMUNITY HEALTH WORKERS (CHWS) TRAINED AS HIV TEST COUNSELORS. THESE LATINO CHWS WILL PROVIDE RAPID HIV/HCV TESTS TO AT-RISK PATIENTS, DELIVER REQUIRED POST-TEST COUNSELING, AND ENSURE LINKAGE TO APPROPRIATE RESOURCES AND CARE. THIS PROJECT ADDRESSES THE LOCALLY DEFINED HIV PREVENTION NEEDS BY EXPANDING HIV SCREENING WITHIN EDS. THE SCREENING APPROACH IS DESIGNED TO BE CULTURALLY AND LINGUISTICALLY APPROPRIATE, ENSURING THAT IT EFFECTIVELY REACHES AND ENGAGES LATINO PATIENTS. RECOGNIZING THE SIGNIFICANT ROLE OF SUBSTANCE USE IN DRIVING HIV TRANSMISSION AMONG THIS POPULATION IN THE AREA, THE PROJECT SPECIFICALLY TARGETS AND ADDRESSES THIS ISSUE. IMPORTANTLY, THE PROJECT BUILDS UPON THE RESOURCES AND SUCCESSES OF A PREVIOUSLY FUNDED EHE DEMONSTRATION PROJECT, OPTIMIZING THE UTILIZATION OF EXISTING INFRASTRUCTURE AND ORGANIZATIONAL EXPERTISE.

NUTRITION DIET AND LIFESTYLE RESEARCH FOR LONGEVITY AND HEALTHY AGING

CLINICAL STUDY TO EVALUATE THE METHYLATION SIGNATURE OF HEAD AND NECK SQUAMOUS CELL CARCINOMA PAIN - ABSTRACT THE PROPOSED RESEARCH AND CAREER DEVELOPMENT PLAN HAVE BEEN DESIGNED TO FACILITATE MY PATH TOWARD BECOMING AN INDEPENDENT SURGEON SCIENTIST FOCUSED ON HIGHLY TRANSLATIONAL HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) RESEARCH. I HAVE DEVOTED MY EARLY RESEARCH CAREER TO EXPLORING EPIGENETIC MECHANISMS (I.E., DNA METHYLATION) OF HNSCC PAIN, AN AREA OF RESEARCH THAT HAS OTHERWISE GONE UNNOTICED. THIS PROPOSAL BUILDS ON MY PREVIOUS RESEARCH IN WHICH I DETERMINE THAT HYPERMETHYLATION OF PAIN-MEDIATING GENES CONTRIBUTE TO HNSCC PAIN IN PATIENTS, AND THAT HYPOMETHYLATING AGENTS TREAT HNSCC PAIN. THE CAREER DEVELOPMENT PLAN IS CAREFULLY STRUCTURED TO HONE MY EXPERTISE IN CLINICAL RESEARCH THROUGH A SERIES OF COURSES, NATIONAL MEETINGS, AND MEETINGS WITH MY MENTORSHIP TEAM. UPON COMPLETION OF THE K23, I WILL BE WELL-PREPARED TO APPLY FOR INDEPENDENT RESEARCH FUNDING THROUGH AN R01 MECHANISM, WHICH WILL SUPPORT MY TRANSLATIONAL RESEARCH PROGRAM FOCUSED ON TREATMENTS FOR HEAD AND NECK CANCER PAIN. IN THIS PROPOSAL I TAKE A SYSTEMATIC APPROACH TO IDENTIFY GENES THAT ARE METHYLATED IN PATIENTS WITH SEVERE HNSCC PAIN. IN AIM 1 I PROSPECTIVELY ENROLL HNSCC PATIENTS, QUANTIFY THEIR PAIN LEVELS WITH VALIDATED PAIN QUESTIONNAIRES, AND COLLECT THEIR CANCER TISSUE FOR ANALYSIS WITH A GENOME-WIDE METHYLATION ARRAY. I WILL ANALYZE THE METHYLATION DATA AND IDENTIFY A SUITE OF HYPERMETHYLATED GENES IN PATIENTS WITH SEVERE PAIN. I HAVE PROVEN FEASIBILITY OF THIS APPROACH THROUGH PRELIMINARY STUDIES, IN WHICH I USED EXISTING METHYLATION DATA IN HNSCC PATIENTS TO IDENTIFY A LIST OF HYPERMETHYLATED GENES. MANY OF THESE GENES HAVE NOT PREVIOUSLY BEEN ASSOCIATED WITH PAIN PROCESSING. IN AIM 2, I FOCUS ON ONE HYPERMETHYLATED GENE AND DETERMINE WHETHER ADENOVIRUS THERAPY TO RE-EXPRESS THE GENE PRODUCES ANTINOCICEPTION IN THE PRECLINICAL MODEL. THE PROJECT IS IMPACTFUL BECAUSE IT EXPLORES A PAIN MECHANISM THAT IS LARGELY UNKNOWN. THE RESULTS WILL ESTABLISH THE METHYLATION SIGNATURE OF HNSCC PAIN. THESE GENES COULD BE TARGETED WITH EITHER GENE THERAPY OR HYPOMETHYLATING AGENTS TO TREAT HNSCC PAIN, OFFERING NON-OPIOID ALTERNATIVES AND MAKING THE RESEARCH CLINICALLY RELEVANT, ESPECIALLY WITH THE CURRENT OPIOID CRISIS. MY MENTORSHIP AND ADVISORY TEAM IS COMPRISED OF INDIVIDUALS WHO HAVE EXPERT KNOWLEDGE IN ALL ASPECTS OF TRANSLATIONAL AND CLINICAL RESEARCH, SPECIFICALLY IN THE AREAS OF CANCER, PAIN, BIOINFORMATICS, AND DRUG DISCOVERY, ALL OF WHICH ARE CRITICAL FOR THE PROPOSED RESEARCH. I RECEIVE PROTECTED TIME, LABORATORY SPACE, START-UP FUNDING, AND PERSONNEL SUPPORT. THE CAREER DEVELOPMENT PLAN AND PROPOSED RESEARCH WILL BRING ME CLOSER TO REALIZING MY CAREER GOAL OF DEVELOPING HIGHLY EFFECTIVE TREATMENTS FOR HEAD AND NECK CANCER PAIN.

PRENATAL COCAINE EXPOSURE AND CARDIAC PROGRAMMING

NON-HUMAN PRIMATE MODELS FOR HUMAN XENOTRANSPLANTATION

EFFECTS OF CHRONIC HYPOXIA ON CEREBRAL BLOOD FLOW AUTOREGULATION IN THE NEWBORN. - PROJECT SUMMARY CEREBRAL AUTOREGULATION (CA) IS A VITAL PHYSIOLOGICAL MECHANISM THAT ENSURES STABLE CEREBRAL BLOOD FLOW (CBF) DESPITE FLUCTUATIONS IN SYSTEMIC BLOOD PRESSURE. IN THE NEWBORN, ESPECIALLY DURING THE PERINATAL PERIOD, FAILURE OF CA IS STRONGLY ASSOCIATED WITH DEVASTATING BRAIN INJURIES SUCH AS INTRAVENTRICULAR HEMORRHAGE (IVH) AND PERIVENTRICULAR LEUKOMALACIA (PVL), LEADING TO LIFELONG NEURODEVELOPMENTAL IMPAIRMENTS. DESPITE THE CLINICAL SIGNIFICANCE OF IMPAIRED CA, THE UNDERLYING MOLECULAR MECHANISMS, PARTICULARLY IN THE CONTEXT OF PERINATAL HYPOXIA, ARE POORLY UNDERSTOOD. THIS PROPOSAL AIMS TO DEFINE THE ROLE OF THE MECHANOSENSITIVE CATION CHANNEL TRPC6 AND ITS DOWNSTREAM TARGET, THE VOLTAGE-SENSITIVE L-TYPE CAV1.2 CA²⁺ CHANNEL (CAV1.2), IN MEDIATING THE MYOGENIC COMPONENT OF CA IN THE NEWBORN BRAIN. PRELIMINARY FINDINGS SUGGEST THAT TRPC6 CHANNELS ARE ESSENTIAL FOR PRESSURE-INDUCED VASOCONSTRICTION IN CEREBRAL ARTERIES OF NEWBORN RODENTS AND LAMBS. THE PROJECT FURTHER INVESTIGATES HOW CHRONIC PERINATAL HYPOXIA IMPAIRS THIS MECHANISM, WITH A FOCUS ON THE EPIGENETIC REGULATOR MICRORNA-210 (MIR210), A KNOWN HYPOXIA-INDUCED MOLECULE THAT MAY SUPPRESS TRPC6 EXPRESSION AND ENHANCE MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, BOTH OF WHICH COULD DISRUPT CA. USING A CLINICALLY RELEVANT NEWBORN LAMB MODEL, THE PROPOSED RESEARCH WILL: (1) DEFINE THE CONTRIBUTIONS OF TRPC6 AND CAV1.2 CHANNELS TO CA IN VIVO AND IN VITRO; (2) CHARACTERIZE HOW CHRONIC PERINATAL HYPOXIA DISRUPTS THIS PATHWAY; AND (3) DETERMINE THE ROLE OF MIR210 AND MITOCHONDRIAL ROS IN MEDIATING HYPOXIA-INDUCED IMPAIRMENT OF CA. BY INTEGRATING MOLECULAR, CELLULAR, AND WHOLE-ANIMAL APPROACHES, THIS STUDY WILL ADVANCE UNDERSTANDING OF THE PHYSIOLOGICAL MECHANISMS UNDERLYING NEONATAL CA AND THEIR DISRUPTION BY HYPOXIA. THE LONG-TERM GOAL IS TO IDENTIFY NOVEL THERAPEUTIC TARGETS TO PRESERVE OR RESTORE CA IN VULNERABLE NEONATES, THEREBY REDUCING THE INCIDENCE OF HYPOXIA-RELATED BRAIN INJURY AND IMPROVING NEURODEVELOPMENTAL OUTCOMES.

ACADEMIC ADMINISTRATIVE UNITS IN PRIMARY CARE

NEUROPATHOLOGICAL SIGNATURES CONNECTING EARLY-LIFE TRAUMA TO COMPULSIVE EATING BEHAVIOR AND OBESITY

RURAL RESIDENCY PLANNING AND DEVELOPMENT PROGRAM - ELIGIBLE ENTITY/FACILITY TYPE (E.G., RURAL HOSPITAL, REFER TO SECTION III.1 ELIGIBLE ENTITIES): SCHOOL OF ALLOPATHIC MEDICINE, RURAL HOSPITAL, RURAL COMMUNITY-BASED AMBULATORY PATIENT CARE CENTER, FAITH-BASED ORGANIZATION -PROJECT DIRECTOR (PD) NAME & CONTACT INFORMATION: KEVIN SHANNON MD, KSHANNON@LLU.EDU, (603) 785-9558 -RESIDENCY PROGRAM DIRECTOR NAME & CONTACT INFORMATION (IF APPLICABLE): JAMIE SNYDER, MD, JASNYDER@LLU.EDU (402) 440-4499 -PROGRAM PATHWAY (SELECT ONE): GENERAL PRIMARY CARE AND HIGH-NEED SPECIALTY -RESIDENCY SPECIALTY AREA: PSYCHIATRY -RESIDENCY FORMAT (SELECT ONE): RURAL TRACK PROGRAM EXPANSION -SPONSORING INSTITUTION ORGANIZATION & LOCATION: LOMA LINDA UNIVERSITY HEALTH EDUCATION CONSORTIUM, LOMA LINDA, CA -RURAL TARGET AREA (S): BIG BEAR AND BARSTOW, CA -FUNDING AMOUNT REQUESTED $750,000 -PROGRAM SUSTAINABILITY OPTION: OPTIONS 1 AND 6 -PROJECTED TOTAL NUMBER OF RESIDENTS AT CAPACITY PGY1-2, PGY2-2, PGY3-2, PG4-2 TOTALING 8 RESIDENTS -EXPECTED ACGME ACCREDITATION AND RESIDENCY MATRICULATION DATES: ESTABLISHED PROGRAM IS ACGME ACCREDITED: RESIDENT MATRICULATION: 7/28 THE LLUHEC PSYCHIATRY RURAL RESIDENCY TRACK PROGRAM IS TARGETING THE RURAL COMMUNITIES OF BEAR VALLEY AND BARSTOW, CA. BIG BEAR VALLEY IS AT 6,750 FEET ELEVATION IN THE SAN BERNARDINO MOUNTAINS, AND BARSTOW IS LOCATED IN THE VAST MOJAVE DESERT. BOTH ARE IN SAN BERNARDINO COUNTY, CA-THE LARGEST COUNTY IN THE CONTIGUOUS UNITED STATES. BOTH REGIONS HAVE INSUFFICIENT PHYSICIANS TO CARE FOR THEIR POPULATIONS AND WILL CONTINUE TO LACK PSYCHIATRISTS, WITHOUT A CONCERTED EFFORT TO DEVELOP, IMPLEMENT, AND MANAGE A RURAL RESIDENCY TRACK. IN THIS GRANT THE LOMA LINDA UNIVERSITY HEALTH EDUCATION CONSORTIUM (LLUHEC) - COMPRISED OF LOMA LINDA UNIVERSITY HEALTH AND SAC HEALTH (AN FQHC WITH SITES IN FEDERAL OFFICE OF RURAL HEALTH PROGRAMS DESIGNATED RURAL COMMUNITIES), AND OTHER PARTNERS INTEND TO BUILD ON OUR SUCCESS OF CREATING A LARGE, VIBRANT AND SUCCESSFUL URBAN TEACHING HEALTH CENTER (HRSA THCGME PROGRAMS) AT SAC HEALTH TO ADDRESS THESE ISSUES IN RURAL PARTS OF OUR REGION WHERE SAC HEALTH ALREADY OPERATES CLINICS, OR PLANS TO DO SO, AND TO COLLABORATE WITH RURAL HOSPITALS IN BOTH RURAL COMMUNITIES. BY COMBINING THE RESOURCES OF AN ESTABLISHED FQHC WITH RURAL SITES, A SPONSORING ACADEMIC INSTITUTION, TWO RURAL HOSPITALS, A MANAGED MEDI-CAL (MEDICAID) PROVIDER, THE DEVELOPMENT OF INLAND EMPIRE TRAINING IN RURAL PSYCHIATRY (DIET-RP) COLLABORATIVE CAN DEMONSTRATE A FRAMEWORK OF PROVIDING OUTSTANDING GRADUATE MEDICAL EDUCATION WITHIN RURAL COMMUNITIES TO PHYSICIANS COMMITTED TO SERVING THERE. THE LLUHEC PSYCHIATRY RESIDENCY PROGRAM WILL ACHIEVE ACGME APPROVAL FOR EXPANSION FOR A NEW RURAL TRACK BY 6/2027 AND MATRICULATE THE FIRST TWO RESIDENTS BY 7/2028, ULTIMATELY TRAINING TWO RESIDENTS PER PGY YEAR FOR A TOTAL OF 8 RURAL TRACK RESIDENTS. LLUH HAS RECEIVED 22 GRANT AWARDS FROM HRSA OVER THE LAST 5 YEARS. GRANTS WERE AWARDED FOR TRAINING A22HP3100, T34HP42140, MC1HP42086, T2946706, TA2HP48941, 1M01HP52150 GRADUATE EDUCATION D40HP33349, D40HP33349 FELLOWSHIPS A22HP31001, T25HP37600 NURSE EDUCATION U4EHP39473 RESIDENCY D33HP49080, RRPD-P1349604 SCHOLARSHIPS T08HP39318, T5246764 CENTERS OF EXCELLENCE D34HP45725 COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING CE1HS46136, CE1HS46422, CE1HS52145 COMMUNITY BASED DENTAL PARTNERSHIP H65HA00004 MATERNAL HEALTH RESEARCH NETWORK UR6MC50347

RURAL RESIDENCY PLANNING AND DEVELOPMENT PROGRAM

ONE OF THE MAIN CONCERNS FOR LONG-TERM DEEP MANNED SPACE MISSIONS ARE HEALTH RISK ASSOCIATED WITH ALTERED GRAVITATIONAL ENVIRONMENT AND PROLONGED EXP

GREGORY NELSON / LOMA LINDA UNIVERSITYEPIGENETIC CONTROL OF RADIOGENIC DAMAGE PROCESSING IN C.ELEGAN

NEURAL BASIS OF SOCIAL COGNITION DEFICITS IN YOUTH WITH AUTISM AND SCHIZOPHRENIA

TREATING EBD CHILDREN IN FOSTER CARE-THE ROLE OF RESIDENTIAL GROUP CARE

IMPACT OF AGING ON CALCIUM AND ELECTRICAL SIGNALING IN MICROVASCULAR ENDOTHELIUM

SALT APPETITE & VASCULAR REMODELING IN FETAL ORIGIN

DENTAL FACULTY LOAN REPAYMENT

HEALTH CAREERS OPPORTUNITY PROGRAM (HCOP) SKILLS TRAINING AND HEALTH WORKFORCE DEVELOPMENT OF PAR

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - LOMA LINDA UNIVERSITY MEDICAL CENTER – MURRIETA (LLUMC-MURRIETA) IS REQUESTING $600,000 IN FEDERAL FUNDING TO FACILITATE THE INSTALLATION OF A MODULAR EMERGENCY OPERATIONS CENTER ON THE NORTH SIDE OF THE LLUMC-MURRIETA HOSPITAL. THIS EOC WOULD HELP LLUMC-MURRIETA BETTER SERVE THE COMMUNITY IN EMERGENCY SITUATIONS.

PFI: INTER-UNIVERSITY TECHNOLOGY BUNDLING PROJECT

BIOLOGICAL AND PSYCHOSOCIAL MANIFESTATIONS OF RELIGION

ACQUISITION OF A ZEISS LSM 900 CONFOCAL MICROSCOPE WITH AIRYSCAN 2 FOR AN IMAGING AND MICROSCOPY CORE - RESEARCH SUMMARY THIS GRANT PROPOSAL SEEKS FUNDING FOR A ZEISS LSM 900 LASER SCANNING CONFOCAL MICROSCOPE WITH AIRYSCAN 2 FOR NIH FUNDED INVESTIGATORS WHO USE THE ADVANCED IMAGING AND MICROSCOPY CORE FACILITY AT LOMA LINDA UNIVERSITY TO PERFORM BOTH HISTOCHEMICAL ANALYSES AND REAL-TIME IMAGING OF CELLS AND TISSUES. ON THE ONE HAND, THE SYSTEM WOULD BE USED TO LOCALIZE VARIOUS PROTEINS AND CELLS USING FLUORESCENT LABELING APPROACHES, WHILE ON THE OTHER IT WOULD BE USED TO EXAMINE THE ACTIVITY OF LIVING CELLS AND TISSUES. THESE TWO IMAGING TECHNOLOGIES ARE REQUIRED AS THE NIH FUNDED MAJOR AND MINOR USER GROUP HAS DIVERSE NEEDS. THEIR RESEARCH ENCOMPASSES CARDIOVASCULAR PHYSIOLOGY, PREGNANCY, DEVELOPMENT, NEUROBIOLOGY, NEUROENDOCRINOLOGY, CANCER BIOLOGY, RADIATION MEDICINE, REGENERATIVE MEDICINE, AND HEALTH DISPARITIES, BUT ALL HAVE COMMON INTERESTS IN MEASURING THE SPATIAL APPOSITION BETWEEN CELLS, CHANGES IN PROTEIN EXPRESSION, LOCALIZATION OF PROTEINS WITHIN CELLS, AND SPATIAL AND TEMPORAL SEQUENCES INVOLVED WITH CELL SIGNALING. THE RESEARCH RECORD OF THE USER GROUP IS EXCELLENT, REPRESENTING SOME OF THE MOST SUCCESSFUL INVESTIGATORS AT THE INSTITUTION. THE ZEISS LSM 900 CONFOCAL WOULD SUPPORT NUMEROUS NIH RESEARCH GRANTS AND INVESTIGATIVE PROGRAMS ACROSS CAMPUS AND TRAINING PROGRAMS. THE CORE FACILITY HAS TWO SHARED-USE CONFOCAL MICROSCOPES THAT ARE NEAR OR AT THEIR END OF FUNCTIONAL USE. ACQUISITION OF A ZEISS LSM 900 WITH A AIRYSCAN 2 WILL SOLVE THIS PRESSING ISSUE AND WILL ENABLE FUNDED RESEARCHERS TO CONTINUE THEIR STUDIES INCLUDING CELL SIGNALING, IN-SITU HYBRIDIZATION, PROTEIN EXPRESSION AND LOCALIZATION, CELL AND TISSUE MORPHOLOGY, INTERACTIONS BETWEEN MOLECULES AND PROTEINS, SPATIAL RECONSTRUCTION, SPATIAL-TEMPORAL RELATIONSHIPS, AND SUBCELLULAR TRANSPORT. THESE QUESTIONS REQUIRE THE ABILITY TO IMAGE SINGLE OR MULTIPLE FLUORESCENT PROBES IN EITHER FIXED OR LIVE PREPARATIONS. BASED ON THE NEEDS OF THE FUNDED PROJECTS, A ZEISS LSM 900 CONFOCAL MICROSCOPE IS AN IDEAL REPLACEMENT INSTRUMENT. THE INSTRUMENT HAS 2 HIGH-SENSITIVITY CONFOCAL CHANNELS FOR RECORDING FLUORESCENCE; ONE FOR TRANSMITTED LIGHT (DIC) AND HAS AN AIRYSCAN 2 UNIT FOR SUPER-RESOLUTION IMAGING ALONG WITH ADAPTIVE FOCUSING CAPABILITIES AND CAN PERFORM MOSAIC TILING FOR MULTIDIMENSIONAL RECONSTRUCTION. THE AIRYSCAN 2 WILL ALSO ALLOW FOR RAPID CONFOCAL IMAGING FOR SPATIAL AND TEMPORAL RECORDINGS OF CELL SIGNALING SYSTEMS, WHICH ARE KEY ASPECTS TO MULTIPLE AWARDS. THE ZEISS LSM 900 OFFERS A FULLY INTEGRATED SYSTEM AVAILABLE FOR THE WIDE BREADTH OF STUDIES OF THE USER GROUP AND WILL PROVIDE CONTINUITY WITH AN EXISTING MULTIPHOTON ZEISS 710 SYSTEM. THE INSTITUTION RECOGNIZES THE QUALITY OF THE FACILITY AND USER GROUP AND HAS STRONGLY SUPPORTED THE FACILITY FOR OVER A DECADE WITH FULL FUNDING FOR STAFFING, SUPPLIES, AND SERVICE CONTRACTS. THE PI HAS CONSIDERABLE EXPERIENCE WITH CONFOCAL MICROSCOPY AND WILL OVERSEE THE DAILY OPERATION OF THE INSTRUMENT AND BE PART OF A MULTIDISCIPLINARY INTERNAL ADVISORY COMMITTEE THAT OVERSEES THE CORE FACILITY. THE INSTRUMENT WILL BE HOUSED IN THE EXISTING AIM FACILITY, PROVIDING CONTINUED CONTEMPORARY INSTRUMENTATION FOR THIS HIGHLY USED SHARED-USE IMAGING CORE.

PRE-DOCTORAL TRAINING IN PRIMARY CARE

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

ADMINISTRATIVE DIVERSITY SUPPLEMENT TO: "ROLE AND THERANOSTICS POTENTIAL OF ENOLASE IN PROSTATE CANCER HEALTH DISPARITIES" - MEN OF AFRICAN ANCESTRY (AA) HAVE A HIGHER INCIDENCE AND MORTALITY FROM PROSTATE CANCER (PCA) THAN MEN OF EUROPEAN ANCESTRY (EA). THESE DISPARITIES ARE DRIVEN BY THE INTERPLAY BETWEEN SOCIOECONOMIC, LIFESTYLE, ENVIRONMENTAL, AND BIOLOGICAL/GENETIC FACTORS. GROWING EVIDENCE INDICATES THAT AA AND EA MEN HAVE DIFFERENCES IN THEIR PCA IMMUNOBIOLOGY RESULTING IN THE DIFFERENTIAL EXPRESSION OF INFLAMMATORY GENE PATHWAYS. THESE DIFFERENCES MAY IMPACT THE ANTI-TUMOR IMMUNE RESPONSE INCLUDING THE IMMUNE TARGETING OF CELL SURFACE TUMOR ASSOCIATED ANTIGENS (TAAS). THERE IS AN URGENCY TO UNDERSTAND THE MOLECULAR MECHANISMS UNDERLYING THESE RACE-RELATED DIFFERENCES AND TO HARNESS THEM FOR IDENTIFYING NOVEL THERAPEUTIC TARGETS. IN THIS MULTI-PI EXPLORATORY APPLICATION, WE PROPOSE TO INVESTIGATE DIFFERENCES IN ANTI-TUMOR AUTOANTIBODY RESPONSES TO THE GLYCOLYTIC ENZYME ENOLASE (ENO) IN AA AND EA MEN WITH PCA AND EXPLOIT THESE DIFFERENCES FOR GUIDING THE DEVELOPMENT OF SMALL MOLECULES TARGETING THIS PROTEIN AS NOVEL THERANOSTICS AGENTS FOR ADVANCED PCA. THE RATIONALE FOR THE PROPOSED STUDIES IS SUPPORTED BY SEVERAL KEY OBSERVATIONS: 1) ENO, PARTICULARLY THE ENO1 ISOFORM, IS EMERGING AS A CELL SURFACE TAA WITH CHARACTERISTICS OF AN IDEAL THERANOSTICS TARGET, WHEREAS THE ENO2 ISOFORM COULD BE A THERANOSTIC BIOMARKER FOR NEPC TUMORS; 2) AA AND EA MEN WITH PCA PRODUCE A DIFFERENTIAL AUTOANTIBODY RESPONSE TO ENO; 3) THIS RESPONSE HAS A DISTINCTIVE IMPACT ON THE MIGRATION OF CHEMORESISTANT PCA CELLS; 4) THE EXPRESSION OF ENO2, A CELL SURFACE NEPC MARKER, BUT NOT THAT OF ENO1, IS LOST IN PCA CELLS WITH NEPC MARKERS AS THEY TRANSITION TO TAXANE RESISTANCE; AND 5) WE HAVE INITIATED THE DESIGN AND CHARACTERIZATION OF NOVEL BORON- BASED ENO1-TARGETING SMALL MOLECULES THAT WILL BE EVALUATED FOR THEIR ANTITUMOR ACTIVITY AND THERANOSTICS POTENTIAL IN PRE-CLINICAL MODELS OF CHEMORESISTANT AA AND EA PCA. THESE OBSERVATIONS SUPPORT THE HYPOTHESIS THAT EA AND AA PATIENTS WITH PCA HAVE DISTINCTIVE IMMUNE RESPONSES TO ENO THAT DIFFERENTIALLY AFFECT TUMOR CELL PROPERTIES, AND THAT THESE RESPONSES MAY REVEAL TUMOR VULNERABILITIES THAT COULD BE EXPLOITED FOR THE DEVELOPMENT OF NOVEL PCA THERANOSTICS AGENTS. AIM 1 WILL DETERMINE THE MECHANISMS UNDERLYING THE DIFFERENTIAL REACTIVITY AND ANTITUMOR EFFECTS OF ANTI-ENO AUTOANTIBODIES IN AA AND EA MEN WITH PCA. AIM 2 WILL SYNTHESIZE AND FUNCTIONALLY CHARACTERIZE NOVEL BORON-BASED SMALL MOLECULE ENO1 COMPOUNDS AS POTENTIAL THERAPEUTICS FOR PCA. THE PROPOSED STUDY HAS HIGH RELEVANCE AS IT WILL UNCOVER THE BIOLOGICAL BASIS FOR THE RACE-RELATED DIFFERENTIAL ANTI- ENO IMMUNOREACTIVITY. THIS WILL PROVIDE KEY INSIGHTS INTO IMMUNE DETERMINANTS CONTRIBUTING TO PCA MORTALITY DISPARITIES. THE STUDY WILL ALSO ESTABLISH ENO AS A POTENTIAL THERANOSTIC TARGET FOR ADVANCED PCA, WHICH COULD LEAD TO INNOVATIVE CLINICAL STRATEGIES TO REDUCE OVERALL PCA MORTALITY AND ITS RACIAL DISPARITIES.

LDS - PHARMACY - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

LTQ-ORBITRAP-XL-ETD MASS SPECTROMETER FOR LLU MASS SPECTROMETRY FACILITY

NURSE EDUCATION PRACTICE QUALITY RETENTION SIMULATION EDUCATION TRAINING

CANCER EPIDEMIOLOGY IN ADVENTISTS--A LOW RISK GROUP

MENTAL HEALTH OUTREACH PROGRAM FOR THE SICKLE CELL COMMUNITY - THE LOMA LINDA UNIVERSITY SICKLE CELL CENTER (LLU-SCC) IS DEVELOPING AN EXPANSION OF OUR BEHAVIORAL HEALTH SERVICES TO INCLUDE A REGIONAL BEHAVIORAL HEALTH OUTREACH PROGRAM, COUPLED WITH A COORDINATED SYSTEM OF CARE TO PROVIDE WRAP-AROUND RESOURCES AND SERVICES LLU-SCC, LOMA LINDA UNIVERSITY SCHOOL OF BEHAVIORAL HEALTH, AND SAN MANUEL GATEWAY COLLEGE WILL COLLABORATE TO CREATE AN INTEGRATED BEHAVIORAL HEALTH CARE SYSTEM FOR SICKLE CELL DISEASE (SCD) / SICKLE CELL TRAIT (SCT) PATIENTS AND CAREGIVERS. COMMUNITY HEALTH WORKERS (CHWS), NAVIGATORS, AND BEHAVIORAL HEALTH PROFESSIONALS WILL DEVELOP A NETWORK OF RESOURCES AND BEHAVIORAL HEALTH SERVICES. TRAINING AND EDUCATION, COORDINATED BEHAVIORAL HEALTH SERVICES, AND OUTREACH AND ENGAGEMENT MAKE UP OUR PROGRAM. OUR PROGRAM WILL TRAIN CHWS AND NAVIGATORS, CONNECT PATIENTS AND CAREGIVERS TO MENTAL HEALTH SERVICES/RESOURCES USING A TIERED CARE APPROACH, AND INVOLVE HUGE SICKLE CELL COMMUNITIES. THIS COORDINATED STRATEGY WOULD EXPEDITE SCD PATIENTS' NEUROPSYCHOLOGICAL ASSESSMENT AND OTHER BEHAVIORAL HEALTH SERVICES, LOWERING BARRIERS TO CARE AND BOOSTING THIS VULNERABLE POPULATION'S WELL-BEING.

GLUCOCORTICOID SIGNALING, TAXANE RESISTANCE, AND PROSTATE CANCER MORTALITY DISPARITY

MATURATION OF CEREBROVASCULAR RELAXANT MECHANISMS

MINDFULNESS AND PARENT STRESS REDUCTION: IMPROVING OUTCOMES FOR CHILDREN WITH AUTISM SPECTRUM DISORDER

TARGETING KINASE INHIBITOR INDUCED SIGNALING PLASTICITY IN PATIENTS WITH PH-LIKE ALL - PROJECT SUMMARY MAJOR SCIENTIFIC AND THERAPEUTIC ADVANCES HAVE IMPROVED OUTCOMES OF PATIENTS WITH B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) OVER THE LAST FOUR DECADES. ADDITION OF ABL1 KINASE INHIBITORS TO CHEMOTHERAPY HAS SIGNIFICANTLY IMPROVED RELAPSE-FREE AND OVERALL SURVIVAL OF CHILDREN AND ADULTS WITH THE PHILADELPHIA CHROMOSOME POSITIVE (PH+) ALL SUBTYPE. THIS GREAT TREATMENT SUCCESS HAS BEEN ATTRIBUTED TO ONCOGENIC ADDICTION OF PH+ LEUKEMIAS TO BCR-ABL1-DRIVEN SIGNALING AND THE ABILITY OF ABL1 KINASE INHIBITORS TO INDUCE PROFOUND CYTOTOXICITY. PHILADELPHIA CHROMOSOME-LIKE (PH-LIKE) ALL IS AN ANALOGOUS HIGH-RISK LEUKEMIA SUBTYPE DRIVEN BY VARIOUS NON- BCR-ABL1 GENETIC LESIONS THAT SIMILARLY ACTIVATE ONCOGENIC KINASE SIGNALING. PH-LIKE B-ALL OCCURS IN 15-40% OF CHILDREN AND ADULTS WITH B-ALL AND IS ASSOCIATED WITH A PARTICULARLY HIGH RISK OF RELAPSE AND DEATH. WE IDENTIFIED CONSTITUTIVELY ACTIVATED JAK2/STAT5, PI3K AND B CELL RECEPTOR-LIKE (BCR) SIGNALING IN CRLF2-REARRANGED PH-LIKE ALL, WHICH CAN BE ABROGATED WITH JAK1/2 (RUXOLITINIB), PI3KD (IDELALISIB), AND SRC (DASATINIB) INHIBITION IN VITRO AND IN VIVO IN PRECLINICAL MODELS. HOWEVER, WHILE THE TRIPLE INHIBITION RESULTS IN COMPLETE CELL DEATH IN VITRO AND SIGNIFICANT DECREASE OF THE LEUKEMIA BURDEN OF MICE, WE DOUBT THAT THIS TREATMENT STRATEGY IS CLINICALLY TRANSLATABLE FOR PATIENTS GIVEN POTENTIAL FOR APPRECIABLE TOXICITY. WE THUS FOCUSED ON DISCOVERING VULNERABILITIES INDUCED BY JAK2-KINASE INHIBITION AND IDENTIFIED I) HIGH ACTIVITY OF SGK1, A MOLECULE KNOWN TO INDUCE DRUG RESISTANCE TO PI3K INHIBITORS IN PI3KA-MUTATED BREAST CANCER PATIENTS, II) COMPLETE INACTIVITY AND DOWNREGULATION OF PTPN6, A PHOSPHATASE KNOWN TO DOWNREGULATE JAK2, PI3K, AND BCR SIGNALING, AND III) ACCUMULATION OF DNA DAMAGE WITH JAK2 INHIBITION. WE HYPOTHESIZED THAT ACTIVATION OF SGK1 AND INACTIVATION OF PTPN6 ARE REQUIRED MECHANISMS TO OVERCOME JAK2 INHIBITOR-INDUCED SIGNALING INHIBITION. STRIKINGLY, OUR PRELIMINARY DATA DEMONSTRATED THAT TARGETING ACTIVATED SGK1 IN JAK2 INHIBITOR TREATED SAMPLES RESULTS IN POTENT IN VITRO CELL DEATH. FURTHERMORE, WE HYPOTHESIZED THAT THE JAK2-INHIBITOR INDUCED DNA-DAMAGE IS MEDIATED BY THE RAG ENDONUCLEASE COMPLEX, WHICH IS ACTIVATED DURING B CELL DIFFERENTIATION TO FORM THE BCR. IT HAS BEEN SHOWN THAT JAK2/STAT5 SIGNALING IS DOWNREGULATED IN DIFFERENTIATING B CELLS TO INDUCE A PROLIFERATION ARREST, WHICH PREVENTS CELLS FROM DYING FROM APOPTOSIS DURING V(D)J RECOMBINATION. OUR PRELIMINARY DATA DEMONSTRATE THAT WE CAN EXPLOIT THIS CONSERVED MECHANISM BY TARGETING THE DNA-DAMAGE RESPONSE MOLECULE CHK1 IN JAK2 INHIBITOR TREATED PH-LIKE ALL CELLS, WHICH MAY RESULT IN MASSIVE LEUKEMIC CELL DEATH DUE TO ACCUMULATION OF UNREPAIRED DNA DAMAGE. THE PROPOSED STUDY AIMS TO UNCOVER PREVIOUSLY UNKNOWN MECHANISMS OF DRUG RESISTANCE AND TO CHARACTERIZE THE UNDERLYING BIOLOGY OF PH-LIKE B-ALL CELLS TO ULTIMATELY ESTABLISH PRECLINICAL TREATMENT PROTOCOLS WITH THE GOAL TO PREVENT RELAPSE AND TO CURE PATIENTS WITH PH-LIKE B-ALL.

A NOVEL APP-DRIVEN MECHANISM OF NEUROPROTECTION IN ALZHEIMER'S DISEASE

RESIDENCY TRAINING IN PRIMARY CARE

MICRORNA210 AND NEUROINFLAMMATION IN ACUTE BRAIN INJURY OF ISCHEMIC STROKE - PROJECT SUMMARY LSCHEMIC STROKE IS THE MAJOR TYPE OF STROKE WITH HIGH MORTALITY AND MORBIDITY, AND THE HEALTH CARE COSTS ARE EXORBITANT AND RESULT IN A SIGNIFICANT SOCIETAL BURDEN. CURRENTLY ALTHOUGH LIMITED THERAPIES INCLUDING THROMBOLYSIS AND ENDOVASCULAR CLOT REMOVAL HAVE BEEN APPROVED FOR THE TREATMENT OF ACUTE ISCHEMIC BRAIN INJURY, MANY PATIENTS STILL DIE OR REMAIN DISABLED. UNDERLYING MECHANISMS REMAIN POORLY UNDERSTOOD, HINDERING THE DEVELOPMENT OF EFFECTIVE AND SPECIFIC TREATMENTS FOR THIS HEALTH CONCERN. THUS, THERE IS AN URGENT NEED TO FURTHER INVESTIGATE THE MOLECULAR MECHANISMS AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. NEUROINFLAMMATION IS A CRITICAL CONTRIBUTOR TO THE PATHOPHYSIOLOGY OF ACUTE ISCHEMIC BRAIN INJURY, IN WHICH MICROGLIAL ACTIVATION PLAYS A CENTRAL ROLE. WE HAVE RECENTLY DISCOVERED THAT MICRORNA210 (MIR210) INHIBITION SIGNIFICANTLY REDUCED BRAIN MICROGLIAL ACTIVATION AND INFLAMMATORY RESPONSE POST-STROKE IN MICE. OUR PRELIMINARY DATA ALSO SHOWED MIR210 MIMIC TRANSFECTION UPREGULATED PRO-INFLAMMATORY CYTOKINE IN PRIMARY MICROGLIA, AND MIR210 INHIBITION REDUCED THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE IL-1 F3 AFTER OXYGEN-GLUCOSE DEPRIVATION (OGD). THESE FINDINGS SUGGEST A NEW MECHANISM OF MIR210 IN MICROGLIAL INFLAMMATORY RESPONSE CONTRIBUTING TO ISCHEMIC BRAIN INJURY. THE MITOCHONDRIA ARE A MAJOR TARGET OF MIR210 DURING HYPOXIA AND REPROGRAMMING OF MITOCHONDRIAL METABOLIC SWITCH FROM OXIDATIVE PHOSPHORYLATION TO GLYCOLYSIS CONTRIBUTES TO PRO-INFLAMMATORY MICROGLIAL ACTIVATION. WE AND OTHERS HAVE DEMONSTRATED THAT MIR210 REDUCES MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION BY NEGATIVELY REGULATING A NUMBER OF ELECTRON TRANSPORT CHAIN (ETC)-RELATED GENES IN MULTIPLE CELLS AND INCREASES MITOCHONDRIAL DYSFUNCTION. HOWEVER, WHETHER MIR210 PROMOTES METABOLIC SHIFT IN HYPOXIC MITOCHONDRIAL RESPIRATION IN FAVOR OF GLYCOLYSIS AND DRIVES PRO-INFLAMMATORY MICROGLIAL RESPONSE IN THE SETTING OF STROKE IS UNKNOWN AND REQUIRES FURTHER INVESTIGATION. THUS, THIS PROPOSAL WILL ATTEMPT TO REVEAL THE MECHANISTIC LINKS OF METABOLIC REPROGRAMMING IN MIR210-MEDIATED PRO-INFLAMMATORY MICROGLIAL ACTIVATION IN ISCHEMIC BRAIN INJURY. WE WILL EVALUATE THE MECHANISM OF MIR210-MEDIATED MITOCHONDRIAL METABOLIC SHIFT IN PROGRAMMING OF PROINFLAMMATORY MICROGLIA AND NEUROTOXICITY. WE WILL ALSO DETERMINE WHETHER AND TO WHAT EXTENT MIR210 DEFICIENCY INHIBITS MICROGLIAL MITOCHONDRIAL DYSFUNCTION AND REDUCES NEUROINFLAMMATION AFTER ACUTE ISCHEMIC BRAIN INJURY. WE EXPECT TO GENERATE UNIQUE INSIGHTS INTO THE NOVEL ROLE OF EPIGENETIC MECHANISM IN THE ACTIVATION OF MICROGLIAL PRO-INFLAMMATORY PHENOTYPE THROUGH METABOLIC SHIFT IN THE BRAIN POST-STROKE. THE OUTCOME OF THIS STUDY WILL DELINEATE THE MECHANISM OF MIR210 IN DRIVING MICROGLIAL INFLAMMATORY RESPONSE. IT REPRESENTS A MAJOR BREAKTHROUGH AND PARADIGM-SHIFTING FOCUS OF RESEARCH AND WILL PROVIDE NEW VISIONS INTO A NOVEL TARGET OF MIR210 IN POTENTIAL THERAPEUTIC STRATEGIES FOR ACUTE ISCHEMIC BRAIN INJURY.

THE ROLE OF VENOUS IMPAIRMENT IN SUBARACHNOID HEMORRHAGE PATHOPHYSIOLOGY - ABSTRACT ANEURYSMAL SUBARACHNOID HEMORRHAGE (SAH) IS A SEVERE TYPE OF HEMORRHAGIC STROKE WITH OVERALL MORTALITY RATE OF 51% AND LONG-TERM MORBIDITY AMONG MORE THAN A THIRD OF SURVIVORS [1-3, 26, 27]. LARGE ARTERY VASOSPASM HAS BEEN THE FOCUS OF SAH RESEARCH FOR PAST 50 YEARS BUT PREVENTING VASOSPASM HAS NOT ALWAYS TRANSLATED INTO IMPROVED PATIENT OUTCOMES. THE CEREBRAL VENOUS CIRCULATION IS CRITICAL SINCE 70% OF THE CEREBRAL BLOOD VOLUME, WHICH CONSTITUTES APPROXIMATELY 6% OF BRAIN VOLUME UNDER NORMAL CONDITIONS, IS LOCATED IN VENOUS VASCULAR BED [15]. VARIATIONS IN CEREBRAL VENOUS DRAINAGE PATTERN, VENOUS OBSTRUCTION, STENOSIS OF INTERNAL JUGULAR VEINS, AND VENOUS SINUS MORPHOLOGICAL ANOMALIES ARE FREQUENTLY ENCOUNTERED WHICH CAN HAVE DIRECT IMPLICATIONS FOR SAH OUTCOMES. A CEREBRAL ANGIOGRAPHY SERIES STUDY SHOWED OVER 50% OF THOSE ANEURYSM CASES HAD BOTH ASYMMETRIC DURAL SINUSES AND SAH [10]. FURTHERMORE, PATIENTS WITH CEREBRAL VENOUS THROMBOSIS CAN PRESENT AS SAH [22, 23]. HOWEVER, THE ROLE OF CEREBRAL VENOUS CIRCULATION IN SAH PATHOPHYSIOLOGY HAS NOT BEEN EXPLORED. THIS PROPOSAL WILL ELUCIDATE THE ROLE OF CEREBRAL VENOUS IMPARIMENT IN SAH PATHOLOGY USING A NEW MOUSE MODEL OF SAH WITH IPSILATERAL JUGULAR VEIN OCCLUSION. WE HYPOTHESIZE THAT IMPAIRED CEREBRAL VENOUS DRAINAGE WILL LEAD TO CEREBROSPINAL FLUID (CSF) OUTFLOW OBSTRUCTION, INCREASE CEREBRAL VENOUS SINUS PRESSURE, AND PROMOTE CSF HYPERSECRETION WHICH WILL CAUSE AN ACUTE AND FATAL ELEVATION IN INTRACRANIAL PRESSURE (ICP) FOLLOWING SAH. WE WILL DEVELOP AND CHARACTERIZE A NEW MOUSE MODEL OF SAH WITH IPSILATERAL JUGULAR VENOUS OUTFLOW OBSTRUCTION AND DETERMINE THE OUTCOMES AFTER SAH. NEXT, WE WILL ELUCIDATE POTENTIAL MECHANISMS HOW IPSILATERAL VENOUS OBSTRUCTION INCREASES ICP AFTER SAH AND EXPLORE POTENTIAL STRATEGIES TO MANAGE INCREASED ICP AFTER SAH WITH IPSILATERAL JUGULAR VENOUS OCCLUSION IN THE NEW MOUSE MODEL. OVERALL, THIS PROPOSAL WILL PROVIDE A NEW PERSPECTIVE ON THE ROLE OF CEREBRAL VENOUS SYSTEM IN SAH PATHOPHYSIOLOGY WHICH CAN POTENTIALLY DISCOVER NEW THERAPEUTIC STRATEGIES FOR SAH PATIENTS.

THE PROTECTIVE FUNCTION OF BLOOD-BORNE MONOCYTES/MACROPHAGES AFTER DELAYED RECANALIZATION IN A PERMANENT MCAO RODENT MODEL - ABSTRACT ISCHEMIC STROKE, WHICH ACCOUNTS FOR 87% OF ALL STROKES, IS ASSOCIATED WITH HIGH MORTALITY AND DISABILITY RATES BRINGING A HEAVY BURDEN TO THE SOCIETY AND FAMILIES. FOCAL CEREBRAL ISCHEMIA, DUE TO LARGE VESSEL OCCLUSION (LVO) OF THE MIDDLE CEREBRAL ARTERY AND INTERNAL CAROTID ARTERY, ACCOUNTS FOR 40-50% ISCHEMIC STROKE PATIENTS. THROMBOLYTIC THERAPY HAS BEEN THE PREFERRED METHOD OF EARLY TREATMENT FOR PATIENTS WITH ISCHEMIC STROKE, HOWEVER, ONLY 15% OF THOSE PATIENTS ARE TREATED WITH RTPA AND 2.6-4% ARE TREATED WITH MECHANICAL EMBOLECTOMY. THIS LEAVES 88-98% OF STROKE PATIENTS WITH PERMANENT OCCLUSION WITHOUT TREATMENT OPTIONS. THE MAIN CHALLENGE IS THE NARROW THERAPEUTIC WINDOW BEYOND WHICH PATIENTS WITH ISCHEMIC STROKE ARE UNABLE TO RECEIVE TREATMENT. RECENT CLINICAL TRIALS HAVE PROMPTED CHANGES IN TREATMENT GUIDELINES, WHICH NOW SUGGEST RECANALIZATION CAN BE PERFORMED UP TO 24 HOURS AFTER STROKE IN SELECT PATIENTS. FURTHERMORE, THERE IS EVIDENCE FROM SEVERAL CLINICAL STUDIES AND CASE REPORTS SHOWING THAT DELAYED RECANALIZATION EVEN 3 DAYS OR LATER AFTER SYMPTOM ONSET CAN IMPROVE CLINICAL OUTCOMES IN ISCHEMIC STROKE PATIENTS. HOWEVER, RECANALIZATION BEYOND 24 HOURS IS NOT ROUTINELY PRACTICED, WHICH WE PROPOSE TO STUDY. WE WILL FOCUS ON THE PATHOLOGICAL AND NEUROLOGICAL OUTCOMES AFTER DELAYED RECANALIZATION USING A CLINICALLY RELEVANT RAT MODEL OF PERMANENT MIDDLE CEREBRAL ARTERY OCCLUSION (PMCAO). OUR COROLLARY HYPOTHESIS IS THAT DELAYED RECANALIZATION WILL RESULT IN A MASSIVE INFILTRATION OF BLOOD-BORNE IMMUNE CELLS INTO THE BRAIN, WITH MONOCYTE/MACROPHAGES REPRESENTING A LARGE SUBSET OF THESE IMMUNE CELLS. MACROPHAGES CAN UNDERGO RE-PROGRAMMING IN THE BRAIN, THUS DRIVING THEM TO ASSUME EFFEROCYTIC AND ANTI-INFLAMMATORY ROLES, THEREBY ALLEVIATING THE PATHOLOGICAL AND NEUROLOGICAL DEFICITS AFTER PMCAO. TWO SPECIFIC AIMS HAVE BEEN PROPOSED TO CHARACTERIZE AND DETERMINE THE ROLES OF THESE MACROPHAGES IN ISCHEMIC CORE AND PENUMBRA AFTER DELAYED RECANALIZATION. WE WILL ALSO DETERMINE HOW BLOOD-BORNE MACROPHAGES RE- PROGRAM TO ASSUME EFFEROCYTIC AND ANTI-INFLAMMATORY PHENOTYPES THAT EXERT A PROTECTIVE FUNCTION AFTER DELAYED RECANALIZATION. THE LONG-TERM GOAL OF THIS PROJECT IS TO ESTABLISH DELAYED RECANALIZATION AS A NOVEL THERAPEUTIC APPROACH FOR PATIENTS THAT HAVE MISSED THE CONVENTIONAL THERAPEUTIC WINDOW TO RECEIVE RTPA.

TARGETED NANO-BORON BASED BORON NEUTRON CAPTURE THERAPY FOR GLIOMA TREATMENT - PROJECT SUMMARY GLIOMAS REPRESENT ONE OF THE MOST FATAL AND DIFFICULT TO TREAT CANCERS. DESPITE THE AGGRESSIVE THERAPIES, INCLUDING SURGICAL RESECTION, RADIOTHERAPY AND CHEMOTHERAPY THE MEDIAN SURVIVAL TIME FOR PATIENTS REMAINS VERY POOR. BORON NEUTRON CAPTURE THERAPY (BNCT) IS A NONINVASIVE THERAPY FOR TREATING LOCALLY INVASIVE MALIGNANT TUMORS SUCH AS GLIOMA. BNCT IS A ROBUST THERAPY WITH CLEAR ADVANTAGES AS IT RELIES ON THE NUCLEAR CAPTURE AND FISSION REACTIONS. DESPITE CLEAR ADVANTAGES, BNCT HAVE NOT BEEN AS EFFECTIVE IN THE CLINIC DUE TO INABILITY TO ACHIEVE ADEQUATE AMOUNTS OF BORON-10 (AN ACTIVE DRUG) CONCENTRATION SELECTIVELY IN THE TARGET CANCER CELLS, WHICH REMAINS AN UNSOLVED PROBLEM. THE STUDIES PROPOSED HERE ARE INTENDED TO FILL A CRITICAL VOID USING A NANOMEDICINE-BASED APPROACH, WHICH IS UNIQUELY POISED TO OFFER A SOLUTION TO THIS UNSOLVED PROBLEM. WE HAVE DEVELOPED NANODRUGS FOR IMAGING AND TREATMENT OF THE PRIMARY AND METASTATIC BRAIN TUMORS. HERE WE PROPOSE A NOVEL NANODRUG (NANO-10BORON), BASED ON A NATURAL, NONTOXIC AND BIODEGRADABLE POLYMER CARRYING IN EXCESS OF 300 MOLECULES OF BORON-10 ENRICHED 4-BORONOPHENYLALANINE (BPA) TO CROSS BLOOD-BRAIN BARRIER (BBB) AND ACTIVELY TARGET AND DELIVER HIGH BOPRON-10 CONCENTRATION TO GLIOMA CELLS FOR EFFECTIVE BNCT. IN AIM 1, WE WILL ESTABLISH OPTIMUM FUNCTIONATING LEAD NANO-10BORON. THIS WILL BE ACHIEVED BY SYNTHESIZING NEXT-GENERATION NANO-10BORONS WITH VARIED LOADING OF BPA AND A TUMOR TARGETING AND BBB TRANSPORT PEPTIDE ANGIOPEP-2 (AP2). IN OUR PRELIMINARY STUDIES, WE USED 12 AP2 MOLECULES AND 300 BPA MOLECULES COVALENTLY ATTACHED TO PMLA TO FORM A FIRST-GENERATION NANO-10BORON. OUR GOAL IS TO PREPARE A LEAD NANO-10BORON WITH MAXIMUM ALLOWABLE NUMBER OF BPA MOLECULES TO ENHANCE INTRACELLULAR BORON-10 CONCENTRATIONS TO BOOST THE TREATMENT OUTCOME. AIM 2 WILL FOCUS ON ESTABLISHING AN IDEAL TIME WINDOW FOR NEUTRON FLUX IRRADIATION FOR GREATER BNCT EFFECT. PK OF OUR FIRST-GENERATION NANO-10BORON IS ABOUT 1.44 H (SEE PRELIMINARY RESULTS FOR DETAILS) WHEREAS, PK OF FREE BPA USED IN CLINICAL STUDIES RANGES IN FEW MINUTES. ADDITIONALLY, PMLA BASED NANODRUGS UTILIZES ACTIVE TARGETING AND REMAINS IN TUMOR FOR RELATIVELY LONGER PERIOD, WHILE CLEARING OUT FROM THE SYSTEMIC CIRCULATION PROVIDING GRATER TUMOR UPTAKE. STUDIES OUTLINES IN THIS AIM WILL DETERMINE THE OPTIMUM TIME WINDOW WHEN WE HAVE THE HIGHEST BORON-10 CONCENTRATIONS IN TUMOR VS SURROUNDING HEALTHY BRAIN, FACILITATING EFFECTIVE BNCT RESPONSE WHILE MINIMIZING ANY POTENTIAL OFF TARGETING TOXICITY TO THE HEALTHY BRAIN. AIM 3 WILL UTILIZE THE LEAD NANO-10BORON TO TREAT GLIOMA BARING MICE TO IMPROVE THE SURVIVAL. LEAD NANO-10BORON WILL BE INJECTED AT THE OPTIMUM DOSE DEVELOPED IN THE PREVIOUS AIM FOLLOWED BY IRRADIATION WITH LOW ENERGY NEUTRONS TO TREAT GLIOMA BARING ANIMALS AND IMPROVE THE SURVIVAL TIME. THE PROPOSED WORK WILL SOLVE THE LONG-STANDING PROBLEM OF BORON-10 DELIVERY, THEREBY MAKING BNCT A PRACTICAL THERAPY FOR GLIOMA TREATMENT, IMPROVE PATIENT SURVIVAL AND ENHANCE THE QUALITY OF LIFE. THE RESULTS OF THIS STUDY COULD LAY THE GROUNDWORK FOR A NOVEL TREATMENT OPTION FOR GLIOMA FOR CLINICAL APPLICATIONS. PAGE 1

UNPACKING THE BLACK BOX OF PROBLEM-SOLVING: DOSAGE, DELIVERY, CULTURE, AND IMPACT ON INTERNALIZING PROBLEMS FOR ADOLESCENTS - ABSTRACT APPROXIMATELY 20% OF YOUNG PEOPLE EXPERIENCE ANXIETY OR DEPRESSION BY THE TIME THEY TURN 18, AND RATES ARE HIGHER AMONG RACIAL/ETHNIC MINORITY YOUTH. IMPROVEMENT IN PROBLEM-SOLVING SKILLS REDUCES DEPRESSION, ANXIETY, SELF-HARM, AND SUICIDAL IDEATION, AND CORRESPONDS TO REDUCED SYMPTOMS AND BETTER ADJUSTMENT FOR YOUTH WITH EXTERNALIZING PROBLEMS, POINTING TO ITS TRANSDIAGNOSTIC POTENTIAL. PROBLEM-SOLVING SKILLS TRAINING (PSST) IS CONSISTENTLY REVEALED TO BE THE MOST COMMON ELEMENT ACROSS YOUTH MENTAL HEALTH PREVENTION AND PROMOTION PROGRAMS; HOWEVER, DOSAGE AND DELIVERY VARY - INCLUDING THE EXTENT TO WHICH QUANTITY, SEQUENCING, TEMPORALITY, STEPS AND STRATEGIES ACCOUNT FOR ITS TRANSDIAGNOSTIC VALUE AND IMPACT. ADDITIONALLY, DESPITE LONG- STANDING PSYCHOTHERAPY LITERATURE DOCUMENTING THAT CULTURAL ADAPTATION AND TAILORING PREDICT ENGAGEMENT, ALLIANCE, AND OUTCOMES FOR RACIAL/ETHNIC MINORITY YOUTH AND FAMILIES, THE PREVENTION LITERATURE HAS BEEN SLOWER TO EXAMINE TO WHAT EXTENT PROGRAMS ARE DESIGNED WITH CULTURAL DIVERSITY OR SPECIFIC GROUPS IN MIND; DELIVERED IN CULTURALLY CONGRUENT WAYS; AND TO WHAT EXTENT THESE LEAD TO BETTER OUTCOMES. AS A RESULT, THE FIELD’S READINESS TO DISSEMINATE EVIDENCE-BASED RECOMMENDATIONS FOR MAXIMUM IMPACT IS LIMITED. WE HAVE ASSEMBLED AN ADVISORY BOARD OF SCIENTIFIC AND COMMUNITY EXPERTS TO INFORM TWO AIMS. SPECIFIC AIMS 1: EXAMINE PSST FOR VARIABILITY IN DOSAGE, DELIVERY, AND CULTURAL CONSIDERATIONS, AND VARIANCE IN INTERNALIZING OUTCOME EFFECT SIZES. WE WILL (A) IDENTIFY UNIVERSAL AND SELECTED PREVENTION PROGRAMS (N=~90) FOR ADOLESCENTS (AGES 14-18) OUTPERFORMING A COMPARISON IN AT LEAST ONE TRIAL ON AT LEAST ONE INTERNALIZING OUTCOME; (B) CODE DOSAGE (QUANTITY, SEQUENCING, TEMPORALITY), DELIVERY (STEPS AND STRATEGIES), CULTURAL CONTENT AND TAILORING, AND IMPACT AND (C) USE RANDOM EFFECTS META-REGRESSION TO EXAMINE VARIANCE ACCOUNTED FOR IN PROBLEM SOLVING SKILLS AND INTERNALIZING OUTCOMES. FINDINGS WILL INFORM SPECIFIC AIM 2: DEVELOP, ASSESS, AND DEPLOY A BEST PRACTICE PSST RESOURCE GUIDE (TIPS = TEACH IT PLAIN & SIMPLE) FOR YOUTH SERVICE PROVIDERS. WE WILL RECRUIT FRONTLINE PROVIDERS (N=15, ~30% NON-HISPANIC BLACK, ~70% HISPANIC) FROM THREE YOUTH SERVICE SETTINGS (5 HIGH SCHOOL COUNSELORS, 5 MIDDLE/HIGH AFTERSCHOOL PROFESSIONALS, 5 COMMUNITY HEALTH WORKERS) TO RECEIVE, REVIEW AND INTEGRATE TIPS INTO THEIR WORK. TWO MONTHS LATER, WE WILL RECEIVE FEEDBACK VIA SURVEYS AND SEMI-STRUCTURED INTERVIEWS IN A SEQUENTIAL MIXED METHOD DESIGN, AND CONDUCT THEMATIC ANALYSIS TO ASSESS USABILITY, APPROPRIATENESS, ACCEPTABILITY AND FEASIBILITY. FINDINGS WILL INFORM MODIFICATIONS TO DESIGN FOR WIDER DISSEMINATION AND AN R01 APPLICATION. ALIGNED WITH STRATEGIC PLAN OBJECTIVE 4.2.C, THE PLANNED DESIGN ALLOWS FOR RAPID INFUSION OF RESEARCH FINDINGS INTO PRACTICE SETTINGS FOR UNDERSERVED COMMUNITIES TO INCREASE THE IMPACT OF MENTAL HEALTH INTERVENTIONS. BY UNPACKING THE BLACK BOX OF PSST, WE HOPE TO SPEED ITS SCALE-UP AS AN EFFICIENT, EFFECTIVE, STAND-ALONE, CULTURALLY CONGRUENT BRIEF INTERVENTION TOOL FOR YOUTH SERVICE PROVIDERS IN A VARIETY OF SETTINGS.

EFFECT OF DAILY CONSUMPTION OF PEANUTS/PEANUT BUTTER ON IMMUNE FUNCTION AND CARDIOMETABOLIC MARKERS AND RISK FACTORS IN FREE-LIVING INDIVIDUALS

MICRORNA 210 AND PERINATAL HYPOXIC-ISCHEMIC BRAIN INJURY

INVESTIGATING THE ROLE OF MAST CELLS IN NEONATAL GERMINAL MATRIX HEMORRHAGE

VAGUS NERVE STIMULATION MODULATES NEUROINFLAMMATION IN DEVELOPING RATS

MECHANISMS FOR THE REPAIR OF OXIDATIVE STRESS-INDUCED DNA DAMAGE IN PORPHYROMONAS - PORPHYROMONAS GINGIVALIS, AS A “KEYSTONE PATHOGEN”, HIGHLIGHTS ITS ABILITY TO ADAPT TO THE HARSH INFLAMMATORY CONDITIONS OF THE PERIODONTAL POCKET. BECAUSE THE ENVIRONMENTAL STRESS RESPONSE IS A MAJOR DETERMINANT OF ITS VIRULENCE, IT IS OUR LONG-TERM GOAL TO GAIN A COMPREHENSIVE UNDERSTANDING OF ITS SURVIVAL STRATEGY(S). DNA DAMAGE IS A MAJOR CONSEQUENCE OF OXIDATIVE STRESS. WHILE MORE THAN 20 DIFFERENT OXIDATIVELY ALTERED BASES MIGHT BE GENERATED BY THIS STRESS, 8-OXO-7,8-DIHYDROGUANINE (8-OXOG) IS ONE OF THE MOST COMMON PRODUCT OF DNA DAMAGE. GUANINE IS THE MOST SUSCEPTIBLE BASE TO OXIDATION AND FORMS MAINLY 8-OXOG DUE TO ITS LOW REDOX POTENTIAL. IN PROKARYOTIC CELLS THE PRESENCE OF 8-OXOG IS MAINLY REPAIRED BY BASE EXCISION REPAIR (BER). A SURVEY OF THE P. GINGIVALIS GENOME INDICATE THAT AN IMPORTANT COMPONENT OF THE BER SYSTEM IS MISSING. BECAUSE THE AVERAGE G + C CONTENT OF THE GENOME OF P. GINGIVALIS IS 49%, A MECHANISM(S) TO PREVENT OR REPAIR LESIONS RESULTING FROM GUANINE OXIDATION IS VITAL. THERE IS A GAP IN OUR COMPREHENSIVE KNOWLEDGE ON A MECHANISM(S) FOR THE REPAIR OF OXIDATIVE STRESS-INDUCED DNA DAMAGE IN P. GINGIVALIS. WE HAVE PREVIOUSLY DEMONSTRATED THAT THERE IS AN ACCUMULATION OF 8-OXOG IN THE CHROMOSOME OF P. GINGIVALIS EXPOSED TO H2O2-INDUCED OXIDATIVE STRESS. NEITHER BER NOR NUCLEOTIDE EXCISION REPAIR (NER), AS OBSERVED IN OTHER STRAINS, APPEAR TO BE INVOLVED IN THE REPAIR OF THE 8-OXOG LESION IN P. GINGIVALIS. DNA AFFINITY FRACTIONATION IDENTIFIED PG1037, A CONSERVED HYPOTHETICAL PROTEIN, AMONG OTHERS, THAT WERE PREFERENTIALLY BOUND TO THE OLIGONUCLEOTIDE FRAGMENT CARRYING THE 8-OXO-G LESION. PG1037 IS PART OF THE UVRA-PG1037-PCRA OPERON IN P. GINGIVALIS WHICH IS KNOWN TO BE UPREGULATED UNDER H2O2- INDUCED STRESS. THE PURIFIED RECOMBINANT PG1037 PROTEIN, LIKELY VIA A REDUCING FUNCTION, HAS THE ABILITY TO PREVENT FENTON CHEMISTRY-MEDIATED DNA DAMAGE IN VITRO AND, UNDER OXIDATIVE STRESS CONDITIONS, REDUCED THE CLEAVAGE OF THE 8-OXOG LESION BY THE E.COLI FORAMIDOPYRIMIDINE GLYCOSYLASE (FPG) ENZYME. IN SILICO ANALYSIS OF PG1037 SHOWS A PROTEIN THAT CONTAINS A ZINC FINGER DOMAIN, TWO PEROXIDASE HOMOLOGOUS MOTIFS AND A CYTIDYLATE KINASE DOMAIN. THE GOAL OF THE PROPOSAL IS TO TEST THE HYPOTHESIS THAT A NOVEL P. GINGIVALIS PROTEIN (PG1037) CARRYING PEROXIDASE MOTIFS AND A ZINC FINGER DOMAIN IS INVOLVED IN THE REPAIR OF OXIDATIVELY DAMAGED DNA. OUR AIMS ARE TO CONFIRM THE SPECIFIC ROLE OF PG1037 IN THE REMOVAL OF 8-OXOG FROM DUPLEX DNA AND TO EVALUATE ANY INTERACTION OF PG1037 WITH OTHER PROTEINS IN THAT PROCESS. THE DATA WILL PROVIDE A MAJOR CONCEPTUAL ADVANCE ON THE MOLECULAR BASES FOR THE REPAIR OF OXIDATIVE STRESS-INDUCED DNA DAMAGE IN P. GINGIVALIS AND COULD LIKELY SUPPORT A UNIQUE AND EFFECTIVE DNA REPAIR MECHANISM WE PROPOSE TO DESIGNATE “BASE REDOX REPAIR”. IT WILL SET THE STAGE, IN A FUTURE RO1 APPLICATION, TO ADDRESS SPECIFIC STRUCTURE-FUNCTION QUESTIONS ON THE VITAL COMPONENTS AND THEIR CORPORATION IN MAINTAINING GENOMIC STABILITY IN ANAEROBES EXPOSED TO ENVIRONMENTAL STRESS. THESE COMPONENTS COULD BE TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTIONS FOR THE CONTROL AND PREVENTION OF P. GINGIVALIS-ASSOCIATED DISEASES.

DLT CONGRESSIONALLY DIRECTED SPENDING - GRANTS

DNA DEMETHYLATION AND BKCA CHANNEL EXPRESSION AND FUNCTION IN UTERINE ARTERIES

ROLE OF LINCRNA IN DEVELOPMENTAL REGULATION OF ANGIOGENESIS

STUDIES ON THE VIRULENCE OF FILLIFACTOR ALOCIS

LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

PREFRONTAL CONTROL OF DOPAMINE NEURONS

RAF KINASE AND EPIGENETIC REGULATION OF FETAL VASCULAR DEVELOPMENT

NOVEL MECHANISMS MEDIATING CARDIAC PROTECTION UPON PRESSURE OVERLOAD

CEREBROVASCULAR ENDOTHELIAL FUNCTION IN AGING AND ALZHEIMER'S DISEASE

USE OF NATURAL LANGUAGE PROCESSING TO IDENTIFY LINGUISTIC MARKERS OF COPING

ACADEMIC ADMINISTRATIVE UNITS IN PRIMARY CARE

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

OPE: HIGHER EDUCATION EMERGENCY RELIEF FUND (HEERF), SECTION 2003 OF THE AMERICAN RESCUE PLAN (ARP) FOR MSI INSTITUTIONS OF HIGHER EDUCATION (IHE) .

INFLUENCE OF DIETARY PATTERN AND RACE ON METABOLIC AND EPIGENETIC ALTERATIONS ASSOCIATED WITH CANCER DEVELOPMENT

STRUCTURAL-FUNCTIONAL STUDIES OF GINGIPAIN BIOGENESIS AND LOCALIZATION - PROJECT SUMMARY THERE IS AN URGENT NEED TO EXPLORE NEW THERAPEUTIC APPROACHES IN THE MANAGEMENT OF PERIODONTITIS, A PREVALENT AND CHRONIC DISEASE THAT CURRENTLY LACKS EFFECTIVE TREATMENT. FURTHER, A GROWING NUMBER OF STUDIES HAVE LINKED PERIODONTITIS TO SYSTEMIC DISEASES SUCH AS ATHEROSCLEROSIS OR RHEUMATOID ARTHRITIS, AS WELL AS SOME CANCERS, DIABETES, AND ALZHEIMER’S DISEASE. PORPHYROMONAS GINGIVALIS, A BLACK-PIGMENTED, GRAM-NEGATIVE ANAEROBE, IS A KEYSTONE PATHOGEN IN MICROBIAL-INDUCED PERIODONTAL DISEASE. A COMPREHENSIVE MECHANISTIC UNDERSTANDING OF SOME OF ITS VIRULENCE FACTORS IS ESSENTIAL AS THE FIRST STEP FOR THERAPEUTIC DEVELOPMENT. THE BACTERIUM USES A TYPE IV SECRETION SYSTEM TO SECRETE AN ARRAY OF VIRULENCE FACTORS, INCLUDING GINGIPAINS [CYSTEINE PROTEASES – ARG-SPECIFIC RGPA AND RGPB, AND LYS-SPECIFIC KGP], WHICH ARE ESSENTIAL FOR ITS PATHOGENICITY. THERE IS STILL A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE MECHANISM OF POST- TRANSLATIONAL PROTEOLYTIC PROCESSING OF PROGINGIPAINS AND MEMBRANE SURFACE ASSEMBLY OF NON- COVALENT COMPLEXES COMPOSED OF A CATALYTIC DOMAIN AND HEMAGGLUTININ (HA) DOMAINS. IN ADDITION, THE ROLE OF HA DOMAINS IN P. GINGIVALIS PATHOGENESIS IS UNCLEAR. OUR OBJECTIVE IS TO EXPAND THE UNDERSTANDING OF THE GINGIPAINS' HEMAGGLUTINATING/ADHESIVE PROPERTIES AND THE FORMATION OF THEIR SURFACE COMPLEXES. THE SPECIFIC AIMS OF THE CURRENT APPLICATION ARE DESIGNED FOR A COMPREHENSIVE ASSESSMENT OF THE GINGIPAIN STRUCTURE-FUNCTION PROPERTIES, INCLUDING ITS BIOGENESIS AND SPECIFIC LOCALIZATION. EXPERIMENTS ARE OUTLINED TO DETERMINE THE POST-TRANSLATIONAL SEQUENTIAL PROCESSING STEPS LEADING TO THE FORMATION OF GINGIPAIN COMPLEXES ON THE BACTERIAL SURFACE. WE WILL CONDUCT A COMPARATIVE ANALYSIS OF PROTEOLYTIC ACTIVITY INDEPENDENT BIOLOGICAL FUNCTIONS OF SINGLE-CHAIN PRO GINGIPAINS AND ASSEMBLY OF NATIVE NON-COVALENT COMPLEXES OF THE CATALYTIC DOMAIN WITH HA DOMAINS. WE WILL DETERMINE THE STRUCTURE OF NON-COVALENT GINGIPAIN SURFACE COMPLEXES. FINALLY, WE WILL EXAMINE THE PATHOGENIC POTENTIAL OF DIFFERENT HA VARIANTS OF KGP EXPRESSED BY P. GINGIVALIS STRAINS. A CONCEPTUAL INNOVATION IS CHARACTERIZING THE STRUCTURES OF FULL-LENGTH GINGIPAINS AND NATIVE RGPA-KGP MEMBRANE COMPLEXES. THIS WILL SHED NEW LIGHT ON THE COOPERATIVE MECHANISM OF PROTEOLYTIC CLEAVAGE AND ADHESION/HEMAGGLUTINATION ACTIVITY EXERTED BY GINGIPAINS. GIVEN THEIR SPECIFIC BACTERIAL SURFACE LOCALIZATION, WE POSIT THAT ONLY SIMULTANEOUS INHIBITION OF BOTH PROPERTIES WILL LEAD TO THE DEVELOPMENT OF EFFECTIVE DRUGS AGAINST PERIODONTITIS AND P. GINGIVALIS-DRIVEN SYSTEMIC DISEASES.

XENOGRAFT MODEL TO STUDY IMPACT OF CRLF2-LIGAND IN HISPANIC CHILDHOOD B-ALL

SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

OXIDATIVE STRESS RESISTANCE MECHANISMS IN FILIFACTOR ALOCIS - A. PROJECT SUMMARY/ABSTRACT RECENT ORAL MICROBIOME STUDIES HAVE RECOGNIZED A MYRIAD OF AS-YET-CULTURABLE AND FASTIDIOUS ORGANISMS THAT HAVE SHOWN A STRONG CORRELATION WITH PERIODONTAL DISEASE SEVERITY. IT IS LIKELY THAT THE EMERGING NEW PATHOGENS MAY PLAY A MORE SIGNIFICANT ROLE IN THE DISEASE COMPARED TO THE TRADITIONAL “RED COMPLEX” BACTERIA PORPHYROMONAS GINGIVALIS, TANNERELLA FORSYTHIA AND TREPONEMA DENTICOLA. ONE SUCH PREVIOUSLY UNRECOGNIZED ORGANISM, FILIFACTOR ALOCIS, IS A GRAM-POSITIVE, ASACCHAROLYTIC, OBLIGATE ANAEROBIC ROD. SEVERAL RECENT STUDIES HAVE FOUND THIS BACTERIUM AT SIGNIFICANTLY HIGHER LEVELS IN ADULT OR REFRACTORY PERIODONTITIS PATIENTS AND HAVE SUGGESTED THAT IT COULD BE INCLUDED AS A DIAGNOSTIC INDICATOR OF PERIODONTAL DISEASE. CURRENTLY, THERE IS LITTLE OR NO INFORMATION ON SURVIVAL MECHANISMS AND VIRULENCE OF F. ALOCIS. PRIMARILY, THIS IS DUE TO THE UNAVAILABILITY OF AN EFFICIENT GENETIC SYSTEM TO ALLOW GENETIC MANIPULATIONS OF THE F. ALOCIS GENOME. IN RESPONSE TO ENVIRONMENTAL STRESS, OUR PRELIMINARY STUDIES SHOWED THAT F. ALOCIS IS RELATIVELY MORE RESISTANT TO H2O2-INDUCED OXIDATIVE STRESS COMPARED TO P. GINGIVALIS. ALSO, UNDER H2O2-INDUCED STRESS CONDITIONS, THE SURVIVAL OF P. GINGIVALIS IS ENHANCED MORE THAN 4-FOLD IN THE PRESENCE OF F. ALOCIS. THESE OBSERVATIONS SUGGEST THAT F. ALOCIS MAY HAVE THE ABILITY TO MODIFY/REDUCE THE OXIDATIVE STRESS ENVIRONMENT AND STABILIZE THE MICROBIAL COMMUNITY OF THE PERIODONTAL POCKET. IN AN RNA-SEQ ANALYSIS, THE TRANSCRIPTIONAL PROFILE OF F. ALOCIS SHOWED THAT IN COCULTURE WITH P. GINGIVALIS (COMPARED TO F. ALOCIS MONOCULTURE) UNDER H2O2-INDUCED STRESS, THE MOST HIGHLY UPREGULATED GENES IN F. ALOCIS ENCODE FOR A PUTATIVE MANGANESE ABC TRANSPORTER FA0894-FA0895-FA0896-FA0897. MANGANESE HAS BEEN PROPOSED TO DETOXIFY REACTIVE OXYGEN SPECIES AND PROTECT BACTERIA FROM OXIDATIVE STRESS. IT IS OUR HYPOTHESIS THAT THE F. ALOCIS HYPOTHETICAL ATP TRANSPORTER, FA0894-FA0897, MAY PLAY AN IMPORTANT ROLE IN ENHANCED PROTECTION/SURVIVAL OF P. GINGIVALIS AGAINST H2O2-INDUCED STRESS. WE WISH TO UNDERSTAND THE MODULATION OF F. ALOCIS POTENTIAL VIRULENCE FACTORS IN RESPONSE TO INTERACTION WITH P. GINGIVALIS AND EVALUATE IF THEY CONTRIBUTE TO PROTECTION/PERSISTENCE OF P. GINGIVALIS AGAINST THE OXIDATIVE ENVIRONMENT OF THE PERIODONTAL COMMUNITY. THE PROPOSED SPECIFIC AIMS ARE: (1) TO EVALUATE THE SPECIFIC ROLE(S) OF F. ALOCIS PUTATIVE ABC TRANSPORTER FA0894-FA0897 IN THE PROTECTION/SURVIVAL OF P. GINGIVALIS UNDER H2O2-INDUCED STRESS. (2) TO DEVELOP AN EFFICIENT GENETIC SYSTEM FOR FILIFACTOR THAT INCLUDES A MARKERLESS, IN-FRAME DELETION SYSTEM AND/OR TRANSPOSON MUTAGENESIS SYSTEM. COLLECTIVELY, THE DATA GENERATED WILL FACILITATE A COMPREHENSIVE ASSESSMENT OF THE MOLECULAR MECHANISM(S) AND OVERALL INTERPLAY INVOLVING F. ALOCIS AND THE ‘KEYSTONE’ PATHOGEN P. GINGIVALIS. IT WILL ALSO GENERATE A POLYMICROBIAL MODEL SYSTEM THAT MAY FACILITATE THE DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTIONS TO AID IN THE CONTROL AND PREVENTION OF PERIODONTAL DISEASE. FURTHERMORE, THE NEW GENETIC MANIPULATION SYSTEM WILL HELP TO UNCOVER THE RELATIVE SIGNIFICANCE OF F. ALOCIS IN THE ETIOLOGY OF PERIODONTAL DISEASE.

EFFECTS OF LOW-DOSE RADIATION ON NEUROVASCULAR REMODELING AND BLOOD-RETINA BARRIER FUNCTION IN MICE RATS AND RABBITS

LOMA LINDA UNIVERSITY BASIC BIOMEDICAL RESEARCH T32 PROGRAM - PROJECT SUMMARY. IMPROVING THE HEALTH OF ALL AMERICANS REQUIRES A WELL-TRAINED AND HIGHLY SKILLED BIOMEDICAL PHD WORKFORCE THAT WILL ULTIMATELY DRIVE SCIENTIFIC BREAKTHROUGHS AND INNOVATION IN LIFE-SAVING MEDICAL RESEARCH. NIH SUPPORT FOR COMPREHENSIVE PRE-DOCTORAL TRAINING PROGRAMS IS VITAL BECAUSE THE EVOLVING CAREER LANDSCAPE FOR BIOMEDICAL PHD GRADUATES DEMANDS A ROBUST AND FLEXIBLE SET OF COMPETENCIES TO COMPLEMENT RESEARCH EXPERTISE. IN RESPONSE, PHD PROGRAMS MUST INCREASINGLY EMPHASIZE CULTIVATING TRANSFERABLE COMPETENCIES AND SKILLS THAT EQUIP STUDENTS FOR LONG-TERM SUCCESS ACROSS THE BIOMEDICAL PROFESSIONS. THESE PROFICIENCIES ARE CRITICAL FOR GRADUATE STUDENTS TO FLOURISH IN TODAY’S COMPLEX WORK ENVIRONMENTS, ADAPT TO CHANGE, AND LEAD SCIENTIFIC AND ORGANIZATIONAL INNOVATION. TO SUCCEED IN THIS DYNAMIC SCIENTIFIC AND BIOMEDICAL CLIMATE, PHD STUDENTS MUST ACQUIRE BROAD PROFESSIONAL SKILLS THAT EXTEND BEYOND THEIR TECHNICAL RESEARCH EXPERTISE INCLUDING EFFECTIVE SCIENTIFIC COMMUNICATION, GRANT WRITING, ETHICAL RESEARCH CONDUCT, RIGOR AND REPRODUCIBILITY, ACQUISITION OF COMPUTATIONAL TOOLS TO MANAGE COMPLEX DATA, RESOURCE MANAGEMENT, LEADERSHIP, MENTORING, AND CAREER GUIDANCE. FROM 2001 TO 2025, OUR PREVIOUS LOMA LINDA UNIVERSITY (LLU)-NIH INITIATIVE FOR MAXIMIZING STUDENT DEVELOPMENT PROGRAM (IMSD) R25 PROGRAM TRAINED AND GRADUATED A LARGE COHORT OF PHD STUDENTS THAT SUCCESSFULLY TRANSITIONED INTO THE BIOMEDICAL WORKFORCE, BECOMING EXPERTS AND LEADERS IN THEIR RESPECTIVE FIELDS. THE PRESENT APPLICATION PROPOSES A PLAN TO IMPLEMENT, IN A PERSONALIZED FASHION, THE NEW LLU BASIC BIOMEDICAL RESEARCH T32 PROGRAM (LLU-BBR T32), WHICH WILL ENTAIL A DYNAMIC, SKILL-BUILDING CO-CURRICULUM AIMED AT ENHANCING THE RESEARCH AND PROFESSIONAL PROFICIENCY OF GRADUATE STUDENTS ENROLLED IN THE LLU SCHOOL OF MEDICINE’S INTEGRATIVE BIOMEDICAL GRADUATE STUDIES (IBGS) PHD PROGRAM. THE IBGS INVOLVES TWO BASIC BIOMEDICAL DEPARTMENTS, SEVERAL AUTONOMOUS CENTERS OF BIOMEDICAL RESEARCH EXCELLENCE (COES), AND FOUR MODERN PHD BIOMEDICAL TRACKS. THE SPECIFIC AIMS ARE: AIM 1: RECRUIT AND SUPPORT FIVE NEW PHD STUDENTS PER YEAR IN THE LLU-BBR T32 PROGRAM, THEREBY SUSTAINING A PIPELINE OF HIGHLY SKILLED BIOMEDICAL RESEARCHERS. AIM 2: PROVIDE A SUPPORTIVE ACADEMIC AND FINANCIAL TRAINING ENVIRONMENT DESIGNED TO ACHIEVE A 90% PHD COMPLETION RATE WITHIN FIVE YEARS, IN ALIGNMENT WITH NATIONAL BENCHMARKS FOR TIMELY DEGREE COMPLETION. AIM 3: ENHANCE THE TRAINEES’ ACADEMIC AND RESEARCH COMPETENCIES THROUGH AN INDIVIDUALIZED TRAINING PLAN INTEGRATING RIGOROUS COURSEWORK, RESEARCH MILESTONES, MENTORING, AND PROFESSIONAL DEVELOPMENT. T32 TRAINEES WILL PARTICIPATE IN A PERSONALIZED TRAINING PROGRAM (PTP) TO ACQUIRE ADDITIONAL SKILLS AND CAREER DEVELOPMENT STARTING THE SUMMER BEFORE THE FIRST YEAR OF GRADUATE SCHOOL AND LASTING DURING THEIR TENURE IN THE PHD PROGRAM. THE T32 PROGRAM'S PROPOSED ENHANCED CURRICULUM, TRAINING PLAN, AND OUTCOMES WILL PROVIDE TRAINEES WITH THE NECESSARY PROFESSIONAL AND SCIENTIFIC SKILLS TO INCREASE THEIR LIKELIHOOD OF SUCCESSFUL COMPLETION OF THE PHD DEGREE IN A TIMELY MANNER AND TRANSITION TO A BIOMEDICAL POSTDOCTORAL CAREER.

A NOVEL THERAPY FOR INFLAMMATORY BOWEL DISEASE - DUAL REGULATORY T-CELL PROGRAMMING

ARRA - EQUIPMENT TO ENHANCE TRAINING FOR HEALTH PROFESSIONALS

STUDIES ON THE VIRULENCE REGULATION IN PORPHYROMONAS

HIGH THROUGHPUT DNA SEQUENCER

GENERAL RESEARCH AND TECHNOLOGY ACTIVITY

INCREASED VULNERABILITY TO FERROPTOSIS IN NIEMANN-PICK DISEASE TYPE C - NIEMANN-PICK DISEASE TYPE C (NPC) IS A FATAL PEDIATRIC NEURODEGENERATIVE DISORDER CAUSED BY MUTATIONS IN NPC1 OR NPC2, AFFECTING FEWER THAN 200,000 INDIVIDUALS GLOBALLY. THERE IS NO CURE OR DISEASE-MODIFYING THERAPY APPROVED FOR NPC IN THE UNITED STATES, AND FURTHER RESEARCH TO ELUCIDATE PATHOGENIC MECHANISMS REMAINS A HIGH PRIORITY FOR EFFECTIVE THERAPEUTIC DEVELOPMENT. DESPITE WELL-CHARACTERIZED CELLULAR PATHOLOGIES, INCLUDING ENDO-LYSOSOMAL ENLARGEMENT, MITOCHONDRIAL DAMAGE, IRON AND CALCIUM DYSREGULATION, LIPID PEROXIDATION, AND CHRONIC INFLAMMATION, HOW THESE DIVERSE PATHOLOGIES CONVERGE TO DRIVE DISEASE PROGRESSION REMAINS UNCLEAR. THIS GAP HAMPERS THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. WE HYPOTHESIZE THAT NPC NEURODEGENERATION ARISES FROM CHRONIC CELLULAR STRESS THAT CULMINATES IN FERROPTOSIS, AN IRON-DEPENDENT CELL DEATH PATHWAY DRIVEN BY LETHAL LIPID PEROXIDE ACCUMULATION, AND FURTHER CHARACTERIZED BY LYSOSOMAL DYSFUNCTION, MITOCHONDRIAL DAMAGE, IRON AND CALCIUM DYSREGULATION, AND CHRONIC INFLAMMATION. AS A COROLLARY, ANTI-FERROPTOTIC DRUGS WILL DELAY OR PREVENT THE PROGRESSION OF THIS HARMFUL PROCESS AND, BY EXTENSION, SLOW DOWN CELL DEATH BY THIS MECHANISM. OUR PRELIMINARY DATA SUPPORTS THIS HYPOTHESIS BY SHOWING: 1) ELEVATED LIPID PEROXIDATION IN NPC PATIENT CELLS COMPARED TO SEX- AND AGED-MATCHED CONTROLS; 2) INCREASED VULNERABILITY OF NPC CELLS TO FERROPTOTIC DEATH, REVERSIBLE BY ANTI-FERROPTOTIC COMPOUNDS J147 AND CMS121, WHICH WERE DEVELOPED BY CO-PI DR. MAHER, AND 3) EVIDENCE OF DIFFERENTIAL ANTERIOR-TO-POSTERIOR FERROPTOTIC ACTIVATION IN CEREBELLAR PURKINJE CELLS THAT MIRRORS THE SPATIOTEMPORAL PATTERN OF NEURODEGENERATION IN NPC. WE PROPOSE TO TEST THIS HYPOTHESIS BY PURSUING THE FOLLOWING SPECIFIC AIM: CHARACTERIZE FERROPTOSIS ALONG THE ANTERIOR-TO-POSTERIOR AXIS OF NEURODEGENERATION IN THE NPC CEREBELLUM AND EVALUATE THE ABILITY OF J147 AND CMS121 TO REDUCE NPC PATHOLOGY AND DELAY CLINICAL SYMPTOMS IN A MOUSE MODEL OF NPC. SIGNIFICANCE: SUCCESSFUL COMPLETION OF OUR STUDY WILL HELP DETERMINE THE EXTENT OF THE CONTRIBUTION OF FERROPTOSIS TO NPC PATHOGENESIS AND COULD ESTABLISH FERROPTOSIS AS A THERAPEUTIC TARGET, ENABLING REPURPOSING OF ANTI-FERROPTOTIC DRUGS TO SLOW NEURODEGENERATION. FURTHERMORE, BOTH J147 AND CMS121 ALREADY HAVE INVESTIGATIONAL NEW DRUG APPROVAL SO THEY COULD BE RAPIDLY MOVED TO THE CLINIC IF PROVEN EFFECTIVE IN THESE STUDIES

RURAL HEALTH CARE SERVICES OUTREACH GRANT PROGRAM - THIS PROPOSAL AIMS TO ESTABLISH AND SUSTAIN CULTURALLY RESPONSIVE, PHARMACY-BASED HIV PREVENTION AND HARM REDUCTION SERVICES IN RURAL SOUTHERN CALIFORNIA, FOCUSING ON UNDERSERVED BLACK AND LATINX COMMUNITIES DISPROPORTIONATELY AFFECTED BY HIV AND SUBSTANCE USE DISORDERS (SUD). THE PROJECT WILL TARGET RURAL AREAS WITHIN THE INLAND EMPIRE (IE), WHICH INCLUDES RIVERSIDE AND SAN BERNARDINO COUNTIES-TWO PRIORITY JURISDICTIONS FOR THE ENDING THE HIV EPIDEMIC (EHE) INITIATIVE. BETWEEN 2020 AND 2021, THE IE EXPERIENCED A 13% INCREASE IN ANNUAL HIV CASES, WITH 79% OF DIAGNOSES AMONG NON-WHITE INDIVIDUALS AND ONE-THIRD LINKED TO SUBSTANCE USE. EXPANDING PREP AND HARM REDUCTION DELIVERY IN PHARMACIES IS CRUCIAL FOR INCREASING UPTAKE AMONG BLACK AND LATINX RESIDENTS IN THE IE. OVER 90% OF IE RESIDENTS LIVE WITHIN 5 MILES OF A PHARMACY. THE PROXIMITY OF PHARMACIES MAKES THEM IDEAL PARTNERS FOR HIV AND SUD PREVENTION SERVICES, OFFERING A NON-STIGMATIZING, ACCESSIBLE SETTING WITH MORE CONVENIENT HOURS THAN TRADITIONAL CLINICS. CALIFORNIA LAWS (SB 159 AND SB 339) SUPPORT PHARMACIST-LED PREP SERVICES. DRAWING ON EVIDENCE FROM SUCCESSFUL PHARMACIST-LED HIV PREVENTION PROGRAMS IN SEATTLE AND SAN FRANCISCO, THIS INTERVENTION LEVERAGES THE UNIQUE ROLE OF PHARMACISTS AS TRUSTED, READILY AVAILABLE HEALTHCARE PROVIDERS. IN 2023, LOMA LINDA UNIVERSITY RECEIVED FUNDING FROM THE NATIONAL ASSOCIATION OF CHAIN DRUG STORES (NACDS) FOUNDATION TO DEVELOP A PHARMACY-BASED HIV PREVENTION PROGRAM. THIS INITIATIVE ESTABLISHED A NETWORK OF 15 COMMUNITY PHARMACIES IN PARTNERSHIP WITH SEVERAL COMMUNITY ORGANIZATIONS. THE IMPLEMENTED PROGRAM ALLOWED PHARMACY CLIENTS TO SELF-SCREEN FOR PREP ELIGIBILITY ON A TABLET, RECEIVE RAPID POINT-OF-CARE HIV TESTING, INITIATE PREP THE SAME DAY, RECEIVE WRAPAROUND SERVICES, AND ACCESS REMOTE SUPPORT FROM PEER NAVIGATORS VIA PHONE OR TEXT. WITH NACDS FUNDING SET TO EXPIRE IN 2025, WE SEEK ADDITIONAL SUPPORT TO SUSTAIN AND EXPAND THIS NETWORK, ENGAGE RURAL COMMUNITIES, AND EXTEND THESE VITAL SERVICES TO REMOTE AREAS OF THE IE. THIS PROJECT HAS FIVE KEY GOALS: 1. EXPAND AND SUSTAIN A RURAL PHARMACY-BASED NETWORK FOR HIV AND SUD PREVENTION SERVICES. 2. INCREASE CLIENT ENGAGEMENT AND INTRODUCE NEW SERVICES, INCLUDING LONG-ACTING PREP, DOXYPEP, AND A BUPRENORPHINE PROGRAM. 3. ENHANCE POINT-OF-CARE TESTING AND USE CLIENT DATA TO IMPROVE SERVICE DELIVERY AND OUTCOMES. 4. STRENGTHEN PHARMACY CAPACITY BY TRAINING TECHNICIANS, REDUCING STIGMA, AND INCORPORATING COMMUNITY FEEDBACK INTO CARE. 5. INCREASE COMMUNITY AWARENESS OF PHARMACY-BASED HIV AND SUD PREVENTION SERVICES AND EVALUATE THE PROGRAM, INCORPORATING COMMUNITY INPUT TO ENSURE SUSTAINABILITY. OUR APPROACH IS GROUNDED IN EVIDENCE-BASED MODELS SHOWN TO INCREASE THE UPTAKE OF HIV PREVENTION AND HARM REDUCTION SERVICES IN UNDERSERVED COMMUNITIES. DECENTRALIZED, PHARMACIST-LED PREP DELIVERY LOWERS BARRIERS TO CARE, WHILE COMMUNITY HEALTH WORKERS PROVIDE CRITICAL NAVIGATION SUPPORT. RAPID POINT-OF-CARE TESTING FOR HIV ENABLES EARLY DETECTION AND TIMELY INTERVENTION. THIS PROGRAM IS SUPPORTED BY THE LOMA LINDA UNIVERSITY EXPERTISE IN HIV PREVENTION, IMPLEMENTATION SCIENCE, AND PHARMACY MANAGEMENT, ALONGSIDE PARTNERSHIPS WITH A CLINICALLY INTEGRATED PHARMACY NETWORK (CPESN) AND ONE OF THE NATION'S LARGEST HEALTH PLANS (IEHP). THIS PROJECT CAN SIGNIFICANTLY IMPROVE HEALTH OUTCOMES FOR RURAL BLACK AND LATINX RESIDENTS IN THE INLAND EMPIRE BY: 1) ADDRESSING PREVENTIVE CARE GAPS THROUGH PHARMACY-BASED HIV PREVENTION AND HARM REDUCTION, 2) FOCUSING ON UNDERSERVED POPULATIONS WITH RISING HIV RATES AND SUBSTANCE USE CHALLENGES, 3) TAILORING SERVICES TO THE NEEDS OF MINORITIZED COMMUNITIES, 4) REDUCING STIGMA AND MISTRUST BY PROVIDING CARE IN TRUSTED PHARMACY SETTINGS, AND 5) USING EVIDENCE-BASED STRATEGIES. WE ARE APPLYING UNDER THE REGULAR PROGRAM TRACK AND REQUEST FUNDING PREFERENCE FOR SERVING A HEALTH PROFESSIONAL SHORTAGE AREA (HPSA).

ARRA - SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

ROLE OF OSTEOACTIVIN IN OSTEOCLASTS

NEUROPROTECTIVE STRATEGIES AFTER REPETITIVE MILD TRAUMATIC BRAIN INJURY

ARRA - SCHOLARSHIPS FOR DISADVANTAGED STUDENTS

DENTAL FACULTY LOAN REPAYMENT

MICROGRAVITY AND RADIATION ARE STRESSORS UNIQUE TO THE SPACEFLIGHT ENVIRONMENT THAT CAN HAVE AN IMPACT ON THE CENTRAL NERVE SYSTEM (CNS). THEY POTENTIALLY COULD LEAD TO SIGNIFICANT RISKS TO ASTRONAUT HEALTH BOTH ACUTELY DURING THE COURSE OF A MISSION OR CHRONICALLY LEADING TO LONG-TERM POST-MISSION DECREMENTS IN QUALITY OF LIFE. TO DATE THE MECHANISMS BEHIND THESE EFFECTS ARE NOT FULLY UNDERSTOOD. STUDIES HAVE SHOWN THAT BOTH MICROGRAVITY ENCOUNTERED BY ASTRONAUTS IN SPACE AS WELL AS MODELED MICROGRAVITY ON EARTH CAN INDUCE MANY DELETERIOUS PHYSIOLOGICAL EFFECTS INCLUDING CHANGES IN BRAIN STRUCTURE AND FUNCTION. A RECENT REPORT ALSO SHOWS THAT MORE THAN 50% OF THE ASTRONAUTS RETURNING FROM SPACE WERE DIAGNOSED WITH EYE PROBLEMS THAT CAN CAUSE HEADACHES AND BLURRY VISION. THE HEALTH RISKS OF SPACE FLIGHT ASSOCIATED SKIN DAMAGE AND CARCINOGENESIS HAVE LONG BEEN A CONCERN. THE SKIN IS A UNIQUE ORGAN BECAUSE IT IS RELATIVELY UNPROTECTED; SOME PART OF IT IS CONSTANTLY EXPOSED TO RADIATION ATMOSPHERIC OXYGEN ENVIRONMENTAL CHEMICALS AND PHYSICAL ABRASION. IN-FLIGHT STRESSES DURING AIRLINE FLIGHTS AS WELL AS SPACE TRAVEL COULD IMPACT CERTAIN BEHAVIORS FROM A DERMATOLOGICAL STANDPOINT. SKIN DISEASES WERE LEADING IN PROBABILITY RANKING FOR OCCURRENCE OF PATHOLOGICAL CHANGES DURING SPACE FLIGHT. LIKE RADIATION ONE OF THE MECHANISMS INVOLVED IN THE RESPONSE TO SPACEFLIGHT IS OXIDATIVE STRESS. THE CNS IS SENSITIVE TO OXIDATIVE INJURY DUE TO HIGH CONCENTRATIONS OF OXIDIZABLE UNSATURATED LIPIDS AND LOW LEVELS OF ANTIOXIDANT DEFENSES. OXIDATIVE STRESS HAS ALSO BEEN IMPLICATED IN THE PATHOGENESIS OF MANY SKIN LESIONS AND DISEASES. THE PURPOSE OF THE PRESENT STUDY WAS TO EVALUATE DAMAGE IN BRAIN EYE AND SKIN IN A GROUND-BASED MODEL FOR SPACEFLIGHT WHICH INCLUDES PROLONGED UNLOADING AND LOW-DOSE RADIATION. LOW-DOSE/LOW-DOSE-RATE (LDR) -RADIATION USING 57CO PLATES (0.04 GY) WAS DELIVERED WHOLE-BODY TO MATURE 6-MONTH OLD FEMALE C57BL/6 MICE TO SIMULATE THE RADIATION COMPONENT. ANTI-ORTHOSTATIC TAIL SUSPENSION WAS USED TO MODEL THE UNLOADING FLUID SHIFT AND PHYSIOLOGICAL STRESS ASPECTS OF THE MICROGRAVITY COMPONENT.

SUPPLEMENTAL ASSISTANCE TO INSTITUTIONS OF HIGHER EDUCATION

A PILOT STUDY OF A DIGITALLY ENHANCED COMMUNITY HEALTH WORKER-LED INTERVENTION TO FACILITATE EARLY PALLIATIVE CARE IN HISPANIC PANCREATIC CANCER PATIENTS.

HTS SCREENING FOR INHIBITORS OF HPV 16 E6/CASPASE 8 BINDING