Childrens Hospital Los Angeles

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ABCD-USA CONSORTIUM: RESEARCH PROJECT

SOUTHERN CALIFORNIA CENTER FOR CHRONIC HEALTH DISPARITIES IN LATINO CHILDREN AND FAMILIES. - OBESITY AND RELATED CHRONIC DISEASES, TYPE 2 DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND DYSLIPIDEMIA CONTINUE TO INCREASE IN THE U.S., AND LATINOS ARE DISPROPORTIONALLY AFFECTED. THESE DISPARITIES BEGIN IN EARLY LIFE, OCCUR WITHIN FAMILIES, AND ARE DRIVEN BY MULTI-LEVEL FACTORS, INCLUDING INDIVIDUAL (DIET, EATING BEHAVIORS), SOCIAL (CULTURAL VALUES, ECONOMIC FACTORS), AND ENVIRONMENTAL (ACCESS TO HEALTHY FOODS, CHEMICAL EXPOSURES SUCH AS AIR POLLUTION). THESE FACTORS INTERACT TO AFFECT LATINO HEALTH BUT ARE RARELY STUDIED IN A HOLISTIC MANNER. OUR OVERARCHING GOAL IS TO UNDERSTAND HOW THESE MULTI-LEVEL FACTORS CONTRIBUTE TO MULTIPLE CHRONIC DISEASE DISPARITIES IN LATINOS ACROSS THE LIFE COURSE, AND TO DEVELOP AND EVALUATE FAMILY-BASED, CULTURALLY SENSITIVE SOLUTIONS. WE PROPOSE TO ACCOMPLISH THIS AMBITIOUS GOAL BY ESTABLISHING THE SOUTHERN CALIFORNIA CENTER FOR CHRONIC HEALTH DISPARITIES IN LATINO FAMILIES AND CHILDREN (SCC-CHDLFC), A COALITION OF ACADEMIC, CLINICAL, GOVERNMENT, AND COMMUNITY STAKEHOLDERS ACROSS THE REGION THAT IS HOME TO 10.8 MILLION LATINOS REPRESENTING 45.2% OF THE POPULATION. THE CENTER IS LED BY DRS. GORAN (CHILDREN’S HOSPITAL LOS ANGELES; CHLA) AND BAEZCONDE-GARBANATI (UNIV. OF SOUTHERN CALIFORNIA; USC), WHO PROVIDE COMPLEMENTARY EXPERTISE IN LATINO HEALTH DISPARITIES RESEARCH. THE ADMINISTRATIVE CORE PROVIDES LEADERSHIP, OVERSIGHT, COMMUNICATION, AND EVALUATION TO STRENGTHEN AND BUILD COLLABORATION, ACCELERATE RESEARCH, AND DRIVE INNOVATION TO ENSURE CENTER SUCCESS AND IMPACT. PROJECT 1 (LED BY DR. GORAN, CHLA) UTILIZES AN ONGOING BIRTH-COHORT TO EXAMINE HOW EARLY-LIFE NUTRITION, ENVIRONMENT, AND SOCIAL FACTORS AFFECT CHRONIC DISEASE RISK BY AGE 5Y, AND HOW THESE FACTORS AFFECT RESPONSE TO FAMILY-BASED INTERVENTIONS IN PROJECTS 2 AND 3. PROJECT 2 (LED BY DR. BOUTELLE, UC SAN DIEGO) TESTS A PARENT-ONLY INTERVENTION FOR TREATMENT OF OBESITY AND CHRONIC DISEASE RISK IN LATINO CHILDREN. THE INTERVENTION, DESIGNED TO ADDRESS CULTURAL ISSUES RELEVANT TO LATINO FAMILIES, IS DELIVERED BY TELEHEALTH TO PARENTS ONLY, INCREASING DISSEMINATION POTENTIAL. PROJECT 3 (LED BY DR. COHEN, KAISER PERMANENTE) EXAMINES THE EFFICACY OF AN AFFORDABLE GROCERY DELIVERY PROGRAM (AT A COST NOT EXCEEDING SNAP DOLLARS), IN CONJUNCTION WITH CULTURALLY APPROPRIATE MEAL PLANNING, ON CHRONIC DISEASE RISK REDUCTION IN LATINO MULTI-GENERATION HOUSEHOLDS. WE WILL SUPPORT SYNERGY AND COLLABORATION ACROSS THESE PROJECTS AND BUILD THE RESEARCH ENTERPRISE THROUGH CENTER CORES. THE METHODS & DATA SUB-CORE LED BY DR. ESPINOZA (CHLA) WILL PROVIDE EXPERTISE IN ASSESSMENT OF DIET, SOCIAL, ENVIRONMENTAL, AND GEOSPATIAL FACTORS, AND DATA ANALYSIS AND MANAGEMENT, TO SUPPORT DATA HARMONIZATION AND SHARING. THE INVESTIGATOR DEVELOPMENT CORE LED BY DRS. SPRUIJT-METZ AND DE LA HAYE (USC) AND ELDER (SAN DIEGO STATE UNIV.) WILL ESTABLISH A MENTORING NETWORK AND PILOT STUDY PROGRAM TO SUPPORT EARLY-STAGE OR UNDERREPRESENTED RESEARCHERS, WHILE ALSO PROMOTING TEAM SCIENCE. THE COMMUNITY ENGAGEMENT CORE LED BY DRS. KIPKE (CHLA) AND BAEZCONDE-GARBANATI (USC) ENGAGES THE COMMUNITY IN THE RESEARCH PROCESS VIA BI-DIRECTIONAL INTERACTION WITH THE OVERALL GOAL TO ACCELERATE THE IMPACT OF CENTER FINDINGS ON THE LATINO COMMUNITY TO MITIGATE CHRONIC DISEASE RISK ACROSS THE REGION.

YOUNG MEN OF COLOR WHO HAVE SEX WITH MEN COHORT STUDY

BIOLOGY AND THERAPY OF HIGH RISK NEUROBLASTOMA

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THE IMPACT OF EARLY MEDICAL TREATMENT IN TRANSGENDER YOUTH

MULTIMODAL BIOPHYSICAL MARKERS OF VASCULAR DISEASE IN HEMOGLOBINOPATHIES

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

USC/UAP LEND PROJECT

FUNCTION AND STRUCTURE ADAPTATIONS IN FOREBRAIN DEVELOPMENT

RANDOMIZED STUDY OF LOW VERSUS MODERATE DOSE BUSULFAN IN TRANSPLANT FOR SEVERE COMBINED IMMUNODEFICIENCY

2/24 HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM - PROJECT SUMMARY/ABSTRACT NEURODEVELOPMENTAL PROCESSES ARE SHAPED BY DYNAMIC INTERACTIONS BETWEEN GENES AND ENVIRONMENTS. MALADAPTIVE EXPERIENCES EARLY IN LIFE CAN ALTER DEVELOPMENTAL TRAJECTORIES, LEADING TO HARMFUL AND ENDURING DEVELOPMENTAL SEQUELAE. PRE- AND POSTNATAL HAZARDS INCLUDE MATERNAL SUBSTANCE EXPOSURE, TOXICANT EXPOSURES IN PREGNANCY AND EARLY LIFE, MATERNAL HEALTH CONDITIONS, PARENTAL PSYCHOPATHOLOGY, MALTREATMENT, STRUCTURAL RACISM, AND EXCESSIVE STRESS. TO ELUCIDATE HOW VARIOUS ENVIRONMENTAL HAZARDS IMPACT CHILD DEVELOPMENT, IT IS IMPERATIVE THAT A NORMATIVE TEMPLATE OF DEVELOPMENTAL TRAJECTORIES OVER THE FIRST 10 YEARS OF LIFE BE ESTABLISHED BASED ON A SUFFICIENTLY LARGE AND DEMOGRAPHICALLY DIVERSE SAMPLE OF THE US POPULATION. TO ACCOMPLISH THIS, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM (HBCD-NC) HAS BEEN FORMED TO DEPLOY A HARMONIZED, OPTIMIZED, AND INNOVATIVE SET OF NEUROIMAGING (MRI, EEG) MEASURES COMPLEMENTED BY AN EXTENSIVE BATTERY OF BEHAVIORAL, PHYSIOLOGICAL, AND PSYCHOLOGICAL TOOLS, AND BIOSPECIMENS TO UNDERSTAND NEURODEVELOPMENTAL TRAJECTORIES IN A SAMPLE OF 7,500 MOTHERS AND INFANTS ENROLLED AT 24 SITES ACROSS THE UNITED STATES (US). THE HBCD-NC WILL CARRY OUT A COMMON RESEARCH PROTOCOL UNDER DIRECTION OF THE HBCD-NC ADMINISTRATIVE CORE (HCAC) AND WILL ASSEMBLE AND DISTRIBUTE A COMPREHENSIVE AND WELL-CURATED RESEARCH DATASET TO THE SCIENTIFIC COMMUNITY AT LARGE UNDER THE DIRECTION OF THE HBCD-NC DATA COORDINATING CENTER (HDCC). THE OVERARCHING GOAL OF THE HBCD-NC IS TO CREATE A COMPREHENSIVE, HARMONIZED, AND HIGH- DIMENSIONAL DATASET THAT WILL CHARACTERIZE TYPICAL NEURODEVELOPMENTAL TRAJECTORIES IN US CHILDREN AND THAT WILL ASSESS HOW BIOLOGICAL AND ENVIRONMENTAL EXPOSURES AFFECT THOSE TRAJECTORIES. A SPECIAL EMPHASIS WILL BE PLACED ON UNDERSTANDING THE IMPACT OF PRE- AND POSTNATAL EXPOSURE TO OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO AND/OR OTHER SUBSTANCES. TO ADDRESS THESE BROAD OBJECTIVES, THE SAMPLE OF WOMEN ENROLLED WILL INCLUDE: 1) A RACIALLY, ETHNICALLY, AND SOCIOECONOMICALLY DIVERSE COHORT THAT IS REPRESENTATIVE OF THE US POPULATION; 2) PREGNANT WOMEN WITH USE OF TARGETED SUBSTANCES (OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO); AND 3) DEMOGRAPHICALLY AND BEHAVIORALLY SIMILAR WOMEN WITHOUT SUBSTANCE USE IN PREGNANCY TO ENABLE VALID CAUSAL INFERENCES. IN ADDITION, THE HBCD-NC WILL IDENTIFY KEY DEVELOPMENTAL WINDOWS DURING WHICH BOTH HARMFUL AND PROTECTIVE ENVIRONMENTS HAVE THE MOST INFLUENCE ON LATER NEURODEVELOPMENTAL OUTCOMES. THE LARGE, MULTI-MODAL, LONGITUDINAL, AND GENERALIZABLE DATASET THAT WILL BE PRODUCED FOR THE FIRST TIME BY THIS STUDY WILL PROVIDE NOVEL INSIGHTS INTO CHILD DEVELOPMENT USING STATE- OF-THE-ART METHODS. THE HBCD-NC STUDY WILL INFORM PUBLIC POLICY TO IMPROVE THE HEALTH AND DEVELOPMENT OF CHILDREN ACROSS THE NATION.

WEST COAST CONSORTIUM FOR TECHNOLOGY AND INNOVATION IN PEDIATRICS

IMPACT OF SUGARS AND HUMAN MILK OLIGOSACCHARIDES ON INFANT MICROBIOME AND OBESITY

USC/UAP LEND PROJECT

PEDIATRIC SOLID TUMOR MICROENVIRONMENT ATLAS - OVERALL SUMMARY/ABSTRACT THE MAJORITY OF SOLID TUMORS IN CHILDREN HAVE A UNIQUE ORIGIN COMPARED TO THOSE IN ADULTS, STEMMING FROM THEIR RISE FROM EMBRYONIC CELLS. DESPITE THIS DISTINCTION, THERE IS STILL LIMITED UNDERSTANDING OF THE DIFFERENCES IN THE MICROENVIRONMENTS OF THESE PEDIATRIC TUMORS COMPARED TO ADULT CANCERS, AND HOW THESE DIFFERENCES MIGHT CONTRIBUTE TO LINEAGE PLASTICITY AND TREATMENT RESISTANCE. TO ADDRESS THIS KNOWLEDGE GAP, WE PROPOSE A COMPREHENSIVE INVESTIGATION INTO THE SPATIAL BIOLOGY OF THESE TUMORS. OUR GOAL IS TO SHED LIGHT ON THE SPECIFIC CELLS AND MECHANISMS WITHIN THE TUMOR MICROENVIRONMENT THAT PLAY A ROLE IN INDUCING THERAPY RESISTANCE IN PEDIATRIC SOLID TUMORS. THIS RESEARCH WILL FOCUS ON PROMINENT PEDIATRIC CANCERS SUCH AS RHABDOMYOSARCOMA, NEUROBLASTOMA, AND WILMS TUMORS. THE PRIMARY GOAL OF THIS MULTI-DISCIPLINARY PROGRAM IS TO ESTABLISH A COMPREHENSIVE PEDIATRIC SOLID TUMOR MICROENVIRONMENT (PSTME) ATLAS THAT WOULD LEAD TO DISCOVERING BASIC MECHANISMS OF DE NOVO AND ACQUIRED RESISTANCE TO MODERN THERAPIES, AND UNCOVERING TUMOR MICROENVIRONMENT (TME) TARGETABLE VULNERABILITIES DRIVEN BY RESISTANCE. THE MOTIVATION FOR CREATING THE PSTME ATLAS IS THE URGENT NEED TO IMPROVE SURVIVAL OF PATIENTS WITH HIGH-RISK SUBTYPES OF THE PROPOSED CANCERS, AND TO DECREASE TREATMENT- RELATED MORBIDITIES. BY DELVING INTO THE INTRICACIES OF THE TUMOR MICROENVIRONMENT AND ITS IMPACT ON TREATMENT RESPONSE, WE AIM TO ADVANCE OUR UNDERSTANDING OF PEDIATRIC SOLID TUMORS AND PAVE THE WAY FOR MORE EFFECTIVE THERAPEUTIC STRATEGIES. THE PROJECT WILL BE SUPPORTED BY COLLABORATION AMONG TWO INSTITUTIONS WITH DISTINCT AND UNIQUE RESOURCES AND TECHNOLOGIES, AND COMPLEMENTARY EXPERTISE: A) CHILDREN’S HOSPITAL LOS ANGELES (CHLA) GROUP WILL PROVIDE WELL ANNOTATED TUMOR SPECIMENS WITH CLINICAL INFORMATION IN AN ETHNICALLY DIVERSE PATIENT POPULATION, AND LEAD IN GENERATING SPATIAL PROTEOMICS DATA USING PEDIATRIC AND TME SPECIFIC ANTIBODY PANELS. B) CALIFORNIA INSTITUTE OF TECHNOLOGY (CALTECH) GROUP WILL PROVIDE INNOVATIVE SPATIAL OMICS TECHNOLOGIES INCLUDING SPATIAL TRANSCRIPTOMICS AND COPY NUMBER, AND NOVEL DATA SCIENCE APPROACHES FOR INTEGRATIVE ANALYSIS OF THE GENERATED DATA. THE SAMPLES WILL BE SELECTED TO REPRESENT SOLID TUMOR DIVERSITY BASED ON ESTABLISHED CLINICAL RISK STRATIFICATIONS, AND CRITICAL POINTS OF TRANSITION (POST CHEMOTHERAPY RESPONSE, RELAPSE) TO ENSURE CAPTURE OF THE DIVERSITY OF PSTME. THE PSTME ATLAS WILL IMPACT THE COMMUNITY THROUGH GENERATION OF EASILY ACCESSIBLE TME ATLAS PROVIDING A USER FRIENDLY, SEARCHABLE DATABASE OF MULTIOMICS SPATIAL ANALYSES OF COMMON EXTRACRANIAL SOLID TUMORS WITH CLINICAL AND OUTCOME DATA. IT WILL ALSO PROVIDE NOVEL COMPUTATIONAL PIPELINES FOR INTEGRATION AND ANALYSIS OF SPATIAL DATA. THESE OPENSOURCE TOOLS WILL BE MADE AVAILABLE TO THE COMMUNITY. IN SUMMARY, THE SIGNIFICANCE OF THE PROPOSED PROJECT IS THE ESTABLISHMENT OF AN ATLAS THAT WILL ALLOW DISCOVERY OF FUNDAMENTAL MECHANISMS OF EXTRINSIC CANCER THERAPY RESISTANCE WITH THE GOAL OF LEADING TO SUBSTANTIVELY IMPROVED PROBABILITY OF CURE COUPLED WITH REDUCED THERAPY-RELATED MORBIDITY FOR CHILDREN AFFLICTED WITH SOLID TUMORS.

MAPPING THE BRAIN, THE FACE AND NEUROCOGNITIVE FUNCTION IN FASD (U01)

BRAIN AND COGNITIVE DEVELOPMENT IN THE PASS COHORT: THE IMPACT OF PRENATAL ALCOHOL EXPOSURE

PERSONAL RESPONSIBILITY EDUCATION PROGRAM (PREP) INNOVATIVE STRATEGIES

ADOLESCENT MEDICINE TRIALS NETWORK FOR HIV/AIDS INTERVE*

CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB - THE DIVISION OF ADOLESCENT AND YOUNG ADULT MEDICINE AT CHILDREN’S HOSPITAL LOS ANGELES (CHLA), ALONG WITH THE TEAM AT OUR INNOVATION STUDIO, ARE APPLYING TO ESTABLISH THE CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB, AN INCUBATOR HUB FOR TEEN PREGNANCY PREVENTION. THE CHLA ADOLESCENT HEALTH AND EQUITY INNOVATION HUB REPRESENTS A UNIQUE APPROACH TO INNOVATION IN THIS FIELD IN THAT IT BRINGS TOGETHER A VAST RESOURCE OF KNOWLEDGE AND SKILL IN TEEN PREGNANCY PREVENTION AND INNOVATION. THE DIVISION OF ADOLESCENT AND YOUNG ADULT MEDICINE CONTAINS THE FULL CONTINUUM OF EXPERTISE IN ADOLESCENT HEALTH AND THE TEEN PREGNANCY PREVENTION ECOSPHERE. THIS INCLUDES DIRECT SERVICE PROVIDERS; INTERNAL SUBJECT MATTER EXPERTS ON REACHING VULNERABLE POPULATIONS; SOCIAL SCIENTISTS AND RESEARCHERS; AND SKILLED TRAINERS AND CAPACITY BUILDING PROFESSIONALS. THIS EXPERTISE WILL BE COMBINED WITH THE CHLA INNOVATION STUDIO’S EXPERIENCE IN GENERATING, CURATING, AND ADVANCING INNOVATIVE SOLUTIONS TO COMPLEX PROBLEMS FACING YOUTH ALONGSIDE ITS ACCESS TO A NATIONAL COMMUNITY OF INDIVIDUALS DEDICATED TO IMPROVING THE LIVES OF YOUNG PEOPLE. TOGETHER, THIS TEAM WILL BE CATALYST FOR RESEARCH-BASED, EQUITABLE, AND YOUTH-INFORMED SOLUTIONS THAT TRANSFORM THE LANDSCAPE OF ADOLESCENT HEALTH BY FOSTERING COLLABORATION, DRIVING INNOVATION, AND IMPROVING OUTCOMES FOR YOUNG PEOPLE. EXTERNAL PARTNERS, INCLUDING CURRENT AND PRIOR TPP GRANTEES AND TITLE X PROVIDERS AND OTHER CBOS, WILL SUPPLEMENT THE CORE TEAM WITH EXPERTISE IN A BROAD RANGE OF VULNERABLE POPULATIONS, AND ENVIRONMENTS. THROUGH OUR INCUBATOR, CHLA STRIVES TO SUPPORT GROUNDBREAKING SOLUTIONS, EMPOWER DIVERSE AND NON-TRADITIONAL STAKEHOLDERS, AND INSPIRE COLLECTIVE ACTION TO ENSURE THAT ALL ADOLESCENTS REACH THEIR FULL POTENTIAL. OUR VISION IS A WORLD WHERE ADOLESCENTS HAVE THE SUPPORT, CONFIDENCE, AND RESOURCES TO THRIVE, BE HEALTHY, AND BUILD THEIR MOST BRILLIANT FUTURES.

ESTABLICHMENT OF CHLA'S CHILDREN CLINICAL CENTER

CELLULAR PREDISPOSITION TO RETINOBLASTOMA TUMORIGENESIS

FUTURE-ORIENTED PREGNANCY PREVENTION INTERVENTION FOR HIGHLY MOBILE YOUTH

HORMONAL AND NUTRITIONAL REGULATION OF HYPOTHALAMIC NEUROGENESIS

PATIENT NAVIGATION FOR IMPROVING TRANSITION SUCCESS AMONG MULTIPLY DISADVANTAGED YOUNG ADULT SURVIVORS OF CHILDHOOD CANCER - IN RECENT YEARS, AGGREGATE 5-YEAR SURVIVAL AFTER CHILDHOOD CANCER SURPASSED 85% AND AT LEAST 500,000 INDIVIDUALS LIVING IN THE US ARE CHILDHOOD CANCER SURVIVORS (CCS). UNFORTUNATELY, TREATMENT-RELATED LATE EFFECTS OCCUR IN MORE THAN TWO THIRDS OF CCS AND IN HALF ARE SEVERE OR LIFE-THREATENING, WITH A STEADILY RISING CUMULATIVE INCIDENCE THAT RESULTS IN PREMATURE MORTALITY, EXCESS MORBIDITY, PSYCHOSOCIAL DISTRESS, AND LOWER QUALITY OF LIFE. GIVEN THIS LIFE-LONG BURDEN, FORMAL TRANSITION OF SURVIVORSHIP CARE FROM PEDIATRIC TO ADULT-FOCUSED PROVIDERS IS RECOMMENDED FOR CCS TO ENSURE CONTINUATION OF MEDICALLY AND DEVELOPMENTALLY APPROPRIATE MANAGEMENT OVER THE LIFE SPAN. DESPITE THIS, USE OF VARIOUS TRANSITIONAL CARE MODELS, KNOWLEDGE OF KEY TRANSITION BARRIERS AND FACILITATORS, AND THE AVAILABILITY OF PUBLISHED GUIDELINES FOR LATE EFFECTS SCREENING INTO ADULTHOOD HAVE LARGELY FAILED TO ACHIEVE SUCCESSFUL TRANSITION AND OPTIMAL SURVIVORSHIP CARE FOR MOST YOUNG ADULT CCS. THESE ISSUES ARE EXACERBATED AMONG CCS WHO ARE LOW SES AND ARE UNDER/UNINSURED. FURTHERMORE, EMERGING EVIDENCE SHOWS THAT CCS REPORT HIGH UNMET HEALTH-RELATED SOCIAL NEEDS (HRSN) SUCH AS FINANCIAL HARDSHIP, FOOD INSECURITY, LACK OF TRANSPORTATION, LOW HEALTH INSURANCE LITERACY, AND PSYCHOLOGICAL BURDEN. SUCH SURVIVORS REPRESENT A POPULATION AT EVEN HIGHER RISK OF EARLY FOLLOW-UP ATTRITION, LOWER RETENTION IN GUIDELINE-CONCORDANT CARE, AND DOWNSTREAM ADVERSE IMPACTS ON HEALTH STATUS. PATIENT NAVIGATION IS AN INTERVENTION THAT HAS ROBUST EVIDENCE IN ADULT CANCER PREVENTION AND TREATMENT BUT HAS NOT BEEN STUDIED FOR IMPROVING SURVIVORSHIP TRANSITION AMONG CCS. THE OVERALL HYPOTHESIS IS THAT A HRSN-INFORMED PATIENT NAVIGATOR (PN) TRANSITION INTERVENTION WILL BE EFFECTIVE IN IMPROVING RATES OF SUCCESSFUL TRANSITION FOR CCS. IN THIS PROPOSED STUDY CONDUCTED AT A SAFETY NET CHILDREN’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

PERSONAL RESPONSIBILITY EDUCATION PROGRAM

TOWARD SCALABLE BIOMARKER-BASED PREDICTION OF ASD IN HIGH-RISK INFANTS

MOLECULAR ANATOMY OF HUMAN ALVEOLAR DEVELOPMENT

MOLECULAR BASIS OF LUNG MORPHOGENESIS INJURY & REPAIR

INVESTIGATING THE MECHANISM OF ITGA4/6-MEDIATED CHEMOPROTECTION OF ALL CELLS

HOME INTERVENTION FOR REDUCING SUGARY DRINKS & OBESITY IN HISPANIC WOMEN-INFANTS

LEADERSHIP EDUCATION IN ADOLESCENT HEALTH (LEAH)

EXOSOMES IN TUMOR CELL-MESENCHYMAL STROMAL CELL INTERACTION

EARLY JOINT CRANIAL AND BRAIN DEVELOPMENT FROM FETAL AND PEDIATRIC IMAGING - PROJECT SUMMARY THE DEVASTATING IMPACTS OF EARLY-CHILDHOOD CRANIAL AND SKULL DEFORMITIES AFFECT NEARLY 25% OF INFANTS FROM SINGLE PREGNANCIES AND 50% OF THOSE FROM MULTIPLE PREGNANCIES. IF NOT DIAGNOSED EARLY AND TREATED EFFECTIVELY, THESE ABNORMALITIES CAN IMPACT BRAIN DEVELOPMENT, LEADING TO COGNITIVE IMPAIRMENT, ELEVATED INTRACRANIAL PRESSURE, AND MOTOR DISABILITIES. CLINICIANS’ CAPACITY TO EFFECTIVELY DIAGNOSE AND TREAT THESE DISORDERS IS HINDERED BY TWO THINGS: FIRST, A LIMITED UNDERSTANDING OF HOW THE CRANIUM AND BRAIN NORMALLY GROW AND CO- DEVELOP; AND, SECOND, A DEARTH OF IMAGING TECHNIQUES THAT ARE SENSITIVE ENOUGH TO ANALYZE JOINT CRANIAL AND BRAIN DEVELOPMENT IN BOTH HEALTHY AND ABNORMAL INSTANCES. TO ADDRESS THESE LIMITATIONS, A STRONG, INTERDISCIPLINARY, COLLABORATIVE TEAM FROM CHILDREN’S NATIONAL HOSPITAL, CHILDREN’S HOSPITAL LOS ANGELES, BROWN UNIVERSITY, UNIVERSITY OF COLORADO AND ARIZONA STATE UNIVERSITY PROPOSES THE CURRENT R01 AIMED AT DEVELOPING THE FIRST NORMATIVE JOINT MODEL OF BRAIN AND CRANIUM DEVELOPMENT BEFORE AND AFTER BIRTH. THIS WORK IS F UELED BY THE TEAM’S ROBUST PRIOR EFFORTS, IN WHICH THEY INDEPENDENTLY COLLECTED LARGE, NORMATIVE DATASETS OF COMPUTED TOMOGRAPHY (CT) AND MAGNETIC RESONANCE (MR) IMAGES OF INFANTS AND FETUSES, AND IMPLEMENTED PRELIMINARY TOOLS TO ANALYZE THEM AS A STARTING POINT FOR NEW METHODS TO BE DEVELOPED AS PART OF THIS PROJECT . THE TEAM’S HYPOTHESIS IS THAT THE DEVELOPMENT OF REGIONAL CORTICAL AND CRANIAL MORPHOLOGIES WILL BE STRONGLY ASSOCIATED. IT WILL BE TESTED USING THE FOLLOWING AIMS: (1) DEVELOP QUANTITATIVE IMAGING TOOLS TO MODEL HEALTHY CRANIAL DEVELOPMENT IN INFANTS; (2) DETERMINE THE JOINT DEVELOPMENT OF CRANIAL AND CORTICAL SHAPE AND THICKNESS IN INFANTS; (3) DEVELOP A PRELIMINARY MODEL OF FETAL BRAIN AND CRANIAL GROWTH ACROSS GESTATION; AND (4) BUILD AND DISSEMINATE A USER-FRIENDLY TOOLBOX FOR CLINICIANS AND RESEARCHERS. THIS PROJECT WILL BE THE RST SYSTEMATIC IN-VIVO STUDY OF JOINT HEALTHY CRANIAL AND BRAIN DEVELOPMENT BEFORE AND AFTER BIRTH. AS SUCH, IT WILL DETERMINE TYPICAL VARIATIONS OF THE CRANIAL SHAPE AND THEIR CORRELATIONS WITH BRAIN PARAMETERS, ADJUSTED FOR AGE AND SEX. THE NORMATIVE MODELS GENERATED HERE WILL SERVE AS CLINICAL RESOURCES FOR MATCHED COMPARISONS IN INDIVIDUAL CHILDREN WITH SUSPECTED DISORDERS THAT INVOLVE ABNORMAL CRANIAL SHAPES. ADDITIONALLY, PRECISE IN-VIVO QUANTITATIVE IMAGING METHODS FOR ASSESSING JOINT CRANIAL AND BRAIN SHAPE IN INF ANTS WILL BE DEVELOPED IN THIS PROJECT AND WILL SERVE AS INVALUABLE TOOLS FOR PHYSICIANS TO BETTER ASSESS, DIAGNOSE, AND PLAN TREATMENT FOR INFANT CRANIAL DEFORMITIES IN THE FUTURE.

REGULATION OF COLON EPITHELIAL CELL SURVIVAL BY NRG4-ERBB4 SIGNALING

GRADUATE PSYCHOLOGY EDUCATION PROGRAMS

DIAGNOSTIC AND PROGNOSTIC SARCOMA SIGNATURES

IMAGING BRAIN, NEUROCOGNITIVE AND PUBERTAL MATURATION DURING ADOLESCENCE

BRAIN ENDOTHELIAL RECEPTOR FOR E. COLI

CHILDRENS HOSPITAL LOS ANGELES CHILD HEALTH RESEARCH CAREER DEVELOPMENT AWARD

NUTRIGENETIC INTERVENTION TO REDUCE LIVER FAT IN HISPANICS

GUT MICROBIAL AND METABOLIC MEDIATORS OF ROTAVIRUS VACCINE RESPONSE

IDENTIFYING AND PREVENTING VENTILATOR INDUCED DIAPHRAGM WEAKNESS IN CHILDREN

EMERGENCE OF ARM REACHING BEHAVIOR AND LATERALIZATION OF MOTOR CONTROL IN INFANCY

MECHANISMS INVOLVED IN PODOCYTE DAMAGE IN ALPORT SYNDROME - DURING THE PROGRESSION OF MOST CHRONIC KIDNEY DISEASES (CKD) PODOCYTES ARE LOST, AND INJURY TO GLOMERULAR ENDOTHELIAL CELLS, AND CHANGES IN THE COMPOSITION OF THE GLOMERULAR BASEMENT MEMBRANE (GBM) LEAD TO ALTERATIONS OF THE STRUCTURE AND FUNCTION OF THE GLOMERULAR FILTRATION BARRIER. UNDERSTANDING THE MECHANISMS THAT INDUCE GLOMERULAR CELL DAMAGE COULD POSSIBLY PAVE THE WAY TO THE DISCOVERY OF NEW PATHWAYS THAT CAN BE TARGETED TO SLOW KIDNEY DISEASE PROGRESSION OR POSSIBLY REVERSE IT. DATA PRESENTED IN THIS PROPOSAL, USING THE GLOMERULUS ON A CHIP PLATFORM AND THE FUCCI MOUSE MODEL THAT ALLOWS TRACKING OF THE CELL CYCLE CHANGES IN VIVO, SHOW THAT PODOCYTES PRESENT AN ALTERED BINDING TO THEIR GBM, THEY EXIT THEIR QUIESCENT STATE, AND ARE LOST DURING DISEASE PROGRESSION IN ALPORT SYNDROME (AS) MICE, OUR MODEL OF CKD CHARACTERIZED BY A DEFECTIVE GBM. WE HAVE EVIDENCE THAT MIR-193A IS UPREGULATED SPECIFICALLY IN MOUSE AND HUMAN AS PODOCYTES AND THAT ITS INHIBITION FAVORS PODOCYTE SURVIVAL AND MODULATE PODOCYTE INTERACTIONS WITH THEIR GBM. BASED ON OUR DATA, WE HYPOTHESIZE THAT RE-ESTABLISHING GLOMERULAR FUNCTION BY MODULATING IMPORTANT MOLECULAR PATHWAYS THAT ARE RESPONSIBLE FOR PODOCYTE SURVIVAL PREVENTS FURTHER INJURY, THUS SLOWING KIDNEY DISEASE PROGRESSION. USING MULTIPLE TRANSGENIC AS FUCCI MICE AND IN VITRO HUMAN SYSTEMS, WE WILL STUDY THE MOLECULAR MECHANISMS THAT REGULATE THE PODOCYTE CELL CYCLE AND THEIR INTERACTION WITH A DEFECTIVE GBM, TYPICAL OF AS. SPECIFICALLY, IN AIM 1 WE WILL STUDY IN VITRO HOW MODULATION OF MIR-193A CAN “RE-PROGRAM” CELLULAR SIGNALING NETWORKS THAT INFLUENCE PODOCYTE BIOLOGY. IN AIM 2 WE WILL PERFORM IN VIVO STUDIES TO DETERMINE THE THERAPEUTIC EFFECT OF MIR-193A INHIBITOR DELIVERED AS CARGO OF AN INNOVATIVE DELIVERY VEHICLE BASED ON PEPTIDE AMPHIPHILE MICELLE NANOPARTICLES SPECIFICALLY DESIGNED TO TARGET PODOCYTES IN OUR AS COLONIES. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL PROVIDE NOVEL INSIGHTS INTO KEY FACTORS CRITICAL FOR MAINTENANCE OF GLOMERULAR STRUCTURE AND FUNCTION. IMPORTANTLY, THIS KNOWLEDGE WOULD LIKELY BE APPLICABLE TO OTHER FORMS OF CKD AND POSSIBLY FACILITATE THE DISCOVERY OF NEW THERAPEUTIC AGENTS TAILORED SPECIFICALLY TO SUSTAIN PODOCYTE SURVIVAL AND MINIMIZE GLOMERULAR DAMAGE.

MECHANISMS OF CHANGE WITH EARLY INTERVENTION IN TUBEROUS SCLEROSIS COMPLEX

THE IMPACT OF OPIOIDS ON HEALTH OUTCOMES FOR HOSPITALIZED INFANTS - PROJECT SUMMARY CARING FOR HOSPITALIZED INFANTS REQUIRES A COMPREHENSIVE PAIN CONTROL PROGRAM AIMED AT REDUCING AND PREVENTING PAIN. WHILE OPIOIDS ARE COMMONLY USED WHEN AN INFANT UNDERGOES A PAINFUL PROCEDURE, OPIOIDS CAN INCREASE THE RISK OF SHORT- AND LONG-TERM MORBIDITY. THE DURATION AND TYPE OF OPIOIDS USED FOR HOSPITALIZED INFANTS VARIES WIDELY BETWEEN INSTITUTIONS AND SUCH WIDE VARIATIONS COULD IMPACT EARLY CHILDHOOD DEVELOPMENT AND OVERALL HEALTHCARE UTILIZATION. IN THIS STUDY, WE WILL CREATE A NOVEL CLINICAL AND DEVELOPMENTAL DATASET BY MERGING THE PEDIATRIC HEALTH INFORMATION SYSTEM (PHIS) AND THE CALIFORNIA PERINATAL QUALITY CARE COLLABORATIVE (CPQCC). THIS MERGED DATASET WILL BE THE FIRST LARGE RETROSPECTIVE, MULTI-CENTER COHORT REPRESENTING DIVERSE POPULATIONS OF CRITICALLY ILL, HOSPITALIZED INFANTS LINKING THEIR IN-HOSPITAL DATA WITH LONG-TERM NEURODEVELOPMENTAL OUTCOMES. USING THIS NOVEL DATASET, WE WILL (1) IDENTIFY VARIATIONS IN OPIOID USE ASSOCIATED WITH NEURODEVELOPMENTAL DISABILITY AND LONG-TERM RESOURCE UTILIZATION FOR HIGH-RISK INFANTS, (2) QUANTIFY CUMULATIVE OPIOID DOSING RECEIVED ASSOCIATED WITH NEURODEVELOPMENTAL DISABILITY FOR HIGH-RISK INFANTS, AND (3) QUANTIFY DIFFERENCES IN HEALTHCARE UTILIZATION AND COSTS ASSOCIATED WITH HIGH VS. LOW OPIOID USE AMONG HIGH-RISK INFANTS. THE EXPECTED OUTCOME IS A COMPREHENSIVE UNDERSTANDING OF THE VARIATIONS IN OPIOID USE FOR HIGH-RISK INFANTS AND ITS IMPACT ON NEURODEVELOPMENT AND HEALTHCARE UTILIZATION. RESULTS WILL LEAD TO INTERVENTIONS FOR HOSPITALIZED INFANTS AIMED AT MINIMIZING VARIATION IN PAIN CONTROL AND WILL ALSO INFORM POLICYMAKERS OF A PREVIOUSLY UNRECOGNIZED INFANT POPULATION IN NEED OF INCREASED RESOURCES TO IMPROVE CLINICAL AND DEVELOPMENTAL OUTCOMES.

KIDS SEEK CURE FOR KIDS

RESPONSIBLE YOUNG FATHERS PROJECT

IMPACT OF EARLY LIFE EXPERIENCE ON VAGAL NEURONS AND CIRCUITS - CHRONIC STRESS PROFOUNDLY AFFECTS PHYSICAL AND MENTAL HEALTH. EVOLUTIONARILY CONSERVED RESPONSES TO EARLY LIFE STRESS (ELS), CHARACTERIZED IN HUMANS AS ADVERSE CHILDHOOD EXPERIENCES (ACES), SUPPORT THEIR INVESTIGATION USING ANIMAL MODELS. NEARLY 1 IN 6 ADULTS IN THE U.S. EXPERIENCE 4 OR MORE ACES, RESULTING IN INCREASED INCIDENCE OF PHYSIOLOGICAL DYSFUNCTIONS LINKED TO CHRONIC BRAIN AND MULTI-ORGAN DISEASES. WE HYPOTHESIZE THAT THE MULTI-SYSTEM CONSEQUENCES OF ELS ARE LINKED TO AS-YET UNDEFINED GENOMIC AND FUNCTIONAL ADAPTATIONS IN VAGAL NEURONS AND CIRCUITS. VAGAL SENSORY NEURONS COMPRISE A MAJOR COMMUNICATION ROUTE FROM VISCERA TO BRAIN THAT SHAPES MOTIVATED BEHAVIOR, METABOLISM, PITUITARY HORMONE SECRETION, INFLAMMATION, AND AUTONOMIC OUTFLOW. IN CONCERT, CORTICO-LIMBIC AND HYPOTHALAMIC CENTERS MODULATE VAGAL PARASYMPATHETIC CONTROL OVER CARDIOVASCULAR, DIGESTIVE, AND IMMUNE-RELATED FUNCTIONS. ELS IS LINKED TO REDUCTIONS IN VAGAL TONE THAT PROMOTE A VARIETY OF PHYSIOLOGICAL DYSFUNCTIONS, AND OUR PUBLISHED AND PILOT PRECLINICAL FINDINGS IN RODENTS INDICATE THAT ELS INDUCES EARLY AND PERSISTENT TRANSCRIPTIONAL AND CONNECTIONAL ADAPTATIONS IN VAGAL NEURONS AND CIRCUITS. GIVEN THAT VAGAL SENSORY-MOTOR FUNCTIONS ARE INTEGRAL TO PHYSIOLOGICAL HEALTH STATUS, SURPRISINGLY FEW STUDIES HAVE EXAMINED DEVELOPMENTAL AND ADULT VAGAL PHENOTYPES THAT CONTRIBUTE TO DISEASE RISK IN THE FACE OF ELS. OUR PUBLISHED AND PRELIMINARY DATA PROVIDE THE FOUNDATION FOR OUR WORKING HYPOTHESIS THAT ELS TRIGGERS EARLY AND LONG-TERM TRANSCRIPTOME-LEVEL MOLECULAR ADAPTATIONS IN VAGAL NEURONS, COUPLED WITH FUNCTIONAL ADAPTATIONS IN CENTRAL VAGAL CIRCUITS. THE PROPOSED RESEARCH BEGINS TO ADDRESS THIS BY PURSUING FOUR SPECIFIC AIMS IN AN ESTABLISHED MOUSE MODEL OF ELS: 1) DETERMINE THE EARLY DEVELOPMENTAL AND LONG-TERM IMPACT OF ELS ON VAGAL SUBCLASS MOLECULAR PHENOTYPES USING ADVANCED TRANSCRIPTOMICS STRATEGIES; 2) DETERMINE LONG-TERM ELS EFFECTS ON THE TRANSCRIPTIONAL PROFILES OF VAGAL NEURON SUBTYPES INNERVATING SPECIFIC DIGESTIVE VISCERA USING MOLECULAR ANATOMICAL STRATEGIES; 3) DETERMINE EARLY AND LONG-TERM EFFECTS OF ELS ON THE CENTRAL VAGAL CONNECTOME USING TRANSSYNAPTIC VIRAL LABELING; AND 4) DETERMINE LONG-TERM FUNCTIONAL EFFECTS OF ELS ON VAGO-VAGAL SIGNALING. THIS RESEARCH PROGRAM ADDRESSES A HIGH-IMPACT PRECLINICAL PROBLEM THROUGH INNOVATIVE DISCOVERY RESEARCH THAT LEVERAGES THE STRENGTHS OF OUR MULTI-PI RESEARCH TEAM. WE INCLUDE SEX AS A BIOLOGICAL VARIABLE IN ALL EXPERIMENTS, BASED ON SOME REPORTED SEX DIFFERENCES IN THE EFFECTS OF ELS ON VISCERAL SENSORY-MOTOR FUNCTIONS IN RODENTS AND IN HUMANS. THE PROPOSED WORK WILL PROVIDE A NOVEL UNDERSTANDING OF EXPERIENCE-DRIVEN DEVELOPMENTAL ADAPTATIONS IN INTEROCEPTIVE SIGNALING PATHWAYS AND VISCERAL MOTOR CONTROL IN MICE, WITH A UNIQUE FOCUS ON VAGAL CIRCUITS THAT BRIDGE CENTRAL AND PERIPHERAL SYSTEMS AT HIGH RISK FOR ELS-INDUCED DYSFUNCTION. THIS COLLABORATIVE, MULTI-PI RESEARCH PROGRAM WILL PROVIDE A NEW PLATFORM FOR FUTURE MECHANISTIC STUDIES PROBING CAUSAL LINKS BETWEEN ELS, CHRONIC DISEASE, AND EXPERIENCE-DRIVEN ADAPTATIONS IN VAGAL SENSORY AND MOTOR SYSTEMS.

TRANSLATION OF PREDICTIVE CANCER BIOMARKERS INTO CLINICAL PRACTICE

PRECISION DOSING FOR CRITICALLY ILL CHILDREN - THE DRUG DEVELOPMENT PROCESS AND FDA-APPROVED PRESCRIBING GENERALLY ASSUME THAT PATIENTS ARE SUFFICIENTLY STABLE AND SIMILAR ENOUGH TO JUSTIFY POPULATION-BASED DOSING FOR A GIVEN GROUP THAT IS USUALLY UNCHANGED DURING THERAPY. UNFORTUNATELY, THERE IS A HUGE BODY OF EVIDENCE THAT DOSING ACCORDING TO THIS “ONE SIZE FITS ALL” PARADIGM RESULTS IN WIDE VARIATION IN PLASMA DRUG CONCENTRATIONS BETWEEN INDIVIDUALS AND EVEN WITHIN THE SAME INDIVIDUAL OVER TIME, ALL OF WHICH CAN COMPROMISE CLINICAL OUTCOMES. POPULATION PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) MODELS CAN CONTROL FOR THIS VARIABILITY BY PROVIDING CLINICIANS WITH TOOLS TO ADJUST DOSES ACCORDINGLY, A PROCESS THAT HAS COME TO BE KNOWN AS MODEL-INFORMED PRECISION DOSING (MIPD). HOWEVER, MIPD HAS BEEN BETTER ABLE TO CONTROL FOR INTER-INDIVIDUAL VARIATION RATHER THAN INTEROCCASION VARIATION (IOV) WITHIN AN INDIVIDUAL OVER TIME. MIPD METHODS EXIST TO TRACK IOV IN THE PAST, BUT NOT TO ACCOUNT FOR POSSIBLE FUTURE IOV. IN THIS PROJECT WE WILL ADDRESS IOV IN THREE NOVEL APPROACHES. OUR FIRST AIM USES OUR UNIQUE VIRTUAL PEDIATRIC INTENSIVE CARE UNIT (VPICU) DATASET WITH >400 CLINICAL VARIABLES OBTAINED FROM ~20,000 UNSTABLE, CRITICALLY ILL CHILDREN IN OUR HOSPITAL SINCE 2009. WE WILL BUILD RECURRENT NEURAL NETWORKS (RNNS) TO PREDICT CHANGES IN RENAL FUNCTION WITHIN INDIVIDUALS, WHICH IS RELEVANT TO THE CONTROL OF RENALLY EXCRETED DRUGS. WHILE MODELS EXIST TO PREDICT RENAL FAILURE, THIS WILL BE THE FIRST APPLICATION OF RNNS TO PREDICT CREATININE CLEARANCE IN CHILDREN. THERE ARE >100,000 SERUM CREATININE MEASUREMENTS TO VALIDATE THIS WORK. OUR SECOND AIM IS TO ACCOUNT FOR CHANGING PK-PD IN MODELS THAT CANNOT BE LINKED TO A SPECIFIC COVARIATE LIKE RENAL FUNCTION. TO DO THIS, WILL INCORPORATE STOCHASTIC DIFFERENTIAL EQUATIONS (SDES) TO CAPTURE CHANGES IN MODEL PARAMETERS OVER TIME. UNIQUE TO OUR WORK, WE WILL APPLY SDES IN THE SETTING OF OUR LONG HISTORY OF NON-PARAMETRIC PK-PD MODELING, WHICH MAKES NO ASSUMPTIONS ABOUT UNDERLYING PROBABILITY DISTRIBUTIONS FOR PARAMETER VALUES IN A MODEL AND IS PARTICULARLY GOOD AT DESCRIBING AND CONTROLLING UNUSUAL PATIENTS, PERFECT FOR A CRITICALLY ILL POPULATION. WE WILL USE >40,000 VANCOMYCIN DOSES AND >5,000 PLASMA CONCENTRATIONS IN VPICU TO TEST OUR ALGORITHMS. OUR THIRD AIM IS TWO-FOLD. FIRST, WE WILL AGAIN USE RNNS TO PREDICT OUTCOMES OF VPICU PATIENTS WITH STAPHYLOCOCCAL BLOODSTREAM INFECTIONS TREATED WITH VANCOMYCIN. WE WILL COMPARE RNNS THAT INCLUDE VANCOMYCIN EXPOSURE ESTIMATED WITH IOV AND WITHOUT IOV. THE SECOND PART IS TO USE OUR IN VITRO HOLLOW FIBER INFECTION MODEL (HFIM) TO DIRECTLY ASSESS THE EFFECT OF VANCOMYCIN IOV ON BOTH METHICILLIN-RESISTANT AND METHICILLIN-SUSCEPTIBLE STAPHYLOCOCCUS AUREUS IN OUR LABORATORY. THE HFIM CAN REPRODUCE PEDIATRIC PK TO MEASURE ANTIBACTERIAL KILL AND EMERGENCE OF LESS SUSCEPTIBLE OR PERSISTER ORGANISMS OVER DAYS TO WEEKS. OUR INCLUSION OF IOV IN THE HFIM IS COMPLETELY NOVEL. WE WILL DELIVER SOFTWARE TOOLS TO CLINICIANS TO CONTROL IOV AND UNDERSTAND THE MAGNITUDE RELEVANT TO OUTCOMES OF ANTI-STAPHYLOCOCCAL THERAPY.

LONGITUDINAL MAPPING OF MATURATIONAL CHANGE IN BRAIN FUNCTION-STRUCTURE RELATIONS

UCEDD

BRAIN-IMAGING MARKERS OF NEUROTOXICITY AND LONG-TERM OUTCOMES AFTER CAR-T CELL THERAPY - PROJECT SUMMARY CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELL THERAPY FOR RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) INDUCES COMPLETE REMISSION IN 70-90% OF OTHERWISE INCURABLE PATIENTS. CAR-T CELL ENGAGEMENT WITH THEIR TARGET ANTIGENS INDUCES EXPANSION OF ACTIVATED CAR-T CELLS, PRODUCING CYTOKINES AND OTHER PRO-INFLAMMATORY MEDIATORS. UNFORTUNATELY, IN APPROXIMATELY 50% OF PATIENTS THIS INFLAMMATORY RESPONSE ALSO PRODUCES AN IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS), A SERIOUS NEUROTOXICITY CHARACTERIZED BY DELIRIUM, ENCEPHALOPATHY, DYSPHASIA, AND IN SEVERE CASES, DIFFUSE CEREBRAL EDEMA THAT CAN BE FATAL. ADDITIONALLY, ICANS INCREASES THE RISK FOR LONG-TERM COGNITIVE IMPAIRMENTS; POSSIBLE CONSEQUENCES THAT HAVE NOT BEEN SYSTEMATICALLY STUDIED. ICANS THEREFORE REMAINS A MAJOR CHALLENGE FOR THE WIDER ADOPTION OF CAR-T CELL THERAPY, CREATING AN URGENT NEED TO MITIGATE OR PREVENT ICANS, TO UNDERSTAND ITS PATHOPHYSIOLOGY, AND TO PREDICT ITS ADVERSE LONG-TERM OUTCOMES. WE HAVE COMPELLING PRELIMINARY DATA DEMONSTRATING THAT SEVERAL PRE-INFUSION NEUROIMAGING MARKERS PREDICT ICANS WITH HIGH ACCURACY. BUILDING UPON THESE FINDINGS, WE WILL DEVELOP A PREDICTIVE ALGORITHM IN THIS PROPOSAL THAT WILL FACILITATE CLOSER MONITORING OF HIGH-RISK PATIENTS, SUPPORT WITH PREVENTIVE TREATMENTS, AND RISK-ADAPTED DOSING OF CAR-T CELLS. OUR PRELIMINARY DATA ALSO SUGGEST THAT NEUROIMAGING BIOMARKERS SERVE AS OBJECTIVE SURROGATES FOR CLINICAL AND SUBCLINICAL ICANS. THESE MARKERS MAY GUIDE FUTURE DEVELOPMENT OF TARGETED ANTI-CYTOKINE AND SMALL MOLECULE INHIBITOR-BASED INTERVENTIONS TO INHIBIT OR BLOCK NEUROTOXICITY-SPECIFIC PATHWAYS. FINALLY, PRELIMINARY DATA SUPPORT OUR HYPOTHESIS THAT ICANS-INDUCED ABNORMALITIES IN ATTENTIONAL NETWORKS OF THE BRAIN CAUSE LONG-TERM NEUROCOGNITIVE IMPAIRMENTS. ADVERSE OUTCOMES ARE ALSO SEEN IN LOW GRADE NEUROTOXICITY, SUGGESTING A GREATER NEED THAN PREVIOUSLY ANTICIPATED FOR COGNITIVE AND BEHAVIORAL INTERVENTIONS IN CAR-T CELL PATIENTS, RATHER THAN ONLY IN PATIENTS WITH FLORID NEUROTOXICITY. EXPANDING ON OUR PILOT STUDY, WE PROPOSE TO CONDUCT A PROSPECTIVE, LONGITUDINAL COHORT STUDY OF 80 CONSECUTIVE PATIENTS WHO RECEIVE CAR-T CELL THERAPY FOR B-ALL. WE WILL COLLECT STATE-OF-THE-ART (A) CLINICAL ASSESSMENTS FOR ICANS AND CRS, (B) MULTI-MODAL MRI TO CHARACTERIZE BRAIN STRUCTURE, FUNCTION, AND METABOLISM, (C) PERIPHERAL BLOOD SAMPLES FOR IMMUNOPHENOTYPING USING CYTOF (MASS CYTOMETRY BY TIME-OF-FLIGHT) AND TO PROFILE CYTOKINES AND BIOMARKERS OF BLOOD BRAIN BARRIER INTEGRITY, AND (D) NEUROCOGNITIVE TESTING TO CHARACTERIZE COGNITIVE CHANGES. LONGITUDINAL DATA WILL BE COLLECTED AT (1) A PRE- INFUSION BASELINE; AND THEN POST-INFUSION ON (2) DAY 10, WHEN THE ICANS RISK IS GREATEST, (3) DAY 28, UPON ICANS RESOLUTION, AND (4) MONTH 12, FOR LONG-TERM OUTCOMES. THESE DATA WILL IDENTIFY, WITH UNPARALLELED INFERENTIAL CAPACITY, BRAIN-BASED PREDICTORS AND INFLAMMATORY MEDIATORS OF ICANS, HELP DEVELOP BRAIN MRI GUIDELINES FOR CAR-T CELL THERAPY, AND HELP RECOMMEND SPECIFIC COGNITIVE TRAINING AND NEUROPROTECTIVE STRATEGIES IN PATIENTS WITH PERSISTENT BRAIN DEFICITS.

PATIENT VENTILATOR ASYNCHRONY IN CRITICALLY ILL CHILDREN - PROJECT SUMMARY MECHANICALLY VENTILATED CHILDREN OFTEN HAVE PATIENT-VENTILATOR ASYNCHRONY (PVA) ALTHOUGH THIS IS INCOMPLETELY CHARACTERIZED IN THE LITERATURE AND INFREQUENTLY RECOGNIZED AT THE BEDSIDE. WHEN A VENTILATED PATIENT HAS SPONTANEOUS EFFORT, THE VENTILATOR ATTEMPTS TO SYNCHRONIZE WITH THE PATIENT, BUT PVA REPRESENTS A MISMATCH BETWEEN WHAT THE PATIENT WANTS AND WHAT THE VENTILATOR DELIVERS. PVA IS COMMON IN VENTILATED ADULTS AND IS ASSOCIATED WITH LONGER DURATION OF VENTILATION, INCREASED RISK OF INFECTION, LUNG INJURY, DIAPHRAGM DYSFUNCTION, AND ADVERSE NEUROCOGNITIVE EFFECTS. WHILE THERE ARE MANY TYPES OF PVA, THEY ARE NOT EQUALLY HARMFUL OR PREVALENT. THERAPEUTIC STRATEGIES SHOULD FOCUS ON THE MOST HARMFUL FORMS OF PVA. ALTHOUGH WE STILL DON’T KNOW WHICH PVA SUBTYPES ARE TRULY MOST HARMFUL, DOUBLE CYCLED (DC) BREATHS (WHERE A SECOND BREATH IS DELIVERED BEFORE THE FIRST BREATH IS COMPLETE) HAVE THE STRONGEST BIOLOGICAL PLAUSIBILITY FOR HARM, BECAUSE DC INDUCES LUNG STRESS, STRAIN, VENTILATOR INDUCED LUNG INJURY AND ECCENTRIC CONTRACTION OF THE DIAPHRAGM. PVA IS UNDERSTUDIED IN CHILDREN, EVEN THOUGH IT MAY BE MORE COMMON AND GOES LARGELY UNRECOGNIZED EVEN BY HIGHLY TRAINED CLINICIANS. MOREOVER, EXISTING PEDIATRIC STUDIES HAVE FAILED TO IDENTIFY A CLEAR RELATIONSHIP BETWEEN PVA AND WORSE CLINICAL OUTCOMES, ALTHOUGH THESE STUDIES HAVE NOT FOCUSED ON THE HIGHEST RISK PATIENTS (SUCH AS THOSE WITH ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)), HAVE USED DIFFERENT DEFINITIONS FOR PVA AND ITS SUBTYPES, AND HAVE BEEN INADEQUATELY POWERED TO EVALUATE THE RELATIONSHIP BETWEEN PVA SUBTYPES AND OUTCOME. THIS PROPOSAL WILL SET THE STAGE FOR THERAPEUTIC STRATEGIES TO MANAGE PVA IN CHILDREN AND WILL FILL CRUCIAL KNOWLEDGE AND IMPLEMENTATION GAPS INCLUDING: (1) HARMONIZING HOW PVA IS MEASURED AND DEFINED, (2) IDENTIFYING THE MOST HARMFUL PVA SUBTYPES AND THE PATIENTS AT RISK, AND (3) USING INNOVATIVE AND ACCURATE BEDSIDE TOOLS TO IMPROVE THE RECOGNITION OF PVA. WE WILL LEVERAGE THE EXPERTISE AND PRELIMINARY DATA FROM THREE PREMIER PEDIATRIC RESEARCH GROUPS WHO HAVE THE EXPERTISE TO USE PRECISE METHODS TO CAPTURE THE PATIENT’S NEURAL RESPIRATORY EFFORT, WHICH IS CRUCIAL TO CORRECTLY IDENTIFY PVA SUBTYPES. THIS PROPOSAL WILL INCLUDE PROSPECTIVE, MULTI-CENTER COLLECTION OF VENTILATOR WAVEFORMS FROM 200 VENTILATED CHILDREN USING PRECISE TECHNIQUES TO CAPTURE NEURAL RESPIRATORY EFFORT, IN ADDITION TO DETAILED SECONDARY ANALYSIS OF EXISTING WAVEFORMS AND CLINICAL DATA FROM OVER 350 CHILDREN. WE WILL USE CAUSAL INFERENCE AND MEDIATION APPROACHES TO EVALUATE THE RELATIONSHIP BETWEEN PVA SUBTYPES AND CLINICAL AND MECHANISTIC OUTCOMES BY LEVERAGING DATA FROM A RANDOMIZED CONTROLLED TRIAL (REDVENT, R01HL124666) WHERE PVA RATES AND SUBTYPES LIKELY DIFFER BETWEEN INTERVENTION AND CONTROL GROUPS. THIS TRIAL IS PRESCRIBING A MECHANICAL VENTILATION STRATEGY PROMOTING MORE SPONTANEOUS BREATHING TO ACHIEVE LUNG AND DIAPHRAGM PROTECTIVE VENTILATION, COMPARED TO USUAL CARE.

POPULATON PHARMACOKINETIC MODELING AND OPTIMAL CONTROL

USC UCEDD 5-YEAR GRANT APPLICATION, CHILDREN'S HOSPITAL LOS ANGELES, 2012-2017

MOLECULAR MECHANISMS OF LUNG BRANCHING MORPHOGENESIS

CENTER FOR ENVIRONMENT-MEDIATED DRUG RESISTANCE IN PEDIATRIC CANCER

MODIFICATION OF GUT MICROBIAL PROFILE IN CHILDREN WITH ULCERATIVE COLITIS

PREDICTING THE EARLY CHILDHOOD OUTCOMES OF PRETERM BRAIN SHAPE ABNORMALITIES

BASIC AND TRANSLATIONAL RESEARCH PROGRAM

CEREBROVASCULAR RESERVE AND WHITE MATTER DISEASE IN PATIENTS WITH ANEMIA

PLASMINOGEN ACTIVATOR INHIBITOR-1 IN TUMOR PROGRESSION AND METASTASIS

PRENATAL AND EARLY POSTNATAL LEAD EXPOSURE ON CHILDHOOD AND ADOLESCENT BRAIN, COGNITIVE AND BEHAVIORAL DEVELOPMENT

ENHANCEMENT AND EXPANSION OF TREATMENT AND RECOVERY SERVICES FOR ADOLESCENTS, TRANSITIONAL AGED YOUTH, AND THEIR FAMILIES THROUGH LINKAGE TO SCHOOLS AND A LARGE PEDIATRIC HOSPITAL EMERGENCY ROOM

PHYSIOLOGICALLY GUIDED VENTILATOR STRATEGIES IN CHILDREN

RISK FACTORS FOR OSTEOPOROSIS IN CHILDREN & ADOLESCENTS WITH MYELOMENINGOCELE

USC UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES AT CHILDREN?S HOSPITAL LOS ANGELES

PROMOTING SAFE AND SUPPORTIVE ENVIRONMENTS FOR LOCAL EDUCATIONAL AGENCIES PROVIDING SCHOOL-BASED HIV/STD PREVENTION - COMPONENT 3C

TARGETING OBESITY TO IMPROVE SURVIVAL FROM CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA - OBESITY IS A WORLDWIDE HEALTH CHALLENGE THAT INCREASES THE RISK OF DEVELOPING AND DYING FROM MULTIPLE TYPES OF CANCER. B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) IS THE MOST COMMON CHILDHOOD CANCER. DESPITE IMPROVED CURE RATES, CHILDREN WITH OBESITY AT DIAGNOSIS ARE MORE THAN TWICE AS LIKELY AS THEIR LEAN PEERS TO RESPOND POORLY TO INDUCTION THERAPY, AND EVENTUALLY TO RELAPSE AND DIE FROM THEIR DISEASE. THUS, SURVIVAL FOR CHILDREN WITH OBESITY HAS NOT IMPROVED IN LOCKSTEP WITH THE BROADER B-ALL POPULATION. CHEMOTHERAPY FOR B-ALL INDUCES MANY OF THE SAME PHYSIOLOGIC CHANGES IN NON-OBESE CHILDREN AS THOSE FOUND IN THE OBESE, THEREBY PLACING EVEN LEAN CHILDREN AT RISK FOR CHEMOTHERAPY RESISTANCE. IN A SERIES OF CLINICAL AND LABORATORY MODELS, CHEMORESISTANCE IN ALL DUE TO OBESE PHYSIOLOGY WAS FOUND TO BE POTENTIALLY REVERSIBLE. A RECENT PHASE I TRIAL DEMONSTRATED PROOF-OF-PRINCIPLE THAT A COMBINATION OF CALORIE, FAT, AND GLUCOSE RESTRICTION (CFGR), ACHIEVED THROUGH DIET AND PHYSICAL ACTIVITY, COULD REVERSE OBESITY-INDUCED CHEMORESISTANCE. THE TRIAL SHOWED THAT CFGR COULD BE INTEGRATED INTO PEDIATRIC B-ALL INDUCTION REGIMENS, AND MOST IMPORTANTLY, THAT CFGR REDUCED BY ~71% THE RATE OF MINIMAL RESIDUAL DISEASE AT THE END OF INDUCTION (EOI MRD); EOI MRD IS ONE OF THE MOST SIGNIFICANT PREDICTORS OF RELAPSE IN B- ALL. IN INVESTIGATING THE MECHANISMS UNDERLYING THE EFFICACY OF CFGR, INSULIN WAS DISCOVERED TO BE A LIKELY KEY INITIATOR OF CHEMORESISTANCE, AND ADIPONECTIN, AN UNDERAPPRECIATED HORMONE COUNTERING INSULIN EFFECTS IN B-ALL. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT CFGR WILL REDUCE MRD IN B-ALL THROUGH IMPROVING CHEMOSENSITIVITY BY LOWERING CIRCULATING INSULIN AND INCREASING ADIPONECTIN, TOGETHER REDUCING SIGNALING IN ALL PRO-SURVIVAL/ANTI-APOPTOTIC PATHWAYS. THE LONG-TERM GOAL OF THIS RESEARCH IS TO REVERSE OBESITY-INDUCED CHEMORESISTANCE TO IMPROVE SURVIVAL FROM B-ALL. IN THIS PROPOSAL, CFGR EFFICACY WILL BE EVALUATED IN A RANDOMIZED, MULTICENTER PHASE II TRIAL CONDUCTED THROUGH A PEDIATRIC LEUKEMIA CONSORTIUM. LEAN AND OBESE ENROLLED PATIENTS WITH HIGH-RISK B-ALL WILL RECEIVE INDUCTION CHEMOTHERAPY WITH OR WITHOUT CFGR FOR FOUR WEEKS. IN AIM 1, PATIENTS RANDOMIZED INTO STRATA BY OBESITY STATUS AND STARTING LEUKEMIA BURDEN (WHITE BLOOD CELL COUNT) WILL RECEIVE EITHER ONE-TIME NUTRITION AND EXERCISE EDUCATION (CONTROL ARM) OR EDUCATION PLUS CFGR (INTERVENTION ARM). PRIMARY ENDPOINTS WILL BE REDUCTIONS IN MRD AND CHANGE IN FAT MASS. SECONDARY ENDPOINTS WILL ASSESS ADHERENCE, FITNESS, MOTOR FUNCTION, TOXICITY, AND QUALITY OF LIFE. IN AIM 2, THE CONTRIBUTION OF CIRCULATING INSULIN AND ADIPONECTIN TO OBESE CHEMORESISTANCE AND CFGR EFFICACY WILL BE EXPLORED. CHANGES IN OBESE PHYSIOLOGY BY CFGR WILL BE ASSESSED VIA HORMONES, CYTOKINES, AND METABOLOMICS. THE OPPOSING EFFECTS OF OBESE PHYSIOLOGY AND CFGR ON INTRACELLULAR ACTIVATION OF AKT, MTOR, AND RAF/RAS CHEMORESISTANCE PATHWAYS WILL BE MEASURED USING MASS CYTOMETRY. RESULTS FROM THIS TRIAL WILL DEMONSTRATE EFFICACY OF CFGR TO IMPROVE DISEASE RESPONSE AND PROVIDE INSIGHT INTO THE MECHANISMS OF OBESITY-INDUCED CHEMORESISTANCE IN B-ALL, POTENTIALLY LEADING TO A PARADIGM SHIFT IN TREATING THIS DEADLY DISEASE.

ONTOGENY OF VORICONAZOLE PHARMAOCKINETICS AND METABOLISM

NAFLD IMPROVEMENT AFTER BARIATRIC SURGERY: THE ROLE OF BILE ACID SIGNALING

BONE DEFICITS AND MECHANICAL LOADING IN AMBULATORY CEREBRAL PALSY

PATHOGENESIS OF MOTHER TO CHILD TRANSMISSION OF HIV

LUNG INJURY; RELATES TO REAL-TIME ENDOSCOPIC MONITORING OF SINCLE CELLS RESPIRATORY HEALTH IN LUNG

MOLECULAR MECHANISMS UNDERLYING SUB-THALAMIC INFLUENCES ON EXTINCTION LEARNING - PROJECT SUMMARY. THE EXPRESSION OF DEBILITATING FEAR TOWARD STIMULI PREVIOUSLY ASSOCIATED WITH TRAUMA EVEN AFTER THEY NO LONGER POSE A THREAT IS A CORE PATHOLOGY OF POST-TRAUMATIC STRESS DISORDER (PTSD). SUCH MALADAPTIVE FEAR IS CAUSED BY AN INABILITY TO LEARN THAT THE STIMULI THAT HAD BEEN PREVIOUSLY LINKED TO TRAUMA ARE NO LONGER THREATENING. THESE DEFICITS IN EXTINCTION LEARNING ARE A HIGHLY PREVALENT DIMENSION OF PTSD AND SIGNIFICANTLY HAMPER QUALITY OF LIFE. COGNITIVE BEHAVIORAL THERAPY IN ISOLATION OR IN COMBINATION WITH PHARMACOTHERAPIES ARE THE MOST WIDELY USED TREATMENTS TO RESCUE DEFICITS IN EXTINCTION LEARNING. SUCH TREATMENTS ARE EFFECTIVE IN APPROXIMATELY 50% OF TREATED CASES, EMPHASIZING THAT THERE IS ROOM TO MORE EFFECTIVELY RESCUE DEFICITS IN EXTINCTION LEARNING. ONE WAY TO ACHIEVE THIS OBJECTIVE IS TO FIRST UNDERSTAND HOW EXTINCTION LEARNING IS FACILITATED BY MOLECULAR AND CELLULAR PROCESSES IN NEURAL CIRCUITRY THAT INFLUENCES EXTINCTION LEARNING. WHILE SEVERAL NEUROMODULATORS HAVE BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF PTSD, AMONG THEM, DOPAMINE HAS BEEN SHOWN TO PLAY A CENTRAL ROLE IN EXTINCTION LEARNING. MOST OF OUR UNDERSTANDING OF DOPAMINERGIC INFLUENCES ON EXTINCTION LEARNING HAS COME FROM A FOCUS ON THE A10 CLUSTER OF DOPAMINERGIC CELLS IN THE VENTRAL TEGMENTAL AREA (VTA). HOWEVER, A10 CELLS ARE ONE OF SEVERAL DISTINCT CLUSTERS OF DOPAMINERGIC CELLS THAT ARE EVOLUTIONARILY CONSERVED IN THE MAMMALIAN BRAIN. GAINING AN APPRECIATION FOR HOW DOPAMINERGIC CELLS OUTSIDE OF THE VTA MAY INFLUENCE EXTINCTION LEARNING WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF HOW DOPAMINERGIC SIGNALING MODULATES EXTINCTION LEARNING. MORE IMPORTANTLY, LEVERAGING ANY PROMISE THAT MANIPULATING DOPAMINERGIC CELLS MAY HOLD TO REDUCE DEFICITS IN EXTINCTION LEARNING REQUIRES UNDERSTANDING MOLECULAR PATHWAYS AND PHYSIOLOGICAL PRINCIPLES THAT ARE SHARED BY OR UNIQUE TO DOPAMINERGIC CELL CLUSTERS ACROSS THE BRAIN TO INFLUENCE EXTINCTION LEARNING. OUR LONG-TERM GOAL IS TO DETERMINE HOW DOPAMINERGIC CELLS OUTSIDE OF THE VTA CONTRIBUTE TO EXTINCTION LEARNING AND RECALL. TO ACHIEVE THIS GOAL, OUR IMMEDIATE OBJECTIVE WITH THIS PROPOSAL IS TO DETERMINE MOLECULAR AND CELLULAR MECHANISMS IN A13 DOPAMINERGIC CELLS IN THE ZONA INCERTA (ZI) THAT CONTRIBUTE TO EXTINCTION LEARNING. TO DO SO, WE BUILD ON OUR WORK THAT HAS STUDIED THE INFLUENCES OF THE ZI AND OF A13 CELLS ON EXTINCTION LEARNING. WE WILL COMBINE AUDITORY FEAR CONDITIONING IN MICE WITH INTERSECTIONAL MOLECULAR-GENETICS, INDUCIBLE RNAI, OPTOGENETIC-BASED INTERFERENCE OF PROTEIN ACTION, AND MANIPULATION OF CELLULAR FIRING AFTER ACTIVITY-BASED TAGGING OF NEURONAL ENSEMBLES TO STUDY MOLECULAR PATHWAYS AND CELLULAR PROCESSES THAT AFFORD A13 CELLS THE ABILITY TO INFLUENCE EXTINCTION LEARNING. THIS WORK WILL ILLUMINATE BASIC NEUROBIOLOGY UNDERLYING A CLINICALLY IMPORTANT DIMENSION OF PTSD (EXTINCTION LEARNING). POSITIVE RESULTS WILL HIGHLIGHT HIGHLY CONSERVED PROCESSES VIA WHICH MANY BRAIN REGIONS INCLUDING DOPAMINERGIC HUBS INFLUENCE EXTINCTION LEARNING. FUTURE STUDIES WILL PROFILE HOW STRESS-INDUCED CHANGES IN THESE PROCESSES IN A13 CELLS INFLUENCE THEIR COMMUNICATION WITH TARGETS LIKE THE PERIAQUEDUCTAL GRAY AND NUCLEUS REUNIENS TO DISRUPT EXTINCTION LEARNING.

SUB-THALAMIC MODULATION OF LEARNING-RELATED DIMENSIONS OF PTSD

PREVENTION OF CEREBROSPINAL FLUID (CSF) SHUNT INFECTIONS

SOUTHERN CALIFORNIA CENTER FOR TECHNOLOGY AND INNOVATION IN PEDIATRICS (CTIP)

EXTRACELLULAR VESICLES DERIVED FROM AMNIOTIC FLUID STEM CELLS NORMALIZE GLOMERULAR FUNCTION DURING PROGRESSIVE KIDNEY DISEASE.

GROWTH FACTORS IN LUNG DEVELOPMENT

UNDERSTANDING AND TARGETING THE PATHOPHYSIOLOGY OF YOUTH-ONSET TYPE2 DIABETES - TYPE 2 DIABETES (T2D) IN CHILDHOOD HAS AN AGGRESSIVE ETIOLOGY, WITH SUBSTANTIAL SHORT- AND LONG-TERM HEALTH COMPLICATIONS AND MEDICAL COSTS. THERE IS AN URGENT NEED TO: 1) IDENTIFY CHILDREN AND ADOLESCENTS AT HIGHEST RISK; 2) IDENTIFY MODIFIABLE CONTRIBUTING FACTORS; 3) UNDERSTAND THE UNDERLYING PATHOPHYSIOLOGY; AND, 4) DETERMINE HOW THESE FACTORS VARY ACROSS SEX AND RACE/ETHNICITY. A COMPREHENSIVE AND HOLISTIC UNDERSTANDING OF THESE ISSUES IS REQUIRED TO DEVELOP MODELS THAT CAN IDENTIFY INDIVIDUAL FACTORS AND SUSCEPTIBLE TIME WINDOWS FOR T2D CONVERSION AND REQUIRES A NATIONWIDE EFFORT AND MULTIDISCIPLINARY CONSORTIUM. WE PROPOSE TO SERVE AS 1 OF THE 15 CLINICAL CENTERS OPERATING WITHIN THE PROPOSED NIDDK CONSORTIUM THAT WILL RECRUIT AND TRACK A NATIONAL COHORT OF CHILDREN (ESTIMATE = 3,750) REPRESENTING THE DIVERSITY OF THE PEDIATRIC POPULATION AT RISK FOR T2D. OUR MULTIDISCIPLINARY TEAM HAS EXTENSIVE EXPERTISE IN LONGITUDINAL STUDIES OF OBESITY AND DIABETES IN CHILDREN, INCLUDING AN NIDDK-FUNDED 15-YEAR LONGITUDINAL STUDY (R01 DK 59211; PI: GORAN) THAT FOLLOWED A COHORT OF 300 LATINO CHILDREN AT RISK FOR T2D, RESULTING IN ALMOST 100 PUBLICATIONS. FROM THIS AND OTHER PRIOR STUDIES, WE HAVE IDENTIFIED THE NEED FOR A LARGER AND MORE DIVERSE COHORT, INCORPORATION OF ENVIRONMENTAL EXPOSURES, AND INCLUSION OF COMPREHENSIVE NUTRITIONAL, METABOLIC, AND SOCIAL DETERMINANTS. AT OUR SITE, WE WILL RECRUIT 250 PARTICIPANTS WITH OBESITY AND FAMILY HISTORY OF T2D WITH BI-ANNUAL ASSESSMENTS. WE WILL WORK WITH STAKEHOLDERS AND OTHER CONSORTIUM SITES TO OPTIMIZE RECRUITMENT AND RETENTION. WE PROPOSE THREE COMPLEMENTARY APPROACHES TO ASSESS THE METABOLIC BASIS OF T2D: INSULIN SECRETION, CLEARANCE, AND SS-CELL FUNCTION FROM AN ORAL GLUCOSE TOLERANCE TEST WITH FREQUENT SAMPLING; HEMOGLOBIN A1C, AND PERCENT TIME IN RANGE FROM CONTINUOUS GLUCOSE MONITORING. WE WILL MONITOR METABOLIC AND ENVIRONMENTAL FACTORS BY MEASURING: 1) TOTAL BODY FAT, VISCERAL AND SUBCUTANEOUS ABDOMINAL ADIPOSE TISSUE, AND LIVER AND PANCREATIC FAT BY DEXA AND MRI; 2) BIOCHEMICAL MARKERS (FREE FATTY ACIDS, SEX STEROIDS, LIPIDS, INFLAMMATORY PROFILES, INCRETINS, AND LIVER ENZYMES); 3) LIFESTYLE (DIET, SLEEP, AND PHYSICAL ACTIVITY); 4) EXPOSURE TO ENDOCRINE-DISRUPTING CHEMICALS AND AIR POLLUTION; 5) SOCIAL DETERMINANTS OF HEALTH. IN ADDITION, WE PROPOSE COLLECTION OF BIOLOGICAL SAMPLES (EG DNA, STOOL, SALIVA) TO CREATE A BIOBANK FOR FUTURE INVESTIGATION. WE WILL WORK WITH THE CONSORTIUM TO DEVELOP A UNIFIED PROTOCOL AND HARMONIZED OUTCOME MEASURES. WE HYPOTHESIZE: 1) CHILDREN WHO DEVELOP T2D WILL HAVE A GREATER PUBERTAL DECLINE IN SS-CELL FUNCTION, AND DECREASED GLUCOSE TIME-IN-RANGE, WHICH WILL BE ASSOCIATED WITH GREATER INCREASE IN OVERALL ADIPOSITY AND LIVER FAT, COMPARED TO CHILDREN WHO DO NOT DEVELOP T2D, AND THAT THESE RELATIONSHIPS WILL DIFFER ACROSS SEX AND ETHNICITY; AND, 2) HIGH DIETARY SUGAR, LIMITED ACCESS TO HEALTHY FOODS, AND HIGHER EXPOSURE TO PERFLUOROALKYL SUBSTANCES AND/OR AIR POLLUTANTS WILL ALSO BE ASSOCIATED WITH RISK OF T2D. THROUGH HARNESSING THE POWER OF THIS CONSORTIUM, WE ALSO PROPOSE DEVELOPMENT OF A STRUCTURED RISK SCORE ANALYSIS TO CHARACTERIZE DIFFERENT ENDOTYPES, EXPOSURES AND RISK FACTORS THAT PREDICT PROGRESSION TO T2D DURING PUBERTAL DEVELOPMENT.

USC UCEDD

HEALTH AND PUBLIC SAFETY WORKFORCE RESILIENCY TRAINING PROGRAM

TARGETING SYK KINASE IN B-LINEAGE ALL WITH CD19-SPECIFIC C-61 NANOPARTICLES

CHROMATIN REMODELING FACTOR CHD7 REGULATES CARDIAC AND CRANIOFACIAL LYMPHATIC VESSEL DEVELOPMENT - PROJECT SUMMARY THE ANTERIOR SECOND HEART FIELD (SHF) CELLS ARE A POPULATION OF LATE DIFFERENTIATING CARDIOVASCULAR PROGENITOR CELLS THAT CONTRIBUTE TO MYOCARDIAL CELLS, SMOOTH MUSCLE CELLS, AND ENDOTHELIAL CELLS IN THE HEART. IT WAS NOT DISCOVERED UNTIL RECENTLY THAT THESE SHF PROGENITORS CAN ALSO CONTRIBUTE TO CARDIAC LYMPHATIC ENDOTHELIAL CELLS (LECS) AS WELL AS THE LYMPHATICS OF THE CRANIOFACIAL AREA IN MICE. LYMPHATICS PLAY ESSENTIAL ROLES IN REGULATING INTERSTITIAL FLUID HOMEOSTASIS AND IMMUNE CELL MODULATION. IT IS UNCLEAR WHETHER LYMPHATIC DEFECTS CAN CAUSE CONGENITAL CARDIAC AND CRANIOFACIAL MALFORMATIONS. MUTATION IN CHD7, A GENE ENCODING CHROMODOMAIN HELICASE DNA BINDING PROTEIN 7 THAT FUNCTIONS AS AN ATP-DEPENDENT CHROMATIN REMODELER, CAUSE CRANIOFACIAL DEFECTS AND CARDIOVASCULAR MALFORMATIONS. IT HAS BEEN REPORTED THAT CHD7 PLAYS A CELL-AUTONOMOUS ROLE IN SHF PROGENITORS TO REGULATE DOWNSTREAM GENE EXPRESSION. OUR PRELIMINARY DATA FURTHER DEMONSTRATED THAT CHD7 IS HIGHLY EXPRESSED IN CARDIAC LYMPHATIC PROGENITORS AND CHD7 MUTANT ZEBRAFISH SHOW DEFECTS IN LYMPHATICS IN THE CRANIOFACIAL AREAS, ON THE OUT FLOW TRACT AND THE HEART VENTRICLE. WE WILL TEST THE HYPOTHESIS THAT CHD7 REGULATES GENE EXPRESSION AND CHROMATIN ACCESSIBILITY IN CARDIAC AND CRANIOFACIAL LECS DERIVED FROM SHF PROGENITORS. WE PROPOSE TWO INDEPENDENT AIMS TO 1) PERFORM CONFOCAL AND LIVE IMAGING AND LINEAGE TRACING TO ANALYZE THE CHD7 MUTANT PHENOTYPES AND SHF CONTRIBUTIONS TO CRANIOFACIAL AND CARDIAC LECS; 2) PERFORM SINGLE NUCLEI MULTIOMIC AMALYSIS, SPATIAL TRANSCRIPTOMICS AND CUT&RUN TO DETERMINE THE MOLECULAR MECHANISMS BY WHICH CHD7 REGULATES DOWNSTREAM GENE EXPRESSION AND CHROMATIN LANDSCAPES. OUR PROPOSED EXPERIMENTS WILL REVEAL PREVIOUSLY UNAPPRECIATED ROLES OF CHD7 IN LECS DERIVED FROM SHF PROGENITORS AND HELP IDENTIFY CHD7 DOWNSTREAM TARGET GENES THAT CAN BE POTENTIAL THERAPEUTIC TARGETS FOR PATIENTS WITH CHD AND LYMPHATIC MALFORMATIONS.

TARGETING THE CSF MICROBIOTA TO OPTIMIZE CSF SHUNT INFECTION TREATMENT

MOLECULAR DIAGNOSTICS FOR RISK STRATIFICATION AND MONITORING OF NEUROBLASTOMA

BRAIN BLOOD FLOW, OXYGENATION, AND COGNITION IN ADULT ONSET IRON DEFICIENCY ANEMIA - MODERATE ANEMIA (HEMOGLOBIN < 11 G/DL) OCCURS 1.5% – 2.0% OF THE GENERAL POPULATION. IN YOUNG AND MIDDLE- AGED ADULTS, IRON DEFICIENCY FROM BLOOD LOSS REPRESENTS THE DOMINANT MECHANISM AND IS HEAVILY OVER- REPRESENTED IN WOMEN AND MINORITY POPULATIONS. IRON DEFICIENCY ANEMIA’S (IDA) NEGATIVE IMPACT ON PEDIATRIC BRAIN FUNCTION IS WELL ESTABLISHED, BUT ITS CONSEQUENCES ON ADULT BRAINS ARE UNDERAPPRECIATED. OUR PRELIMINARY DATA DEMONSTRATES SIGNIFICANT (ONE STANDARD DEVIATION) DEFICITS IN VISUAL AND VERBAL MEMORY, FLUID AND VISUOSPATIAL REASONING, AND VERBAL LEARNING. WE ALSO DEMONSTRATE DECREASED CEREBRAL METABOLIC RATE OF OXYGEN AND ABNORMAL BLOOD BRAIN BARRIER PERMEABILITY TO WATER THAT SUGGEST IMPAIRED MICROVASCULAR BLOOD FLOW REGULATION IN THE BRAIN. THE OVERARCHING GOAL FOR THIS STUDY IS TO DEEPLY PHENOTYPE THE COGNITIVE AND CEREBROVASCULAR DERANGEMENTS CAUSED BY ADULT-ONSET IDA AND TO DETERMINE THEIR REVERSIBILITY WITH IRON REPLACEMENT THERAPIES. WE WILL RECRUIT 96 WOMEN AGES 14-60 YEARS DIAGNOSED WITH MODERATE IDA, AND 40 HEALTHY CONTROL SUBJECTS FROM FOUR DONOR CENTERS IN THE LOS ANGELES AREA AS WELL AS WOMEN RECRUITED FROM SOCIAL MEDIA. MOST OF THESE SUBJECTS WILL BE OTHERWISE ENTIRELY HEALTHY BUT WE WILL EXCLUDE INDIVIDUALS WITH OTHER MECHANISMS FOR THEIR ANEMIA AS WELL AS RISK FACTORS FOR SMALL VESSEL DISEASE INCLUDING HYPERTENSION, SLEEP DISORDERED BREATHING, AND DIABETES. ALL ANEMIC AND CONTROL SUBJECTS WILL UNDERGO COMPREHENSIVE CEREBROVASCULAR MRI, BASELINE BLOODWORK, PATIENT REPORTED OUTCOMES, AND NEUROCOGNITIVE TESTING. AIMS 1 AND 2 FOCUS ON CAREFUL CHARACTERIZATION OF THE COGNITIVE, METABOLIC, FLOW, OXYGENATION, AND CONNECTIVITY CHANGES IN RESPONSE TO IDA. THESE DATA WILL PROVIDE NEW INSIGHTS INTO THE NEUROSCIENTIFIC BASIS FOR COGNITIVE DYSFUNCTION IN IDA. AIM 3 IS INTERVENTIONAL; WE WILL RESTUDY ALL THE PREVIOUSLY ACQUIRED BIOMARKERS AFTER NORMALIZING HEMOGLOBIN LEVEL TO PROVE REVERSIBILITY/IRREVERSIBILITY OF THE MRI AND COGNITIVE DEFICITS. ALL PATIENTS WITH CONFIRMED MODERATE IDA WILL BE RANDOMIZED TO INTRAVENOUS FERRIC CARBOXYMALTOSE VERSUS STANDARD-OF-CARE THERAPY (REFERRAL TO PRIMARY CARE PHYSICIAN FOR ORAL IRON THERAPY). THE PRIMARY ENDPOINT WILL BE THE CEREBRAL METABOLIC RATE BY MRI AND NEUROCOGNITION AT 12 MONTHS. SECONDARY MARKERS INCLUDE REGIONAL BRAIN BLOOD FLOW, CEREBROVASCULAR REACTIVITY, TISSUE OXYGENATION, BLOOD-BRAIN BARRIER FUNCTION, AND FUNCTIONAL CONNECTIVITY. EXPLORATORY MARKERS INCLUDE BRAIN IRON DEPOSITION, WHITE MATTER DAMAGE, AND BRAIN MORPHOMETRY. WE WILL EXPLOIT THE RAPID CORRECTION OF IRON SUFFICIENCY IN THE IV IRON TREATED SUBJECTS TO UNCOUPLE THE RELATIVE IMPACTS OF IRON AND ANEMIA. WE POSIT THAT ALL SUBJECTS WHO SUCCESSFULLY REPLACE THEIR IRON STORES WILL NORMALIZE THEIR MRI AND COGNITIVE FUNCTION. HOWEVER, WE ANTICIPATE THAT IRON RESTORATION AND DURABILITY IN THE STANDARD-OF- CARE ARM WILL NOT BE AS ROBUST AS FOR INTRAVENOUS IRON BECAUSE OF POOR COMPLIANCE, INSUFFICIENT THERAPY DURATION, AND/OR LACK OF ADEQUATE MEDICAL FOLLOW-UP. TAKEN TOGETHER, THIS STUDY WILL DETERMINE THE URGENCY OF IDENTIFYING AND CORRECTING IDA IN ADULTS, THE MECHANISMS OF BRAIN TOXICITY, AND POTENTIAL TARGETS TO IMPROVE CARE PRACTICES.

MOLECULAR MECHANISMS OF ZEBRAFISH HEART REGENERATION

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

INCREASING ENGAGEMENT OF YOUNG GAY AND BISEXUAL MALE IDENTIFIED PEOPLE OF COLOR (YGBMC) WITH SUD AND/OR COD WHO ARE AT RISK FOR OR ARE LIVING WITH HIV IN LOS ANGELES COUNTY - THE PROJECT, "INCREASING ENGAGEMENT OF YOUNG GAY AND BISEXUAL MALE IDENTIFIED PEOPLE OF COLOR (YGBMC) WITH SUD AND/OR COD WHO ARE AT RISK FOR OR ARE LIVING WITH HIV IN LOS ANGELES COUNTY," WILL INCREASE ENGAGEMENT IN CARE FOR YOUNG GAY AND BISEXUAL MALE IDENTIFIED PEOPLE OF COLOR (YGBMC), PARTICULARLY AFRICAN AMERICAN AND LATINO, AGES 18-29 WITH SUBSTANCE USE DISORDER OR CO-OCCURRING DISORDERS WHO ARE AT RISK FOR OR ARE LIVING WITH HIV/AIDS AND RECEIVE HIV/AIDS SERVICES/TREATMENT SERVICES IN LOS ANGELES COUNTY. THE PROJECT IS FOCUSED ON THE CENTRAL AREA OF LOS ANGELES COUNTY AND WILL HAVE IMPACT COUNTYWIDE. CENTRAL LOS ANGELES IS A DENSELY POPULATED AREA OF LOS ANGELES CHARACTERIZED BOTH BY SHARP DISPARITIES IN INCOME AND AS THE SOCIAL, CULTURAL, AND SERVICE HUB FOR YGBMC. LOS ANGELES COUNTY IS ALSO ONE OF THE LOCALITIES IDENTIFIED AS HARDEST HIT BY HIV. THE PROPOSED PROJECT IS EXPECTED TO SERVE 100 YGBMC ANNUALLY AND 475 OVER THE LIFETIME OF THE PROJECT. THE PROJECT GOALS ARE TO: 1) EXPAND AVAILABLE YOUTH-SPECIFIC TREATMENT SERVICES FOR SUBSTANCE USE (SUD) AND/OR CO-OCCURRING DISORDERS (COD), AND HIV SERVICES FOR YGBMC; AND 2) ENHANCE AVAILABLE YOUTH-SPECIFIC SUBSTANCE USE TREATMENT, BEHAVIORAL HEALTH, AND HIV SERVICES FOR YGBMC. THE OBJECTIVES INCLUDE SCREENING AND ENROLLMENT OF YBMC IN SUBSTANCE USE AND/OR CO-OCCURRING DISORDER TREATMENT; ENROLLING YGBMC IN AN ADAPTED EVIDENCE-BASED INTERVENTION; TO DECREASE SUBSTANCE USE AND INCREASE POSITIVE COPING STRATEGIES AND DECREASE MENTAL HEALTH SYMPTOMS; INCREASE COMMUNITY SUPPORT; INCREASE RESILIENCE FACTORS; INCREASE SCREENING FOR SUD/COD, HIV/STIS, AND VIRAL HEPATITIS; LINK YGBMC TESTING POSITIVE FOR HIV AND HEPATITIS TO TREATMENT; ENROLL YOUNG PEOPLE INTO ADDITIONAL ESSENTIAL SUPPORT AND/OR RECOVERY SERVICES; INCREASE INSURANCE COVERAGE FOR ELIGIBLE YGBMC; AND USE A CERTIFIED ELECTRONIC HEALTH RECORD FOR DOCUMENTATION OF TREATMENT NOTES.

TRANS COMMUNITY TRAUMA TREATMENT CENTER FOR CHILDREN AND ADOLESCENTS

ASSISTANCE FOR DEVELOPMENTALLY-APPROPRIATE EVIDENCE-BASED PREVENTION TECHNOLOGY

ALVEOLAR EPITHELIAL CELLS: DEVELOPMENT AND REPAIR

DELIVERY CONTEXT, YOUTH CHARACTERISTICS AND TEEN PREGNANCY PREVENTION: SECONDARY ANALYSIS

DEVELOPMENTAL-BEHAVIORAL PEDIATRICS TRAINING PROGRAM

NOVEL MECHANISMS OF GLOMERULAR INJURY IN PRIMARY MEMBRANOUS NEPHROPATHY

CAK-RARA SIGNALING IN HSC AND LEUKEMIC CELL COMMITMENT TO DIFFERENTIATION

INVASION OF BRAIN ENDOTHELIAL CELLS BY C. NEOFORMANS

AFRICAN AMERICAN YOUNG MENS STUDY

PATHOGENESIS AND TREATMENT OF EXPERIMENTAL PERITONITIS

CARDIAC LYMPHATIC VESSELS IN HEART DEVELOPMENT AND REGENERATION.

KIR-FAVORABLE HAPLOIDENTICAL TRANSPLANTATION IN CHILDREN

CXC12 CHEMOKINE SIGNALING REGULATES SYNCHRONOUS DEVELOPMENT OF CORONARY VESSELS AND MYOCARDIUM

SUMMER ONCOLOGY RESEARCH FELLOWSHIP FOR MEDICAL STUDENTS

PEDIATRIC PULMONARY CENTERS

VALIDATION OF AN AQUEOUS HUMOR LIQUID BIOPSY FOR MOLECULAR PROGNOSTICATION AND MONITORING OF CHILDREN WITH RETINOBLASTOMA. - PROJECT SUMMARY THERE IS A SIGNIFICANT BODY OF RESEARCH INTO THE GENETIC, GENOMIC AND EPIGENOMIC ALTERATIONS OF RETINOBLASTOMA (RB), A PRIMARY EYE CANCER THAT FORMS IN THE DEVELOPING RETINA IN YOUNG CHILDREN. HOWEVER, THESE STUDIES WERE DONE ON TUMOR TISSUES FROM SURGICALLY REMOVED (ENUCLEATED) EYES WITH ADVANCED RB, AS TUMOR BIOPSY IS NOT POSSIBLE DUE TO THE REAL RISK OF TUMOR EXTRAOCULAR DISSEMINATION. AS A RESULT, RB TUMOR DNA WAS NEVER PREVIOUSLY ACCESSIBLE ASIDE FROM THESE ENUCLEATED SPECIMENS, AND THERE IS LIMITED UNDERSTANDING OF THE MOLECULAR ALTERATIONS THAT MAY DRIVE TUMOR BEHAVIOR. FURTHERMORE, ANY APPLICATION OF MOLECULAR DIAGNOSTIC OR USE OF PROGNOSTIC BIOMARKERS FOR PERSONALIZED MEDICINE IN VIVO IS LIMITED BY THE LACK OF TUMOR TISSUE AT DIAGNOSIS OR DURING THERAPY. THUS, A LIQUID BIOPSY APPROACH, WHICH OVERCOMES THIS CRITICAL LACK OF TUMOR TISSUE, WAS NEEDED FOR THIS DISEASE. WITH SUPPORT OF AN NCI K08, WE DEMONSTRATED THAT THE AQUEOUS HUMOR (AH), AN INTRAOCULAR FLUID, IS AN ENRICHED SOURCE OF TUMOR-DERIVED CELL-FREE DNA (CFDNA). WE DEVELOPED A LIQUID BIOPSY ASSAY TO DETECT SOMATIC COPY NUMBER ALTERATIONS (SCNAS) AND PATHOGENIC VARIANTS IN THE RB1 TUMOR SUPPRESSOR GENE FROM A SINGLE 100 L SAMPLE OF AH. WE IDENTIFIED THAT THE GENOMIC ALTERATIONS FROM THE AH ARE HIGHLY CONCORDANT (>94%) WITH THOSE FOUND IN THE TUMOR OF ENUCLEATED EYES. WE IDENTIFIED POTENTIAL CANDIDATE BIOMARKERS, CHROMOSOME 6P GAIN AND/OR FOCAL MYCNA IN THE AH CFDNA THAT ARE ASSOCIATED WITH A 16.5-FOLD INCREASED RISK OF TREATMENT FAILURE REQUIRING SURGICAL REMOVAL OF THE EYE. WE DEMONSTRATED THAT CHANGES IN AH CFDNA TUMOR FRACTION (TFX) CORRELATE WITH TREATMENT RESPONSE, WITH INCREASES IN TFX INDICATIVE OF RECURRENCE OR MINIMAL RESIDUAL INTRAOCULAR DISEASE. THIS SUGGESTS THAT TFX ALONE MAY SERVE AS A RELIABLE REAL-TIME BIOMARKER FOR TREATMENT RESPONSE. WE ALSO DEMONSTRATED THE FEASIBILITY OF EVALUATING TUMOR METHYLATION PROFILES USING THE AH, THEREBY FACILITATING A BETTER UNDERSTANDING OF TUMOR BIOMARKERS THAT MAY PREDICT TUMOR BEHAVIOR AND POTENTIALLY TREATMENT RESPONSE. BASED IN THESE RESULTS, WE HYPOTHESIZE THAT AH CFDNA CAN BE USED FOR MOLECULAR CHARACTERIZATION OF IN VIVO RB TUMORS TO INFORM DIAGNOSIS AND PROGNOSIS FOR EYE SALVAGE BASED ON VALIDATED GENOMIC AND EPIGENOMIC BIOMARKERS. TO TEST THIS HYPOTHESIS, WE NOW PROPOSE A MULTI-CENTER, MULTI-OMICS, PROSPECTIVE STUDY TO CHARACTERIZE PROGNOSTIC AH BIOMARKERS PROSPECTIVELY AND LONGITUDINALLY TO DETERMINE TREATMENT OUTCOMES. BENEFITS FROM THIS STUDY WILL INCLUDE ADVANCING KNOWLEDGE ABOUT THE COURSE OF THE DISEASE AT ANY STAGE, PROVIDING BIOMARKERS TO GUIDE TREATMENT, AND FORMING THE BASIS FOR FUTURE MOLECULAR-BASED, PRECISION MEDICINE CLINICAL TRIALS FOR RB.

SUBST. ABUSE & HIV PREVENTION PROJECT FOR HOMELESS YOUTH

HUMAN SPECIFIC SIGNALING CIRCUITRY IN CONE PRECURSOR DEVELOPMENT

DEAD SPACE AND INHALED NITRIC OXIDE IN PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME - PROJECT SUMMARY MORTALITY REMAINS HIGH (20%) FOR THE 8,000 US CHILDREN EACH YEAR THAT DEVELOP PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). NO PHARMACOLOGIC THERAPIES HAVE BEEN IDENTIFIED THAT DECREASE THE MORTALITY RISK FROM ARDS. THIS IS LIKELY DUE TO UNDERLYING BIOLOGIC HETEROGENEITY AMONG PATIENTS WITH ARDS THAT MAY RESULT IN SOME BENEFITING FROM A THERAPY WHEREAS OTHERS ARE HARMED, LIMITING THE ABILITY TO FIND EFFECTIVE THERAPIES IN CLINICAL TRIALS OF GENERAL COHORTS. INFLAMMATORY PHENOTYPES HAVE BEEN DESCRIBED IN ARDS THAT MAY HELP IDENTIFY UNDERLYING BIOLOGIC DIFFERENCES CONTRIBUTING TO HETEROGENEITY IN TREATMENT EFFECT. HOWEVER, THESE PHENOTYPES CANNOT CURRENTLY BE IDENTIFIED IN REAL-TIME. THERE IS AN URGENT NEED FOR EASILY AVAILABLE MARKERS TO IDENTIFY CLINICALLY RELEVANT HETEROGENEITY IN PATIENTS WITH ARDS. MARKERS OF DEAD SPACE MAY BE PROMISING FOR THIS PURPOSE. DEAD SPACE IS AREA OF THE LUNG THAT RECEIVE VENTILATION WITHOUT PERFUSION AND REFLECTS ABNORMAL PULMONARY PERFUSION (MICROVASCULAR DYSFUNCTION, LOW CARDIAC OUTPUT) AND ALVEOLAR OVERDISTENSION. WITH ROUTINE PATIENT MONITORING DATA (TIME-BASED CAPNOGRAPHY, BLOOD GASES), DEAD SPACE CAN BE ESTIMATED WITH THE END TIDAL ALVEOLAR DEAD SPACE FRACTION (AVDSF). WE HAVE FOUND IN SINGLE-CENTER STUDIES THAT AVDSF IS MORE STRONGLY ASSOCIATED WITH MORTALITY RISK THAN ARE MARKERS OF THE SEVERITY OF HYPOXEMIA (OXYGENATION INDEX [OI]) IN EARLY PEDIATRIC ARDS. DEAD SPACE MAY ALSO BE AN ATTRACTIVE MARKER FOR IDENTIFYING HETEROGENEITY OF TREATMENT EFFECT FOR THERAPIES SUCH AS INHALED NITRIC OXIDE (INO) THAT TARGET PULMONARY PERFUSION. INO IS A SELECTIVE PULMONARY VASODILATOR, WITH ADDITIONAL ANTI-INFLAMMATORY AND ANTICOAGULATION EFFECTS, THAT IS COMMONLY USED OFF-LABEL FOR REFRACTORY HYPOXEMIA IN ARDS. BUT ALMOST ALL CLINICAL TRIALS OF INO THERAPY HAVE FAILED TO DEMONSTRATE A BENEFIT WHEN ENROLLING GENERAL COHORTS OF PATIENTS OR SELECTING PATIENTS BASED ON SEVERITY OF HYPOXEMIA. ONE SMALL PEDIATRIC TRIAL FOUND HIGHER EXTRACORPOREAL MEMBRANE OXYGENATION FREE SURVIVAL SUGGESTING THE POTENTIAL FOR SOME SUBGROUPS TO BENEFIT FROM INO THERAPY. OUR PRELIMINARY DATA SUGGEST THAT INO THERAPY DECREASES THE AVDSF ASSOCIATED MORTALITY RISK AND THAT A DECLINE IN AVDSF WITH INO THERAPY IS ASSOCIATED WITH IMPROVING PLASMA MARKERS OF MICROVASCULAR DYSFUNCTION. OUR CENTRAL HYPOTHESES ARE THAT THE ROUTINELY AVAILABLE AVDSF IS MORE STRONGLY TIED TO MORTALITY RISK THAN OI AND THAT AVDSF IS AN IMPORTANT MARKER OF HETEROGENEITY IN THE INO TREATMENT EFFECT IN PATIENTS WITH ARDS. THESE HYPOTHESES WILL BE TESTED THROUGH THE FOLLOWING SPECIFIC AIMS: 1) VALIDATE AVDSF FOR RISK STRATIFICATION OF MORTALITY IN PEDIATRIC ARDS 2) DETERMINE IF THERE IS HETEROGENEITY IN TREATMENT EFFECT FOR INO DEFINED BY AVDSF, AND 3) DETECT THE ASSOCIATION BETWEEN AVDSF AND MICROVASCULAR DYSFUNCTION TRAJECTORY AND WHETHER INO THERAPY MODIFIES THE ASSOCIATION. DEMONSTRATING THAT AVDSF OUTPERFORMS OI FOR MORTALITY RISK STRATIFICATION IN PATIENTS WITH ARDS AND THAT AVDSF MAY IDENTIFY THE PATIENTS MOST LIKELY TO BENEFIT FROM INO THERAPY, HAS THE POTENTIAL TO BE FRAMESHIFTING FOR FUTURE CLINICAL TRIALS OF ARDS INTERVENTIONS, INCLUDING THOSE OF INO THERAPY.

CLINICAL CORRELATIVE STUDIES OF NEUROBLASTOMA

GROWTH FACTORS AND SMOOTH MUSCLE CELL LINEAGE DURING LUNG ORGANOGENESIS

TARGETING SYK TYROSINE KINASE TO OVERCOME RADIATION RESISTANCE IN ALL

INVESTIGATING THE ROLE OF ADIPOCYTES ON LEUKEMIA RELAPSE

PRENATAL INFLAMMATION DISRUPTS BLOOD-BRAIN BARRIER DEVELOPMENT AND LONG-TERM FUNCTION. - SUMMARY MATERNAL IMMUNE ACTIVATION (MIA) DURING FETAL DEVELOPMENT INCREASES RISK FOR NEURODEVELOPMENTAL DISORDERS (NDDS) LATER IN THE OFFSPRING LIFE. CHRONIC MICROGLIAL ACTIVATION IN THE ADULT OFFSPRING EXPOSED TO GESTATIONAL MIA LEADS TO A RANGE OF ALTERED BEHAVIORS. YET, THE DEVELOPMENTAL MECHANISMS WHEREBY MIA INDUCES THIS SUSTAINED ACTIVATION OF OFFSPRING BRAIN MICROGLIA ACROSS THE LIFESPAN ARE NOT UNDERSTOOD. SYSTEMIC INFLAMMATION TRIGGERED DURING ADULTHOOD WAS SHOWN TO DISRUPT BLOOD-BRAIN BARRIER (BBB) FUNCTION, INDUCING MICROGLIAL ACTIVATION, NEUROINFLAMMATION AND LEADING TO THE PROGRESSIVE EMERGENCE OF NEUROPATHOLOGIES. EVEN THOUGH COMPARABLE OUTCOMES ARE OBSERVED IN ADULT OFFSPRING WHO EXPERIENCED GESTATIONAL MIA, WHETHER THERE IS SIMILAR BBB DISRUPTION AND THE MECHANISMS LEADING TO THESE PHENOTYPES IN UTERO ARE NOT KNOWN. THIS IS AN IMPORTANT KNOWLEDGE GAP BECAUSE MIA IS A RISK FACTOR FOR NNDS AND THERE IS GROWING EVIDENCE OF VASCULAR DYSFUNCTION CONTRIBUTING TO THE MOLECULAR PATHOLOGY OF THESE DISORDERS. THE INVESTIGATORS OBTAINED PRELIMINARY DATA SHOWING THAT MIA TRIGGERED BY THE VIRAL MIMETIC POLY(I:C) IN PREGNANT MICE DISRUPTS FETAL BBB FORMATION LEADING TO INCREASED NASCENT BBB PERMEABILITY MEASURED USING LIVE FETAL MRI. THEIR DATA FURTHER SUGGEST THAT ACTIVATION OF THE CYCLOOXYGENASE-2 (COX2; PTGS2) PATHWAY IN FETAL BRAIN MICROGLIA IS CAUSAL TO MIA EFFECTS. IMPORTANTLY, LONGITUDINAL MRI ANALYSES SUGGEST THAT DISRUPTION OF FETAL BBB FORMATION INDUCES PERSISTENT BBB HYPERPERMEABILITY AND LIFE-LONG BRAIN MICROGLIAL ACTIVATION, CEREBROVASCULAR INFLAMMATION, AND BEHAVIORAL ALTERATIONS IN THE OFFSPRING. THROUGH THE COMBINED EXPERTISES OF FOUR DIFFERENT RESEARCH GROUPS, THE INVESTIGATORS DEVELOPED AND VALIDATED NEW METHODS FOR MEASURING FETAL BRAIN BBB PERMEABILITY IN VIVO (MRI) AND EX VIVO (WHOLE FETUS PERFUSION) WHICH, TOGETHER WITH CONDITIONAL KNOCKOUT MOUSE LINES, WILL BE USED TO TEST: 1) IF AND HOW MIA ACTIVATION OF THE COX2 PATHWAY IN FETAL MICROGLIA PERTURBS FETAL BBB FORMATION AT A CRITICAL TIME OF DEVELOPMENT, LEADING TO INCOMPLETE MATURATION, AND 2) IF AND HOW THE RESULTING PROTRACTED ACTIVATION OF COX2 PATHWAY IN RESIDENT MICROGLIA PROLONGS BBB STRUCTURAL DISRUPTION AND NEUROINFLAMMATION OVER THE OFFSPRING LIFESPAN. THIS SELF- PERPETUATING CYCLE OF BRAIN INFLAMMATION AND BBB DISRUPTION WOULD ULTIMATELY PROMOTE INCREASED RISK FOR NEUROPATHOLOGY IN THE OFFSPRING. FROM AN ETIOLOGICAL STANDPOINT, THIS PRE-CLINICAL PROPOSAL WILL DEFINE NOVEL CELLULAR AND MOLECULAR PATHWAYS INVOLVED IN LIFE-LONG EFFECTS OF PRENATAL INSULTS, SHEDDING LIGHT ON THE MECHANISMS BY WHICH EARLY INFLAMMATION IS CAUSALLY LINKED TO VASCULAR DISRUPTIONS IN NEURODEVELOPMENTAL DISORDERS.

MANEUVERING OF MACROPHAGE FUNCTION BY ESCHERICHIA COLI K1

TRAINING IN BASIC RESEARCH IN ONCOLOGY

COMMUNITY TRAUMA TREATMENT FOR RUNAWAY AND HOMELESS YOUTH

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - CHILDREN’S HOSPITAL LOS ANGELES (CHLA), RANKED IN THE TOP 5 CHILDREN’S HOSPITALS IN THE WORLD, IS A LEADER IN DEVELOPING AND IMPLEMENTING GENOMIC MEDICINE FOR ALL CHILDREN, INCLUDING MANY FROM UNDERPRIVILEGED AND UNDERSERVED MINORITIES. AT OUR CENTER FOR PERSONALIZED MEDICINE (CPM), WE HAVE DEVELOPED GOLD STANDARD GENOMICS-BASED DIAGNOSTIC TESTING FOR PEDIATRIC CANCER, LAUNCHED COMPREHENSIVE GENOMIC TESTING FOR RARE DISEASE IN NEWBORNS AND CHILDREN, AND HAVE SERVED AS A NATIONAL RESOURCE FOR SARS-COV2 GENOME SEQUENCING FOR COVID-19 PEDIATRIC PATIENTS. WE ARE ESPECIALLY PROUD OF OUR ABILITY TO PROVIDE THE MOST ADVANCED GENOMIC TESTING TO PATIENTS WHO ARE AMONG THE SICKEST, LEAST ECONOMICALLY ADVANTAGED, AND MOST DIVERSE ANYWHERE IN THE UNITED STATES. THE NEXT LEVEL OF GENOMIC TESTING FOR CHILDREN REQUIRES WHOLE GENOME SEQUENCING (WGS). WGS PROVIDES INFORMATION FROM A PATIENT’S ENTIRE GENOME, AS COMPARED TO CURRENT TECHNOLOGY WHICH IS LIMITED TO ONLY SELECTED GENES OR SPECIFIC PORTIONS OF THE GENOME. AS A RESULT, WGS HAS BEEN DEMONSTRATED TO HAVE SUPERIOR DIAGNOSTIC RATES WHEN COMPARED TO OTHER GENOMIC TESTS. WGS THEREFORE ENABLES THE MOST ADVANCED DIAGNOSIS AND PERSONALIZED CARE FOR NEWBORNS, AS WELL AS CHILDREN OF ALL AGES WITH COMPLEX CONDITIONS INCLUDING AUTISM AND DEVELOPMENTAL DISORDERS. SEVERAL STATES, INCLUDING CALIFORNIA, HAVE APPROVED CRITERIA FOR RAPID WHOLE GENOME SEQUENCING (RWGS) FOR PEDIATRIC INPATIENTS IN INTENSIVE CARE SETTINGS. THIS APPROACH HAS SHORTENED DIAGNOSTIC ODYSSEYS FOR CHILDREN, IMPROVED CLINICAL OUTCOMES AND REDUCED COSTS. MORE THAN 500 CHILDREN PER YEAR MEET THESE CRITERIA AT CHLA, A QUATERNARY CARE REFERRAL INSTITUTION. HOWEVER, FULL IMPLEMENTATION OF THIS NEXT STEP TO IMPLEMENT GENOMIC MEDICINE FOR CHILDREN REQUIRES SIGNIFICANTLY INCREASED SEQUENCING CAPACITY AND COMPUTATIONAL POWER. IN THIS APPLICATION, WE REQUEST FUNDS TO UPGRADE OUR GENOMIC SEQUENCING TO TAKE ADVANTAGE OF THE INCREASED CAPACITY AND F ASTER SEQUENCING TIMES OF THE ILLUMINA NOVASEQ 6000 TO MEET THIS NEED. WE ALSO REQUEST COMPLEMENTARY FUNDS TO ACCORDINGLY UPGRADE OUR COMPUTATIONAL CAPACITY TO ACCOMMODATE THE SIGNIFICANT INCREASE IN DATA THAT THIS WILL REQUIRE. TOGETHER, THE IMPROVED DIAGNOSTIC CAPABILITY OF WGS AND COMPUTATIONAL INFRASTRUCTURE WILL ENABLE US TO PROVIDE THE NEXT GENERATION OF PEDIATRIC DIAGNOSTICS. THIS IS CRITICAL TO ENSURE THAT ALL CHILDREN HAVE ACCESS TO STATE OF THE ART PERSONALIZED CARE ENABLED BY GENOMIC MEDICINE.

BETA CELL DYSFUNCTION AS AN ACUTE AND A POST ACUTE SEQUELAE OF COVID19 - PROJECT SUMMARY BETA CELL DYSFUNCTION AND DEATH ARE SIGNIFICANT PATHOLOGIES UNDERLYING THE DEVELOPMENT OF TYPE 2 DIABETES. OUR LONG-TERM GOAL IS TO IDENTIFY MOLECULAR MECHANISMS RESTRICT BETA CELL FUNCTION AND SURVIVAL. DURING THE SARS- COV2-DRIVEN COVID19 PANDEMIC, THERE ARE REPORTS OF ADULT COVID19+ PATIENTS PRESENTING WITH DIABETIC KETOACIDOSIS IN EMERGENCY ROOMS. 25% OF NEW-ONSET TYPE 1 DIABETES (T1D) PATIENTS PRESENTING WITH DIABETIC KETOACIDOSIS IN THE T1D EXCHANGE REGISTRY ARE COVID19+. OUR GROUP HAS REPORTED A SIGNIFICANT INCREASE IN THE NUMBER OF NEW-ONSET TYPE 2 DIABETES PATIENTS PRESENTING IN DIABETIC KETOACIDOSIS. THIS SUGGESTS THAT THE PATHOGENESIS OF COVID19 MAY HAVE ACUTE AND SPECIFIC EFFECTS ON PANCREATIC BETA CELL FUNCTION. ONE OF THE BARRIERS TO UNDERSTANDING HOW SARS-COV2 INFECTION MAY AFFECT BETA CELL FUNCTION AND SURVIVAL IN PATIENTS IS THE LIMITED NUMBER OF PHYSIOLOGICALLY RELEVANT ANIMAL MODELS TO STUDY. WE HAVE CAPITALIZED ON UNIQUE ACCESS THE PANCREAS OF SCV2-INNOCULATED ANIMALS TO MODEL AND UNDERSTAND HOW THE INFECTION MAY AFFECT BETA CELL FUNCTION AND SURVIVAL. OUR PRELIMINARY DATA THAT SHOWS: (1) SARS-COV2 DIRECTLY INFECTS BETA CELLS, (2) SARS-COV2 INFECTION CAUSES DRAMATIC MORPHOLOGICAL CHANGES IN ISLET, (3) SARS-COV2 INFECTION SHIFTS BETA CELL METABOLISM TO GLYCOLYTIC PROFILE, AND (4) SARS-COV2 INFECTION RESULTS IN DECREASED IN BETA CELL FUNCTION AND SURVIVAL. THE OBJECTIVE OF THIS PROPOSAL IS TO DEFINE THE MECHANISMS THAT DRIVE THE POST-ACUTE CONSEQUENCES OF COVID19-MEDIATED BETA CELL INJURY IN VIVO. THERE IS CONTROVERSY IN THE LITERATURE REGARDING IF SARS-COV2 DIRECTLY INFECTS BETA CELLS AND AFFECTS BETA CELL FUNCTION AND SURVIVAL OR IF THE DISRUPTION OF GLUCOSE HOMEOSTASIS IN PATIENTS IS SECONDARY. WE HYPOTHESIZE THAT SARS-COV2 INFECTION REPROGRAMS CELLULAR METABOLISM AND INDUCES NECROPTOSIS, THUS LEAVING HOSTS SUSCEPTIBLE TO BETA CELL DYSFUNCTION ACUTELY AND AS A POST-ACUTE SEQUELAE OF COVID19. THESE HIGHLY INNOVATIVE EXPERIMENTS CAPITALIZE ON A UNIQUE AND CLINICALLY RELEVANT MODEL SYSTEM AND EMPLOYS CUTTING EDGE TECHNIQUES TO ASSESS HOW BETA CELL SURVIVAL AND METABOLISM ARE AFFECTED BY SARS-COV2 INFECTION. THESE EXPERIMENTS WILL PROVIDE CRITICAL MECHANISTIC INSIGHT TO THE UNDERPINNINGS OF THE EMERGING CLINICAL PHENOTYPE OF ACUTE HYPERGLYCEMIA, DIABETIC KETOACIDOSIS, AND POTENTIALLY LIFELONG DIABETES THAT MAY AFFLICT A SIGNIFICANT NUMBER OF PATIENTS WHO HAVE RECOVERED FROM COVID19.

PHOTODYNAMIC THERAPY AFFECTS ON THE TUMOR MICROENVIRONMENT

THE ROLE OF SPRY2 IN THE COLONIC EPITHELIAL RESPONSE TO INFLAMMATION

OPTIMIZING TISSUE IRON QUANTIFICATION AT 3 TESLA

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION - ADDRESS: 4650 SUNSET BLVD. LOS ANGELES, CA 90027 PROJECT DIRECTOR: JENNIFER KLUNDER PH: 323-361-0747 FAX: 323-361-3688 JKLUNDER@CHLA.USC.EDU GRANT PROGRAM FUNDS: SIEMEN’S EMERGE 0.55T WITH CARDIAC GRADIENTS: $1,000,000 HIGH SPEED SURFACE COILS: $150,000 IMAGING ACQUISITION PULSE SEQUENCES (ACCESSI, CS-CARDIAC CINE, MYOMAPS): $115,000 ADVANCED REAL TIME INTERFACE AND MONITOR: $100,000 GPU RECONSTRUCTION ACCELERATOR: $60,000 PHYSIOLOGIC DATA MONITORING: $75,000 TOTAL: $1,500,000 THE REQUESTED FUNDS WILL BE USED TO PURCHASE A REVOLUTIONARY HIGH-PERFORMANCE, LOW FIELD 0.55T MRI. LOW FIELD MAGNETS ARE QUIETER AND DEPOSIT LESS RADIOFREQUENCY ENERGY INTO THE BODY THAN STRONGER MAGNETS, MAKING THEM SAFER FOR CHILDREN, FETUSES, AND ANY PERSON WITH A METAL IMPLANT. SPECIFICALLY, THE REQUESTED FUNDING WOULD BE USED TO PURCHASE THE 0.55T MAGNET AND THE SUPPORTING ANCILLARY HARDWARE AND SOFTWARE NECESSARY TO PERFORM RADIATION-FREE MRI GUIDED CARDIAC PROCEDURES IN CHILDREN. SECURING THIS FUNDING FOR CHILDREN’S HOSPITAL LOS ANGELES WOULD ENSURE THAT HUNDREDS IF NOT THOUSANDS OF CHILDREN IN SOUTHERN CALIFORNIA WOULD HAVE ACCESS TO THE HIGHEST QUALITY CARE, AND PERMIT OUR INSTITUTION TO CONTINUE TO PLAY A LEADING ROLE IN THE CARE OF CHILDREN FROM ACROSS THE STATE, THE NATION AND AROUND THE WORLD WHO NEED SOPHISTICATED CARDIAC INTERVENTIONS.

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

YOUTH PARTNERSHIPS FOR SUCCESS IN NORTHEAST LOS ANGELES

UNDERSTANDING CELLULAR AND MOLECULAR LEGACIES OF PATERNAL STRESS - PROJECT SUMMARY: FAMINES, THE HOLOCAUST AND OTHER NATURAL AND ANTHROPOGENIC EVENTS ARE PROVIDING EVIDENCE THAT THE EFFECTS OF TRAUMA AND STRESS EXTEND BEYOND THE ANCESTRAL GENERATION AND AFFECT MENTAL HEALTH IN OFFSPRING. REMEDYING PARENTAL BEHAVIOR THAT IS PERTURBED BY STRESS AND MITIGATING STRESS DURING PREGNANCY HAVE RECEIVED ATTENTION FOR THEIR UTILITY IN HALTING SUCH LEGACIES OF STRESS. IN CONTRAST, LESS IS KNOWN ABOUT HOW TO HALT LEGACIES OF PATERNAL STRESS THAT OCCURRED PRIOR TO CONCEPTION OF THE AFFECTED OFFSPRING. TO FILL THIS GAP IN KNOWLEDGE, WE MUST FIRST UNDERSTAND HOW STRESS-INDUCED ALTERATIONS IN PATERNAL SPERM PERTURB NEUROBIOLOGY AND DERAIL MENTAL HEALTH. WITH THIS INTENT, OUR GOAL IS TO DETERMINE HOW CELL-TYPE SPECIFIC OFFSPRING NEUROBIOLOGY IS IMPACTED BY STRESS-INDUCED ALTERATIONS IN SPERM RNA THAT HAVE EMERGED AS ONE MECHANISM VIA WHICH PATERNAL LINEAGES BEQUEATH LEGACIES OF STRESS TO OFFSPRING. TO ACHIEVE THIS GOAL, WE RELY ON OUR EXPERIENCE STUDYING LEGACIES OF PATERNAL STRESS, LEARNING AND MEMORY IN MICE AND BUILD ON UNPUBLISHED DATA DEMONSTRATING THAT INJECTIONS OF RNA FROM SPERM OF MALE MICE EXPOSED TO STRESS INTO SINGLE CELL ZYGOTES RESULTED IN DEFICITS IN EXTINCTION LEARNING IN ADULTHOOD. TO BEGIN OUR INVESTIGATION INTO THE NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THESE DEFICITS IN EXTINCTION LEARNING BEING SET INTO MOTION BY RNA IN SPERM EXPOSED TO STRESS, WE PROPOSE A FOCUS ON GLUCOCORTICOID RECEPTORS (GRS) IN THE INFRA-LIMBIC PREFRONTAL CORTEX (IL-PFC), LACTATE-BASED ACTIVITY OF NEURONS IN THE IL-PFC, AND DEVELOPMENT OF THE IL-PFC. OUR FOCUS IS SHAPED BY THE FOLLOWING BACKGROUND. FIRST, THE IL-PFC IS IMPORTANT FOR EXTINCTION LEARNING. SECOND, EPIGENETIC-BASED REGULATION OF THE GR GENE HAS RECEIVED THE MOST ATTENTION IN STUDIES THAT HAVE INVESTIGATED INTERGENERATIONAL LEGACIES OF STRESS ARISING FROM ABUSIVE CARE-GIVING AND GESTATIONAL STRESS, IN BOTH HUMANS AND RODENTS. THIRD, LACTATE-BASED SIGNALING BETWEEN ASTROCYTES AND NEURONS IS AN IMPORTANT MODE OF COMMUNICATION BETWEEN THESE CELL TYPES, PLAYS A ROLE IN LEARNING AND MEMORY, AND IS PERTURBED IN OFFSPRING BY ANTE-NATAL STRESS. FOURTH, ALTERED DEVELOPMENT OF THE PFC IN HUMANS AND RODENTS AS A CONSEQUENCE OF IMPOVERISHED CAREGIVING AND GESTATIONAL STRESS DERAILS BEHAVIOR IN OFFSPRING DURING ADULTHOOD. MOTIVATED BY THIS BACKGROUND, WE HYPOTHESIZE THAT DEFICITS IN EXTINCTION LEARNING THAT ARE SET INTO MOTION BY RNA CONTAINED IN SPERM OF MICE EXPOSED TO STRESS RESULT IN PART, FROM ALTERED GR AVAILABILITY IN THE IL-PFC, DISRUPTED LACTATE-BASED ACTIVITY OF IL-PFC NEURONS, AND AN IMMATURITY OF THE ADULT IL-PFC. TO TEST THIS HYPOTHESIS, WE WILL USE BIOCHEMISTRY, MOLECULAR GENETICS, DEVELOPMENTAL BIOLOGY AND IN VIVO MANIPULATION OF NEURONAL ACTIVITY WITH A FOCUS ON THE IL- PFC OF ANIMALS GENERATED FROM EMBRYOS INTO WHICH RNA FROM SPERM OF MALE MICE EXPOSED TO STRESS HAD BEEN INJECTED. VIA CELL- AND REGION-SPECIFIC INVESTIGATIONS, OUR WORK WILL PROVIDE NEW INSIGHTS INTO HOW STRESS- INDUCED ALTERATIONS IN SPERM RNA ARE TRANSLATED INTO NEUROBIOLOGICAL LEGACIES AND MAY HAVE TRANSLATIONAL IMPACT BY IDENTIFYING BIOLOGY THAT COULD BE THERAPEUTICALLY TARGETED TO LIGHTEN THE BURDEN OF SUCH LEGACIES.

PLACODE LINEAGE CONTRIBUTION TO HIRSCHSPRUNG'S DISEASE

IMPROVED FETAL SCREENING USING 0.55T MRI - PROJECT SUMMARY THIS PROJECT WILL DEVELOP A NEW APPROACH FOR SECONDARY FETAL SCREENING IN MOTHERS WITH POOR ACOUSTIC WINDOWS. RATIONALE: MAJOR CONGENITAL ANOMALIES OCCUR IN APPROXIMATELY 3% OF ALL BIRTHS AND ACCOUNT FOR 20% OF INFANT DEATHS. IN PATIENTS WITH GOOD ACOUSTIC WINDOWS, MOST CARDIAC AND EXTRACARDIAC MALFORMATIONS CAN BE CHARACTERIZED BY ULTRASOUND. FETAL MRI IS TYPICALLY RESERVED FOR PATIENTS WITH CENTRAL NERVOUS SYSTEM PATHOLOGY, MAJOR PULMONARY MALFORMATIONS, OR EXTRACARDIAC VASCULAR MALFORMATIONS; ITS SUPERIOR SOFT TISSUE CONTRAST AND LARGE FIELD OF VIEW REFINE THE DIAGNOSIS AND IMPROVE THE FAMILY COUNSELING, PREGNANCY MANAGEMENT, AND DELIVERY PLANNING, YIELDING FEWER NEONATAL COMPLICATIONS. HOWEVER, WOMEN WITH OLIGOHYDRAMNIOS, OBESITY, ADVERSE FETAL LIE, OR LATE PRESENTATION TO MEDICAL CARE OFTEN HAVE POOR ACOUSTIC WINDOWS THAT COMPROMISE THE DIAGNOSTIC UTILITY OF FETAL ULTRASOUND; THESE WOMEN ARE OVERREPRESENTED IN UNDERREPRESENTED AND MEDICALLY UNDERSERVED MINORITY POPULATIONS. APPROACH: FETAL MRI REPRESENTS AN EXCELLENT ALTERNATIVE FOR IMAGING IN THESE PATIENTS BUT ITS EXPENSE, INCONVENIENCE, LACK OF AVAILABILITY, AND SAFETY CONCERNS CURRENTLY LIMIT ITS UTILIZATION IN THIS CONTEXT. OUR HYPOTHESIS IS THAT CONTEMPORARY 0.55 TESLA WIDE BORE MRI CAN PROVIDE RAPID, SECONDARY FETAL SCREENING FOR HIGH-RISK PREGNANCIES, PROVIDING GREATER PATIENT COMFORT, SAFETY, AND ACCESS, AND THESE BENEFITS WILL BE ESPECIALLY STRONG IN MOTHERS WITH POOR ACOUSTIC WINDOWS. OUR SPECIFIC AIMS ARE TO: 1) ASSESS THE POTENTIAL OF 0.55T TO SERVE AS A SECONDARY FETAL SCREENING MODALITY IN WOMEN WITH POOR ACOUSTIC WINDOWS AND DIAGNOSTICALLY COMPROMISED ULTRASOUND STUDIES, 2) COMPARE 0.55T FETAL MRI IMAGE QUALITY, DIAGNOSTIC CONFIDENCE, AND EASE OF INTERPRETATION TO CLINICALLY INDICATED 1.5T FETAL MRI, AND 3) TO DEVELOP NEW 0.55T FETAL MRI METHODS THAT LEVERAGE THE ADVANTAGES OF THIS FIELD STRENGTH. BROADER IMPACT: THIS WORK SIGNALS A FUNDAMENTAL PARADIGM SHIFT IN THE ROLE OF FETAL MRI IN PRENATAL DIAGNOSIS BY IMPROVING THE SPEED, COMFORT, SAFETY, AND DIAGNOSTIC YIELD OF FETAL MRI. THIS PROJECT WILL DETERMINE IF 0.55T MRI SYSTEMS ARE SUITABLE FOR SITING IN MATERNAL FETAL MEDICINE CLINICS.

TARGETED CAPACITY EXPANSION-HIV PROGRAM: SUBSTANCE USE DISORDER TREATMENT FOR YOUNG GAY AND BISEXUAL MEN OF COLOR AGES 18-24 AT HIGH-RISK FOR HIV/AIDS IN LOS ANGELES, CA

ENDOTHELINS AND SYMPATHETIC INNERVATION OF THE HEART

CHILDREN'S HOSPITAL LOS ANGELES PYO TREAT PROGRAM - THE PROPOSED PROJECT, CHLA PYO TREAT PROGRAM (PREVENTING YOUTH OVERDOSE: TREATMENT, RECOVERY, EDUCATION, AWARENESS, AND TRAINING NO. TI-23-022), IS A MULTI-LEVEL PROGRAM DESIGNED TO INCREASE THE TARGET COMMUNITY’S UNDERSTANDING OF SUD/OUD AND RELATED ISSUES AFFECTING YOUTH AND YOUNG ADULTS (AYA) BY DELIVERING A SERIES OF SPECIALIZED TRAININGS THAT WILL ADDRESS OVERDOSE PREVENTION, FENTANYL, AND HARM REDUCTION PRACTICES TO SCHOOL PERSONNEL, PARENTS/CAREGIVERS, YOUTH, AND HEALTHCARE WORKERS AND BY INCREASING AYA ACCESS TO SUBSTANCE USE DISORDER (SUD) TREATMENT AND RECOVERY SERVICES, INCLUDING OPIOID USE DISORDER AND CO-OCCURRING DISORDER (COD) TREATMENT AND RECOVERY SERVICES. THE CENTRAL/METRO AREA OF LOS ANGELES COUNTY (LAC) IS THE GEOGRAPHIC TARGET AND IS A DENSELY POPULATED AND DIVERSE COMMUNITY, MARKED BY SHARP DISPARITIES IN INCOME. LAC IS THE LARGEST COUNTY IN THE UNITED STATES, WITH A POPULATION GREATER THAN 10 MILLION. THE PROPOSED PROGRAM HAS A SPECIAL FOCUS ON ENGAGING LATINX, INDIGENOUS AND LGBTQ POPULATIONS. THE GOALS OF THE PROJECT ARE: 1) INCREASE SCHOOL AND COMMUNITY CAPACITY TO REDUCE HIGH RISK BEHAVIORS OF ADOLESCENTS AND YOUNG ADULTS THAT MAY CONTRIBUTE TO SUBSTANCE USE, INCLUDING OPIOIDS, FENTANYL, CANNABIS, AND PRESCRIPTION MEDICATIONS AND OTHER SUBSTANCES OF INTEREST; 2) INCREASE ACCESS TO SUBSTANCE USE DISORDER TREATMENT AND RECOVERY SERVICES TO ADOLESCENTS AND YOUNG ADULTS, AND 3) INCREASE THE CAPACITY OF HEALTHCARE WORKERS TO IDENTIFY AND ADDRESS SUBSTANCE USE IN THEIR ADOLESCENT AND YOUNG ADULT PATIENTS. IF FUNDED, CHLA WILL REACH OVER 2700 INDIVIDUALS OVER THE THREE YEARS OF THE PROGRAM THROUGH EDUCATION AND TRAINING, CAPACITY BUILDING, AND DIRECT SUBSTANCE USE TREATMENT SERVICES. THE PROGRAM EXPECTS TO REACH 610 INDIVIDUALS IN YEAR 1 AND 1108 EACH IN YEARS 2 AND 3. THE TARGETS OF THESE SERVICES WILL INCLUDE SCHOOL PERSONNEL, PARENTS AND CAREGIVERS, HEALTH CARE PROVIDERS, STUDENTS, AND INDIVIDUALS SEEKING TREATMENT. SERVICES WILL BE PROVIDED THROUGH PARENT/CAREGIVER GROUPS, TOWN HALLS, COMMUNITY SUMMITS, SCHOOL ASSEMBLIES, PROFESSIONAL EDUCATION PRESENTATIONS, SCHOOL CLUBS AND LEADERSHIP GROUPS, AND THROUGH INDIVIDUAL TREATMENT SESSIONS.

GRADUATE PSYCHOLOGY EDUCATION PROGRAMS

NEURODIAGNOSTIC, PROTEOMIC, AND METABOLOMIC INVESTIGATIONS INTO DOWN SYNDROME REGRESSION DISORDER - ABSTRACT: DR. JONATHAN D. SANTORO IS A PHYSICIAN-SCIENTIST FOCUSED ON EXPLORING THE INTERFACE BETWEEN NEUROINFLAMMATION AND NEUROPSYCHIATRIC DISEASE IN PERSONS WITH DOWN SYNDROME (DS). DR. SANTORO IS AN INTERNATIONAL EXPERT IN DOWN SYNDROME REGRESSION DISORDER (DSRD), A NEUROPSYCHIATRIC CONDITION IN PERSONS WITH DS WHICH CAUSES ACUTE OR SUBACUTE ONSET BRADYKINESIA, CATATONIA, DELUSIONS, HALLUCINATIONS, MUTISM AND THE LOSS OF ABILITY TO PERFORM ACTIVITIES OF DAILY LIVING. THIS DISEASE IS DEVASTING TO BOTH THE PATIENT AND THEIR CAREGIVERS GIVEN THE HIGH DEGREE OF DISABILITY ASSOCIATED WITH IT. DR. SANTORO HAS SPENT THE LAST FIVE YEARS IDENTIFYING THE POTENTIAL ROLE OF NEUROINFLAMMATION IN INDIVIDUALS WITH THIS DISEASE AND HAS LED MULTIPLE SUCCESSFUL INITIATIVES TO TREAT THIS DISEASE WITH IMMUNOTHERAPY. THIS FIVE-YEAR PROPOSAL WILL BE THE FIRST COMPREHENSIVE ASSESSMENT UTILIZING NEURODIAGNOSTIC STUDIES (EEG, MRI, TCD, AND LUMBAR PUNCTURE) AND “MULTI-OMICS” ANALYSIS OF THE SERUM AND CEREBROSPINAL FLUID TO DIRECTLY COMPARE INDIVIDUALS WITH DSRD TO INDIVIDUALS WITH DS WITHOUT REGRESSION (DSWR). PRELIMINARY DATA HAS FOUND THAT INDIVIDUALS WITH DSRD HAVE SIGNIFICANTLY HIGHER RATES OF NEURODIAGNOSTIC ABNORMALITIES COMPARED TO INDIVIDUALS WITH DSWR AND THIS IS ASSOCIATED WITH HIGHER RATES OF RESPONSE TO IMMUNOTHERAPEUTICS. FURTHER, EARLY STAGE “MULTI-OMICS” ANALYSIS HAS IDENTIFIED THAT UPREGULATED IMMUNOGLOBULIN PRODUCTION AND INCREASED PERMEABILITY OF THE BLOOD-BRAIN BARRIER MAY BE A POTENTIAL PATHOLOGIC MECHANISM FOR THIS CONDITION. THIS STUDY WILL ALSO EMPLOY ADVANCED MACHINE-BASED LEARNING TECHNIQUES TO DETERMINE IF ADVANCED NEURODIAGNOSTIC PROFILING CAN PREDICT RESPONSES TO TREATMENTS AND POTENTIALLY YIELD A UNIFYING MECHANISM FOR THIS DREADFUL CONDITION. BY COMBINING A MULTIDISCIPLINARY TEAM OF EXPERTS IN DS, NEURORADIOLOGY, MULTI-OMICS, AND MACHINE-BASED LEARNING, THE PI HOPES TO YIELD CRITICALLY IMPORTANT DATA ON THE ROLE OF NEUROINFLAMMATION IN DSRD WITH THE HOPES OF EXPANDING INVESTIGATIONS TO AUTISM SPECTRUM DISORDER, EPILEPSY AND MOYAMOYA DISEASE IN THE FUTURE.

GENE EXPRESSION OF NEUROBLASTOMA AND NORMAL CELLS IN BONE MARROW PREDICTS OUTCOME

NON-INVASIVE BIOMETRIC SCREENING FOR CEREBROVASCULAR DISORDERS IN PERSONS WITH DOWN SYNDROME. - ABSTRACT: DR. JONATHAN SANTORO IS A CLINICIAN-SCIENTIST FOCUSED ON EXPLORING THE INTERFACE BETWEEN VASCULAR DISEASE, CEREBROVASCULAR DISEASE (CEVD) AND INFLAMMATION IN PERSONS WITH DOWN SYNDROME (DS). THIS FIVE-YEAR MENTORED CAREER DEVELOPMENT AWARD WILL PROVIDE HIM WITH ADVANCED TRAINING AND SKILLS IN POPULATION-BASED DATA ANALYSIS, BIOSTATISTICS, NEUROIMAGING, AND CLINICAL TRIALS DEVELOPMENT TO ENSURE A SUCCESSFUL TRANSITION TO AN INDEPENDENT RESEARCH CAREER. THE OUTLINED PROPOSAL BUILDS ON PREVIOUSLY PUBLISHED WORK BY DR. SANTORO AND LEVERAGES A MENTORSHIP TEAM OF EXPERTS IN DS, NEURODEVELOPMENT, VASCULAR DISEASE, AND CEREBROVASCULAR- INFLAMMATORY DISORDERS IN PERSONS WITH DS AT HIS HOME INSTITUTION AND OTHER LARGE ACADEMIC DS CENTERS. RESEARCH CONTEXT: PERSONS WITH DS HAVE AN INCREASED RISK OF EARLY CEVD, SPECIFICALLY MOYAMOYA SYNDROME, AND THE INITIAL PRESENTATION IS OFTEN IRREVERSIBLE NEUROLOGIC INSULT SECONDARY TO CEREBROVASCULAR ACCIDENT. FOR PERSONS WITH DS, THERE EXISTS NO VALIDATED MEANS OF ASSESSING RISK FOR CEVD. THIS K23 CAREER DEVELOPMENT BUILDS ON PREVIOUS WORK BY DR. SANTORO WHO IDENTIFIED NON-INVASIVE WAYS TO SCREEN FOR CEVD IN CHILDREN WITH DS. THIS STUDY WILL PROSPECTIVELY ASSES BLOOD PRESSURE (BP) IN PERSONS WITH DS AND SUBSEQUENTLY USE THIS TO PREDICT PRE-SYMPTOMATIC CEVD (AIM 1). NEXT, THIS STUDY WILL COMPARE GOLD STANDARD CEVD NEUROIMAGING STUDIES TO VARIOUS NON-INVASIVE, LOW-COST, BIOMETRIC TOOLS SUCH AS REPEATED BP MEASUREMENTS, TRANSCRANIAL DOPPLER ULTRASOUND AND NEUROCOGNITIVE TESTING TO ASSESS INTERNAL AND PREDICTIVE VALIDITY OF THESE MEASURES IN THE PREDICTION OF CEVD (AIM 2). AS PERSONS WITH DS ARE ESTABLISHED TO HAVE IMMUNE DYSREGULATION AND SYSTEMIC INFLAMMATORY PROFILES, WE WILL ALSO EXPLORE THE ROLE OF SYSTEMIC AND VASCULAR INFLAMMATORY BIOMARKERS IN THE DEVELOPMENT OF CEVD WITH THE GOAL OF IDENTIFYING CONTRIBUTORY INFLAMMATORY CASCADES THAT COULD BE TARGETED WITH THERAPEUTIC INTERVENTIONS GEARED TOWARDS PREVENTING CEVD IN SUBSEQUENT STUDIES (AIM 3). CAREER DEVELOPMENT PLAN: DR. SANTORO WILL COMPLETE COURSEWORK IN HEALTHCARE AND SCIENCE COMMUNICATION, DATA ANALYSIS, EPIDEMIOLOGY, CLINICAL TRIAL DESIGN AND BIOMEDICAL INFORMATICS. THIS PLAN ALSO WILL STRENGTHEN HIS COMPETENCE IN BOTH BIOINFORMATICS AND NEUROIMAGING AND BE SUPPLEMENTED BY INSTITUTIONAL WORKSHOPS AND SEMINARS. THIS EXPERIENTIAL LEARNING IS DESIGNED TO PROMOTE KNOWLEDGE AND SKILLSET DEVELOPMENT NEEDED TO BOTH EXECUTE HIS RESEARCH AND ENSURE THAT SKILLS ARE DEVELOPED FOR HIS TRANSITION TO AN INDEPENDENT RESEARCHER. DR. SANTORO’S CAREER DEVELOPMENT GOALS WILL BE SUPPORTED THROUGH CLOSE MENTORSHIP BY AN EXPERIENCED AND COMMITTED INTERDISCIPLINARY TEAM AND A COMBINATION OF DIDACTIC, EXPERIENTIAL, AND TEAM-BASED LEARNING. THIS PROPOSAL AND SUBSEQUENT R01 PROPOSALS SEEK TO IMPROVE THE NEUROLOGIC CARE OF YOUNG PERSONS WITH DS.

DEVELOPMENTAL TYPE II PNEUMOCYTE PROTEIN PHOSPHORYLATION

SIRNA INHIBITION OF KELOID FIBROSIS IN FIBRIN MATRIX SKIN EQUIVALENT MOUSE MODELS