Childrens Hospital Medical Center

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

ADMINISTRATIVE COORDINATING CENTER: CARDIOVASCULAR DEVELOPMENT AND PEDIATRIC CARDIAC GENOMICS CONSORTIA

THE IMPACT OF COVID-19 ON PEOPLE LIVING WITH RARE DISEASES AND THEIR FAMILIES

IMPACT OF THE INITIAL INFLUENZA EXPOSURE ON THE QUALITY, MAGNITUDE, BREADTH, POTENCY AND DURABILITY OF INFLUENZA IMMUNITY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

EPITHELIAL GENES IN ALLERGIC INFLAMMATION

XENBASE: A XENOPUS MODEL ORGANISM DATABASE

DIGESTIVE HEALTH CENTER: BENCH TO BEDSIDE RESEARCH IN PEDIATRIC DIGESTIVE DISEASE

CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER VACCINE AND TREATMENT EVALUATION UNITS (UM1 CLINICAL TRIAL REQUIRED)

TCD WITH TRANSFUSIONS CHANGING TO HYDROXYUREA

SIGNALING PROCESSES UNDERLYING CARDIOVASCULAR FUNCTION

CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

CONSORTIUM OF EOSINOPHILIC GASTROINTESTINAL DISEASE RESEARCHERS

DEVELOPMENTAL MECHANISMS OF TRACHEA-ESOPHAGEAL BIRTH DEFECTS

CHILDHOOD CV RISK AND ADULT CVD OUTCOMES: AN INTERNATIONAL LONG-TERM FOLLOW-UP

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

CLINICAL CENTER FOR BILIARY ATRESIA: ETIOPATHOGENESIS A*

BUILDING MODULAR PEDIATRIC CHRONIC DISEASE REGISTRIES FOR QI AND CE RESEARCH

US ENHANCED SURVEILLANCE NETWORK TO ASSESS BURDEN, NATURAL HISTORY, AND EFFECTIVENESS OF VACCINES TO PREVENT ENTERIC AND RESPIRATORY VIRUSES IN CHILDREN

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

THE LUNGMAP DATA COORDINATION CENTER FOR NEXT GEN SYSTEMS BIOLOGY OF RESPIRATION

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

NATIONAL BIOLOGICAL SAMPLE AND DATA REPOSITORY FOR PAH

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

4/6 HBCD PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM - PROJECT SUMMARY/ABSTRACT BRAIN DEVELOPMENT OCCURS AT A RAPID PACE PRENATALLY AND THROUGHOUT CHILDHOOD, IMPACTED BY DYNAMIC GENETIC AND ENVIRONMENTAL INFLUENCES. STUDIES USING ADVANCED NEUROIMAGING HAVE PROVIDED SIGNIFICANT INSIGHTS INTO BRAIN DEVELOPMENT BUT HAVE BEEN LIMITED BY SMALL SAMPLE SIZE, ESPECIALLY FOR HIGH-RISK POPULATIONS. SUBSTANCE- EXPOSED INFANTS ARE AT PARTICULARLY HIGH RISK FOR ADVERSE OUTCOMES; HOWEVER, FINDINGS ARE INCONSISTENT, MAKING IT DIFFICULT TO DISENTANGLE PRENATAL EXPOSURE EFFECTS FROM OTHER ADVERSE INFLUENCES. THE OBJECTIVES OF OUR HEALTHY BRAIN AND CHILD DEVELOPMENT (HBCD) PRENATAL EXPERIENCES AND LONGITUDINAL DEVELOPMENT (PRELUDE) CONSORTIUM ARE TO CHARACTERIZE TYPICAL TRAJECTORIES OF BRAIN DEVELOPMENT FROM BIRTH THROUGH CHILDHOOD, MEASURING THE INFLUENCE OF KEY BIOLOGIC AND ENVIRONMENTAL FACTORS AND THEIR INTERACTIONS ON CHILD SOCIAL, COGNITIVE, AND EMOTIONAL DEVELOPMENT. WE WILL ASSESS HOW CHILDREN PRENATALLY EXPOSED TO OPIOIDS AND OTHER SUBSTANCES, AS WELL AS ENVIRONMENTAL ADVERSITY, DIFFER IN THOSE BRAIN TRAJECTORIES AND OUTCOMES. OUR CONSORTIUM CONSISTS OF SIX CENTERS (ARKANSAS CHILDREN’S RESEARCH INSTITUTE, CASE WESTERN RESERVE UNIVERSITY, CINCINNATI CHILDREN’S HOSPITAL, CHILDREN’S NATIONAL MEDICAL CENTER, UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, AND VANDERBILT UNIVERSITY) WHICH HAVE COLLABORATED PREVIOUSLY AND HAVE COMPLEMENTARY EXPERTISE IN NEUROIMAGING, NEUROPHYSIOLOGY, LONGITUDINAL CLINICAL RESEARCH, CHILD DEVELOPMENT, SUBSTANCE EXPOSURE AND ADDICTION, ETHICAL/LEGAL ISSUES, AND CLINICAL CARE OF HIGH-RISK INFANTS/CHILDREN. THE PRELUDE CONSORTIUM WILL RECRUIT 680 PREGNANT WOMEN WITH SUBSTANCE USE, 680 AT-RISK PREGNANT WOMEN WITHOUT SUBSTANCE USE, AND 1360 COMPARISON PREGNANT WOMEN REPRESENTATIVE OF THE GENERAL POPULATION TO CONTRIBUTE TO THE OVERALL HBCD STUDY. WE WILL WORK CLOSELY WITH THE OTHER SITES, THE HBCD CONSORTIUM ADMINISTRATIVE CORE, AND THE HBCD DATA COORDINATING CENTER TO DEVELOP A COMPREHENSIVE STUDY PROTOCOL AND ENSURE COMPLIANCE OF STUDY WORKFLOW AND DATA TRANSFER. OUR CONSORTIUM HAS AN OPTIMIZED RESEARCH PROTOCOL AND 4 SPECIFIC AIMS: 1) EMPLOY ETHICAL AND EVIDENCE-BASED BEST PRACTICES TO ENROLL AND RETAIN A DIVERSE COHORT OF PREGNANT WOMEN INTO A LONGITUDINAL STUDY OF INFANT/CHILD BRAIN DEVELOPMENT, OVERSAMPLING MOTHERS FROM HIGH-RISK BACKGROUNDS AND THOSE USING SUBSTANCES DURING PREGNANCY; 2) ENGAGE A COMPREHENSIVE ARRAY OF MATERNAL- AND CHILD-ORIENTED COMMUNITY STAKEHOLDERS TO IDENTIFY COMMUNITY CONCERNS AND PRIORITIES REGARDING THIS RESEARCH, MINIMIZE RISKS, AND PROMOTE LONG-TERM ENGAGEMENT OF THE RECRUITED CHILD-MOTHER DYADS; 3) COLLECT RICH DATA TO EXAMINE HOW MATERNAL HEALTH CONTEXT AND BROADER ENVIRONMENTAL FACTORS MAY AFFECT THE MATERNAL-FETAL DYAD AND NEURODEVELOPMENT OF CHILDREN; 4) CAPTURE KEY DEVELOPMENTAL WINDOWS DURING WHICH MATERNAL AND ENVIRONMENTAL FACTORS MAY INTERACT WITH BRAIN AND BEHAVIORAL DEVELOPMENT OF CHILDREN. THE INSIGHTS FROM THESE DATA WILL PROVIDE GREATER UNDERSTANDING OF FACTORS AFFECTING EARLY CHILDHOOD BRAIN DEVELOPMENT, ALLOWING TARGETED INTERVENTIONS AND IMPROVED OUTCOMES FOR MOTHER-CHILD DYADS.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

REALIZING EFFECTIVENESS ACROSS CONTINENTS WITH HYDROXYUREA(REACH): A PHASE I/II PILOT STUDY OF HYROXYUREA FOR CHILDREN WITH SICKLE CELL ANEMIA

PERSONALIZED CYSTIC FIBROSIS THERAPY AND RESEARCH CENTER

GENETICS, MECHANISMS AND CLINICAL PHENOTYPES OF ARRHYTHMOGENIC CARDIOMYOPATHY

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CINCINNATI CENTER OF EXCELLENCE IN HEMOGLOBINOPATHIES RESEARCH

AMITRIPTYLINE AND TOPIRAMATE IN THE PREVENTION OF CHILDHOOD MIGRAINE

MULTI-SITE RANDOMIZED CLINICAL TRIAL OF FIT TEENS FOR JUVENILE FIBROMYALGIA

PEDIATRIC GASTROENTEROLOGY AND NUTRITION TRAINING GRANT

RANDOMIZED CONTROL TRIAL OF OXYGEN THERAPY IN CHILDREN AND ADOLESCENTS WITH DOWN SYNDROME AND OBSTRUCTIVE SLEEP APNEA - ABSTRACT: A LARGE PERCENTAGE OF CHILDREN WITH DOWN SYNDROME (DS) HAVE OBSTRUCTIVE SLEEP APNEA (OSA) THAT IS SUBOPTIMALLY TREATED BY FIRST-LINE SURGICAL INTERVENTIONS. THE PERSISTENCE OF OSA-RELATED NIGHTLY INTERMITTENT HYPOXEMIA AND FRAGMENTED SLEEP MAY CONTRIBUTE TO A COGNITIVE IMPAIRMENT, AS WELL AS PULMONARY VASCULAR DISEASE, MYOCARDIAL DYSFUNCTION, REDUCED QUALITY OF LIFE AND DAILY FUNCTIONAL IMPAIRMENT. WHILE OXYGEN IS SOMETIMES USED WHEN OTHER OSA THERAPIES FAIL, ITS EFFICACY AND SAFETY HAVE NOT BEEN SYSTEMATICALLY STUDIED. THIS R61/R33 IS THEREFORE DESIGNED TO TEST THE HYPOTHESIS THAT INDIVIDUALS WITH DS AND MODERATE TO SEVERE OSA WILL HAVE A SAFE AND FAVORABLE RESPONSE TO LOW-FLOW OXYGEN TREATMENT DUE TO ITS EFFECTS ON DIRECTLY ATTENUATING HYPOXIC EPISODES, WITH SUBSEQUENT INCREASED VENTILATORY STABILITY AND IMPROVEMENT IN OSA. WE FURTHER HYPOTHESIZE THAT OXYGEN SUPPLEMENTATION WILL LEAD TO IMPROVEMENT IN NEUROCOGNITION, CARDIAC FUNCTION, SLEEP, AND QUALITY OF LIFE. THE R61 PHASE WILL ACTIVELY ENGAGE FAMILIES OF PATIENTS WITH DS AND OUR MULTI-STAKEHOLDER TEAM TO REFINE AND PILOT THE PROTOCOL AND RECRUITMENT STRATEGIES TO ENSURE THAT WE MEET OUR RECRUITMENT/RETENTION MILESTONES IN THE R33 PHASE AND WE GENERATE DATA MOST RELEVANT TO OUR PATIENT POPULATION. IN TOTO, WE WILL SCREEN APPROXIMATELY 328 CHILDREN WITH DS AND MODERATE TO SEVERE OSA, 5-17 YRS OF AGE, WHO FAILED ADENOTONSILLECTOMY, TO IDENTIFY OXYGEN RESPONDERS, AND THEN RANDOMIZE 230 CHILDREN TO OXYGEN PLUS CONSERVATIVE THERAPY (OXT; ADMINISTERED USING A PATIENT-SPECIFIC DOSE) OR CONSERVATIVE THERAPY (CT) ALONE (WEIGHT MANAGEMENT, SLEEP HYGIENE, NASAL DILATORS) FOR 6 MONTHS. THE PRIMARY OUTCOME OF THE TRIAL IS WORKING MEMORY MEASURED BY CO-PRIMARY ENDPOINTS THAT RESPECTIVELY ASSESS CAREGIVER-REPORTED AND OBJECTIVELY MEASURED FUNCTIONS. SECONDARY OUTCOMES INCLUDE CARDIAC FUNCTION AND STRUCTURE, RIGHT VENTRICULAR PRESSURE, QUALITY OF LIFE AND SLEEP MEASURES THAT WILL BE COLLECTED UNDER THE SUPERVISION OF EXPERIENCED, CENTRAL CORE LABORATORIES. SIX CLINICAL SITES EXPERIENCED WITH PEDIATRIC CLINICAL TRIALS AND ESTABLISHED DS CENTERS WILL PARTICIPATE IN THE TRIAL. A DATA COORDINATING CENTER EXPERIENCED WITH PEDIATRIC SLEEP TRIALS WITH A STRONG HISTORY OF WORKING WITH THESE CLINICAL SITES WILL IMPLEMENT AND MONITOR DATA QUALITY CONTROL PROCESSES THAT ADDRESSES ALL STAGES OF DATA HANDLING. THIS STUDY WILL FILL A KEY KNOWLEDGE GAP IN A POTENTIALLY EFFICACIOUS THERAPY FOR OSA, AND PROVIDE EVIDENCE TO SUPPORT (OR REFUTE) THE USE OF SUPPLEMENTAL OXYGEN, AS WELL AS IDENTIFY PHYSIOLOGICAL MARKERS TO POTENTIALLY IDENTIFY PATIENT SUBGROUPS MOST LIKELY TO EXPERIENCE BENEFIT FROM THIS THERAPY.

CHILDREN'S HOSPITALS GRADUATE MEDICAL EDUCATION PAYMENT PROGRAM

CRITICAL TRANSLATIONAL STUDIES IN PEDIATRIC NEPHROLOGY

EDITING ALVEOLAR PROGENITOR CELLS FOR CORRECTION OF MONOGENIC DISEASE

TRANSLATIONAL MEDICINE AND MECHANISTIC STUDIES OF BRAIN NEUROPHYSIOLOGY IN FRAGILE X SYNDROME

GENE EXPRESSION IN PEDIATRIC ARTHRITIS

ADOLESCENT BARIATRICS: CONTROLLED LONGITUDINAL STUDY OF PSYCHOSOCIAL DEVELOPMENT

MITOGENIC ACTIVITIES IN NEUROFIBROMATOSIS

HARNESSING THE THERAPEUTIC POTENTIAL OF NEURAL CREST CELLS BY MANIPULATING THE PRIMARY CILIUM

MOLECULAR, CELLULAR AND PHYSIOLOGICAL MECHANISMS OF THE MAMMALIAN CIRCADIAN CLOCK

THROMBOSPONDIN 4 REGULATES ADAPTIVE ER STRESS RESPONSE

RANDOMIZED CONTROL TRIAL OF OXYGEN THERAPY IN CHILDREN AND ADOLESCENTS WITH DOWN SYNDROME AND OBSTRUCTIVE SLEEP APNEA - ABSTRACT: A LARGE PERCENTAGE OF CHILDREN WITH DOWN SYNDROME (DS) HAVE OBSTRUCTIVE SLEEP APNEA (OSA) THAT IS SUBOPTIMALLY TREATED BY FIRST-LINE SURGICAL INTERVENTIONS. THE PERSISTENCE OF OSA-RELATED NIGHTLY INTERMITTENT HYPOXEMIA AND FRAGMENTED SLEEP MAY CONTRIBUTE TO A COGNITIVE IMPAIRMENT, AS WELL AS PULMONARY VASCULAR DISEASE, MYOCARDIAL DYSFUNCTION, REDUCED QUALITY OF LIFE AND DAILY FUNCTIONAL IMPAIRMENT. WHILE OXYGEN IS SOMETIMES USED WHEN OTHER OSA THERAPIES FAIL, ITS EFFICACY AND SAFETY HAVE NOT BEEN SYSTEMATICALLY STUDIED. THIS R61/R33 IS THEREFORE DESIGNED TO TEST THE HYPOTHESIS THAT INDIVIDUALS WITH DS AND MODERATE TO SEVERE OSA WILL HAVE A SAFE AND FAVORABLE RESPONSE TO LOW-FLOW OXYGEN TREATMENT DUE TO ITS EFFECTS ON DIRECTLY ATTENUATING HYPOXIC EPISODES, WITH SUBSEQUENT INCREASED VENTILATORY STABILITY AND IMPROVEMENT IN OSA. WE FURTHER HYPOTHESIZE THAT OXYGEN SUPPLEMENTATION WILL LEAD TO IMPROVEMENT IN NEUROCOGNITION, CARDIAC FUNCTION, SLEEP, AND QUALITY OF LIFE. THE R61 PHASE WILL ACTIVELY ENGAGE FAMILIES OF PATIENTS WITH DS AND OUR MULTI-STAKEHOLDER TEAM TO REFINE AND PILOT THE PROTOCOL AND RECRUITMENT STRATEGIES TO ENSURE THAT WE MEET OUR RECRUITMENT/RETENTION MILESTONES IN THE R33 PHASE AND WE GENERATE DATA MOST RELEVANT TO OUR PATIENT POPULATION. IN TOTO, WE WILL SCREEN APPROXIMATELY 328 CHILDREN WITH DS AND MODERATE TO SEVERE OSA, 5-17 YRS OF AGE, WHO FAILED ADENOTONSILLECTOMY, TO IDENTIFY OXYGEN RESPONDERS, AND THEN RANDOMIZE 230 CHILDREN TO OXYGEN PLUS CONSERVATIVE THERAPY (OXT; ADMINISTERED USING A PATIENT-SPECIFIC DOSE) OR CONSERVATIVE THERAPY (CT) ALONE (WEIGHT MANAGEMENT, SLEEP HYGIENE, NASAL DILATORS) FOR 6 MONTHS. THE PRIMARY OUTCOME OF THE TRIAL IS WORKING MEMORY MEASURED BY CO-PRIMARY ENDPOINTS THAT RESPECTIVELY ASSESS CAREGIVER-REPORTED AND OBJECTIVELY MEASURED FUNCTIONS. SECONDARY OUTCOMES INCLUDE CARDIAC FUNCTION AND STRUCTURE, RIGHT VENTRICULAR PRESSURE, QUALITY OF LIFE AND SLEEP MEASURES THAT WILL BE COLLECTED UNDER THE SUPERVISION OF EXPERIENCED, CENTRAL CORE LABORATORIES. SIX CLINICAL SITES EXPERIENCED WITH PEDIATRIC CLINICAL TRIALS AND ESTABLISHED DS CENTERS WILL PARTICIPATE IN THE TRIAL. A DATA COORDINATING CENTER EXPERIENCED WITH PEDIATRIC SLEEP TRIALS WITH A STRONG HISTORY OF WORKING WITH THESE CLINICAL SITES WILL IMPLEMENT AND MONITOR DATA QUALITY CONTROL PROCESSES THAT ADDRESSES ALL STAGES OF DATA HANDLING. THIS STUDY WILL FILL A KEY KNOWLEDGE GAP IN A POTENTIALLY EFFICACIOUS THERAPY FOR OSA, AND PROVIDE EVIDENCE TO SUPPORT (OR REFUTE) THE USE OF SUPPLEMENTAL OXYGEN, AS WELL AS IDENTIFY PHYSIOLOGICAL MARKERS TO POTENTIALLY IDENTIFY PATIENT SUBGROUPS MOST LIKELY TO EXPERIENCE BENEFIT FROM THIS THERAPY.

TRANSPIRE: A PROSPECTIVE COHORT STUDY OF LUNG INJURY AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. - PROJECT SUMMARY HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) IS INCREASINGLY USED FOR NON-MALIGNANT HEMATOLOGIC DISORDERS SUCH AS SICKLE CELL ANEMIA AND MARROW FAILURE, AND COMPLICATIONS OF HSCT ARE MORE PREVALENT AND IMPORTANT AS CAUSES OF LONG TERM MORBIDITY. IMPROVED DIAGNOSIS AND TREATMENT AND TREATMENT ARE URGENT ISSUES. LUNG INJURY IS FREQUENT AFTER HSCT, WITH AS MANY AS 15% OF CHILDREN TRANSPLANTED HAVING REDUCED FEV1, LATER LEADING TO OVERT BRONCHIOLITIS OBLITERANS (BO) WHICH IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. DIAGNOSIS OF BO IN ADULTS DEPENDS ON SPIROMETRY, AND EVIDENCE SUGGESTS THAT EARLY DIAGNOSIS MAY IMPROVE CHANCES OF RECOVERY OF LUNG FUNCTION AND SURVIVAL. SMALL CHILDREN, AND EVEN OLDER CHILDREN AND TEENAGERS WHO FEEL UNWELL AND ARE UNCOOPERATIVE, ARE UNABLE TO PERFORM SPIROMETRY, MEANING THAT LUNG IMPAIRMENT IS “INVISIBLE” UNTIL SEVERE AND CLINICALLY MANIFEST. PROGRESS IN IMPROVING LUNG OUTCOMES OF HSCT IN CHILDREN HAS BEEN HINDERED BY LACK OF DIAGNOSTIC STRATEGIES, AND BY THE NEED FOR A LARGE GROUP OF CASES TO ALLOW TESTING OF BIOLOGICAL, PATHOLOGICAL AND DIAGNOSTIC HYPOTHESES TO ADVANCE THE FIELD. WE PROPOSE ASSEMBLING A PROSPECTIVE COHORT STUDY OF ALL CHILDREN RECEIVING HSCT AT 6 MAJOR US TRANSPLANT CENTERS. WE WILL PERFORM STANDARDIZED PROSPECTIVE TESTING OF LUNG FUNCTION AND CLINICAL DATA COLLECTION IN ALL CHILDREN IN THE COHORT, TO DETERMINE THE FREQUENCY, CLINICAL PHENOTYPES AND RISK FACTORS FOR BO (SPECIFIC AIM 1). BO IS A RARE DISEASE SO PROGRESS WILL NOT BE MADE ABSENT A MULTI-CENTER COHORT STUDY THAT UNIFORMLY DEFINES CLINICAL PHENOTYPE AND PROSPECTIVELY COLLECTS SAMPLES, ALLOWING RETROSPECTIVE STUDY OF EARLY MOLECULAR EVENTS THAT PREDICT LATER DISEASE. IN SPECIFIC AIM 2 WE WILL COLLECT CALENDAR AND EVENT-DRIVEN BIOLOGICAL SAMPLES, INCLUDING SERUM, PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS AND BRONCHIOLAR LAVAGE FLUID, WHICH WILL BE STORED AND USED TO IDENTIFY BIOMARKERS OF ONSET OF BO AND OF RESPONSE TO THERAPY. MOREOVER, WE WILL COLLECT PATHOLOGICAL SAMPLES THAT WILL BE ANALYZED USING A PRE- EXISTING RARE LUNG DISEASE PATHOLOGY PLATFORM TO IDENTIFY GENETIC AND ANATOMIC CHANGES THAT DEFINE BO. LASTLY, IN SPECIFIC AIM 3 WE WILL TEST AND DISSEMINATE NOVEL LUNG TESTING STRATEGIES, INCLUDING INNOVATIVE IMAGING, TO ADDRESS THE CRITICAL CLINICAL CHALLENGE OF LATE DIAGNOSIS OF LUNG IMPAIRMENT IN CHILDREN. WE PROVIDE EXAMPLES OF ESSENTIAL BIOLOGICAL STUDIES THAT CAN ONLY BE PERFORMED USING THE RESOURCES OF THE COHORT, FOR WHICH WE WILL SEEK ADDITIONAL R01 FUNDING. TAKEN TOGETHER, THIS COHORT STUDY CAN FUNDAMENTALLY CHANGE THE PARADIGM OF LUNG INJURY AFTER TRANSPLANT AND PROVIDE A PLATFORM FOR TESTING PREVENTIVE AND THERAPEUTIC TREATMENTS.

POLYGENIC RISK SCORES FOR HEALTHIER AFRICAN AMERICAN FAMILIES

PEDIATRIC CENTER FOR GENE EXPRESSION AND DEVELOPMENT

GENE REGULATION AS A FOUNDATION FOR AUTOIMMUNE DISEASE PREVENTION

OPEN SOURCE SCIENCE: TRANSFORMING CHRONIC ILLNESS CARE

THE ROLE OF HUMAN MILK IN INFANT NUTRITION AND HEALTH

UTE MRI TO MONITOR CF LUNG DISEASE AND RESPONSE TO CFTR MODULATION IN YOUNG CHILDREN

CINCINNATI CENTER OF NEUROFIBROMATOSIS RESEARCH

A NEW MODEL TO IDENTIFY PRETERM NEONATES AT HIGH-RISK FOR COGNITIVE DEFICITS

DATA COORDINATING CENTER: B2B CHANGE COHORT - PROJECT ABSTRACT CONGENITAL HEART DISEASE (CHD) OCCURS IN APPROXIMATELY 40,000 INFANTS IN THE UNITED STATES EACH YEAR. THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NLHBI) LAUNCHED ITS BENCH TO BASSINET PROGRAM (B2B) IN 2009 TO OVERCOME THE MAJOR BARRIERS IN TRANSLATIONAL RESEARCH, IDENTIFY THE CAUSES OF HUMAN CHD, AND IMPROVE OUTCOMES FOR INDIVIDUALS WITH CHD. THROUGH THE CONGENITAL HEART DISEASE GENETIC NETWORK STUDY (CHD GENES), THE B2B PROGRAM HAS ENROLLED OVER 14,000 PARTICIPANTS WITH CHD AND 18,000 FAMILY MEMBERS, CONDUCTING GENOMIC SEQUENCING TO IDENTIFY AN ESTIMATED 25% OF PREVIOUSLY UNEXPLAINED CHD CASES. DESPITE THESE ADVANCES, CRITICAL GAPS PERSIST IN OUR UNDERSTANDING OF HOW GENETIC VARIANTS INFLUENCE GENOTYPE- PHENOTYPE CORRELATIONS AND LONG-TERM OUTCOMES IN CHD. ALTHOUGH NOT INITIALLY DESIGNED AS A LONGITUDINAL COHORT, THE NHLBI RECOGNIZED THE UNIQUE POTENTIAL OF THE CHD GENES AND DIRECTED THE COORDINATING CENTER (CC) TO ORGANIZE DEEP PHENOTYPING AND RE-ENROLLMENT OF A SUBSET OF PARTICIPANTS FOR AN IN-PERSON CLINICAL ASSESSMENT AND TO MAKE THE DATA AVAILABLE TO THE SCIENTIFIC COMMUNITY AS THE B2B CONGENITAL HEART DISEASE ADVANCING NEW UNDERSTANDING IN GENOMICS (CHANGE) COHORT. THE NEW ITERATION OF THE CC IS A UNIQUE, INTEGRATED COMBINATION OF WORLD-LEADING CARDIOVASCULAR AND CLINICAL/TRANSLATIONAL RESEARCH EXPERTISE, ADVANCED INFRASTRUCTURE, OUTSTANDING OPERATIONAL SUPPORT, AND STATE-OF-THE-ART TECHNOLOGY. THE SPECIFIC AIMS ARE TO: 1) ESTABLISH AND MAINTAIN THE B2B CHANGE COHORT, 2) CREATE A UNIQUE RESOURCE FOR CHD RESEARCH BY INTEGRATING NEW DATA SOURCES WITH THE EXISTING CLINICAL AND GENOMIC INFORMATION MAINTAINED IN THE B2B DATAHUB (HEARTSMART) AND SHARED WITH NHLBI’S BIODATA CATALYST SYSTEM, AND 3) ENSURE THE CHD COMMUNITY HAS THE NECESSARY ACCESS, TOOLS, AND SUPPORT TO TRANSLATE B2B DATA INTO IMPROVED HEALTH AND QUALITY OF LIFE FOR THOSE AFFECTED BY CHD. B2B CHANGE WILL BE ESTABLISHED USING A MULTIFACETED AND PATIENT-INFORMED COHORT OUTREACH AND ENGAGEMENT APPROACH INCORPORATING NATIONALLY RECOGNIZED EXPERT LEADERSHIP AND CONSULTATION AND ADAPTATION TO LOCAL CONTEXTS AS APPROPRIATE. INNOVATIVE CLINICAL ASSESSMENTS AND TECHNICAL ADVANCEMENTS TO HEARTSMART WILL EXPAND AND ENRICH EXISTING PHENOTYPING APPROACHES, EXTEND THE DURATION OF FOLLOW-UP, AND ALLOW FOR NEW BIOLOGICAL SAMPLE ACQUISITION FOR FUTURE MECHANISTIC AND TRANSLATIONAL STUDIES. THROUGH RESOURCES INCLUDING HEARTSMART AND BIODATA CATALYST, AND EXTENSIVE OUTREACH, EDUCATION, AND ENGAGEMENT, THE CC WILL ENSURE THE CHD COMMUNITY HAS ACCESS TO THIS VITAL RESOURCE TO SUPPORT RIGOROUS, INDEPENDENTLY FUNDED, INVESTIGATOR-INITIATED ANCILLARY STUDIES. THE B2B CC HAS PROVIDED EXCELLENCE IN ADMINISTRATIVE SUPPORT AND COORDINATION FOR THE B2B PROGRAM FOR THE PREVIOUS TWO FUNDING CYCLES AND WILL CONTINUE TO BE A SUCCESSFUL PARTNER WITH SITE INVESTIGATORS, THE NHLBI, AND THE CHD COMMUNITY, LEADING THE COORDINATION OF KNOWLEDGE AND DATA FOR THIS IMPORTANT CARDIOVASCULAR RESEARCH EFFORT.

SICKLE CELL TREATMENT DEMONSTRATION PROGRAM

ADOLESCENT BARIATRICS: ASSESSING HEALTH BENEFITS & RISKS

CINCINNATI RHEUMATIC DISEASES RESOURCE CENTER

COGNITIVE OUTCOME MEASURES IN SCHOOL AGE CHILDREN WITH DOWN SYNDROME

ROLE OF ANTI-GM-CSF ANTIBODIES IN MYELOID CELL FUNCTION & INNATE IMMUNITY

SELECTIVE DISRUPTION OF HIPPOCAMPAL DENTATE GRANULE CELLS IN AUTISM: IMPACT OF PT

CARDIAC FIBROBLASTS IN POSTNATAL DEVELOPMENT AND ADULT INJURY RESPONSE

HEALTHY START INITIATIVE-ELIMINATING RACIAL/ETHNIC DISPARITIES

CINCINNATI MULTIDISCIPLINARY CLINICAL RESEARCH CENTER

MOLECULAR EXAMINATION OF MITOCHONDRIAL CALCIUM CONTROL

GENETIC AND IMMUNOLOGICAL DISSECTION OF EOSINOPHILIC ESOPHAGITIS

COMPREHENSIVE SICKLE CELL CENTER

EPIDEMIOLOGIC IMPACT OF HPV VACCINATION

IMMUNOPATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE

IMMUNOLOGICAL IDENTITY REDEFINED BY GENETICALLY FOREIGN MICROCHIMERIC CELLS

IMMUNOLOGIC DYSFUNCTION IN BILIARY ATRESIA

MODELING DIABETES USING AN INTEGRATED PLATE SYSTEM

LONGITUDINAL IMPACT OF AIR POLLUTION ON MENTAL HEALTH AND NEUROIMAGING OUTCOMES DURING ADOLESCENCE IN THE CINCINNATI COMBINED CHILDHOOD COHORTS (C4) - PROJECT SUMMARY / ABSTRACT MORE THAN ONE IN FIVE ADOLESCENTS WILL EXPERIENCE A MENTAL HEALTH DISORDER, INCLUDING DEPRESSION AND ANXIETY, AND THE PREVALENCE OF THESE CONDITIONS IS INCREASING. AMONG ADOLESCENTS, DEPRESSION AND ANXIETY ARE LINKED TO INCREASED RISK OF SUICIDE, A LEADING CAUSE OF DEATH IN THIS AGE GROUP. IDENTIFYING UNDERLYING AND MODIFIABLE CONTRIBUTORS TO THESE CONDITIONS IS CRUCIAL AS CURRENT RESEARCH AND INTERVENTIONS FOCUS ON SCREENING AND TREATMENT RATHER THAN PREVENTION. HERE, WE POSIT THAT AIR POLLUTION, IN ADDITION TO GENETIC SUSCEPTIBILITY, SOCIAL DETERMINANTS, FAMILIAL AND SCHOOL ISSUES, AND OTHER FACTORS, IS A CONTRIBUTOR TO MENTAL HEALTH DISORDERS. TOXICOLOGICAL STUDIES DEMONSTRATE THAT FINE PARTICULATE MATTER (PM2.5) AND TRAFFIC-RELATED AIR POLLUTION (TRAP) ARE NEUROTOXIC, AND EPIDEMIOLOGIC STUDIES CONSISTENTLY LINK THESE POLLUTANTS TO REDUCED COGNITIVE ABILITIES AND INCREASED EXTERNALIZING BEHAVIORS. HOWEVER, FEW STUDIES HAVE PROSPECTIVELY EVALUATED THE ROLE OF AIR POLLUTION EXPOSURE ON MENTAL HEALTH DISORDERS IN CHILDHOOD. RECENTLY, WE FOUND THAT CHILDHOOD AIR POLLUTION EXPOSURE IS ASSOCIATED WITH INCREASED RISK FOR DEPRESSION AND ANXIETY AT AGE 12 YEARS. HOWEVER, THE ROLE OF AIR POLLUTION IN THE ONSET AND PERSISTENCE OF MENTAL HEALTH DISORDERS DURING ADOLESCENCE, AND CHANGES IN BRAIN STRUCTURE, ORGANIZATION, AND FUNCTION LINKED TO THESE OUTCOMES, REMAIN POORLY UNDERSTOOD. THEREFORE, WE HYPOTHESIZE THAT EXPOSURE TO AIR POLLUTION DURING CRITICAL PERIODS OF BRAIN DEVELOPMENT, INCLUDING ADOLESCENCE, IS ASSOCIATED WITH ADVERSE MENTAL HEALTH OUTCOMES. WE WILL LEVERAGE EXISTING LONGITUDINAL DATA FROM THE CINCINNATI CHILDHOOD ALLERGY AND AIR POLLUTION STUDY (CCAAPS) AND THE HEALTH OUTCOMES AND MEASURES OF THE ENVIRONMENT (HOME) STUDY, TWO PROSPECTIVE COHORTS LOCATED IN CINCINNATI, OHIO, TO ADDRESS THIS HYPOTHESIS. BOTH COHORTS HAVE BEEN FOLLOWED FROM BIRTH AND EVALUATED WITH CONCORDANT MEASURES OF MENTAL HEALTH AND NEUROIMAGING AT AGE 12 YEARS. WE WILL CONDUCT NEW FOLLOW-UP AT AGE 18 YEARS TO ASSESS THE ONSET AND PERSISTENCE OF MENTAL HEALTH OUTCOMES THROUGH ADOLESCENCE AND APPLY VALIDATED MODELS FOR PM2.5 AND TRAP TO CHARACTERIZE AIR POLLUTION EXPOSURE FROM CONCEPTION THROUGH AGE 18 YEARS. WE WILL ALSO ACQUIRE NOVEL NEUROIMAGING OUTCOMES, INCLUDING BRAIN -AMINOBUTYRIC ACID AND GLUTATHIONE CONCENTRATIONS ACCOMPANIED BY ANATOMICAL AND FUNCTIONAL MAGNETIC RESONANCE IMAGING. OUR AIMS ARE TO: 1) DETERMINE THE ASSOCIATION BETWEEN EXPOSURE TO PM2.5 AND TRAP DURING DISTINCT DEVELOPMENTAL PERIODS AND THE ONSET AND PERSISTENCE OF MENTAL HEALTH OUTCOMES IN ADOLESCENCE; 2) DETERMINE THE ASSOCIATION BETWEEN EXPOSURE TO PM2.5 AND TRAP DURING DISTINCT DEVELOPMENTAL PERIODS AND NEUROIMAGING OUTCOMES IN LATE ADOLESCENCE; AND 3) DETERMINE WHETHER CHANGES IN BRAIN VOLUME, ORGANIZATION, METABOLISM, AND FUNCTION MEDIATE ASSOCIATIONS BETWEEN PM2.5 AND TRAP EXPOSURE AND MENTAL HEALTH OUTCOMES. EXAMINING AIR POLLUTION AS A NOVEL AND MODIFIABLE RISK FACTOR WILL PROVIDE CRITICAL DATA TO GUIDE PRIMARY PREVENTION AIMED AT REDUCING THE BURDEN OF MENTAL HEALTH DISORDERS IN ADOLESCENCE.

MOLECULAR SIGNALING IN UTERINE RECEPTIVITY TO IMPLANTATION

CONTINUED STUDIES OF ENVIRONMENT IMPACT ON PUBERTY

INTRAMUSCULAR VS. ENTERAL PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHEUMATIC HEART DISEASE: A NON-INFERIORITY RANDOMIZED TRIAL. (GOALIE) - PROJECT SUMMARY ABSTRACT RHEUMATIC HEART DISEASE (RHD) REMAINS A HIGH PREVALENCE CONDITION IN LOW-AND-MIDDLE-INCOME COUNTRIES, CURRENTLY AFFECTING AT LEAST 40 MILLION PEOPLE, MANY OF WHOM SUFFER PREMATURE DEATH. MOST PATIENTS WITH RHD PRESENT LATE, MISSING THE OPPORTUNITY TO BENEFIT FROM SECONDARY ANTIBIOTIC PROPHYLAXIS. SCREENING ECHOCARDIOGRAPHY IN RHD ENDEMIC SETTINGS IDENTIFIES MANY CHILDREN WITH EARLY, LATENT RHD, BUT UNTIL RECENTLY THE EFFECTIVENESS OF PROPHYLAXIS TO PROTECT CHILDREN WITH LATENT RHD WAS NOT KNOWN. THE GOAL TRIAL (CONDUCTED IN UGANDA BY THIS INVESTIGATIVE TEAM) FOUND THAT CHILDREN WITH LATENT RHD WHO RECEIVE PROPHYLAXIS WITH INTRAMUSCULAR PENICILLIN ARE LESS LIKELY TO PROGRESS AT TWO-YEARS (0.8% PENICILLIN VS. 8.3% NO PENICILLIN, P<0.001). HOWEVER, DESPITE THESE RESULTS, SCALE-UP OF ECHOCARDIOGRAPHIC SCREENING AND EARLY INITIATION OF PROPHYLAXIS WITH INTRAMUSCULAR (IM) PENICILLIN FOR RHD HAS A MYRIAD OF CHALLENGES. AMONG THE MOST CRITICAL ARE SUBSTANTIAL PATIENT (INCLUDING PAIN AND MISSED WORK/SCHOOL) AND HEALTH SYSTEM-LEVEL BARRIERS (INCLUDING COST, TIME, AND TRAINING) TO DELIVERING PROLONGED COURSES OF IM INJECTIONS IN LOW-RESOURCE SETTINGS. INTRAMUSCULAR VS. ENTERAL PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHEUMATIC HEART DISEASE (GOALIE) WILL DETERMINE IF A LESS BURDENSOME FORM OF PROPHYLAXIS, ORAL PENICILLIN, IS NON- INFERIOR TO IM PENICILLIN IN PREVENTING LATENT RHD PROGRESSION. GOALIE IS A RANDOMIZED NON-INFERIORITY TRIAL COMPARING THE EFFICACY OF INTRAMUSCULAR TO ENTERAL (ORAL) PENICILLIN PROPHYLAXIS TO PREVENT PROGRESSION OF LATENT RHD AT TWO YEARS. BASED ON OUR STRONG HISTORY OF RECRUITMENT AND RETENTION, WE WILL CONDUCT SCHOOL- BASED ECHOCARDIOGRAPHIC SCREENING OF ~100,000 CHILDREN AND ENROLL 1004 CHILDREN INTO GOALIE, WHICH WILL PROVIDE 90% POWER TO DETERMINE IF ORAL PENICILLIN PROPHYLAXIS IS NON-INFERIOR TO IM PENICILLIN PROPHYLAXIS. GOALIE WILL ALSO EXAMINE ECONOMIC EQUIVALENCE AND COST-EFFECTIVENESS OF THESE TWO PROPHYLAXIS STRATEGIES (AIM 2) AND THE PATIENT REPORTED OUTCOMES BETWEEN THESE TWO STRATEGIES (AIM 3), PROVIDING CRITICAL DATA TO INFORM THE INTEGRATION OF PROPHYLAXIS FOR LATENT RHD INTO CLINICAL PRACTICE. GOALIE BUILDS OFF OUR DECADE LONG COLLABORATION, INCLUDING STRONG MINISTRY OF HEALTH AND COMMUNITY SUPPORT. GOALIE WILL LEVERAGE THE STRUCTURE OF THE GOAL TRIAL WHICH DEVELOPED STREAMLINED PROTOCOLS FOR ECHOCARDIOGRAPHIC SCREENING (>102,000 SCREENED) AND HIGHLY SUCCESSFUL RECRUITMENT (>99% ELIGIBLE CHILDREN), RETENTION (97% COMPLETION), AND ADHERENCE SUPPORT (99% ADHERENCE) STRATEGIES. THE RESULTS OF OUR STUDY WILL HAVE HIGH CLINICAL AND PUBLIC HEALTH IMPACT, IMMEDIATELY INFORMING INTERNATIONAL POLICY ON THE STANDARD OF CARE FOR CHILDREN DIAGNOSED WITH LATENT RHD.

A GENERALIZABLE FRAMEWORK FOR LINKING SINGLE-CELL GENOMIC STATES WITH CELL FATE OUTCOMES IN HEMATOPOIESIS

BONE MINERAL ACCRETION IN YOUNG CHILDREN

EMERGENCY MEDICAL SERVICES FOR CHILDREN: NETWORK DEVELOPMENT DEMONSTRATION PROJECT

CINCINNATI RHEUMATIC DISEASES CENTER

RESEARCH TRAINING IN CHILD BEHAVIOR AND NUTRITION

HUMAN GENE TRANSFER & MACROPHAGE CELL TRANSPLANTATION THERAPY OF HEREDITARY PAP (HPAP) - ABSTRACT GENE COMPLEMENTATION AND PULMONARY MACROPHAGE TRANSPLANTATION (PMT THERAPY) IS A PROMISING POTENTIAL THERAPY OF HEREDITARY PULMONARY ALVEOLAR PROTEINOSIS (HPAP) – A DISORDER OF PROGRESSIVE OF ALVEOLAR SURFACTANT ACCUMULATION AND RESPIRATORY FAILURE – FOR WHICH NO PHARMACOTHERAPY THERAPY EXISTS. WE DEFINED THE PATHO- GENESIS, PRESENTATION, DIAGNOSIS, AND MANAGEMENT OF HPAP, SHOWED IT IS CAUSED BY THE LOSS OF GM-CSF RE- CEPTOR SIGNALING AND DISRUPTION OF ALVEOLAR MACROPHAGE (AM) FUNCTIONS INCLUDING THE REMOVAL OF SURFACTANT FROM ALVEOLI. WE DEMONSTRATED LENTIVIRAL VECTOR-MEDIATED COMPLEMENTATION OF FUNCTION-DISRUPTING CSF2RA MUTATIONS RESTORED GM-CSF RECEPTOR SIGNALING IN HUMAN AMS INCLUDING RESCUE OF SURFACTANT CLEARANCE. DESPITE OUTSTAND- ING PROGRESS, INCLUDING DEMONSTRATION OF THE SAFETY, TOLERABILITY, EFFICACY, AND DURABILITY OF PMT THERAPY IN TWO VALIDATED HPAP ANIMAL MODELS, LACK OF CLINICAL STUDIES OF PMT THERAPY IN HUMANS IS A CRITICAL BARRIER TO ITS FUR- THER THERAPEUTIC DEVELOPMENT. OUR LONG-TERM GOAL IS TO DEVELOP PMT THERAPY AS THE AN EFFECTIVE, DISEASE- SPECIFIC THERAPY OF HPAP (AND POSSIBLY OTHER DISEASES). THE OBJECTIVE HERE IS TO COMPLETE PREPARATIONS FOR, AND THEN TO CONDUCT, A PHASE I TRIAL TO ESTABLISH THE SAFETY OF PMT IN HUMAN PATIENTS WITH HPAP AND ALSO IDENTIFY USEFUL CLINICAL AND BIOLOGICAL OUTCOME MEASURES INFORMING THE DESIGN OF A FUTURE PHASE II EFFICACY TRIAL. THE CENTRAL HYPOTHESIS IS THAT AFTER PMT OF AUTOLOGOUS CD34+ CELL-DERIVED CSF2RA GENE-CORRECTED MACRO- PHAGES WITHOUT MYELOABLATION, THE TRANSPLANTED CELLS WILL SURVIVE, ENGRAFT, ADOPT THE PHENOTYPE AND FUNCTION OF NORMAL AMS, REPLACE ENDOGENOUS AMS, REESTABLISH A NORMAL-SIZED AM POPULATION THAT REMAINS IN THE LUNGS AND RESULTS IN A SAFE, WELL-TOLERATED, EFFECTIVE, AND DURABLE TREATMENT BENEFIT. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A ‘FIRST-IN-HUMAN’ STUDY ESTABLISHING THE SAFETY OF PMT THERAPY IN HUMANS WILL UNBLOCK FURTHER CLINICAL DEVELOPMENT OF PMT THERAPY INCLUDING PREPARATION FOR CONDUCT OF A FUTURE PHASE 2 CLINICAL EFFICACY TRIAL. WE PLAN TO ADDRESS OUR HYPOTHESIS BY PURSUING FOUR SPECIFIC AIMS IN THE R61 PHASE AND THREE AIMS IN THE R33 PHASE: 1) FINALIZE STABILITY TESTING OF CSF2RA GENE-CORRECTED MACROPHAGES; COMPLETE 2) TRIAL-RELATED AND 3) IND-RELATED DOCUMENTS; 4) OBTAIN REGULATORY APPROVALS (INSTITUTIONAL REVIEW BOARD AND BIOSAFETY COMMITTEE, DATA, SAFETY, AND MONITORING BOARD, FDA); 5) ASSESS THE SAFETY, 6) MEASURE THE PHARMACOKINETICS AND PHAR- MACODYNAMICS, AND 7) IDENTIFY USEFUL MEASURES OF THE CLINICAL OUTCOMES AND BIOLOGICAL SIGNATURE OF PMT THER- APY IN HPAP PATIENTS. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT REPRESENTS A MARKED DEPARTURE FROM THE CURRENT TREATMENT APPROACH, WHOLE LUNG LAVAGE (AN INVASIVE, INEFFICIENT, PROCEDURE TO PHYSICALLY REMOVE SURFAC- TANT) BY ESTABLISHING, IN HPAP PATIENTS, THE FEASIBILITY OF A NEW APPROACH TO RESTORE A GM-CSF-RESPONSIVE, FUNCTIONAL AM POPULATION. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE ESTABLISHING THE SAFETY, PHARMACOKI- NETICS AND PHARMACODYNAMICS, AND IDENTIFYING USEFUL CLINICAL OUTCOME MEASURES OF PMT THERAPY IN HUMANS IS THE NEXT STEP IN OUR CLINICAL RESEARCH PROGRAM TO DEVELOP PMT AS THE FIRST SPECIFIC THERAPY OF HPAP.

PROGESTERONE INDUCED IMMUNE MODULATION DURING PREGNANCY

DOSING AND PILOT EFFICACY OF 2'-FUCOSYLLACTOSE IN INFLAMMATORY BOWEL DISEASE

SUPRASPINAL PROCESSING OF SENSORY ASPECTS OF PAIN

EMERGENCY MEDICAL SERVICES FOR CHILDREN: NETWORK DEVELOPMENT DEMONSTRATION PROJECT

VENOUS MALFORMATIONS (VM): A MURINE MDOEL TO IDENTIFY THERAPIES TO TARGER ABERRANT VENOUS DEVELOPMENT

MOLECULAR MECHANISMS CONTROLLING FORMATION OF BASAL GANGLIA CIRCUITRY

THE PEDIATRIC LUPUS NEPHRITIS MYCOPHENOLATE MOFETIL (PLUMM) STUDY - TITLE EFFICACY & SAFETY OF PHARMACOKINETICALLY-DRIVEN DOSING OF MYCOPHENOLATE MOFETIL FOR THE TREATMENT OF PEDIATRIC PROLIFERATIVE LUPUS NEPHRITIS - A DOUBLE-BLIND CONTROLLED CLINICAL TRIAL THE PEDIATRIC LUPUS NEPHRITIS MYCOPHENOLATE MOFETIL (PLUMM) STUDY PROJECT SUMMARY: META-ANALYSES IN ADULTS SUGGEST EQUIVALENCE OF CLINICAL EFFICACY OF INTRAVENOUS CYCLOPHOSPHAMIDE AND MYCOPHENOLATE MOFETIL WHEN DOSED BASED ON PATIENT WEIGHT OR BODY-SURFACE-AREA (MMFBSA) AS IS THE CURRENT STANDARD FOR THE TREATMENT OF PROLIFERATIVE LUPUS NEPHRITIS (LN) TREATMENTS IN THE U.S. PHARMACOKINETICALLY- GUIDED PRECISION DOSING OF MMF (MMKPK) MAY OFFER A BENEFICIAL MODIFICATION OF THE CURRENT STANDARD TREATMENT IN THAT MMKPK PROMISES OVER 30% HIGHER LN RESPONSE RATES THAN MMFBSA. THE OBJECTIVE OF THE PROPOSED, ADEQUATELY POWERED, RANDOMIZED, DOUBLE-BLIND CONTROLLED CLINICAL TRIAL IS TO COMPARE THE EFFICACY AND SAFETY OF PHARMACOKINETICALLY-GUIDED PRECISION DOSING OF MMF (MMFPK) WITH CONVENTIONAL DOSING REGIMENS OF MMF (MMFBSA) AMONG CHILDREN WITH PROLIFERATIVE LN. THE PRINCIPAL HYPOTHESIS TO BE TESTED IN THIS 2-ARM 104-WEEK STUDY IS THAT, COMPARED TO MMFBSA, MMFPK RESULTS IN SIGNIFICANTLY HIGHER RATES OF RENAL REMISSION IN CHILDREN WITH PROLIFERATIVE LN. THE PRIMARY ENDPOINT IS THE PROPORTION OF SUBJECTS ACHIEVING AT LEAST PARTIAL RENAL REMISSION (PRR) AT WEEK 26 OF THE STUDY IN THE INTENTION TO TREAT POPULATION. THE KEY SECONDARY ENDPOINT IS ACHIEVEMENT OF COMPLETE RENAL REMISSION (CRR) AT WEEK 26 OF THE STUDY. OUR APPROACH WILL BE TO ENROLL 105 PEDIATRIC SUBJECTS, AGES 8 YEARS OR OLDER, WHO HAVE BEEN NEWLY DIAGNOSED WITH PROLIFERATIVE LN PLUS HAVE CHOSEN MMF FOR INDUCTION THERAPY PLUS TOLERATE ORAL MMF. RANDOMIZATION WILL OCCUR AT BASELINE (1:1) TO THE MMKPK ARM OR THE MMFBSA ARM, RESPECTIVELY. AFTER WEEK 26, NON-RESPONDERS WILL BE DISCONTINUED FROM THE ACTIVE STUDY INTERVENTION, AND SUBJECTS RANDOMIZED AT BASELINE TO THE MMFBSA ARM WHO ACHIEVED PRR BUT NOT CRR WILL CROSS OVER TO THE MMFPK ARM. VOLUMETRIC ABSORPTIVE MICROSAMPLING (VAMS) DEVICES WILL BE USED TO FACILITATE ESTIMATION OF THE EXPOSURE TO MYCOPHENOLIC ACID (MPA) IN WHOLE BLOOD AS IS NEEDED TO PERSONALIZE MMF DOSING IN THE MMFPK ARM. USE OF CORTICOSTEROID WILL BE STANDARDIZED AND CLOSELY REGULATED DURING THE STUDY, AND ADHERENCE TO MMF WILL BE MONITORED. PATENTED BIOMARKERS WILL BE ASSAYED IN THE URINE IN SUPPORT OF THE SUPERIORITY OF MMFPK OVER MMFBSA IN CONTROLLING LN ACTIVITY. UPON COMPLETION OF THIS TRIAL, WE EXPECT TO HAVE UNEQUIVOCAL EVIDENCE OF THE SUPERIORITY MMFPK THERAPY COMPARED TO MMFBSA USE, AND TO SHOW THAT MMFPK DOSAGE IS WELL TOLERATED AND HAS AN ACCEPTABLE SAFETY PROFILE IN CHILDREN. RELEVANCE: THE PROPOSED TRIAL IS RELEVANT TO PUBLIC HEALTH BECAUSE THERAPIES FOR LN ARE INVESTIGATED, I.E. DISEASE COMPLICATIONS THAT CONCERN THE MAJORITY OF CHILDREN WITH CSLE. IN THIS SETTING, OPTIMIZING DRUG USE PROMISES TO IMPROVE LONG-TERM DISEASE OUTCOMES THROUGH RAPID CONTROL OF KIDNEY INFLAMMATION, WHILE MINIMZING UNNECESSARY EXPOSURES TO AN IMMUNOSUPPRESSIVE AND TERATOGENIC MEDICATION. THIS IS RELEVANT TO THE PART OF NIH’S MISSION THAT PERTAINS TO FOSTERING RESEARCH IN TREATMENT; AND THE DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN LUPUS. LN IS CENTRAL TO NIAMS STRATEGIC PLAN AND ITS LUPUS RESEARCH AGENDA IN PURSUANCE OF IMPROVED PUBLIC HEALTH AND PATIENT-CENTERED PERSONALIZED CARE.

NOVEL VACCINE AGAINST NOROVIRUS

MOLECULAR CONTROL OF NEUROGENESIS IN THE ADULT SUBVENTRICULAR ZONE

TRANSCRIPTIONAL PROGRAMMING OF ASTHMA RELATED PATHOLOGY IN RESPIRATORY EPITHELIA

LONGITUDINAL ASSESSMENT OF MANIC SYMPTOMS

MECHANISMS OF GRANULOCYTE HOMEOSTASIS

DECODING INNATE IMMUNE SIGNALING IN NORMAL AND MYELODYSPLASTIC HEMATOPOIESIS

PULMONARY AND CARDIOVASCULAR DEVELOPMENT TRAINING GRANT

PBPK PREDICTION OF ONTOGENY MEDIATED ALTERATION IN HEPATIC DRUG ELIMINATION

IMPLEMENTATION OF SCREENING, BRIEF INTERVENTION, AND REFERRAL TO TREATMENT SERVICES TO REDUCE ALCOHOL AND OTHER DRUG CONSUMPTION AMONG FOSTER YOUTH - THERE ARE MORE THAN 420,000 CHILDREN IN FOSTER CARE IN THE UNITED STATES; 38% ARE AGED 10 YEARS OR OLDER. THIS HIGH-RISK GROUP HAS BEEN IDENTIFIED TO HAVE INCREASED HEALTH PROBLEMS COMPARED WITH PEERS IN THE GENERAL POPULATION AND, DUE TO A LACK OF COORDINATED PREVENTION SERVICES, INCREASED EXPOSURE TO POVERTY AND MALTREATMENT, AND OTHER SYSTEMIC CHALLENGES, ARE UP TO 5 TIMES MORE LIKELY TO RECEIVE A SUBSTANCE USE DISORDER (SUD) DIAGNOSIS BY AGE 18 COMPARED TO THE GENERAL POPULATION. HOWEVER, SBIRT HAS HAD LIMITED IMPACT ON YOUTH IN FOSTER CARE. THIS IS RELATED TO A FAILURE TO SPREAD SBIRT IN SPECIALIZED FOSTER CARE HEALTH CENTERS IN PEDIATRIC SETTINGS, FEW EFFECTIVE IMPLEMENTATION EFFORTS WITH CHILDREN’S SERVICES, AND FREQUENT DISRUPTIONS IN BEHAVIORAL HEALTHCARE AND SCHOOL EXPERIENCED BY FOSTER YOUTH. THIS STUDY SEEKS TO INCREASE ABSTINENCE OF ALCOHOL AND OTHER DRUG (AOD) USE AMONG ADOLESCENTS IN FOSTER CARE, REDUCE FREQUENCY OF AOD USE AMONG FOSTER YOUTH WHO HAVE INITIATED USE, AND INCREASE REFERRAL TO TREATMENT FOR ADOLESCENTS AT HIGHEST RISK FOR SUD THROUGH STANDARDIZED IMPLEMENTATION OF SBIRT INTO SPECIALIZED FOSTER CARE HEALTH CENTERS IN OUR REGION. IN PARTNERSHIP WITH CHILDREN’S SERVICES AND COMMUNITY BEHAVIORAL HEALTH, INCLUDING ORGANIZATIONS PROVIDING SUBSTANCE USE DISORDER TREATMENT TO YOUTH IN FOSTER CARE, WE WILL SCREEN ALL YOUTH IN FOSTER CARE IN OUR REGION (N = 2240) AND PROVIDE BRIEF INTERVENTION DURING MANDATED VISITS FOR PHYSICAL HEALTH CONCERNS THAT OCCUR WHEN CHILDREN 10 AND OLDER ENTER FOSTER CARE OR EXPERIENCE A CHANGE IN PLACEMENT SETTING. WHEN CLINICALLY INDICATED, YOUTH WILL ALSO BE REFERRED TO TREATMENT. AN EVALUATION OF SBIRT FOR FOSTER YOUTH WITH N = 832 YOUTH WILL INCLUDE A COMPARISON SAMPLE COLLECTED IN YEARS 1-3 AT A SITE DELAYING IMPLEMENTATION OF SBIRT. RESULTS WILL DEMONSTRATE THAT 1) SBIRT CAN BE EFFECTIVELY IMPLEMENTED AND SUSTAINED IN SETTINGS TAILORED TO MEET THE UNIQUE NEEDS OF FOSTER YOUTH; 2) EXISTING COMMUNITY BEHAVIORAL HEALTH SERVICES FOR FOSTER YOUTH CAN BE ENHANCED TO ADDRESS TREATMENT NEEDS WITH THIS POPULATION, IN PARTNERSHIP WITH FOSTER YOUTH HEALTHCARE CENTERS; AND 3) WHEN STANDARDIZED SUBSTANCE USE SCREENING AND RESPONSE (SBIRT) IS IMPLEMENTED, IT IS ASSOCIATED WITH AN INCREASE IN ABSTINENCE, A REDUCTION IN THE FREQUENCY OF AOD USE, AND AN INCREASE IN YOUTH WHO ARE SUCCESSFULLY REFERRED AND RECEIVE TREATMENT FOR SUD. ADDITIONAL EFFORTS FOCUSED ON TRAINING PROVIDERS AND STAKEHOLDERS WHO WORK WITH FOSTER YOUTH IN SBIRT (E.G., CLINICIANS, THERAPISTS, CASEWORKERS) AND IN DEMONSTRATING SUSTAINABILITY THROUGH STANDARDIZED AUTOMATION OF SCREENING AND REFERRAL PRACTICES AND MODIFICATIONS TO BILLING AND REIMBURSEMENT WILL PROMOTE GENERALIZABILITY OF THE FINDINGS FROM THIS PROJECT TO THE MORE THAN 50 SPECIALIZED FOSTER CARE CLINICS ACROSS THE US, ENSURING FURTHER BENEFIT OF THIS PROPOSED WORK.

HOX REGULATION OF SENSORY ORGAN DEVELOPMENT IN DROSOPHILA

LUNGMAP PHASE II - BUILDING A MULTIDIMENSIONAL MAP OF DEVELOPING HUMAN LUNG

MACROPHAGE BASED GENE THERAPY FOR HEREDITARY PULMONARY ALVEOLAR PROTEINOSIS

THE ROLE OF REGULATORY T CELLS IN BILIARY ATRESIA

INNATE MECHANISMS OF REGULATION OF MEMORY TH17 CELL RESPONSES

ROLES OF GSH1 & GSH2 IN TELENCEPHALIC NEUROGENESIS

GENETIC LINKAGE IN LUPUS

SELF-MANAGEMENT OF TYPE 1 DIABETES DURING ADOLESCENCE

DECODING INNATE IMMUNE SIGNALING IN NORMAL AND MYELODYSPLASTIC HEMATOPOIESIS - ABSTRACT MYELODYSPLASTIC SYNDROMES (MDS) ARE HETEROGENOUS AND POORLY UNDERSTOOD HEMATOPOIETIC STEM CELL (HSC) FAILURE SYNDROMES COMMON IN INDIVIDUALS >60 YEARS OF AGE. WITH INCREASED LIFE EXPECTANCIES, THE INCIDENCE OF MDS CONTINUES TO RISE, AND WILL SOON BE THE MOST PREVALENT HEMATOLOGIC DISORDER IN ELDERLY. THERE ARE NO EFFECTIVE TREATMENTS FOR MDS PATIENTS, DUE TO AN INSUFFICIENT UNDERSTANDING OF THE UNDERLYING PATHOBIOLOGY AND A LACK OF FAITHFUL MOUSE MODELS. OUR RESEARCH PROGRAM IS FOCUSED ON FILLING THESE GAPS, AND THEN LEVERAGING THE RESULTING KNOWLEDGE AND TOOLS TO DEVELOP EFFECTIVE DRUG THERAPIES. ALREADY, WE HAVE DISCOVERED GENETICALLY-DRIVEN ABERRANT ACTIVATION OF INNATE IMMUNE PATHWAYS IN MDS HSCS. WE HAVE ALSO IDENTIFIED A CRITICAL FUNCTION OF INNATE IMMUNE PATHWAYS IN NORMAL HSCS, WHICH HAS IMPLICATIONS FOR CHRONIC IMMUNE-RELATED DISORDERS, CARDIOVASCULAR DISEASES, AND HEMATOPOIESIS. WE HYPOTHESIZE THAT DYSREGULATED INNATE IMMUNE SIGNALING IS A MAJOR CONTRIBUTOR TO THE INITIATION AND DEVELOPMENT OF MDS, AND IS A FEASIBLE THERAPEUTIC TARGET. HEREIN, WE PROPOSE TO TEST THIS HYPOTHESIS BY CARRYING OUT THE FOLLOWING COMPLIMENTARY 3-PART RESEARCH PROGRAM: (1) DISSECT THE GENETIC AND CELLULAR UNDERPINNINGS OF MDS HSCS, WITH AN EMPHASIS ON CELL-INTRINSIC AND CELL-EXTRINSIC IMMUNE-INFLAMMATORY FACTORS. (2) IDENTIFY AND CHARACTERIZE NOVEL SIGNALING PATHWAYS DRIVING MDS PHENOTYPE IN HSCS. (3) DEVELOP NOVEL THERAPEUTIC STRATEGIES FOR THE TREATMENT OF MDS. THE RESULTS OF OUR RESEARCH PROGRAM WILL ADVANCE OUR PARADIGM-SHIFTING MODEL OF THE INITIATION, PROGRESSION, AND TREATMENT OF MDS.

CINCINNATI COOPERATIVE CENTER OF EXCELLENCE IN HEMATOLOGY - SUMMARY/ABSTRACT: THE LONG-TERM GOAL OF THE CINCINNATI COOPERATIVE CENTER OF EXCELLENCE IN HEMATOLOGY (CCCEH) IS TO UNDERSTAND AND CORRECT, AT THE MOLECULAR LEVEL, HEMATOLOGICAL DISEASES OF VARIOUS LINEAGES. TO ATTAIN THIS GOAL, WE MUST UNDERSTAND BASIC BIOLOGICAL PROCESSES THAT AFFECT BEHAVIORS OF HEMATOPOIETIC STEM CELLS AND THEIR VARIOUS DIFFERENTIATED PROGENIES IN VITRO AND IN VIVO. WE ENVISION THIS LONG-TERM GOAL WILL BE BEST ACCOMPLISHED BY INTERDISCIPLINARY AND COLLABORATIVE APPROACHES USING STATE-OF-THE-ART METHODS, ALONG WITH TIMELY AND RATIONAL USE OF TRANSLATIONAL STUDIES INTO THE PRECLINICAL AND CLINICAL SETTINGS. CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER (CCHMC) HAS DEVELOPED A RICH AND STIMULATING INTELLECTUAL ENVIRONMENT THAT BRINGS TOGETHER OUTSTANDING EXPERTISE AND BASIC RESEARCH IN STEM CELL BIOLOGY, VIRUS VECTOR TECHNOLOGY, IMMUNOHEMATOLOGIC CELL BIOLOGY, GENOMICS AND GENETICS, AND HEMATOPOIESIS; IN ADDITION, THE CCCEH HAS WORLD-CLASS EXPERTISE IN TRANSLATIONAL AND CLINICAL RESEARCH IN HEMATOLOGY, IMMUNOLOGY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION. THIS FOCUS HAS BEEN GREATLY STRENGTHENED BY THE RECRUITMENT OF OVER 30 FACULTY MEMBERS IN THESE AREAS OF HEMATOLOGY RESEARCH OVER THE LAST 15 YEARS AT CCHMC, AND THE INCLUSION OF OVER 15 EXTERNAL HEMATOLOGY RESEARCHERS AROUND US. BASIC RESEARCH IS LINKED WITH CINCINNATI NIH-FUNDED CLINICAL AND TRANSLATIONAL SCIENCE AWARD (CTSA), WHICH HAS FACILITATED INTERDISCIPLINARY INTERACTIONS AND DEVELOPED AN INFRASTRUCTURE THAT SUPPORTS STATE-OF-THE-ART CLINICAL TRIALS IN CELL AND GENE THERAPY. HERE WE SEEK TO SOLIDIFY THE EXCITING AND SYSTEMIC GROWTH OF RESEARCH IN HEMATOLOGY AT CCHMC TO SUPPORT A NATIONAL CENTER OF EXCELLENCE, USING THE SHARED SERVICES AND ADMINISTRATIVE STRUCTURE OF THE CENTER GRANT MECHANISM. THE CCCEH ADMINISTRATIVE CORE SUPPORTS AN EXCEPTIONAL ARRAY OF RESEARCH CORES, WHICH FUNCTION TOGETHER TO SUPPORT INNOVATIVE BASIC AND TRANSLATIONAL RESEARCH BOTH LOCALLY AND NATIONALLY, IN NON-MALIGNANT HEMATOLOGY. OUR THREE PROPOSED RESEARCH CORES INCLUDE (1) XENOTRANSPLANT AND GENOME EDITING CORE, WHICH MAINTAINS SPECIALIZED MOUSE STRAINS AND PROVIDES MOUSE TRANSPLANT AND TRANSGENIC SERVICES; (2) SINGLE CELL CHARACTERIZATION AND PROCUREMENT CORE THAT INCLUDES STATE- OF-THE-ART IMAGING AS WELL AS SINGLE CELL CAPTURE AND GENE EXPRESSION CAPABILITIES; AND (3) GENE DELIVERY CORE THAT COVERS SERVICES SUCH AS EX VIVO MANIPULATION OF BLOOD CELLS BY LENTIVIRUS AND RETROVIRUS TRANSDUCTION AND SHRNA/SGRNA SCREENING. FINALLY, THIS CENTER SEEKS SUPPORT FOR AN INNOVATIVE ENRICHMENT PROGRAM THAT FOSTERS A COLLABORATIVE AND EDUCATIONAL ENVIRONMENT IN THE CENTER AND FOR OUTREACH TO THE BROAD HEMATOLOGY RESEARCH COMMUNITY AROUND US.

THE MOLECULAR DETERMINANTS OF VIRUS INDUCED BILIARY ATRESIA

PURSUING PERFECTION IN PEDIATRIC THERAPUTICS

BINDING OF EPSTEIN BARR VIRUS EBNA2 UNIFIES MULTIPLE SCLEROSIS GENETIC MECHANISMS

BETTER OUTCOMES FOR CHILDREN: PROMOTING EXCELLENCE IN HEALTHCARE GENOMICS TO INFORM POLICY

EVALUATING ASSESSMENT AND MEDICATION TREATMENT OF ADHD IN CHILDREN WITH DOWN SYNDROME - PROJECT SUMMARY CHILDREN WITH DOWN SYNDROME (DS) HAVE A 3-5 TIMES GREATER PREVALENCE OF ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) THAN TYPICALLY DEVELOPING CHILDREN. DESPITE THIS HIGHER RISK OF ADHD, RATES OF STIMULANT MEDICATION TREATMENT ARE DISPROPORTIONATELY LOW IN CHILDREN WITH DS+ADHD EVEN THOUGH STIMULANTS ARE THE MOST EFFICACIOUS ADHD TREATMENT AND ARE RECOMMENDED BY CONSENSUS GUIDELINES FOR USE IN CHILDREN WITH INTELLECTUAL DISABILITY (ID) AND COMORBID ADHD. POSSIBLE REASONS FOR UNDER-UTILIZATION OF STIMULANT TREATMENT IN DS+ADHD INCLUDE: 1) DIAGNOSTIC UNCERTAINTY REGARDING HOW TO ACCURATELY DIAGNOSE ADHD IN CHILDREN WITH DS, MAKING PROVIDERS PRONE TO “DIAGNOSTIC OVERSHADOWING” (I.E., ATTRIBUTING ADHD TO THE ID); 2) THERE IS NOT A SINGLE CLINICAL TRIAL EXAMINING THE SAFETY AND EFFICACY OF STIMULANT MEDICATION IN CHILDREN WITH DS+ADHD; AND 3) CONCERNS ABOUT CARDIAC SAFETY, GIVEN THE HIGH INCIDENCE OF CONGENITAL HEART DISEASE OR DEFECTS (CHD) IN THE DS POPULATION. WE PROPOSE A PILOT STUDY TO DEFINE THE CLINICAL FEATURES OF DS+ADHD THEREBY ENABLING MORE ACCURATE DIAGNOSIS AND A PILOT CLINICAL TRIAL TO INFORM SAMPLE SIZE ESTIMATES FOR A LARGER CLINICAL TRIAL. WE PROPOSE TO PERFORM THE FIRST RANDOMIZED CLINICAL TRIAL OF STIMULANT MEDICATION IN CHILDREN WITH DS+ADHD TO PROVIDE EVIDENCE REGARDING THE SHORT AND LONG-TERM SAFETY AND EFFICACY OF STIMULANT USE IN CHILDREN WITH DS+ADHD, BOTH WITH AND WITHOUT CHD. ONE HUNDRED (100) CHILDREN WITH DS+ADHD AND 70 CHILDREN WITH DS AND NO ADHD (DS-ADHD), ALL AGED 6-12 AND MATCHED ON AGE, GENDER, AND IQ, WILL PARTICIPATE. ALL 170 CHILDREN ENROLLED IN THE STUDY WILL COMPLETE A COMPREHENSIVE ASSESSMENT BATTERY EVALUATING ADHD DIAGNOSTIC CRITERIA AS WELL AS BEHAVIORAL, COGNITIVE, ACADEMIC, AND FUNCTIONAL IMPAIRMENTS. THE 100 CHILDREN IN THE DS+ADHD GROUP WILL ALSO COMPLETE A MULTI-PHASED RANDOMIZED, DOUBLE-BLIND CLINICAL TRIAL WITH CROSSOVER TO PLACEBO AND LONG-TERM FOLLOW- UP TO ASSESS THE SHORT- AND LONG-TERM EFFICACY AND SAFETY OF STIMULANT MEDICATIONS FOR TREATING ADHD SYMPTOMS AND IMPAIRMENT IN CHILDREN WITH DS. STUDY AIMS WILL FOCUS ON 1) IDENTIFYING BEHAVIORAL, COGNITIVE, ACADEMIC, AND FUNCTIONAL IMPAIRMENTS THAT DIFFERENTIATE CHILDREN WITH DS+ADHD FROM CHILDREN WITH DS-ADHD; 2) INFORMING SAMPLE SIZE OF LARGER CLINICAL TRIAL; 3) ASSESSING THE SHORT- AND LONG-TERM SAFETY OF STIMULANT TREATMENT IN CHILDREN WITH DS+ADHD WITH A SPECIFIC FOCUS ON CARDIAC SAFETY; 4) DETERMINING THE SHORT- AND LONG-TERM EFFICACY OF STIMULANT TREATMENT AT REMEDIATING COGNITIVE, BEHAVIORAL, AND FUNCTIONAL IMPAIRMENTS IN CHILDREN WITH DS+ADHD; AND 5) EXPLORING MODERATORS (E.G., IQ, ADHD SUBTYPE, EXECUTIVE FUNCTIONING, COMORBID INTERNALIZING DISORDERS, CHD) OF STIMULANT RESPONSE AND SIDE EFFECTS. RESULTS FROM THIS STUDY WILL PROVIDE MUCH NEEDED DIAGNOSTIC AND TREATMENT DATA THAT WILL DIRECTLY IMPACT THE OUTCOMES OF THE APPROXIMATELY 45,000 CHILDREN WITH DS+ADHD NATIONWIDE.

"IMPROVING ADHD TEEN DRIVING"

DECIPHERING MECHANISMS OF MYOBLAST FUSION

FOX TRANSCRIPTION FACTORS IN DEVELOPMENT OF PULMONARY CAPILLARIES

HOST INTEGRATION OF COMMENSAL AND PATHOGENIC BACTERIAL-DERIVED SIGNALS

BIOCHEMICAL AND GENETIC ANALYSIS OF NOTCH SIGNALING

BETTER OUTCOMES FOR CHILDREN: GWAS & PHEWAS IN EMERGEII.

INVESTIGATION OF REGIONAL IDENTITY IN HUMAN INTESTINAL STEM CELLS

NATIONAL RESEARCH SERVICE AWARD

CINCINNATI CENTER FOR EXCELLENCE IN MOLECULAR HEMATOLOGY

DIAGNOSTIC VALIDITY AND SAFETY OF HIGH-GAMMA LANGUAGE MAPPING WITH INTRACRANIAL EEG

ROLE OF FA PROTEIN COMPLEXES IN HEMATOPOIESIS

IMAGING AND MOLECULAR PHENOTYPING OF CYSTIC FIBROSIS LUNG DISEASE - CYSTIC FIBROSIS (CF) IS AMONG THE MOST COMMON FATAL GENETIC DISEASES IN THE U.S. AND INVOLVES PROGRESSIVE LUNG FUNCTION LOSS AND STRUCTURAL REMODELING, LEADING TO LUNG TRANSPLANT OR DEATH. THOUGH LIFE EXPECTANCY IN CF PATIENTS HAS INCREASED DUE TO IMPROVED TREATMENTS, PATHOLOGICAL CHANGES STILL OCCUR WITHIN THE FIRST YEAR OF LIFE. IT HAS BEEN DIFFICULT TO DETECT THESE EARLY CHANGES, BECAUSE CONVENTIONAL MEASURES OF LUNG FUNCTION SUCH AS SPIROMETRY (E.G., FORCED EXPIRATORY VOLUME IN 1 SECOND, FEV1) ARE LAGGING INDICATORS AND INSENSITIVE TO EARLY DISEASE. IN CONTRAST, ULTRA-SHORT ECHO-TIME (UTE) AND HYPERPOLARIZED (HP) 129XE MRI CAN DETECT PATHOLOGY YEARS BEFORE FEV1. ADDI- TIONALLY, PROTEOMIC BIOMARKERS FROM HIGH-PRECISIONS MASS SPECTROMETRY (MS), WHEN COUPLED WITH MODELING BASED ON FUNCTIONAL DATA (FD) ANALYSIS, ACCURATELY FORECAST CF LUNG DISEASE PROGRESSION. HOWEVER, THESE BIOMARKERS HAVE ONLY BEEN VALIDATED IN PATIENTS WITH ESTABLISHED DISEASE. THE LONG-TERM GOAL OF THIS RESEARCH IS TO VALIDATE PROTEOMIC MARKERS THAT DETECT AND PREDICT LUNG FUNCTION DECLINE AND STRUCTURAL REMODELING IN EARLY LUNG DISEASE. THE OBJECTIVE OF THIS APPLICATION IS TO USE STATE-OF-THE-ART HP 129XE AND UTE MRI TO VALIDATE PROTEOMIC MARKERS IN EARLY CF. THIS WILL BE ACCOMPLISHED USING BLOOD SERUM AND CLINICALLY OBTAINED BRONCHOALVEOLAR LAVAGE (BAL) FLUID FROM CF PATIENTS WITH KNOWN LUNG PATHOLOGY. OUR CENTRAL HYPOTHESIS IS THAT IMAGE-GUIDED PROTEOMICS CAN FORECAST PATHOPHYSIOLOGY BEFORE SPIROMETRIC CHANGES ARE OBSERVED. OUR RATIONALE IS THAT, WHILE 129XE AND UTE MRI ARE CURRENTLY LIMITED TO SPECIALIZED CENTERS, MS PROTEOMICS CAN BE PERFORMED ON READILY OBTAINED CLINICAL SPECIMENS, AND TRANSLATED WITH FD ANALYSIS INTO AN EASILY DISSEMINATED TOOL TO PREDICT IMPENDING LUNG DISEASE PROGRESSION, AND THUS ENABLE INTERVENTIONS BEFORE PERMANENT LUNG DAMAGE OCCURS. GUIDED BY COMBINED MRI AND PROTEOMIC DATA AND THE UTILITY OF FD ANALYSIS TO PREDICT LUNG FUNCTION DECLINE, OUR CENTRAL HYPOTHESIS WILL BE TESTED BY COMPLETING THE FOLLOWING SPECIFIC AIMS: 1) VALIDATE OUR PREDICTIVE BIOMARKERS IN CF PATIENTS WITH NORMAL SPIROMETRY BUT ABNORMAL VENTILATION; 2) DETERMINE THE SENSITIVITY AND SPECIFICITY OF SYSTEMIC BIOMARKERS IN PRE- DICTING EARLY STRUCTURAL RE-MODELING IN CF LUNG DISEASE; AND 3) PERFORM CLINICAL BRONCHOSCOPY TO IDENTIFY MOLECULAR SIGNATURES OF IRREVERSIBLE LUNG REMODELING. WE HAVE DEVELOPED THE MRI SEQUENCES AND RECONSTRUCTION PIPELINE NEEDED TO COMPLETE THE WORK. FOR AIMS 1 & 2, WE HAVE USED MRI AND MS PROTEOMICS TO IDENTIFY KEY BIOMARKERS TO PREDICT STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN CF. FOR AIM 3, WE HAVE USED BAL PROTEOMICS TO IDENTIFY MOLECULAR CHANGES AT THE PATHWAY LEVEL IN CF PATIENTS. THE PROPOSED RESEARCH IS INNOVATIVE, BECAUSE IT WILL USE CUTTING-EDGE IMAGING TO VALIDATE MOLECULAR TOOLS TO ASSESS EARLY LUNG DISEASE. THESE RESULTS WILL BE SIGNIFICANT, BECAUSE THEY WILL PRODUCE AN EASILY DISSEMINATED TOOL TO PREDICT PERMANENT STRUCTURAL REMODELLING AND IRREVERSI- BLE FUNCTIONAL LOSSES. THIS WORK WILL HAVE AN IMMEDIATE POSITIVE IMPACT BY DEVELOPING AND TRANSLATING NON-INVA- SIVE TESTS TO IDENTIFY CF PATIENTS AT HIGH RISK OF LUNG DAMAGE AND INTERVENE BEFORE IRREVERSIBLE CHANGES OCCUR. IT WILL ALSO PROVIDE A UNIQUE PLATFORM TO ASSESS PATHOLOGICAL PROGRESSION IN A WIDE RANGE OF LUNG DISEASES.

MOLECULAR MECHANISMS OF ATRIAL DEVELOPMENT AND REGENERATION

"LUNG MAP" ATLAS RESEARCH CENTER

GENOMICS OF INFLAMMATORY BOWEL DISEASE

A REVOLUTIONARY VACCINE APPROACH TO PREVENT HIV INFECTION IN SUBSTANCE ABUSE

MRI PHENOTYPING OF EARLY BPD AND PREDICTION OF OUTCOMES

A PHASE 3 CLINICAL TRIAL OF AN E-HEALTH BEHAVIORAL INTERVENTION TO IMPROVE EXECUTIVE FUNCTIONING IN ADOLESCENTS WITH EPILEPSY - EPILEPSY IS A COMMON PEDIATRIC NEUROLOGICAL CONDITION AFFECTING ~470,000 YOUTH IN THE UNITED STATES. ADOLESCENTS WITH EPILEPSY ARE AT SIGNIFICANT RISK FOR NEUROBEHAVIORAL COMORBIDITIES (I.E., DEPRESSIVE/BEHAVIORAL SYMPTOMS) AND SUBOPTIMAL SOCIAL, ACADEMIC, AND QUALITY OF LIFE OUTCOMES. RESEARCH SUGGESTS THAT DEFICITS IN EXECUTIVE FUNCTIONING (EF), DEFINED AS THE SKILLS NECESSARY FOR GOAL-DIRECTED AND COMPLEX ACTIVITIES, INCLUDING PROBLEM-SOLVING, INITIATION, MONITORING, ORGANIZATION, PLANNING, SELF-REGULATION AND WORKING MEMORY, CONTRIBUTE TO SUBOPTIMAL FUNCTIONING. EF DEFICITS HAVE BEEN DOCUMENTED IN UP TO 50% OF YOUTH WITH EPILEPSY, WHICH IS 3 TIMES THE PREVALENCE IN HEALTHY YOUTH. EVIDENCE-BASED INTERVENTIONS TO IMPROVE EF COULD PLAY A CRITICAL ROLE IN PREVENTING ADVERSE OUTCOMES AND PROMOTING OPTIMAL FUNCTIONING IN ADOLESCENTS WITH EPILEPSY; HOWEVER NONE EXISTS FOR THIS VULNERABLE POPULATION. TO FILL THIS GAP, WE SUCCESSFULLY DEVELOPED AND TESTED EPILEPSY JOURNEY (EJ), A COMPREHENSIVE E-HEALTH BEHAVIORAL MULTI-COMPONENT PROBLEM-SOLVING INTERVENTION THAT COMBINES 10 SELF-GUIDED LEARNING MODULES WITH 10 TELEHEALTH SESSIONS. THE PROMISING PROOF-OF-CONCEPT TRIAL (N=39) SHOWED HIGH FEASIBILITY, ACCEPTABILITY, PATIENT SATISFACTION, AND SIGNIFICANT IMPROVEMENTS IN PARENT-REPORTED EF BEHAVIORS, NEUROBEHAVIORAL FUNCTIONING, AND QUALITY OF LIFE. THE NEXT LOGICAL PHASE OF THIS RESEARCH IS TO CONDUCT A DEFINITIVE RANDOMIZED CLINICAL TRIAL TO EXAMINE: 1) WHETHER THE TWO COMPONENTS OF TREATMENT (EJ MODULES AND TELEHEALTH) ARE BOTH ESSENTIAL, 2) IF THE INTERVENTION GENERALIZES TO A RACIALLY DIVERSE SAMPLE, AND 3) HAS A DURABLE IMPACT ON IMPROVING PARENT-REPORTED AND PERFORMANCE-BASED EF BEHAVIORS. THUS, THE AIM OF THE CURRENT PROPOSAL IS TO CONDUCT A MULTI-SITE PHASE 3 RANDOMIZED CONTROLLED CLINICAL TRIAL (RCT) USING A 2X2 FACTORIAL DESIGN TO EXAMINE THE EFFICACY OF SEPARATE (EJ MODULES AND EJ TELEHEALTH) AND COMBINED COMPONENTS OF EJ ON EF. PARTICIPANTS POSITIVE FOR EF DEFICITS (N=232) WILL BE RANDOMIZED TO ONE OF FOUR ARMS: 1) EJ MODULES WITH TELEHEALTH SESSIONS, 2) EJ MODULES ALONE, 3) EJ TELEHEALTH SESSIONS ALONE, OR 4) USUAL CARE (NO EJ MODULES OR TELEHEALTH SESSIONS). TREATMENT PARTICIPANTS WILL EITHER INDEPENDENTLY REVIEW EJ MODULES FOCUSED ON EF SKILLS (~15-30 MIN.) AND/OR HAVE WEEKLY TELEHEALTH SESSIONS (~30-45 MIN.) WITH A THERAPIST FOR THREE MONTHS. THE GROUPS WILL LEARN AND APPLY PROBLEM-SOLVING STRATEGIES TO THEIR INDIVIDUAL EF DIFFICULTIES. PARTICIPANTS WILL COMPLETE MEASURES AT BASELINE, POST-TREATMENT, 3- AND 12-MONTHS POST-TREATMENT TO EXAMINE MAINTENANCE OF EFFECTS. THERE IS A CRITICAL NEED FOR EVIDENCE-BASED INTERVENTIONS TO IMPROVE EXECUTIVE FUNCTIONING BEHAVIORS IN YOUTH WITH EPILEPSY. IF THE AIMS OF THIS UG3/UH3 ARE ACHIEVED, WE WILL HAVE DEFINITIVE EVIDENCE FOR ADDRESSING EF DEFICITS. WE EXPECT THAT EJ MODULES AND EJ TELEHEALTH WILL DEMONSTRATE EFFICACY ALONE AND IN COMBINATION, WHICH WILL ALLOW PATIENTS TO SELECT THE APPROACH BEST SUITED TO THEIR SPECIFIC SITUATION. CONSEQUENTLY, WE CAN IMPROVE LONG-TERM OUTCOMES (E.G., NEUROBEHAVIORAL COMORBIDITIES, ACADEMIC SUCCESS, SOCIAL RELATIONSHIPS, AND QOL) IN ADOLESCENTS WITH EPILEPSY, A HIGH-RISK POPULATION.

ROLE AND REGULATION OF TSLP IN CHILDHOOD ALLERGIC DISEASE

MOLECULAR GENETIC ANALYSIS OF CRANIOFACIAL DEVELOPMENT

EARLIEST PREDICTORS OF LANGUAGE OUTCOMES IN HIGH-RISK INFANTS

LONGITUDINAL EXAMINATION OF SLUGGISH COGNITIVE TEMPO AND INTERNALIZING PSYCHOPATHOLOGY IN ADOLESCENCE - PROJECT SUMMARY/ABSTRACT SLUGGISH COGNITIVE TEMPO (SCT) IS A SET OF BEHAVIORAL SYMPTOMS CHARACTERIZED BY EXCESSIVE DAYDREAMING, SLOWED THINKING, AND MENTAL CONFUSION AND FOGGINESS. IT IS NOW ESTABLISHED THAT SCT CAN BE RELIABLY MEASURED ACROSS PARENT, TEACHER, AND SELF-REPORT RATINGS AND IS DISTINCT FROM OTHER PSYCHOPATHOLOGY DIMENSIONS INCLUDING ADHD AND INTERNALIZING SYMPTOMS. A RAPIDLY GROWING BODY OF RESEARCH ALSO DEMONSTRATES SCT TO BE STRONGLY ASSOCIATED WITH FUNCTIONAL IMPAIRMENT, ABOVE AND BEYOND OTHER PSYCHOPATHOLOGIES. HOWEVER, SCT REMAINS ABSENT FROM CURRENT MODELS OF PSYCHOPATHOLOGY, IN LARGE PART BECAUSE THE FIELD LACKS RIGOROUS LONGITUDINAL RESEARCH EXAMINING SCT IN RELATION TO OTHER PSYCHOPATHOLOGIES. IN CROSS-SECTIONAL STUDIES, SCT SYMPTOMS ARE CONSISTENTLY AND STRONGLY ASSOCIATED WITH INTERNALIZING SYMPTOMS. PRELIMINARY FINDINGS ALSO DOCUMENT ASSOCIATIONS BETWEEN SCT AND INCREASED SUICIDE RISK. IMPORTANTLY, OUR PILOT DATA SHOW SCT PREDICTS INCREASED INTERNALIZING SYMPTOMS RATHER THAN THE REVERSE. FURTHER, SCT SYMPTOMS UNIQUELY PREDICT INTERNALIZING PROBLEMS AND NOT EXTERNALIZING BEHAVIORS, SUGGESTING THAT SCT MAY BE A UNIQUE FACTOR IN UNDERSTANDING THE DEVELOPMENT OF INTERNALIZING PROBLEMS SPECIFICALLY. YET STUDIES LINKING SCT TO INTERNALIZING SYMPTOMS IN YOUTH ARE LIMITED IN SEVERAL WAYS, INCLUDING: (A) USE OF CROSS-SECTIONAL DESIGNS THAT PRECLUDE ESTABLISHMENT OF TEMPORAL ASSOCIATIONS, (B) USING CONVENIENCE SAMPLES (E.G., ADHD) RATHER THAN A SAMPLE ENRICHED FOR SCT SPECIFICALLY, (C) FAILING TO EXAMINE POSSIBLE MECHANISMS OR VULNERABILITIES LINKING SCT TO INTERNALIZING SYMPTOMS, AND (D) FOCUSING ON SCHOOL-AGED CHILDREN EVEN THOUGH SCT SYMPTOMS AND INTERNALIZING PROBLEMS SHARPLY INCREASE IN ADOLESCENCE. THIS STUDY WILL ADDRESS THESE LIMITATIONS BY USING A PROSPECTIVE LONGITUDINAL, MULTI-INFORMANT, MULTI-METHOD DESIGN ACROSS THE DEVELOPMENTALLY SENSITIVE PERIOD OF EARLY ADOLESCENCE TO EXAMINE SCT SYMPTOMS AS A PREDICTOR OF DIVERSE INTERNALIZING OUTCOMES AND TO TEST MECHANISMS AND VULNERABILITIES LINKING SCT TO INTERNALIZING SYMPTOMS IN A COMMUNITY SAMPLE ENRICHED FOR SCT SYMPTOMATOLOGY. SPECIFICALLY, A COMMUNITY-BASED SAMPLE OF 330 YOUNG ADOLESCENTS (AGES 10-12 YEARS) ENRICHED FOR SCT SYMPTOMATOLOGY WILL BE RECRUITED AND ASSESSED AT THREE TIMEPOINTS ONE YEAR APART. CONSISTENT WITH THE NIMH RESEARCH DOMAIN CRITERIA (RDOC) INITIATIVE AND A DEVELOPMENTAL PSYCHOPATHOLOGY FRAMEWORK, A MULTI-INFORMANT, MULTI-METHOD BATTERY THAT CUTS ACROSS PHYSIOLOGICAL, BEHAVIORAL, AND SELF-REPORT UNITS OF ANALYSIS WILL BE USED. WE WILL EXAMINE DIMENSIONAL SCT SYMPTOMS AS A PREDICTOR OF INTERNALIZING PSYCHOPATHOLOGY CHANGE OVER TIME, TEST MECHANISMS OF THE LONGITUDINAL RELATION BETWEEN SCT AND INTERNALIZING PSYCHOPATHOLOGIES, AND EXPLORE VULNERABILITIES (PHYSIOLOGICAL REACTIVITY, PUNISHMENT SENSITIVITY) THAT EXACERBATE THESE LONGITUDINAL RELATIONS. FINDINGS ESTABLISHING LONGITUDINAL EFFECTS AND IDENTIFYING MECHANISMS AND VULNERABILITIES THAT CUT ACROSS UNITS OF ANALYSIS WILL ADVANCE THE DEVELOPMENT OF THEORETICAL MODELS OF SCT. FINDINGS FROM THIS STUDY WILL ALSO PROVIDE AVENUES FOR TARGETED CLINICAL ASSESSMENT AND TREATMENT.

DISSECTING NEURAL MECHANISMS SUPPORTING MIND AND BODY APPROACHES TO PAIN REDUCTION IN YOUTH WITH MIGRAINE

VALIDATING QUANTITATIVE MAGNETIC RESONANCE IMAGING BIOMARKERS OF IDIOPATHIC PULMONARY FIBROSIS

DYNAMIC COMPUTATIONAL MODELING OF OBSTRUCTIVE SLEEP APNEA IN DOWN SYNDROME

EFFECT OF REPRODUCTIVE HISTORY ON LONGITUDINAL CHANGE IN CARDIAC, VASCULAR AND LIPID PARAMETERS - ABSTRACT PREGNANCY IS OFTEN DESCRIBED AS A PHYSIOLOGIC “STRESS TEST” THAT MAY UNCOVER LATENT RISK FOR HYPERTENSION, DIABETES AND CVD. EVEN IN UNCOMPLICATED PREGNANCIES, WOMEN EXPERIENCE RAPID CARDIOMETABOLIC CHANGES TO SUPPORT FETAL DEVELOPMENT. WHILE MANY OF THESE ADAPTATIONS NORMALIZE SOON AFTER DELIVERY, SOME CHANGES PERSIST, INCLUDING ECHOCARDIOGRAPHIC CHANGES IN CARDIAC STRUCTURE AND LOWER HIGH-DENSITY LIPOPROTEIN CHOLESTEROL (HDL-C). WHETHER THESE PREGNANCY-RELATED CHANGES, OR ALTERATIONS IN HDL PARTICLE STRUCTURE OR FUNCTION, CONTRIBUTE TO LONG-TERM CARDIOVASCULAR RISK IS UNKNOWN. PARITY, OR THE TOTAL NUMBER OF LIVE BIRTHS, AMONG POST- MENOPAUSAL WOMEN IS ALSO ASSOCIATED WITH GREATER RISK OF CARDIOVASCULAR DISEASE AND ALTERATIONS IN HDL-C LEVELS, HDL STRUCTURE AND FUNCTION, AND CARDIAC AND VASCULAR FUNCTION. HOWEVER, A SIGNIFICANT RESEARCH GAP EXISTS IN LINKING OBSERVED CARDIOVASCULAR CHANGES ACROSS PREGNANCY TO THE OBSERVED ASSOCIATIONS OF PARITY WITH CARDIOVASCULAR HEALTH POST-MENOPAUSE. WE WILL ADDRESS THIS GAP BY LEVERAGING EXISTING DATA AND SAMPLES FROM THE NHLBI GROWTH AND HEALTH STUDY (NGHS) AND CONDUCT A NEW IN-PERSON VISIT IN 350 PARTICIPANTS AT MEDIAN AGE 46, WHEN THE WOMEN WILL BE PRE- OR PERI-MENOPAUSAL. NGHS ENROLLED 871 GIRLS (50% AFRICAN- AMERICAN AND 50% WHITE) IN 1987 AT AGE 9 OR 10 AND EXAMINED THEM UP TO 17 TIMES, TO AGE 27, INCLUDING 7 ECHOCARDIOGRAMS BETWEEN AGES 20-27, MULTIPLE SAVED SAMPLES AND REPRODUCTIVE HISTORY QUESTIONNAIRES. THIS STUDY WILL CONDUCT DETAILED LIPOPROTEIN SIZING AND FUNCTIONALITY ASSESSMENTS FROM STORED AND NEW SAMPLES AND CONDUCT CARDIOVASCULAR IMAGING AND REPEAT ECHOCARDIOGRAMS AT MEDIAN AGE 46 TO: 1) DETERMINE THE SPECIFIC LIPOPROTEIN PARTICLE SIZE DISTRIBUTION AND FUNCTION CHANGES WHICH OCCUR FROM BEFORE TO SHORT- AND LONG-TERM POST PREGNANCY; 2) DETERMINE WHETHER PREGNANCY-RELATED CARDIAC ADAPTATIONS RESULT IN LONG-TERM ALTERATIONS IN CARDIAC STRUCTURE AND FUNCTION, THEREBY INCREASING CVD RISK FOR WOMEN IN THEIR FORTIES; AND 3) TEST WHETHER PARITY INCREASES CV RISK INDEPENDENTLY OF SOCIOECONOMIC STATUS (SES) IN AFRICAN-AMERICAN AND WHITE WOMEN. WITH THE COMPLETION OF OUR AIMS, WE WILL HAVE DETERMINED THE PROSPECTIVE PATHWAYS BETWEEN PREGNANCY-RELATED LIPOPROTEIN AND CARDIOVASCULAR CHANGES AND PRE-MENOPAUSAL CARDIOVASCULAR HEALTH FOR WOMEN IN THEIR FORTIES. RESULTS FROM OUR PROPOSED STUDIES WILL FILL A CRITICAL GAP IN OUR UNDERSTANDING OF HOW SUCH RISKS MAY ACCUMULATE DURING A WOMAN'S REPRODUCTIVE LIFE, AS WELL AS HOW SOCIOECONOMIC STATUS CONTRIBUTES TO PARITY- RELATED RISK LONG-TERM. WOMEN IN THIS STUDY HAVE ALSO BEEN EXPOSED TO THE OBESITY EPIDEMIC, LENDING GREATER UNDERSTANDING TO CONTEMPORARY REPRODUCTIVE DEVELOPMENT.

NICHD COOPERATIVE MULTICENTER NEONATAL RESEARCH NETWORK

RLDC: MOLECULAR PATHWAY-DRIVEN DIAGNOSTICS & THERAPEUTICS FOR RARE LUNG DISEASES

REGULATION OF GASTROINTESTINAL EOSINOPHILS

ENGAGING ADOLESCENTS IN DECISIONS ABOUT RETURN OF GENOMIC RESEARCH RESULTS

CONTRIBUTIONS OF ABERRANT GRANULE CELL INTEGRATION TO THE DEVELOPMENT OF EPILEPSY

INJURY PREVENTION IN A HOME VISITATION POPULATION

SICKLE CELL TREATMENT DEMONSTRATION PROGRAM

ENHANCING TREATMENT ADHERENCE AND HEALTH OUTCOMES

REHABILITATION RESEARCH AND TRAINING CENTERS

FOSTERING MEDICATION ADHERENCE IN CHILDREN WITH EPILEPSY USING MHEALTH TECHNOLOGY

IMPACT OF EMERGENCY DEPARTMENT PROBIOTIC TREATMENT OF PEDIATRIC GASTROENTERITIS

MOLECULAR MECHANISMS OF OLIGODENDROCYTE DIFFERENTIATION AND MYELINATION

PRECISE INFLIXIMAB EXPOSURE AND PHARMACODYNAMIC CONTROL TO ACHIEVE DEEP REMISSION IN PEDIATRIC CROHN'S DISEASE - PROJECT SUMMARY/ABSTRACT CROHN'S DISEASE IS A CHRONIC ILLNESS THAT RESULTS IN INTESTINAL INFLAMMATION AND UNWANTED GASTROINTESTINAL SYMPTOMS. THE ONLY BIOLOGIC (MONOCLONAL ANTIBODY) APPROVED FOR MODERATE TO SEVERE CROHN'S DISEASE IN CHILDREN (<18 YEARS OLD) ARE THOSE THAT ANTAGONIZE TUMOR NECROSIS FACTOR-ALPHA (ANTI-TNF). WHILE THERE IS A HIGH INITIAL RESPONSE RATE TO LABELED INFLIXIMAB (ANTI-TNF) DOSING, ONLY HALF OF INFLIXIMAB EXPOSED PATIENTS WILL ACHIEVE CLINICAL REMISSION AND LESS THAN 40% WILL ACHIEVE ENDOSCOPIC HEALING AFTER ONE YEAR ON THERAPY. SEVERAL STUDIES HAVE SHOWN THAT RATES OF SUSTAINED CORTICOSTEROID-FREE REMISSION ARE IMPROVED WHEN PATIENTS RECEIVE ANTI-TNF DOSE OPTIMIZATIONS FOLLOWING REACTIVE OR PROACTIVE THERAPEUTIC DRUG MONITORING. MOREOVER, ANTI-TNF DOSE INTENSIFICATION FOLLOWING PHARMACODYNAMIC MONITORING HAS LED TO IMPROVED RATES OF ENDOSCOPIC (INTESTINAL) HEALING. THEREFORE, GIVEN THE LIMITED THERAPEUTIC OPTIONS FOR CHILDREN WITH ACTIVE CROHN'S DISEASE, THERE IS A CRITICAL UNMET NEED FOR THE DEVELOPMENT OF A DATA-DRIVEN, INDIVIDUALIZED, AND SCALABLE ANTI-TNF DOSING INTERVENTION USED FROM DRUG START AND CONTINUED THROUGHOUT THERAPY TO OPTIMIZE DRUG EXPOSURE AND ULTIMATELY, IMPROVE RATES OF INTESTINAL HEALING. OUR TEAM HAS DEVELOPED A PRECISION DOSING STRATEGY THAT USES AN INNOVATIVE PHYSICIAN DECISION SUPPORT DASHBOARD THAT INSTANTANEOUSLY APPLIES PHARMACOKINETIC MODEL-INFORMED PRECISION DOSING TO GENERATE AN INDIVIDUAL INFLIXIMAB DOSING REGIMEN STARTING WITH INDUCTION AND TARGETING PHASE-SPECIFIC PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS THROUGHOUT THERAPY. THE CENTRAL HYPOTHESIS IS PRECISION DOSING (INTERVENTION ARM) WITH INFLIXIMAB DURING INDUCTION AND MAINTENANCE WILL IMPROVE RATES OF DEEP REMISSION VS. CONVENTIONAL CARE (PRAGMATIC DOSING; CONTROL ARM). THE CENTRAL HYPOTHESIS WILL BE TESTED WITH TWO SPECIFIC AIMS. AIM1: CONDUCT A CLUSTER-RANDOMIZED (BY CENTER) CLINICAL TRIAL TO ASSESS RATES OF DEEP REMISSION AT YEAR1 BETWEEN CROHN'S DISEASE PATIENTS RECEIVING INFLIXIMAB WITH PRECISION DOSING VS. CONVENTIONAL CARE. AIM2: REFINE MODEL- INFORMED PRECISION DOSING USING A CONTINUOUS LEARNING APPROACH AND IDENTIFY ANTI-TNF PK/PD TARGETS FROM INDUCTION TO MAINTENANCE ASSOCIATED WITH DEEP REMISSION. OUR APPROACH IS CONCEPTUALLY INNOVATIVE WITH AN EMPHASIS ON PRACTICAL IMPLEMENTATION. THIS IS THE FIRST CLINICAL TRIAL IN CHILDREN TO PROVIDE ANTI-TNF DOSE OPTIMIZATION DURING INDUCTION TO TARGET A SPECIFIC EARLY (WEEK6) TROUGH CONCENTRATION WHILE THE MAINTENANCE REGIMEN IS SELECTED BY SPECIFIC TREAT-TO-TARGET PHARMACOKINETIC AND PHARMACODYNAMIC BIOMARKERS. ADDITIONALLY, PRECISION DOSING REGIMENS ARE PRODUCED WITH A NOVEL WEB-BASED DECISION SUPPORT DASHBOARD AND THE STUDY IS BEING PERFORMED WITHIN THE IMPROVECARENOW NETWORK TO STREAMLINE CLINICAL TRIAL LOGISTICS. IN AIM2, A CONTINUOUS LEARNING APPROACH WILL BE APPLIED TO OUR PUBLISHED PHARMACOKINETIC MODEL TO ITERATIVELY REFINE THE MODEL BY CAPTURING NEW REAL-WORLD DATA TO BETTER DESCRIBE SPECIFIC PATIENT POPULATIONS AND FURTHER REDUCE PREDICTION ERROR. THE LONG-TERM GOAL IS FOR THE PRECISION DOSING STRATEGY TO GENERATE A PARADIGM SHIFT AS THE PREFERRED DOSING APPROACH TO OPTIMIZE EXPOSURE TO ALL BIOLOGICS AND CHANGE THE NATURAL HISTORY OF CROHN'S DISEASE.

RANDOMIZED TRIAL OF VIRAL SPECIFIC T-CELL INFUSION TO PREVENT VIRAL INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANT. - ABSTRACT HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IS A HIGHLY EFFECTIVE TREATMENT, BUT SERIOUS VIRUS INFECTIONS OCCUR IN 82% OF CHILDREN UNDERGOING HSCT AT OUR INSTITUTION AND OTHERS. CURRENT ANTI- VIRAL DRUGS HAVE INADEQUATE RESPONSE RATES, PROLONG HOSPITALIZATIONS, AND ARE FREQUENTLY ASSOCIATED WITH ORGAN TOXICITY. AN ALTERNATIVE CELLULAR THERAPY APPROACH USES ENGINEERED VIRAL SPECIFIC T-LYMPHOCYTES (VSTS) MANUFACTURED FROM BLOOD DONATED BY A PATIENT’S STEM CELL DONOR. VST THERAPY IS HIGHLY EFFECTIVE WHEN CELLS ARE INFUSED IN RESPONSE TO VIREMIA, WITH RESPONSE RATES OF OVER 80%. WE SEEK TO MAKE A CRITICAL ADVANCE IN THIS TECHNOLOGY BY TESTING WHETHER SCHEDULED ADMINISTRATION OF BONE MARROW DONOR DERIVED VSTS 21 DAYS AFTER HSCT WILL BE SAFE AND AT LEAST AS EFFECTIVE AS OUR CURRENT PRE-EMPTIVE TREATMENT APPROACH OF ONLY ADMINISTERING VSTS ONCE VIRAL REACTIVATION OR INFECTION HAS OCCURRED. WE PROPOSE TWO SPECIFIC AIMS. SPECIFIC AIM 1: RANDOMIZED COMPARISON OF DONOR-DERIVED SCHEDULED VS TREATMENT VSTS IN HSCT RECIPIENTS TO PREVENT VIRAL INFECTIONS. HYPOTHESIS: RECIPIENTS OF SCHEDULED VSTS GIVEN 21 DAYS AFTER STEM CELL INFUSION WILL HAVE A SIGNIFICANTLY LOWER FREQUENCY OF VIREMIA AND INVASIVE VIRAL INFECTIONS 100 DAYS AFTER HSCT THAN PATIENTS RANDOMIZED TO TREATMENT USE OF VST’S. SPECIFIC AIM 2: IDENTIFY PRODUCT CHARACTERISTICS THAT PREDICT RESPONSE TO THERAPY AND COMPARE RESPONSES IN THOSE WITH AND WITHOUT EXPOSURE TO VIRAL LIGAND. HYPOTHESIS: SPECIFIC PRODUCT CHARACTERISTICS CAN BE ESTABLISHED THAT WILL IDENTIFY VST PRODUCTS LIKELY TO BE CLINICALLY EFFECTIVE, AND VSTS WILL PERSIST IN SCHEDULED VST RECIPIENTS WITHOUT STIMULATION FROM VIRAL LIGAND. AIM 2A: WE WILL STUDY THE T CELL RESPONSE TO ADENOVIRUS, EBV, CMV OR BK VIRUS, AND PRODUCT PERSISTENCE BY ELISPOT TESTING, TCR CLONOGRAM AND VST PERSISTENCE USING TCR SEQUENCING TO DEFINE MORE AND LESS EFFECTIVE VST PRODUCTS, AND TO DETERMINE IF VSTS EXPAND AND PERSIST IF THEY ARE INFUSED ON A SCHEDULE INTO A PERSON WITH NO ACTIVE VIRAL REPLICATION TO PROVIDE LIGAND. AIM 2B: WE WILL SYSTEMATICALLY ASSESS HLA RESTRICTION OF PRESENTATION OF VIRAL ANTIGENS, USING PEPTIDE MAPPING AND SINGLE ANTIGEN CELL LINES (SALS). THESE DATA ARE VITAL FOR FUTURE “THIRD PARTY” USE OF VSTS IN PERSONS WITHOUT DONOR DERIVED PRODUCT. THIS CLINICAL TRIAL MAY CHANGE THE PARADIGM OF TREATMENT FOR VIRAL INFECTIONS IF WE ARE ABLE TO SHOW THAT PROPHYLACTIC VST INFUSION PREVENTS INFECTIONS.

HOMEOSTASIS AND FUNCTION OF REGULATORY T CELLS IN AGING

AN EXPERIMENTALLY-REFINED, DYNAMIC GENE REGULATORY NETWORK MODEL OF T-CELL MEMORY - AN EXPERIMENTALLY-REFINED, DYNAMIC GENE REGULATORY NETWORK MODEL OF T-CELL MEMORY SUMMARY T CELL MEMORY INDUCED BY PRIOR EXPOSURE TO A PATHOGEN OR VACCINATION PROVIDES ENHANCED PROTECTION AGAINST A SUBSEQUENT INFECTION WITH THE SAME PATHOGEN. ENHANCED PROTECTION IS PARTIALLY DRIVEN BY CLONAL EXPANSION, WHICH LEADS TO AN INCREASED NUMBER OF T CELLS CAPABLE OF RECOGNIZING THE ANTIGEN. ADDITIONALLY, MEMORY T CELLS POSSESS A “RAPID RECALL ABILITY” THAT ALLOWS THEM TO FIGHT PATHOGENS BY PRODUCING CYTOKINES AND OTHER EFFECTOR MOLECULES WITHIN MINUTES OF RE-EXPOSURE (AS OPPOSED TO DAYS, UPON INITIAL EXPOSURE). WE RECENTLY SHOWED THAT RAPID RECALL CORRELATES WITH THE EPIGENETIC POISING OF ENHANCERS AND PROMOTERS OF THE “RAPID-RECALL GENES” IN MEMORY T CELLS. IMPORTANTLY, THE SITES OF EPIGENETIC CHANGE SIGNIFICANTLY OVERLAP WITH THE RISK LOCI FOR AUTOIMMUNE AND ATOPIC DISEASE, SUGGESTING THAT THIS MECHANISM IS IMPORTANT FOR HUMAN HEALTH. HOWEVER, IT IS STILL UNCLEAR IF AND HOW THE EPIGENETIC POISING CAUSES ENHANCED EXPRESSION OF RAPID RECALL GENES. FURTHERMORE, MEMORY T CELLS PERSIST FOR A LIFETIME; YET THE MECHANISMS THAT MAINTAIN THE MEMORY EPIGENOME – FOR DECADES– ARE NOT KNOWN. OUR PRELIMINARY DATA SUGGEST THAT RAPID RECALL IS COORDINATED BY SEVERAL FAMILIES OF TRANSCRIPTION FACTORS (TFS) AND THOUSANDS OF PUTATIVE DNA REGULATORY ELEMENTS. THIS COMPLEXITY REQUIRES A SYSTEMS-LEVEL, ENGINEERING APPROACH. THUS, THIS PROPOSAL IS A COLLABORATION BETWEEN THE GROUPS OF ARTEM BARSKI, A T CELL BIOLOGIST, AND EMILY MIRALDI, A MATHEMATICAL MODELER, TO CREATE EXPERIMENTALLY VALIDATED, GENOME-SCALE MODELS OF MEMORY IMMUNE RESPONSES ACROSS HETEROGENEOUS T CELL POPULATIONS. AIM 1. USING SINGLE-CELL GENOMICS, WE WILL CHARACTERIZE THE GENE EXPRESSION AND CHROMATIN DYNAMICS OF T CELL ACTIVATION IN NAÏVE AND MEMORY CELLS AND BUILD MATHEMATICAL MODELS THAT INTEGRATE THESE DATA (ALONG WITH RELEVANT EXISTING GENOMICS RESOURCES) INTO A DYNAMIC GENE REGULATORY NETWORK (GRN). OUR GRN MODEL WILL PREDICT THE MOLECULAR DRIVERS (TFS) AND REGULATORY ELEMENTS THAT ORCHESTRATE RAPID RECALL. AIM 2. ALTHOUGH T-CELL ACTIVATION IN NAÏVE AND MEMORY CELLS SIMILARLY PROMOTES NUCLEAR TRANSLOCATION OF INDUCIBLE TFS, OUR DATA LEAD US TO HYPOTHESIZE THAT CHROMATIN REMODELING UPON INITIAL PATHOGEN EXPOSURE ALTERS THE OCCUPANCY OF INDUCIBLE TFS IN MEMORY T CELLS AND THAT THIS IS THE BASIS OF RAPID RECALL. WE WILL COMBINE DYNAMIC TF PERTURBATION AND OCCUPANCY EXPERIMENTS TO ESTABLISH THE MOLECULAR INTERACTIONS DRIVING RAPID RECALL. AIM 3. WE WILL IDENTIFY THE MECHANISMS BY WHICH MEMORY T CELLS MAINTAIN THE EPIGENOME CONDUCIVE FOR RAPID RECALL – OVER THE HUMAN LIFESPAN. WE HYPOTHESIZE THAT CONSTITUTIVE TFS MAINTAIN THE EPIGENOME POISED FOR RAPID RECALL. WE PROPOSE DYNAMIC TF PERTURBATION EXPERIMENTS TO UNCOVER THE IDENTITIES OF THESE REGULATORS. THIS STUDY WILL HELP UNCOVER BASIC MECHANISMS OF T CELL MEMORY AND IDENTIFY POTENTIAL TARGETS FOR MANIPULATING IMMUNOLOGIC MEMORY RESPONSES. BECAUSE RAPID RECALL IS THE BASIS FOR VACCINATION AND CENTRAL TO ALLERGY, ASTHMA, AND CANCER IMMUNITY, THIS STUDY WILL HAVE A BROAD IMPACT ON HUMAN HEALTH.

UNDERSTANDING CARDIOVASCULAR DISEASE MECHANISMS

REGULATION OF TLR SIGNALING, INFLAMMATION AND ANTIGEN PRESENTATION BY VPS33B - PROJECT SUMMARY INITIATION OF INNATE IMMUNE RESPONSES DEPENDS ON COGNATE INTERACTION BETWEEN GERMLINE-ENCODED PATTERN RECOGNITION RECEPTORS AND THEIR LIGANDS (EXPRESSED BY MICROBES). FOLLOWING RECOGNITION, THE RECEPTORS INITIATE ACTIVATION OF DOWNSTREAM SIGNAL TRANSDUCTION PATHWAYS THAT OFTEN INVOLVE RECRUITMENT OF DOWNSTREAM ADAPTERS AND KINASES. THE TOLL-LIKE RECEPTOR FAMILY OF PRRS, WHICH ARE THE SUBJECT OF CURRENT INVESTIGATION, ARE EXPRESSED BOTH ON THE PLASMA MEMBRANE AND IN THE ENDOSOMES. SEVERAL RECENT STUDIES HAVE DEMONSTRATED THAT ENDOCYTOSIS OF THE PLASMA MEMBRANE TLRS (ESPECIALLY TLR4) PLAYS A CRITICAL ROLE IN REGULATING BOTH QUALITY AND MAGNITUDE OF INFLAMMATORY RESPONSES IN A RESPONDING MACROPHAGE. OTHER STUDIES HAVE DEMONSTRATED THAT TLR SIGNALING ENHANCES PHAGOCYTOSIS OF MICROBIAL CARGO BUT NOT OF APOPTOTIC CELL CARGO SUGGESTING A DEGREE OF SPECIFICITY THAT IS NOT UNDERSTOOD. IN ADDITION, ALTHOUGH ENDOCYTOSIS OF TLR4 AND THE EVENTS FOLLOWING ENDOCYTOSIS OF TLR4 THAT INFLUENCE SIGNAL TRANSDUCTION ARE VERY WELL STUDIED, IT IS NOT ENTIRELY CLEAR IF AND HOW ENDOCYTOSIS INFLUENCES SIGNALING DOWNSTREAM OF OTHER PLASMA MEMBRANE AND ENDOSOMAL TLRS. IN OUR STUDIES, WE FIND THAT A PROTEIN CALLED VPS33B REGULATES HANDLING OF THE PHAGOCYTIC AND ENDOCYTIC CARGO FOLLOWING PATTERN RECOGNITION RECEPTOR ACTIVATION. MORE IMPORTANTLY, VPS33B DIRECTLY INFLUENCES THE OUTCOME OF SIGNALING DOWNSTREAM OF TLRS IN MICE AND TOLL- AND IMD PATHWAYS IN DROSOPHILA. MUTATIONS IN THE GENES VPS33B AND VPS16B ARE LINKED TO A RARE HUMAN DISEASE CALLED ARC (ARTHROGRYPOSIS-RENAL DYSFUNCTION-CHOLESTASIS) SYNDROME. BOTH OF THESE ARC GENES ENCODE PARALOGS OF HOPS COMPLEX SUBUNITS SUGGESTING A ROLE IN MEMBRANE FUSIONS BUT HOW PERTURBATION OF FUNCTION OF THESE PROTEINS RESULTS IN A DIVERSE SPECTRUM OF DISEASE SYMPTOMS IN ARC PATIENTS IS NOT ENTIRELY CLEAR. IT HAS HOWEVER BEEN DOCUMENTED THAT ARC PATIENTS SUFFER FROM SEPSIS AND RECURRENT BACTERIAL INFECTIONS AND WE WERE THEREFORE INVESTIGATED THE ROLE OF THESE PROTEINS IN INFLUENCING IMMUNE RESPONSES. WE FIND THAT IN THE ABSENCE OF VPS33B, DROSOPHILA RESPOND VIGOROUSLY TO MICROBIAL INSULT. EXAGGERATED IMMUNE RESPONSES ARE GENERATED IN RESPONSE TO LIVE OR DEAD BACTERIA AND PURIFIED LIGANDS OF THE TOLL AND IMD PATHWAY RESULTS IN DEATH OF VPS33B MUTANT, BUT NOT WILD-TYPE FLIES. THIS FUNCTION OF VPS33B IS CONSERVED IN VERTEBRATES AND WE FIND THAT MOUSE MACROPHAGES LACKING VPS33B SECRETE VERY HIGH QUANTITIES OF INFLAMMATORY CYTOKINES, WHEN STIMULATED BY EITHER PLASMA MEMBRANE OR ENDOSOMAL TLR LIGANDS. WE THEREFORE HYPOTHESIZE THAT ACTIVATION OF PATTERN RECOGNITION RECEPTORS AND SPECIFICALLY TLRS LEADS TO FORMATION OF SPECIALIZED ENDOSOMES THAT DEPEND ON VPS33B FOR LYSOSOMAL FUSION. LACK OF VPS33B IS LIKELY TO AFFECT SEVERAL ASPECTS OF INNATE AND ADAPTIVE IMMUNITY AND TO TEST THIS HYPOTHESIS, WE PROPOSE TO 1. DEFINE THE MOLECULAR EVENTS THAT REGULATE VPS33B FUNCTION IN ENDOSOMAL MATURATION, 2. DEFINE THE ROLE OF VPS33B-REGULATED TLR TRAFFICKING AND SIGNALING 3. INVESTIGATE THE ROLE OF VPS33B IN REGULATING CARGO HANDLING BY DCS AND 4. INVESTIGATE THE ROLE OF VPS33B IN REGULATING ANTIGEN PRESENTATION AND ADAPTIVE IMMUNITY.

MIR-155 AND RUNX FUNCTION IN NEUROFIBROMA TUMORIGENESIS AND THERAPY

MOLECULAR PATHWAYS CONTROLLING CARDIAC GENE EXPRESSION

LEVEL AND TIMING OF DIABETIC HYPERGLYCEMIA IN UTERO: THE TRANSGENERATIONAL EFFECT ON ADULT MORBIDITY (TEAM STUDY)

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASE

EPIGENOME-WIDE VARIATIONS AND SOCIO-ENVIRONMENTAL EXPOSURES IN AFRICAN AMERICAN ASTHMATIC CHILDREN - ABSTRACT ASTHMA IS A MAJOR PUBLIC HEALTH PROBLEM IN THE UNITED STATES, AFFECTING 11 MILLION CHILDREN. DESPITE ADVANCES IN ASTHMA CARE, AFRICAN AMERICANS (AAS) ARE 4 TIMES MORE LIKELY TO BE HOSPITALIZED AND 5 TIMES MORE LIKELY TO DIE FROM ASTHMA THAN EUROPEAN AMERICANS (EAS). SEVERAL FACTORS COULD BE RESPONSIBLE FOR THE OBSERVED ASTHMA RACIAL DISPARITIES INCLUDING GENETIC AND NON-GENETIC FACTORS. WHILE EPIGENETICS APPEAR TO SERVE AS A CRITICAL BIOLOGICAL SWITCH BETWEEN GENETIC VULNERABILITY AND SOCIO-ENVIRONMENTAL EXPOSURES, LIMITED STUDIES ARE AVAILABLE THAT DIRECTLY MAP THE SOCIO- ENVIRONMENTAL EXPOSURES WITH ASTHMATIC EPIGENOME/GENOME INFORMATION. IN ADDITION, CURRENT APPROACH DO NOT LEVERAGE EXISTING GEOSPATIAL DATA SUCH AS ENVIRONMENTAL EXPOSURE AND NEIGHBORHOOD SOCIOECONOMIC CONDITIONS TO IMPROVE ASTHMA RISK PREDICTION. IN THIS PROPOSAL, WE WILL UTILIZE COMPREHENSIVE GEOCODING ALGORITHMS, NOVEL STATISTICAL METHODS TO INTEGRATE SOCIAL, CLINICAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC DATA INTO A COMPOSITE SCORE FOR ASTHMA RISK STRATIFICATION AND PREDICTION. THE OVERALL OBJECTIVE OF THIS RESEARCH IS TO CONDUCT GENOME-WIDE METHYL-SEQ ANALYSIS AND LEVERAGE EXISTING WELL-PHENOTYPED AA PEDIATRIC ASTHMA COHORT WITH EXTENSIVE SOCIO-ENVIRONMENTAL EXPOSURES AND ANCESTRY-TAILORED MULTI-ETHNIC GENOTYPING ARRAY (MEGA) DATA FROM CINCINNATI PEDIATRICS REPOSITORY TO ACCURATELY DETERMINE AND DEVELOP ANCESTRY- SPECIFIC ASTHMA RISK STRATIFICATION AND PREDICTION MODELS. THE OBJECTIVE OF THIS APPLICATION IS TO UNDERTAKE AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), INCORPORATING GEOCODED NEIGHBORHOOD- AND INDIVIDUAL-LEVEL SOCIO-ENVIRONMENTAL PREDICTORS, AND NOVEL ANALYTICAL STRATEGIES TO CREATE A COMPOSITE RISK SCORE INCORPORATING METHYLATION RISK SCORE (MRS), ANCESTRY, ENVIRONMENTAL EXPOSURES AND SOCIAL CHARACTERISTICS TO PREDICT ASTHMA. WE WILL ACCOMPLISH THESE OBJECTIVES THROUGH THE FOLLOWING SPECIFIC AIMS: 1) DEVELOP AN ANCESTRY-SPECIFIC METHYLATION RISK SCORE (MRS) FOR ASTHMA AND TEST ITS ASSOCIATION WITH SOCIO-ENVIRONMENTAL EXPOSURES CONTRIBUTING TO ASTHMA RISK. 2) DETERMINE THE MEDIATION EFFECTS OF MRS BETWEEN GENETIC ANCESTRY AND ASTHMA RISK. 3) DEVELOP A MULTIVARIABLE RISK PREDICTIVE MODEL FOR ASTHMA INCORPORATING MRS, GENETIC ANCESTRY, CLINICAL, AND SOCIO-ENVIRONMENTAL RISK FACTORS. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE THIS WILL BE THE FIRST TIME A MRS APPROACH WILL BE USED TO DEVELOP A POPULATION-BASED RISK PROFILE IN ASTHMATICS. THE STUDY WILL PROVIDE INSIGHTS IN THE USE OF RISK STRATIFICATION FOR SCREENING AND TARGETED INTERVENTIONS. THIS WORK IS SIGNIFICANT BECAUSE IT CAN SERVE AS A MODEL TO STUDY THE COMPOSITE EFFECT OF MRS, ANCESTRY, SOCIO-ENVIRONMENTAL, AND CLINICAL RISK FACTORS ON RACIAL DISPARITIES IN OTHER WELL-DOCUMENTED COMMON COMPLEX DISEASES BEYOND ASTHMA.

MOLECULAR PATTERNING OF MAMMALIAN DENTITION

TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS OF ALVEOLOGENESIS AND RE-ALVEOLOGENESIS - PROJECT SUMMARY LUNG DISEASES IMPACTING THE GAS EXCHANGE ALVEOLI, INCLUDING COVID-19, ARE BECOMING THE LEADING CAUSE OF DEATH. A MULTI-LINEAGE, TRANSCRIPTIONAL, AND EPIGENETIC UNDERSTANDING OF ALVEOLOGENESIS AND RE- ALVEOLOGENESIS UPON INJURY IS A TIMELY RESPONSE TO THE DISEASE BURDEN AND LEVERAGES LATEST SINGLE-CELL TECHNOLOGY. MY LAB’S TRACK RECORD IN STUDYING THE LUNG EPITHELIAL, ENDOTHELIAL, AND MESENCHYMAL LINEAGES LAYS THE FOUNDATION FOR PURSUING A POORLY UNDERSTOOD PROCESS OF CELLULAR MATURATION (THEME 1), A RECENTLY IDENTIFIED CAPILLARY CELL TYPE (THEME 2), AND A NOVEL SIGNALING REGULATION OF DISTINCT MESENCHYMAL CELL POPULATIONS (THEME 3). THE ANTICIPATED KNOWLEDGE WILL TACKLE FUNDAMENTAL QUESTIONS OF CELL FATE, PLASTICITY, AND SIGNALING; SHED LIGHT ON BRONCHOPULMONARY DYSPLASIA, PULMONARY HYPERTENSION, ACUTE LUNG INJURY, AS WELL AS NON-CODING VARIANTS FROM GENOME-WIDE ASSOCIATION STUDIES; AND OPENS THE DOOR TO SINGLE-CELL FUNCTIONAL GENOMICS APPLICABLE TO ANY ORGAN.

UNRAVELING ANCESTRY AND ENVIRONMENTAL EXPOSURE INTERACTIONS IN CHILDHOOD ASTHMA

SURGICAL OR MEDICAL TREATMENT FOR PEDIATRIC TYPE 2 DIABETES (ST2OMP)

MIND BODY BALANCE FOR PEDIATRIC MIGRAINE - PROJECT SUMMARY MIND AND BODY APPROACHES, SPECIFICALLY DIAPHRAGMATIC BREATHING, PROGRESSIVE MUSCLE RELAXATION, GUIDED IMAGERY, AND BIOFEEDBACK, IMPROVE OUTCOMES FOR CHILDREN AND ADOLESCENTS WITH CHRONIC PAIN. ONE PREVALENT CAUSE OF CHRONIC PAIN IS MIGRAINE. WORLDWIDE, IT IS THE 2ND MOST DISABLING NEUROLOGICAL DISEASE. WHEN YOUTH LEARN AND PRACTICE MIND AND BODY SKILLS, THE NUMBER OF HEADACHE DAYS AND ASSOCIATED DISABILITY ARE REDUCED. TYPICALLY, TRIALS HAVE TESTED NON-PHARMACOLOGICAL INTERVENTION PACKAGES TAUGHT BY PSYCHOLOGISTS, IN FACE-TO-FACE SESSIONS, OCCURRING OVER 4 TO 8 WEEKLY MEETINGS. WHILE EFFICACIOUS, THIS MODEL IS NOT ACCESSIBLE TO MOST FAMILIES BECAUSE OF LACK OF TRAINED PROVIDERS, DISTANCE AND TRAVEL BARRIERS, AND TIME COMMITMENT TO SESSIONS. OUR RECENT PILOT STUDIES (BOTH STAKEHOLDER ENGAGEMENT AND HEALTH CARE PROVIDER SKILLS TRAINING PROJECTS) SHOW THAT YOUTH WHO RECEIVE OUTPATIENT PSYCHOLOGICAL CARE REPORT THAT LEARNING BREATHING, MUSCLE RELAXATION, GUIDED IMAGERY, AND BIOFEEDBACK ARE THE MOST USEFUL AND IMPACTFUL COMPONENTS OF THE LARGER TREATMENT PACKAGE. ALSO, NURSES IN HEADACHE CENTERS REPORT THAT THEY WOULD FEEL COMFORTABLE WITH AND ARE INTERESTED IN LEARNING HOW TO INTRODUCE THESE SKILLS TO PATIENTS; AND PEDIATRIC HEADACHE SPECIALISTS AND PRIMARY CARE PROVIDERS ARE SEARCHING FOR EFFICIENT AND EFFECTIVE WAYS TO INTRODUCE MIND AND BODY SKILLS TO THEIR PATIENTS. THUS, WE NEED TO CONDUCT PRAGMATIC TRIALS TO TEST THE DELIVERY OF THESE INTEGRATED APPROACHES WITHIN THE CONTEXT OF TYPICAL MEDICAL CARE TO CONFIRM IF THEY CAN PROVIDE BENEFIT OR NOT. BUT, DESPITE EVIDENCE OF SAFETY, EFFICACY, AND SUCCESSFUL PRIOR TRIAL EXECUTION, IT IS NECESSARY TO OPTIMIZE A TREATMENT PACKAGE BY EVALUATING WHICH COMPONENTS AND DOSES OF A COMPLEX INTERVENTION ARE CRITICAL FOR CHANGES IN OUTCOMES PRIOR TO IMPLEMENTING A MULTI-SITE EFFECTIVENESS TRIAL. IN THIS NCCIH U01, WE WILL OPTIMIZE A MIGRAINE PREVENTION TREATMENT PACKAGE FOCUSED ON 4 MIND AND BODY SKILLS THAT WILL BE DELIVERED BY HEALTH CARE PROVIDERS (FOR THIS PROJECT, NURSES) IN TWO OUTPATIENT HEADACHE CENTERS (CINCINNATI & DENVER). AN INNOVATIVE INTERVENTION REFINEMENT APPROACH, THE MULTIPHASE OPTIMIZATION STRATEGY (MOST) (HTTPS://METHODOLOGY.PSU.EDU/RA/MOST) WILL BE EMPLOYED TO DETERMINE NECESSARY COMPONENTS AND DOSES OF AN EFFICIENT, EFFECTIVE TREATMENT THAT CAN THEN BE TESTED AGAINST STANDARD CARE (PATIENT EDUCATION WITHOUT ANY SKILLS = TRAINING) VIA A PRAGMATIC TRIAL. FOR THIS FACTORIAL EXPERIMENT, WE WILL ENROLL 200 YOUTH AGES 10 TO 17 YEARS WITH A DIAGNOSIS OF MIGRAINE WHO ARE EXPERIENCING 4 HEADACHE DAYS PER MONTH (N = 25 PER EACH OF 8 CONDITIONS). THREE COMPONENTS WILL BE TESTED: SESSION TIME WITH NURSES FOR INTRODUCTION TO THE SKILLS (DOSE OF 20 OR 40 MINUTES); DAILY HOME PRACTICE OF SKILLS FOR 8 WEEKS (DOSE OF A SIMPLE HANDOUT APPROACH OR USE OF AN ACTIVE, GUIDED EHEALTH APPLICATION); AND ADHERENCE PROMPT PHONE CALL AT 1-MONTH (DOSE OF A CALL OR NO CALL). THE ENDPOINTS ARE HEADACHE DAYS AND MIGRAINE-RELATED DISABILITY (PLUS TREATMENT FIDELITY, FEASIBILITY, DROP-OUT RATES, ACCEPTANCE, & CREDIBILITY; SLEEP; DEPRESSION; ANXIETY; AND FUNCTIONAL DISABILITY). THE MOST EFFICIENT COMBINATION OF DOSES OF THE 3 COMPONENTS WILL BE DETERMINED USING THE MOST APPROACH, GUIDED BY THE RESOURCE MANAGEMENT AND THE OPTIMIZATION PRINCIPLES.

LEVERAGING THE ELECTRONIC HEALTH RECORD TO CHARACTERIZE AND OPTIMIZE CARE DELIVERY FOR CHILDREN WITH CEREBRAL PALSY. - ABSTRACT/SUMMARY LEVERAGING THE ELECTRONIC HEALTH RECORD TO CHARACTERIZE AND OPTIMIZE CARE DELIVERY FOR CHILDREN WITH CEREBRAL PALSY: CEREBRAL PALSY (CP) IS THE MOST COMMON PHYSICAL DISABILITY OF CHILDHOOD, BUT IT IS HIGHLY HETEROGENEOUS WITH RESPECT TO ITS SEVERITY, RESPONSE TO THERAPY, CARE NEEDS, AND IMPACT ON WELLNESS FOR THE CHILD AND FAMILY. TO OPTIMIZE HEALTH AND WELLNESS THROUGHOUT LIFE AND ENABLE NEW RESEARCH AVENUES TO BE EFFECTIVELY TESTED, IT IS CRITICAL TO DEVELOP A COMPREHENSIVE CLINICAL CARE AND BIOPSYCHOSOCIAL DATA MODEL. DEVELOPMENT OF A COMPREHENSIVE MODEL WOULD BOTH ACCELERATE AND IMPROVE UNDERSTANDING, CARE, AND FURTHER RESEARCH, INCLUDING THE IDENTIFICATION OF NOVEL TARGETS FOR INTERVENTIONS. THE OVERRIDING OBJECTIVE OF THIS PROPOSAL IS TO DEVELOP A PRECISION HEALTH MODEL FOR CP-RELATED PHENOTYPES, HEALTH STATUS, CARE ACTIVITIES, AND PSYCHOSOCIAL WELL-BEING THAT WILL INDIVIDUALIZE CARE. TO ACCOMPLISH THIS OBJECTIVE, WE WILL AUTOMATE THE COLLECTION, CLEANING, AND INTEGRATION OF MULTI-DIMENSIONAL, MULTI-DOMAIN AND MULTI-COHORT BASED "BIG DATA" EXTRACTED FROM THE ELECTRONIC HEALTH RECORD (EHR), AND COMBINE THIS EHR DATA WITH PROSPECTIVELY COLLECTED, HIGH-RESOLUTION CLINICAL, FUNCTIONAL, ENVIRONMENTAL AND PSYCHOSOCIAL DATA. THE FOCUS OF THIS PROPOSAL WILL BE ON CHILDREN BETWEEN AGES 6 AND 12 YEARS. PRELIMINARY WORK INDICATES THAT THE MEDICAL CENTER PROVIDES CARE FOR APPROXIMATELY 1,800 PATIENTS WITH CP WHO ARE BETWEEN THE AGES OF 6 AND 12 YEARS AND HAVE AT LEAST THREE YEARS OF EHR DATA. FROM THIS EHR COHORT, WE WILL PROSPECTIVELY RECRUIT 200 CHILDREN AND THEIR FAMILIES FOR DETAILED PHENOTYPING. RECRUITMENT WILL BE STRATIFIED BY GROSS MOTOR FUNCTIONAL CLASSIFICATION SYSTEM (GMFCS) LEVELS: 60% GMFCS I, II, OR III (ABLE TO WALK) AND 40% GMFCS IV OR V (USE A WHEELCHAIR). USING THIS MULTI-COHORT DESIGN WILL ALLOW FOR ROBUST CHARACTERIZATION OF MULTI-DIMENSIONAL FACTORS THAT IMPACT CARE RECEIPT, FUNCTIONAL OUTCOMES, QUALITY OF LIFE AND PARTICIPATION. AIM 1 WILL FOCUS ON CREATING A DIVERSE AND COMPREHENSIVE DATA REPOSITORY USING BOTH RETROSPECTIVE AND PROSPECTIVE DATA TO CHARACTERIZE ACTUAL VERSUS OPTIMAL CARE (DEFINED BY CURRENT EVIDENCE-BASED LITERATURE). AIM 2 WILL LEAD TO DEVELOPMENT OF A RECEIPT OF CARE COEFFICIENT SCORE AND CHARACTERIZE HOW THE DEGREE OF OPTIMAL CARE RELATES TO FUNCTION, QUALITY OF LIFE AND PARTICIPATION, CONTROLLING FOR FUNCTIONAL STATUS AND AGE. [MODELS DEVELOPED IN AIM 2 WILL BE TRANSLATED INTO A CLINICAL DECISION TOOL PROTOTYPE. AIM 3 WILL DEMONSTRATE PROOF OF CONCEPT FOR SCALABILITY OF MACHINE LEARNING ALGORITHMS WITH THE PEDSNET LEARNING HEALTH SYSTEM. THIS PROJECT INNOVATIVELY COMBINES RETROSPECTIVE EHR DATA WITH PROSPECTIVE CLINICAL DATA TO ELUCIDATE INDIVIDUAL, TREATMENT, FAMILY, AND ENVIRONMENTAL FACTORS ASSOCIATED WITH GREATER RECEIPT OF EVIDENCE-BASED CARE AND/OR BETTER OUTCOMES. THIS PROJECT WILL MOVE THE FIELD TOWARD PRECISION MEDICINE FOR CP AND CREATE A FOUNDATION FOR DEVELOPMENT OF CLINICAL DASHBOARDS TO OPTIMIZE PRACTICE.]

SENSITIZATION OF DEVELOPING SENSORY NEURONS AFTER INCISION

REGULATION OF CRANIOFACIAL DEVELOPMENT BY ALX TRANSCRIPTION FACTORS

NOVEL GENETIC AND SALIVARY GLYCAN BIOMARKERS FOR RISK OF NEC IN ELBW INFANTS.

2/2-ANOMALOUS MOTOR PHYSIOLOGY IN ADHD

AIRWAY PROGENITOR CELL PROFILERATION AND DIFFERENTIATION DURING LUNG REPAIR

NATIONAL RESEARCH SERVICE AWARD

ANIMAL MODELS TO DEVELOP NEW REGIMENS FOR S. AUREUS IMPLANT-ASSOCIATED INFECTIONS - STAPHYLOCOCCUS AUREUS IS THE LEADING CAUSE OF SERIOUS DEEP-SEATED OSTEOARTICULAR AND IMPLANT- ASSOCIATED INFECTIONS. S. AUREUS ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS ARE DIFFICULT TO TREAT, REQUIRING SURGERY AND / OR PROLONGED SYSTEMIC ANTIBIOTICS (WEEKS-MONTHS). THEY ARE ALSO ASSOCIATED WITH EXTENDED DISABILITY AND REHABILITATION, CONTRIBUTING TO WORSE OVERALL OUTCOMES. ALTHOUGH INFECTION RATES OF ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS HAVE REMAINED AT 1-2% AFTER PRIMARY AND 3-6% AFTER REVISION ARTHROPLASTY, INPATIENT COSTS AVERAGE $25,000-$107,000 PER CASE, AND AN ANNUAL HEALTHCARE BURDEN OF $3 BILLION IN THE U.S. ALONE. THE INCREASING PREVALENCE OF METHICILLIN-RESISTANT S. AUREUS (MRSA) IN THE U.S. AND WORLDWIDE, POSES YET ANOTHER CHALLENGE FOR THE TREATMENT OF THESE INFECTIONS, REQUIRING PROLONGED INTRAVENOUS ANTIBIOTICS. WE HAVE DEVELOPED ANIMAL MODELS OF S. AUREUS ORTHOPEDIC IMPLANT-ASSOCIATED INFECTIONS THAT REPLICATE KEY PATHOLOGICAL FEATURES OF HUMAN DISEASE AS WELL AS NOVEL, CLINICALLY TRANSLATABLE POSITRON EMISSION TOMOGRAPHY (PET) BIOIMAGING FOR HOLISTIC, NONINVASIVE LONGITUDINAL MEASUREMENTS IN LIVE SUBJECTS - BACTERIA-SPECIFIC DETECTION OF S. AUREUS INFECTIONS [11C-PARA-AMINOBENZOIC ACID (PABA), SELECTIVELY METABOLIZED VIA THE BACTERIAL FOLATE PATHWAY] AND 11C-RIFAMPIN, 18F-LINEZOLID, 18F-SUTEZOLID, ALL CHEMICALLY IDENTICAL TO THE PARENT ANTIBIOTIC, TO MEASURE ANTIBIOTIC AREA UNDER THE CURVE (AUC). RECENTLY, WE CONDUCTED FIRST-IN-HUMAN 11C-PABA (ORDONEZ ET AL. JCI INSIGHT 2022) AND 11C-RIFAMPIN (GORDON ET AL. SCI TRANSL MED. 2021) PET STUDIES IN HEALTHY VOLUNTEERS AND NEWLY IDENTIFIED PATIENTS WITH S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, RESPECTIVELY. WE SHOW THAT RIFAMPIN BONE EXPOSURES ARE SUBSTANTIALLY LOWER THAN PREVIOUSLY THOUGHT (BASED ON SINGLE TIME-POINT BIOPSY STUDIES). PHARMACOKINETIC MODELING OF THIS RICH PET DATA ENABLED THE DEVELOPMENT OF OPTIMIZED, SHORTER RIFAMPIN-BASED TREATMENTS FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, WHICH AMELIORATED THE DEVELOPMENT OF ANTIBIOTIC RESISTANT BACTERIA, REDUCED MUTATIONS CONFERRING BACTERIAL PERSISTENCE, AND MITIGATED ADVERSE BONE REMODELING. HERE, WE WILL LEVERAGE OUR EXPERTISE IN BIOIMAGING, PHARMACOLOGY AND ANIMAL MODEL APPROACHES TO PERFORM COMPREHENSIVE PROOF-OF-PRINCIPLE STUDIES AND GAIN MECHANISTIC INSIGHTS INTO THE INTERPLAY OF SPATIOTEMPORALLY COMPARTMENTALIZED ANTIBIOTIC EXPOSURES (RIFAMPIN, LINEZOLID AND SUTEZOLID) AND BACTERIAL EVOLUTION / ACQUIRED DRUG RESISTANCE (ADR) DURING ANTIBIOTIC TREATMENTS, TO ESTABLISH RELAPSE-FREE CURE FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS. INTEGRATION OF FINDINGS FROM ANIMAL AND HUMAN STUDIES WILL ENABLE US TO REFINE OUR MODELS AND ADDRESS CLINICALLY RELEVANT CHALLENGES. KNOWLEDGE GAINED FROM THESE STUDIES WILL NOT ONLY PROVIDE UNIQUE MECHANISTIC INSIGHTS INTO BACTERIAL EVOLUTION AND ADR AND INFORM THE DEVELOPMENT OF NOVEL, SHORT, ORAL-ONLY THERAPEUTIC (ANTIBIOTIC) REGIMENS FOR S. AUREUS ORTHOPEDIC IMPLANT INFECTIONS, BUT WILL ALSO BE A MAJOR STRIDE TOWARDS DEVELOPING PRECISION MEDICINE TOOLS FOR AT-RISK PATIENTS WITH COMPLICATED S. AUREUS INFECTIONS.

SIROLIMUS TSC EPILEPSY PREVENTION STUDY (STEPS) IND#145820 11/8/2019 - SUMMARY/ABSTRACT EPILEPSY IS VERY PREVALENT AND HIGHLY REFRACTORY TO CURRENTLY AVAILABLE MEDICAL TREATMENTS IN TUBEROUS SCLEROSIS COMPLEX (TSC), A GENETIC DISORDER AFFECTING 1:6000 LIVE BIRTHS. MEDICALLY-REFRACTORY EPILEPSY IN TSC IS ASSOCIATED WITH LIFELONG INTELLECTUAL DISABILITY AND NEURODEVELOPMENTAL DEFICITS. EVEROLIMUS AND SIROLIMUS, PHARMACOLOGICAL INHIBITORS OF THE MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1 (MTORC1), HAVE BEEN SUCCESSFULLY REPURPOSED TO TREAT MAY CLINICAL MANIFESTATIONS OF TSC, INCLUDING FOCAL-ONSET EPILEPSY. HOWEVER, FEW PATIENTS BECOME SEIZURE- FREE FOLLOWING TREATMENT WITH MTORC1 INHIBITORS AND 60% OF PATIENTS WITH TSC ARE STILL IN NEED OF EFFECTIVE TREATMENT. MOUSE MODELS OF TSC AND HUMAN CLINICAL TRIALS INDICATE EARLY TREATMENT WITH MTORC1 INHIBITORS, BEFORE THE ONSET OF SEIZURES, MAY BE A MORE EFFECTIVE TREATMENT STRATEGY AGAINST EPILEPSY AND EPILEPSY- ASSOCIATED DEFICITS IN NEURODEVELOPMENT IN PATIENTS DIAGNOSED WITH TSC. THE CURRENT STUDY PROPOSES A PHASE IIB MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL WITH SIROLIMUS TO TEST THIS HYPOTHESIS. THE PRIMARY AIMS OF THE CLINICAL TRIAL ARE (1) TO DEMONSTRATE THAT SIROLIMUS PREVENTS OR DELAYS SEIZURES IN INFANTS WITH TSC THAT ARE 0-12 MONTHS OF AGE; AND (2) TO DEMONSTRATE THAT SIROLIMUS IS SAFE AND WELL-TOLERATED IN INFANTS WITH TSC THAT ARE 0-12 MONTHS OF AGE. ADDITIONAL (SECONDARY) AIMS OF THE TRIAL ARE: (1) TO DEMONSTRATE THAT EARLY SIROLIMUS TREATMENT IMPROVES DEVELOPMENTAL DELAY, LANGUAGE IMPAIRMENT, ADAPTIVE SKILLS, AND AUTISM RISK; (2) TO ASSESS THE UTILITY OF EEG AND MRI BIOMARKERS FOR MEASURING MTORC1 INHIBITION IN THE BRAIN; AND (3) TO VALIDATE PRECISION DOSING OF SIROLIMUS IN INFANTS WITH TSC.

PATIENT-SPECIFIC, COMBINATORIAL NAMS FOR GASTROINTESTINAL DISEASES AND DRUG RESPONSE PREDICTION - ABSTRACT MILLIONS OF PEOPLE IN THE US ARE IMPACTED BY GASTROINTESTINAL DISEASES INCLUDING INFLAMMATORY BOWEL DISEASE (IBD), METABOLIC DISFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND PANCREATITIS. THERE ARE ONLY A SMALL NUMBER OF DRUGS FOR IBD AND MASLD, AND NONE FOR PANCREATITIS, MAKING THIS A CRITICALLY SIGNIFICANT CLINICAL QUESTION. ANIMAL MODELS HAVE PROVEN INADEQUATE SURROGATES FOR THESE DISEASES AND RELIANCE ON CURRENT PRECLINICAL EVALUATIONS ARE CONSIDERED TO BE AMONG THE MOST PROBLEMATIC STEPS IN DRUG DISCOVERY. THE GOAL OF CINCINNATI ADVANCED NAM DEVELOPMENT AND OPERATIONAL RESEARCH CENTER (CANDOR) IS TO DEVELOP COMBINATORIAL NEW APPROACH METHODOLOGIES (NAMS) THAT MORE ACCURATELY MODEL THE PATHOPHYSIOLOGIC COMPLEXITY AND DRUG RESPONSES IN PATIENTS WITH THESE GASTROINTESTINAL (GI) DISEASES. WE HAVE ESTABLISHED AN INTERDISCIPLINARY TEAM OF COLLABORATORS OF CLINICIANS, SCIENTISTS, EXPERIMENTAL AND COMPUTATIONAL BIOLOGISTS WITH A HISTORY OF DEVELOPING IN VITRO ORGANOID AND IN SILICO NAMS WITH A FOCUS ON INFLAMMATORY DISEASES OF THE GI TRACT. CANDOR WILL PROVIDE A COLLABORATIVE PIPELINE STARTING WITH EXISTING COHORTS OF DEEPLY PHENOTYPED PATIENTS WITH IBD, MASLD, AND PANCREATITIS. CLINICAL DATA AND PATIENT SAMPLES WILL BE USED TO BUILD IN SILICO NAMS, BASED ON MOLECULAR PATHWAYS AND CELL-CELL INTERACTIONS THAT CORELATE WITH PATIENT OUTCOME AND DRUG RESPONSE. EACH DISEASE WILL HAVE A CORRESPONDING IN VITRO NAM COMPRISING INTESTINAL, LIVER, AND PANCREATIC ORGANOIDS EACH WITH IMMUNE CELLS. PLURIPOTENT STEM CELL BANKS HAVE BEEN GENERATED FROM PATIENTS WITH EACH OF THESE DISEASES, AND HEALTHY CONTROLS, AND ALL ORGANOID PLATFORMS ARE ESTABLISHED AND BENCHMARKED TO HUMAN SAMPLES. THE AIMS OF CANDOR ARE TO ESTABLISH IN VITRO NAMS THAT ACCURATELY MODEL CLINICAL FEATURES OF IBD, MASLD, AND PANCREATITIS; TO BUILD DISEASE-FOCUSED IN SILICO NAMS THAT ARE BASED ON GENE REGULATORY, CELL-CELL INTERACTIONS, AND PHARMACOMETRIC MODELS FROM PATIENTS AND COMBINE THESE WITH DATA FROM IN VITRO NAMS; AND TO VALIDATE AND DISSEMINATE COMBINATORIAL NAM TECHNOLOGIES THROUGH TRAINING, OUTREACH, AND DISTRIBUTION.

PREDICTING UVEITIS ONSET IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

MANDIBLE DEVELOPMENT

SCREEN SMART: USING DIGITAL HEALTH TO IMPROVE HIV SCREENING AND PREVENTION FOR ADOLESCENTS IN THE EMERGENCY DEPARTMENT - PROJECT SUMMARY: ADOLESCENTS AND YOUNG ADULTS (AYA) ARE DISPROPORTIONATELY AFFECTED BY HIV IN THE US. DESPITE ADOLESCENTS ACCOUNTING FOR OVER 20% OF NEW INFECTIONS, THIS AGE GROUP IS THE LEAST LIKELY TO BE TESTED FOR HIV, LINKED TO CARE, AND ACHIEVE VIRAL SUPPRESSION WHEN COMPARED TO THEIR ADULT COUNTERPARTS. FURTHER, AYA ALSO HAVE LOW RATES OF HIV AWARENESS AND INITIATION OF HIV PRE-EXPOSURE PROPHYLAXIS (PREP). THEREFORE, THERE IS AN URGENT NEED TO EXPAND HIV SCREENING AND PREVENTION STRATEGIES TO NONTRADITIONAL HEALTHCARE SETTINGS SUCH AS EMERGENCY DEPARTMENTS (ED) TO REACH THOSE ADOLESCENTS WHO WOULD OTHERWISE NOT RECEIVE PREVENTIVE HEALTHCARE. THE GOAL OF THIS APPLICATION IS TO LEVERAGE OUR RECENT INSIGHTS OBTAINED FROM A MULTI-CENTER, ED-BASED, ADOLESCENT GONORRHEA AND CHLAMYDIA SCREENING STUDY AND APPLY THEM ACROSS A NATIONAL PEDIATRIC ED RESEARCH NETWORK BY (1) ADAPTING, REFINING, AND TESTING THIS PROCESS TO INCREASE UNIVERSALLY OFFERED, OPT-OUT HIV SCREENING AMONG ADOLESCENTS IN THE PEDIATRIC ED AND (2) LINK AT-RISK ADOLESCENTS TO PREP SERVICES AND PREVENTIVE CARE. THIS WILL BE ACCOMPLISHED THROUGH A NETWORK OF CHILDREN’S HOSPITAL EDS WITH A TRACK RECORD OF ROBUST RESEARCH COLLABORATION (PEDIATRIC EMERGENCY CARE APPLIED RESEARCH NETWORK OR PECARN). THIS RESEARCH WILL CONTRIBUTE TO THE EVIDENCE BASE FOR CREATING CLINICALLY EFFECTIVE AND SUSTAINABLE HIV SCREENING PROGRAMS THAT CAN BE SUCCESSFULLY IMPLEMENTED INTO THE CLINICAL WORKFLOW OF THE ED. IT WILL ALSO IMPROVE IDENTIFICATION AND LINKAGE TO PREP CARE FOR AT RISK ADOLESCENTS USING MHEALTH STRATEGIES BY FIRST IDENTIFYING AYA WHO ARE PREP CANDIDATES BASED ON THEIR RESPONSES TO A COMPUTERIZED SEXUAL HEALTH SCREEN (CSHS) AND SUBSEQUENTLY (1) PROVIDING CLINICAL DECISION SUPPORT TO PROVIDERS VIA THE ELECTRONIC HEALTH RECORD AND (2) DIRECT TEXT MESSAGING FROM THE CSHS TO PREP CANDIDATES PROVIDING EDUCATIONAL CONTENT AND CONNECTING YOUTH TO A PREP NAVIGATOR. THIS INTERVENTION WILL RELY ON AN INNOVATIVE APPROACH THAT ELECTRONICALLY INTEGRATES PATIENT-REPORTED DATA TO GUIDE CLINICAL DECISION SUPPORT. THIS WORK IS SIGNIFICANT BECAUSE IT HAS THE POTENTIAL TO SHIFT CURRENT ED CLINICAL PRACTICE PARADIGMS FROM ONLY ACUTE HEALTH ENCOUNTERS TO PARTICIPATION IN THE BROADER MANAGEMENT OF PUBLIC HEALTH AND PREVENTION, AND IT WILL FILL GAPS IN THE LITERATURE NEEDED TO PROVIDE EVIDENCE FOR THE BEST METHOD OF HIV SCREENING IN A PEDIATRIC ED SETTING. USING A PREVIOUSLY DEVELOPED TABLET-BASED, BROAD SCALE GC/CT SCREENING PROCESS, WE WILL ADAPT, REFINE, AND TEST THIS PROCESS WITH THE AIM OF INCREASING UNIVERSALLY OFFERED, OPT-OUT HIV SCREENING IN THE PEDIATRIC ED THROUGH ELECTRONIC INTEGRATION OF PATIENT REPORTED DATA FOR PROVISION OF CLINICAL DECISION SUPPORT FOR HIV SCREENING AND IDENTIFICATION OF PREP CANDIDACY, AND THEN USE MHEALTH TO LINK PATIENTS TO PREP SERVICES. THIS RESEARCH IS NOVEL IN THAT IT SHIFTS THE USUAL CLINICAL PRACTICE PARADIGM OF HIV SCREENING AND PREVENTION IN THE PEDIATRIC ED FROM A SCATTERED APPROACH TO A CONSISTENT AND SUSTAINABLE APPROACH THAT IS CRITICAL TO ADDRESSING THE HIV EPIDEMIC AMONG ADOLESCENTS.

PREVENTION OF OTOTOXICITY WITH EFFECTIVE MONITORING (POEM) PHARMACOKINETIC AND AUDITORY LINKAGES

CUTANEOUS BIOMARKERS OF PEDIATRIC NON-ALCOHOLIC FATTY LIVER DISEASE - PROJECT SUMMARY/ABSTRACT THE OBJECTIVE OF THIS MULTICENTER STUDY IS TO DEVELOP AND VALIDATE A NOVEL, NON-INVASIVE BIOMARKER FOR PEDIATRIC NAFLD. THE SPECIFIC AIMS ARE TO RECRUIT A COHORT OF 80 YOUTH (6-21 YEARS OF AGE) WITH NAFLD AND 80 CONTROLS WITH OBESITY AND STUDY THEIR SKIN SURFACE LIPIDS USING STATE OF THE ART LIPIDOMIC ANALYSES TO: 1. DETERMINE THE CUTANEOUS LIPIDS THAT DIFFERENTIATE YOUTH WITH NAFLD FROM CONTROLS; 2. INVESTIGATE THE SKIN LIPIDOME THAT DETECTS THE PRESENCE OF ADVANCED DISEASE (NON-ALCOHOLIC STEATOHEPATITIS [NASH], FIBROSIS) AMONG THOSE WITH NAFLD; AND, 3. FURTHER SUPPORT THE USE OF SKIN SURFACE LIPIDS AS A BIOMARKER OF NAFLD IN CHILDREN BY STUDYING ITS REPEATABILITY AND VARIABILITY. PARTICIPANTS WILL UNDERGO MAGNETIC RESONANCE IMAGING WITH PROTON DENSITY FAT FRACTION (MRI-PDFF) AT BASELINE TO DETERMINE THE PRESENCE/ABSENCE OF NAFLD. THIS METHODOLOGY HAS BEEN SHOWN TO BE ACCURATE IN DETERMINING THE PRESENCE OF HEPATIC STEATOSIS. THEY WILL THEN HAVE THEIR CUTANEOUS LIPIDOME SAMPLED USING TAPE STRIPPING. THE LATTER IS A RAPID (<5 MIN), PAINLESS PROCEDURE THAT SAMPLES THE LIPIDS OF THE MOST SUPERFICIAL LAYER OF THE SKIN (FROM THE STRATUM CORNEUM AND THE LIPIDS SECRETED BY THE SEBACEOUS GLANDS). ALL PATIENTS WITH NAFLD WILL HAVE HAD PRIOR HISTOLOGIC CONFIRMATION OF THEIR DISEASE, WHICH WILL BE RE-REVIEWED AND SCORED BY A SINGLE PATHOLOGIST, WITH EXPERTISE IN PEDIATRIC NAFLD, WHO WILL BE MASKED TO PATIENT CLINICAL AND DEMOGRAPHIC CHARACTERISTICS. UNTARGETED LIPIDOMIC ANALYSES OF THE COLLECTED SKIN SAMPLES WILL BE PERFORMED USING ULTRA HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-QUADRUPOLE TIME OF FLIGHT MASS SPECTROMETRY TO DETERMINE THE SKIN SURFACE LIPIDS THAT ALONE OR IN COMBINATION PREDICT THE PRESENCE OF NAFLD. THE PERFORMANCE OF THE CUTANEOUS LIPIDOME IN PREDICTING THE PRESENCE OF NAFLD IN YOUTH WITH OBESITY WILL BE COMPARED AGAINST THAT OF THE CURRENTLY USED SCREENING TEST, NAMELY SERUM ALANINE AMINOTRANSFERASE LEVELS. AMONG THOSE WITH NAFLD, THE PERFORMANCE OF SKIN SURFACE LIPIDS IN PREDICTING THE PRESENCE OF NASH AND FIBROSIS WILL BE ASSESSED. LASTLY, A SUBSET OF PATIENTS WITH NAFLD WILL HAVE REPEAT SKIN SAMPLING: A. ON THE SAME DAY FROM THE OPPOSITE ARM, TO TEST THE REPEATABILITY OF CUTANEOUS LIPIDOME, AND B. 1 MONTH LATER, TO TEST THE VARIABILITY OF THE LIPIDOME AS A BIOMARKER. VARIABLES THAT MAY AFFECT THE SKIN SURFACE LIPIDS, SUCH AS SEX, AGE/PUBERTAL STATUS, CHANGE IN DIET, OBESITY SEVERITY AND INSULIN RESISTANCE STATUS, WILL BE ASSESSED AND CONTROLLED FOR IN THESE ANALYSES. A NON-INVASIVE BIOMARKER FOR PEDIATRIC NAFLD IS URGENTLY NEEDED, DUE TO THE STAGGERING PREVALENCE OF THIS DISEASE AND THE FACT THAT THE CURRENTLY AVAILABLE INVASIVE DIAGNOSTIC MODALITIES (LIVER BIOPSY) ARE NOT PRACTICAL AND HINDER THERAPEUTIC DISCOVERY AND PROGRESSION.

TARGETING NATURAL KILLER CELLS TO ENHANCE HIV VACCINE RESPONSES

A CLINIC-BASED INTERDISCIPLINARY INTERVENTION FOR PARENTS OF CHILDREN WITH CANCER

DISSECTING INNATE IMMUNE SIGNALING IN PRE-LEUKEMIA EVOLUTION - ABSTRACT CLONAL HEMATOPOIESIS (CH) IS AN AGING ASSOCIATED CONDITION CHARACTERIZED BY THE CLONAL OUTGROWTH OF MUTATED PRE-LEUKEMIC CELLS. ALTHOUGH INDIVIDUALS WITH CH ARE HEALTHY, THEY ARE AT AN INCREASED RISK OF DEVELOPING HEMATOPOIETIC MALIGNANCIES. TO IDENTIFY COOPERATING MOLECULAR ALTERATIONS REQUIRED FOR MALIGNANT TRANSFORMATION OF CLONAL PRE-LEUKEMIC HSPC, WE PERFORMED AN IN VIVO SHRNA SCREEN AND FOUND THAT SHRNAS TARGETING TRAF6 WERE OVERWHELMINGLY ENRICHED IN FOLLOWING TRANSFORMATION TO OVERT MYELOID LEUKEMIAS. TRAF6 IS AN UBIQUITIN E3 LIGASE THAT SYNTHESIZES LYSINE (K) 63-LINKED UBIQUITIN CHAINS ON SUBSTRATES LEADING TO TOLL-LIKE RECEPTOR (TLR) SUPERFAMILY PATHWAY ACTIVATION. IN SUPPORT OF OUR IN VIVO SHRNA SCREEN, PROMOTER HYPERMETHYLATION AND REDUCED EXPRESSION OF TRAF6 IS OBSERVED IN SUBSETS OF MYELOID MALIGNANCY PATIENTS, INCLUDING ~40-50% OF ACUTE MYELOID LEUKEMIA (AML). MOREOVER, OUR PRELIMINARY DATA SHOWS THAT DELETION OF TRAF6 IN PRE-LEUKEMIC TET2-DEFICIENT HSPC RESULTS IN AN AGGRESSIVE MYELOID NEOPLASM IN PART THROUGH A NOVEL MYC-DEPENDENT MECHANISM. BASED ON OUR FINDINGS, WE HYPOTHESIZE THAT LOSS OF TRAF6 DRIVES SUBSETS OF GENETICALLY-DEFINED MYELOID MALIGNANCIES, SPECIFICALLY VIA A NOVEL POST-TRANSLATIONAL MODIFICATION OF MYC RESULTING IN ITS ACTIVATION. THE OBJECTIVES OF THE PROPOSAL ARE TO UNCOVER THE MOLECULAR AND CELLULAR BASIS OF TRAF6 DELETION ON PRE-LEUKEMIC HSPC FUNCTION WITH THE LONG-TERM GOAL OF UNCOVERING IMPROVED THERAPEUTIC APPROACHES BY INVESTIGATING THE CONSEQUENCES OF TRAF6 DELETION IN MODELS OF CH AND ON LEUKEMIA DEVELOPMENT (AIM 1), IDENTIFYING THE MOLECULAR BASIS OF THE TUMOR SUPPRESSOR-LIKE FUNCTION OF TRAF6 IN AML (AIM 2), AND EVALUATING THE ONCOGENIC POTENTIAL OF A NOVEL TRAF6-DEPENDENT MYC POST-TRANSLATIONAL MODIFICATION (AIM 3). THESE STUDIES ARE HIGHLY SIGNIFICANT AS THEY WILL PROVIDE CRITICAL INSIGHT INTO THE PROGRESSION OF PRE-LEUKEMIC STATES TO OVERT LEUKEMIA AS A RESULT OF SUBVERTING SELECT INNATE IMMUNE PATHWAYS, DESCRIBE A NOVEL DISEASE-MODIFYING ROLE OF TLR-TRAF6, AND REVEAL AN UNREPORTED MECHANISM OF MYC REGULATION. THESE STUDIES HAVE DIRECT TRANSLATIONAL IMPLICATIONS AND FILL AN UNMET CLINICAL NEED FOR GENETICALLY- AND PHENOTYPICALLY-DEFINED SUBTYPES OF AML/MPN.

RISK STRATIFICATION IN PULMONARY ARTERIAL HYPERTENSION: INTERSECTION OF OMICS AND LONGITUDINAL PHENOTYPES THROUGH THE PAH BIOBANK - PULMONARY ARTERIAL HYPERTENSION (PAH) IS A RARE, FATAL CONDITION CHARACTERIZED BY THE GRADUAL OCCLUSION OF THE PULMONARY ARTERIOLES LEADING TO PROGRESSIVELY INCREASED PULMONARY VASCULAR RESISTANCE WITH WORSENING RIGHT HEART FAILURE AND DEATH. WHILE RARE MUTATIONS (E.G., IN BMPR2) HAVE BEEN REPORTED IN A MINORITY OF PATIENTS, MOST PATIENTS CARRY NO ESTABLISHED MUTATIONS. WE RECENTLY PUBLISHED ON COMMON GENETIC VARIATION IN 2,085 IDIOPATHIC/HERITABLE (I/H) PAH CASES AND 9,659 CONTROLS OF EUROPEAN ANCESTRY USING A GENOME-WIDE ASSOCIATION (GWA) APPROACH. DISCOVERY AND REPLICATION ANALYSES WERE CONDUCTED IN FOUR INDEPENDENT COHORTS WITH GENOTYPING ARRAYS FROM OUR US-BASED PAH BIOBANK (PAHB) STUDY AND THREE INTERNATIONAL COHORTS WITH WHOLE GENOME SEQUENCE DATA. WE REPORTED TWO NOVEL LOCI, AT HLA-DPA1/DPB1 AND NEAR SOX17 ASSOCIATED I/H PAH. HLA-DPA/DPB1 LOCUS PREDICTS A REDUCED ANNUAL MORTALITY RATE BY 25-37% IN I/H PAH. THE LEAD SOX17 VARIANT IS LOCATED IN A PUTATIVE ENHANCER REGION IN CLOSE SPATIAL PROXIMITY TO THE SOX17 GENE IN ENDOTHELIAL CELL (EC) PRECURSORS, WHICH INFLUENCES ITS EXPRESSION BASED ON OUR EXPERIMENTAL VALIDATION. OUR FINDINGS PROVIDE THE FIRST SUPPORT FOR THE CONTRIBUTION OF COMMON GENETIC VARIANCE TO PAH RISK AND, COMBINED WITH THE RECENTLY REPORTED DATA ON RARE MUTATIONS IN SOX17 IN PAH, HIGHLIGHT THE CAUSAL ROLE OF SOX17 IN PAH. BEYOND PAH RISK, WE NOW HYPOTHESIZE THAT PAH PROGRESSION AND OUTCOMES ARE ALSO GENETICALLY MODIFIED INCLUDING FROM SOX17, A TRANSCRIPTION FACTOR, AND HLA-DPA1/DPB1 AS BOTH NOVEL CANDIDATE GENES AND POSSIBLE THERAPEUTIC TARGETS. TO TEST THIS HYPOTHESIS, WE HAVE DEVELOPED 3 SPECIFIC AIMS (SAS) THAT WILL FURTHER EXPAND THE PAHB, THE WORLD’S LARGEST PAH BIOBANK, REGISTRY, AND MULTI-OMICS DATASET WITH WHOLE EXOME SEQUENCING (WES), RNASEQ, WHOLE GENOME GENOTYPING, AND NON-TARGETED METABOLOMICS DATA ON NEARLY ALL SUBJECTS. SA #1 WILL COLLECT SERIAL LONGITUDINAL DATA IN PAHB TO INTERROGATE ASSOCIATIONS BETWEEN DISEASE RISK LOCI (SOX17, HLA-DPA/B1) WITH MARKERS OF PAH PROGRESSION. WE WILL ALSO EVALUATE EXPRESSION (EQTL) AND METABOLOMICS (MQTL) QUANTITATIVE TRAIT LOCI ANALYSES FOR FUNCTIONAL VALIDATION. BEYOND DISEASE RISK SOX17/HLA LOCI, WE GENERATED ADDITIONAL PRELIMINARY DATA REVEALING GENOME-WIDE SIGNIFICANCE FOR SEVEN NOVEL GENETIC LOCI ASSOCIATED DIRECTLY WITH SURVIVAL IN PAH IN A SECOND, INDEPENDENT PAH COHORT. SA #2 WILL NOW REPLICATE THESE NEW FINDINGS WITH OUTCOMES (PROGRESSION AND SURVIVAL) COLLECTED IN PAHB FROM SA #1. AS A UNIQUE FEATURE OF THIS PROPOSAL, WE WILL INTERROGATE OUR TOP LOCI IN TWO OTHER GLOBAL PAH COHORTS WITH AVAILABLE EQTL AND MQTL DATA AND PERFORM A META-ANALYSIS OF ALL COHORTS. WE WILL ALSO CONSTRUCT A RISK STRATIFICATION TOOL COMBINING CLINICAL RISK FACTORS AND GENETICS (SOX17, HLA, 7 SNPS) FOR PAH OUTCOMES. FINALLY, BASED ON PRELIMINARY DATA ON THE PROTECTIVE ROLE OF SOX17 IN EC FUNCTION, SA #3 WILL VALIDATE THE BIOLOGICAL ROLE OF SOX17 PATHWAY IN THE DEVELOPMENT OF PAH USING ECS/SMCS ISOLATED FROM PAH PATIENTS AS WELL AS PRE-CLINICAL TESTING IN MURINE PH MODELS. STRONG CLINICAL ASSOCIATION OF THESE TWO NEW LOCI HAS IMPLICATIONS FOR PREDICTION OF CLINICAL OUTCOMES, CLINICAL TRIAL DESIGN, AND THE DEVELOPMENT OF NOVEL DRUG TARGETS.

SEARCH 3 COHORT STUDY TO ASSESS INCIDENCE OF ACUTE AND CHRONIC DIABETES-RELATED C

DENDRITIC CELL INTRINSIC UPR IS CRITICAL FOR PATHOGEN SPECIFIC TH17 RESPONSES - PROJECT SUMMARY FOLLOWING AC+VA+ON, CD4 T CELLS DIFFEREN+ATE INTO ONE OF THREE MAIN EFFECTOR LINAGES. THE TH1, TH2 AND TH17 LINEAGE CELLS ARE GENERATED IN RESPONSE TO SPECIFIC CLASS OF PATHOGENS AND ARE NECESSARY TO COMBAT THOSE INFEC+ONS. WHILE WE HAVE COMPREHENSIVE UNDERSTANDING OF THE SPECIFIC CYTOKINE CUES AS WELL AS MASTER TRANSCRIP+ON FACTORS THAT ARE CRI+CAL FOR DIFFEREN+A+ON OF EACH OF THESE DIS+NCT T CELL EFFECTOR LINEAGES, THE INNATE SENSING MECHANISMS THAT DICTATE SPECIFIC DIFFEREN+A+ON OF EACH OF THE T EFFECTOR LINEAGES ARE NOT CLEAR. THE PATHOGENS THAT DRIVE TH2 RESPONSES ARE FAIRLY DIS+NCT BUT THE TH1 AND TH17 INDUCING PATHOGENS SHARE MANY STRUCTURAL SIMILARI+ES. CLASSICAL PAFERN RECOGNI+ON RECEPTOR AC+VA+ON BY MICROBIAL LIGANDS LEADS TO GENERA+ON OF INFLAMMATORY CYTOKINE CUES IN THE FORM OF TNF, IL-6, IL-12, IL-1B, ETC BUT WE DO NOT UNDERSTAND HOW CD4 T CELLS INTEGRATE SPECIFIC CUES TO GENERATE A TH1 VS TH17 RESPONSE. WE POSIT HERE THAT HOST SENSING MECHANISMS THAT EXTEND BEYOND THE CLASSICAL PAFERN RECOGNI+ON RECEPTORS MIGHT BE INVOLVED IN GENERA+NG UNIQUE CYTOKINE CUES THAT SPECIFICALLY DICTATE GENERA+ON OF TH1 VS TH17 LINEAGE CELLS. OUR PREVIOUS WORK HAS DEMONSTRATED THAT FOLLOWING SENSING OF PATHOGENS, CONVEN+ONAL DCS CAN INDUCE PRIMING OF NAÏVE PATHOGEN SPECIFIC CD4 T CELLS IN VITRO AND THE QUALITY OF THE T CELL RESPONSE IS DICTATED BY THE NATURE OF THE PRIMING PATHOGEN. SPECIFICALLY, S+MULA+ON OF CONVEN+ONAL DCS WITH THE GUT PATHOGEN C. RODEN)UM DRIVES TH17 DIFFEREN+A+ON AS OPPOSED TO L. MONOCYTOGENES, SUGGES+NG A DC-DEPENDENT MECHANISM FOR TH17 DIFFEREN+A+ON. TRANSCRIP+ONAL PROFILING OF DCS UPON EXPOSURE TO TH17 INDUCING (C. RODEN)UM) VERSUS NON-INDUCING PATHOGENS (L. MONOCYTOGENES AND S. AUREUS) AND DISCOVERED THAT C. RODEN+UM INDUCED AC+VA+ON OF THE PERK PATHWAY OF UNFOLDED PROTEIN RESPONSE (DC- UPR) THAT WAS INTEGRAL TO ITS ABILITY TO INDUCE TH17 RESPONSES. C. RODEN+UM’S ABILITY TO INDUCE DC-UPR WAS SHARED BY ITS COUNTERPARTS, THE HUMAN ENTERIC PATHOGENS, EHEC AND EPEC SUGGES+NG THAT THIS PROPERTY WAS EVOLU+ONARILY CONSERVED IN BOTH THE MICROBES AND THE HOSTS. MORE IMPORTANTLY, SEVERAL AUTOIMMUNE DISEASES CAUSED BY TH17 CELLS ARE ASSOCIATED WITH THE UNFOLDED PROTEIN RESPONSE SUGGES+NG AN INTEGRAL LINK BETWEEN ER STRESS AND OUTCOME OF T CELL RESPONSES. IN THIS APPLICA+ON WE PROPOSE TO INVES+GATE THE IMPORTANCE OF THIS UPR INDUC+ON FROM THE PERSPEC+VE OF THE MICROBE AS WELL AS THE HOST AND DISSECT THE MOLECULAR MECHANISMS OF INDUC+ON OF THE UPR AND ITS IMPACT ON TH17 PRIMING AND DIFFEREN+A+ON. IN AIM 1, WE WILL INVES+GATE THE ROLE OF DC-UPR IN DRIVING TAILORED IMMUNE RESPONSES AGAINST TH17 INDUCING PATHOGENS. IN AIM, 2 WE WILL IDEN+FY AND CHARACTERIZE THE NATURE OF THE C. RODEN+UM LIGAND THAT AC+VATES THE PERK PATHWAY OF UPR IN DCS. IN AIM 3, WE WILL INVES+GATE THE CONSERVED NATURE OF THE UPR PATHWAY IN HUMAN ENTERIC PATHOGENS AND HUMAN MYELOID CELLS. SUCCESSFUL COMPLE+ON OF THESE AIMS WILL ADD TO OUR FUNDAMENTAL UNDERSTANDING OF GENERA+ON OF TH17 RESPONSES AND WILL PROVIDE US WITH TOOLS TO EITHER INCREASE OR MI+GATE DEVELOPMENT OF TH17 RESPONSE TO ENHANCE PROTEC+ON AGAINST PATHOGENS OR PROTECT AGAINST AUTO-IMMUNE INFLAMMA+ON.

COMMENSAL CANDIDA ALBICANS PRIMED TH17 IMMUNITY - ABSTRACT. THE HUMAN INTESTINE HARBORS AN ESTIMATED 100 TRILLION MICROBES THAT ARE INCREASINGLY RECOGNIZED TO PROMOTE HEALTH THROUGH TONIC IMMUNE STIMULATION. THESE INCLUDE INNOCUOUS COMMENSAL MICROBES ALONG WITH PATHOBIONTS - THOSE CAPABLE OF CAUSING GUT DYSBIOSIS OR INVASIVE INFECTION. MOST OF WHAT WE CURRENTLY UNDERSTAND ABOUT HOST-MICROBE COMMENSALISM HAS BEEN EVALUATED THROUGH THE LENS OF BACTERIA. HOWEVER, MICROBES FROM OTHER TAXONOMIC DOMAINS, INCLUDING EUKARYOTES, ALSO UBIQUITOUSLY COLONIZE MUCOSAL TISSUES AND YET OUR UNDERSTANDING OF HOW THESE MICROBES ESTABLISH COMMENSALISM AND DRIVE IMMUNOLOGICAL CHANGES REMAINS RUDIMENTARY. THIS GAP IN KNOWLEDGE IS ESPECIALLY SIGNIFICANT FOR THE MOST COMMON FUNGAL PATHOBIONT CANDIDA ALBICANS, WHICH CAN TRANSLOCATE OUT OF THE GASTROINTESTINAL (GI) TRACT AND CAUSE LIFE-THREATENING SYSTEMIC INFECTION, PARTICULARLY IN IMMUNOCOMPROMISED INDIVIDUALS. TO ADDRESS THESE FUNDAMENTAL GAPS IN KNOWLEDGE, AN INSTRUCTIVE MODEL OF C. ALBICANS INTESTINAL COLONIZATION IN MICE WAS DEVELOPED. RECOMBINANT C. ALBICANS CELLS WERE ENGINEERED TO EXPRESS DEFINED MODEL ANTIGENS AND USED TO ESTABLISH COLONIZATION SO THAT T CELLS WITH SURROGATE C. ALBICANS SPECIFICITY COULD BE IDENTIFIED. USING THIS MODEL, WE SHOW THAT C. ALBICANS CELLS COLONIZING THE GI TRACT RESULT IN ACTION AT A DISTANCE - THEY DRIVE THE SYSTEMIC ACCUMULATION OF FUNGAL-SPECIFIC TH17 CD4+ T CELLS. THESE T CELLS WORK TOGETHER WITH IL-17 AND ACTIVATED NEUTROPHILS TO PROVIDE PROTECTION AGAINST A SYSTEMIC INFECTION BY C. ALBICANS AS WELL AS BY EXTRACELLULAR BACTERIAL PATHOGENS. THESE RESULTS HIGHLIGHT THE PROTECTIVE BENEFITS OF COMMENSAL C. ALBICANS CELLS RESIDING IN THE GI TRACT, AND SUGGEST THAT CO-EVOLUTION WITH THIS SPECIES HAS LED TO A MUTUALLY BENEFICIAL RELATIONSHIP. HOWEVER, IMPORTANT QUESTIONS REMAIN AS TO HOW C. ALBICANS CELLS IN THE GUT PRIME SYSTEMIC IMMUNE RESPONSES, AND HOW TH17 SIGNALS CAN BE TRIGGERED WITHOUT EXCESSIVE INFLAMMATION. THIS LINE OF INVESTIGATION BUILDS UPON EXCITING PRELIMINARY DATA GENERATED TOGETHER BY THE LABORATORIES OF DR. WAY AND DR. BENNETT, TWO INVESTIGATORS WITH COMPLEMENTARY EXPERTISE IN CLINICAL INFECTIOUS DISEASE/CELLULAR IMMUNOLOGY AND MYCOLOGY/FUNGAL PATHOGENESIS, RESPECTIVELY. THIS PROPOSAL WILL ADDRESS THE MOLECULAR AND CELLULAR MECHANISMS BY WHICH C. ALBICANS CELLS INTERACT WITH MUCOSAL HOST TISSUES TO DRIVE GUT LOCAL AND SYSTEMIC IMMUNITY THROUGH THE FOLLOWING SPECIFIC AIMS: (1) DEFINE HOW C. ALBICANS MORPHOLOGICAL CHANGES DRIVE SYSTEMIC TH17 IMMUNITY, (2) ESTABLISH THE FUNGAL LIGAND AND HOST PATTERN RECOGNITION RECEPTOR(S) THAT PRIME SYSTEMIC TH17 IMMUNITY, AND (3) INVESTIGATE THE ROLE OF REACTIVE OXYGEN SPECIES AND DUOX2 (DUAL OXIDASE 2) FOR LOCAL AND TH17 IMMUNITY PRIMED BY C. ALBICANS CELLS. EACH OF THESE SPECIFIC AIMS IS SUPPORTED BY EXTENSIVE PUBLISHED AND UNPUBLISHED PRELIMINARY DATA. SUCCESSFUL COMPLETION OF THESE AIMS WILL SHED LIGHT ON THE IMPORTANT SYMBIOSIS BETWEEN FUNGAL COMMENSAL AND MAMMALIAN HOST, AND THE MECHANISMS RESPONSIBLE FOR PRIMING SYSTEMIC TH17 IMMUNITY THROUGH INTESTINAL STIMULATION.

MURINE ATLASOF A GENITOURINARY SMOOTH MUSCLE DEVELOPMENT

PATHO-GENETIC ANALYSIS OF INVASIVE MUCINOUS ADENOCARCINOMA OF THE LUNG

NEUROBEHAVIORAL AND NEUROIMAGING EFFECTS OF TRAFFIC EXPOSURE IN CHILDREN

11/15/18. BOWERS. RESUB R01. LINKING PRE- AND POST-NATAL PSYCHOSOCIAL DETERMINANTS, DNA METHYLATION, AND EARLY DEVELOPMENTAL HEALTH DISPARITIES

TRAJECTORIES OF REGIONAL CARDIOPULMONARY STRUCTURE AND FUNCTION IN A LONGITUDINAL COHORT OF EXTREMELY PRETERM INFANTS - ABSTRACT PREMATURE BIRTH IS THE LEADING CAUSE OF NEONATAL INTENSIVE CARE UNIT ADMISSIONS AND EXERTS A HIGH BURDEN OF DISEASE AND HEALTH CARE COST, APPROACHING $13.4 BILLION ANNUALLY IN THE UNITED STATES. ADVANCES IN NEONATAL MEDICINE SUCH AS ANTENATAL STEROIDS AND SURFACTANT HAVE IMPROVED SURVIVAL, PARTICULARLY IN INFANTS BORN EXTREMELY PREMATURE (BEFORE 30 WEEKS’ GESTATIONAL AGE). CONSEQUENTLY, BRONCHOPULMONARY DYSPLASIA (BPD) IS INCREASING IN PREVALENCE. THIS OFTEN RESULTS IN LIFELONG CARDIOPULMONARY SEQUELAE THAT OVERLAP WITH CHRONIC DISEASES SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND PULMONARY HYPERTENSION, INCREASING THE RISK OF PREMATURE DEATH. UNFORTUNATELY, THE IMPACT OF EXTREME PREMATURITY OR POSTNATAL STEROID TREATMENT ON CARDIOPULMONARY STRUCTURE AND FUNCTION HAS NOT BEEN RIGOROUSLY EVALUATED DURING EARLY SCHOOL AGE (6-8 YEARS), WHEN EARLY IDENTIFICATION COULD PREVENT LONG-TERM ADVERSE OUTCOMES. THUS, SIGNIFICANT CHANGES CAN OCCUR AND REMAIN UNDETECTED DURING THIS CRITICAL AGE OF RAPID LUNG GROWTH AND ALVEOLARIZATION, A TIME DURING WHICH INTERVENTION COULD BE THE MOST ADVANTAGEOUS. TO ADDRESS THIS UNMET NEED, WE WILL CAPITALIZE ON TWO OUTSTANDING RESOURCES ALREADY IN PLACE AT CINCINNATI CHILDREN’S: 1) CUTTING-EDGE PROTON AND HYPERPOLARIZED-GAS MAGNETIC RESONANCE IMAGING (MRI) THAT CAN PRECISELY CHARACTERIZE PHENOTYPES OF BPD IN THE CINCINNATI BPD CENTER AND 2) A WELL- CHARACTERIZED POPULATION-BASED COHORT OF PRETERM INFANTS FROM THE NIH-FUNDED CINCINNATI INFANT NEURODEVELOPMENT EARLY PREDICTION STUDY (CINEPS) THAT WILL REACH SCHOOL AGE DURING THIS FUNDING PERIOD. WE WILL RECRUIT THE CINEPS SUBGROUP OF EXTREMELY PRETERM INFANTS (140 WITH BPD; 68 WITHOUT BPD) AND A NEW COHORT OF 50 TERM-BORN CONTROLS AND STUDY THEM LONGITUDINALLY AT 6 AND 8 YEARS OF AGE WITH PROTON AND HYPERPOLARIZED GAS MRI, SPIROMETRY, PLETHYSMOGRAPHY, DIFFUSION CAPACITY, AND A PARENT QUESTIONNAIRE. THE PRIMARY GOAL OF THIS PROPOSAL IS TO DEFINE CHANGES IN CARDIOPULMONARY STRUCTURE AND FUNCTION IN EXTREMELY PRETERM INFANTS DURING EARLY SCHOOL AGE. WE WILL FURTHER EVALUATE THE EFFECTS OF POSTNATAL STEROIDS THERAPY ON LUNG STRUCTURE AND FUNCTION COMPARED TO UNTREATED INFANTS MATCHED USING PROPENSITY SCORE WEIGHTING. THIS NOVEL PROPOSAL REPRESENTS THE FIRST APPLICATION OF HYPERPOLARIZED GAS MRI IN A COHORT OF EXTREMELY PRETERM CHILDREN. FURTHER, THIS PROPOSAL REPRESENTS THE MOST DETAILED EVALUATION OF THE TRAJECTORY OF EXTREME PREMATURITY ON CARDIOPULMONARY STRUCTURE AND FUNCTION THROUGH EARLY SCHOOL AGE. THIS HIGH-IMPACT RESEARCH WILL DEFINE THE PROGRESSION OF LUNG, HEART, AND PULMONARY VASCULAR DISEASE AS WELL AS RESPONSE TO POSTNATAL THERAPIES AND PROVIDE A UNIQUE OPPORTUNITY FOR EARLY IDENTIFICATION OF PATIENTS WHO WILL DEVELOP CHRONIC CHANGES RELATED TO EXTREMELY PRETERM BIRTH AND BPD.

PENETRATING THE ?BLACK BOX?: PREDICTION OF EARLY BRONCHIOLITIS OBLITERANS IN PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS - ABSTRACT BRONCHIOLITIS OBLITERANS SYNDROME (BOS) IS AN OBSTRUCTIVE LUNG DISEASE CAUSED BY A COMBINATION OF INFLAMMATION AND IMMUNE RESPONSE THAT IS IRREVERSIBLE IN ITS LATE STAGE. CHILDREN WITH BOS ARE TYPICALLY DIAGNOSED LATE BECAUSE THEY ARE UNABLE TO PERFORM SPIROMETRY, AND MORBIDITY AND MORTALITY ARE HIGH. THE LONG-TERM GOAL OF THIS WORK IS TO IMPROVE SURVIVAL AND REDUCE MORBIDITY FROM BOS BY IDENTIFYING STRATEGIES FOR ACCURATE SCREENING AND PREDICTION OF BOS IN CHILDREN AND YOUNG ADULTS AFTER HSCT AND USING THESE TOOLS TO IDENTIFY NOVEL DRUG TARGETS FOR EARLY INTERVENTION OR PREVENTION OF BOS. THE OBJECTIVE OF THIS APPLICATION IS TO VALIDATE NOVEL PREDICTIVE PLASMA PROTEIN BIOMARKERS AND ESTABLISH A DYNAMIC PREDICTION MODEL FOR BOS FOR EARLY DIAGNOSIS, RISK STRATIFICATION AND DISEASE TRAJECTORY PREDICTION FOR BOS AFTER HSCT. WE WILL ACHIEVE THESE GOALS THROUGH THE FOLLOWING SPECIFIC AIMS: 1) VALIDATE LONGITUDINAL PREDICTIVE PERFORMANCE OF NEWLY DISCOVERED PLASMA BIOMARKERS OF BOS RISK IN SAMPLES FROM BANKED AND PROSPECTIVE STUDIES BY MASS SPECTROMETRY AND ELISA IN BOTH PEDIATRIC AND ADULT COHORTS. 2) OPTIMIZE AND VALIDATE OUR DYNAMIC PREDICTION ALGORITHM USING PULMONARY FUNCTION AND CLINICAL DATA AS WELL AS BIOMARKER LEVELS (NEEDED WHEN NO SPIROMETRY CAN BE OBTAINED) AS COVARIATES TO PROJECT RISKS OF BOS AND RAPID BOS LUNG-FUNCTION DECLINE TO INFORM TREATMENT DECISIONS. THERE ARE CURRENTLY NO BIOMARKERS OR PREDICTIVE TOOLS FOR BOS SO THIS WORK IS ENTIRELY NOVEL. THE USE OF A DYNAMIC PREDICTION ALGORITHM IN THIS CLINICAL SETTING IS INNOVATIVE ALLOWING FOR THE FIRST TIME THE ABILITY TO PREDICT AND DIAGNOSE EARLY LUNG DISEASE IN HSCT SUBJECTS PRIOR TO THE CLINICAL DIAGNOSIS OF BOS. IDENTIFICATION OF BOS RISK AND STRATIFICATION OF SCREENING AND TREATMENT PROCEDURES ACCORDING TO RISK AND PREDICTED DISEASE COURSE WOULD ALLOW US TO MODIFY POST-TRANSPLANT CARE AND REDUCE MORBIDITY AND MORTALITY. WE WILL USE OUR DATA TO INFORM PROSPECTIVE CLINICAL TRIALS OF BOTH EARLY ACTIVE TREATMENT PRIOR TO DEVELOPMENT OF EARLY FIBROSIS AND TO TEST NOVEL PROPHYLACTIC THERAPIES TO REDUCE INCIDENCE IN HIGH RISK INDIVIDUALS. OUR STUDIES WILL PROVIDE BLOOD BIOMARKERS THAT CAN BE USED AS FREQUENTLY AS NECESSARY WITHOUT REQUIRING ACTIVE PARTICIPATION FROM SMALL AND OFTEN VERY SICK CHILDREN. OUR PRELIMINARY BIOMARKER AND HSCT SPECIFIC ALGORITHM DATA DEMONSTRATE DETECTION OF BOS AS SOON AS 2 WEEKS TO 6 MONTHS PRIOR TO CLINICAL DIAGNOSIS OF BOS. THIS WORK IS BOTH SIGNIFICANT AND VITAL BECAUSE IMPROVEMENTS IN HSCT TECHNIQUES AND SUPPORTIVE CARE HAVE LED TO IMPROVED SURVIVAL. IMPROVED SURVIVAL INCREASES THE NUMBER OF CHILDREN AT RISK FOR LATE COMPLICATIONS OF HSCT THAT ARE ASSOCIATED WITH LIFE-CHANGING MORBIDITY AND LATE MORTALITY AND THERE IS URGENT NEED TO ADDRESS THESE ISSUES. THIS WORK WILL ADVANCE PREDICTION AND EARLY DIAGNOSIS OF BOS, AS WELL AS PROVIDING THE FRAMEWORK FOR FUTURE PREVENTION AND TREATMENT TRIALS.

CLINIC AND HOME FAMILY BASED BEHAVIORAL TREATMENT FOR OBESE PRESCHOOLERS: LAUNCH