Hospital For Sick Children

BIOGRID: AN OPEN INTEGRATED RESOURCE FOR BIOLOGICAL INTERACTION DATA

5/9: DISSECTING THE EFFECTS OF GENOMIC VARIANTS ON NEUROBEHAVIORAL DIMENSIONS IN CNVS ENRICHED FOR NEUROPSYCHIATRIC DISORDERS

VISCERAL FAT, SYSTEMIC INFLAMMATION AND BRAIN-TISSUE HEALTH: TOWARDS EARLY DETECTION AND PREVENTION OF ALZHEIMER?S DISEASE.

ENVIRONMENTAL FACTORS IN PLACENTAL PATHOLOGY: A NEW DIAGNOSTIC METHOD BASED ON UMBILICAL VESSEL WAVE MECHANICS

SYMPTOM SCREENING LINKED TO CARE PATHWAYS FOR CHILDREN WITH CANCER: A CLUSTER RANDOMIZED TRIAL

IMPROVING GROWTH AND NEURODEVELOPMENT OF VERY LOW BIRTH WEIGHT INFANTS THROUGH PRECISION NUTRITION: THE OPTIMIZING NUTRITION AND MILK (OPTI-NUM) PROJECT. - PROJECT SUMMARY SIGNIFICANCE: INFANTS BORN OF VERY LOW BIRTH WEIGHT (VLBW) ACCOUNT FOR 50% OF ALL LONG-TERM NEUROLOGICAL MORBIDITY AMONG NORTH AMERICAN CHILDREN; THEY COMMONLY HAVE SUB-OPTIMAL GROWTH AND LIFE THREATENING MORBIDITIES SUCH AS NECROTISING ENTEROCOLITIS AND SEPSIS. IT IS NOW WIDELY RECOGNIZED THAT HUMAN MILK (HM) FEEDING IS THE BEST STRATEGY TO PREVENT SERIOUS MORBIDITY IN VLBW INFANTS, YET GROWTH AND NEURODEVELOPMENT OFTEN REMAIN SUB-OPTIMAL WITH CURRENT ONE-SIZE-FITS-ALL FEEDING REGIMES. THERE IS INCREASING INTEREST IN “PRECISION NUTRITION” APPROACHES, BUT IT IS UNCLEAR WHICH HM COMPONENTS REQUIRE PERSONALIZED TITRATION. PREVIOUS EFFORTS HAVE FOCUSED ON MACRONUTRIENTS, BUT HM ALSO CONTAINS ESSENTIAL MICRONUTRIENTS AS WELL AS NON- NUTRIENT BIOACTIVE COMPONENTS THAT SHAPE THE GUT MICROBIOME. FURTHER, IT IS UNCLEAR IF OR HOW PARENTAL FACTORS (E.G. STRESS, BODY MASS INDEX, DIET) AND INFANT FACTORS (E.G. GENETICS, GUT MICROBIOTA, SEX, ACUITY) INFLUENCE RELATIONSHIPS BETWEEN EARLY NUTRITION AND GROWTH, NEURODEVELOPMENT AND MORBIDITY. UNDERSTANDING THESE COMPLEX RELATIONSHIPS IS PARAMOUNT TO DEVELOPING EFFECTIVE PERSONALIZED HM FEEDING STRATEGIES FOR VLBW INFANTS. THIS IS THE OVERARCHING GOAL OF THE PROPOSED OPTIMIZING NUTRITION AND MILK (OPTI-NUM) PROJECT. APPROACH: WE WILL LEVERAGE TWO ESTABLISHED RESEARCH PLATFORMS LED BY PIS OF THIS GRANT: 1) THE MAXIMIZING MOTHER’S MILK (MAXIMOM) PROGRAM WITH ITS NEONATAL FEEDING TRIAL NETWORK AND 2) THE INTERNATIONAL MILK COMPOSITION (IMIC) CONSORTIUM. THIS PARTNERSHIP UNITES THE COMPREHENSIVE NUTRITION AND CLINICAL DATA (DAILY FEED VOLUMES AND COMPOSITION) AND PRISTINELY COLLECTED BIOSPECIMENS FROM MAXIMOM (N=1105) WITH THE SYSTEMS BIOLOGY AND MACHINE LEARNING PIPELINES FROM IMIC CONSORTIUM. WE AIM TO DEFINE OPTIMAL NUTRIENT INTAKE RANGES (AIM 1) AND MICROBIALLY-RELEVANT NON-NUTRIENT INTAKE PROFILES (AIM 2) ASSOCIATED WITH OPTIMAL GROWTH AND NEURODEVELOPMENT AND LOW RISK OF SERIOUS MORBIDITY IN DIFFERENT CLINICAL SUB-POPULATIONS OF HM-FED VLBW INFANTS. ADDITIONALLY, WE WILL EXPLORE THE ROLE OF INFANT GUT MICROBIOTA, INFANT GENETICS AND PARENT STRESS IN ASSOCIATIONS BETWEEN EARLY NUTRITION AND GROWTH, NEURODEVELOPMENT AND MORBIDITY (AIM 3). INNOVATION: THE MAXIMOM PLATFORM IS UNIQUE IN THE WORLD IN TERMS OF SIZE, SCOPE OF NUTRITIONAL DATA, BIOBANKED SAMPLES AND LONGITUDINAL FOLLOW UP DATA. THE IMIC CONSORTIUM APPROACH TO STUDYING HM AS A BIOLOGICAL SYSTEM USING SOPHISTICATED MODELLING AND MACHINE LEARNING APPROACHES IS PUSHING THE BOUNDARIES OF HM RESEARCH. COMBINED, THESE PLATFORMS OFFER AN UNPARALLELED OPPORTUNITY TO DECIPHER HOW HM SUPPORTS THE GROWTH AND DEVELOPMENT OF VLBW INFANTS, AND TO ACCELERATE THE DEVELOPMENT OF NOVEL PRECISION NUTRITION APPROACHES FOR THIS VULNERABLE POPULATION.

THE PLURIPOTENCY REGULATOR PRDM14 INITIATES CANCER BY EPIGENETIC MECHANISMS

TYPE 1 DIABETES TRIALNET: TORONTO CLINICAL CENTER

TYPE 1 DIABETES TRIALNET: TORONTO CLINICAL CENTRE

NOVEL GENE BASED THERAPY FOR NEMALINE MYOPATHY

THE ROLE OF NEURONAL ENSEMBLES SUPPORTING AUDITORY FEAR CONDITIONING (ENGRAMS) IN THE AMYGDALA IN MEMORY FORMATION, GENERALIZATION AND EXTINCTION

PEDIATRIC HEART NETWORK - THE HOSPITAL FOR SICK CHILDREN, TORONTO

PEDIATRIC HEART NETWORK - THE HOSPITAL FOR SICK CHILDREN, TORONTO

THE LUNG CLEARANCE INDEX AS A MARKER OF EARLY LUNG DISEASE IN PRESCHOOL CHILDREN

PHYSICAL, PSYCHOLOGICAL, FINANCIAL LATE EFFECTS AND HEALTH CARE USE IN SURVIVORS OF ADOLESCENT AND YOUNG ADULT CANCER: A POPULATION-BASED STUDY

INTEGRATING A NATURAL HISTORY REGISTRY AND BIOBANK FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD): ADVANCING KNOWLEDGE AND THERAPEUTIC STRATEGIES

NATIONAL CENTER FOR EDUCATION RESEARCH

GENETIC STUDIES OF MAMMOGRAPHIC DENSITY

ENZYME THERAPEUTICS FOR BIOFILM PREVENTION AND DISRUPTION

UNDERSTANDING CHOLESTATIC DISORDERS IN A COLLABORATIVE NETWORK: THE ROLE OF SICKK

DEVELOPMENT OF NEW THERAPEUTICS TARGETING BIOFILM FORMATION BY THE OPPORTUNISTIC PULMONARY PATHOGENS PSEUDOMONAS AERUGINOSA AND ASPERGILLUS FUMIGATUS

DEVELOPMENT OF A BIOBANK FOR RARE PEDIATRIC EYE CANCERS

A GLOBAL PLATFORM FOR TRANSLATIONAL RESEARCH IN RARE PEDIATRIC BRAIN TUMORS

MODELING AND TARGETING METASTATIC DRIVERS IDENTIFIED IN SLEEPING BEAUTY SCREENS AND CODING FOR CYTOPLASMIC SIGNALING PROTEINS

NEUROLOGICAL OUTCOME OF GLYCEMIA IN NEONATAL ENCEPHALOPATHY

BIOPHYSICAL MECHANISMS REGULATING SYNCHRONY TRANSFER IN SOMATOSENSORY CORTEX

GENETIC FACTORS THAT REGULATE THE ONSET OF PUBERTY

SEASONAL IMPACT OF IRON FORTIFICATION ON MALARIA INCIDENCE IN GHANAIAN CHILDREN

APOBEC3, A HIT-AND-RUN DRIVER RESPONSIBLE FOR BREAST CANCER INITIATION AND/OR PROGRESSION?

PATIENT IPS CELLS WITH COPY NUMBER VARIATIONS TO MODEL NUROPSYCHIATRIC DSORDERS

CLINICAL AND GENOMIC RESPONSES TO REMOTE ISCHEMIC PRECONDITIONING

DEFINING THE ROLE OF AND MECHANISM BY WHICH THE CHLORIDE CHANNEL CLIC1 REGULATES BRAIN TUMOR GROWTH

THE IMPACT OF CHILDHOOD-ONSET LUPUS ON THE DEVELOPING BRAIN

NEUROCOGNITIVE FUNCTION IN CHILDHOOD-ONSET SLE (CSLE)

TRANSFORMING BEHAVIORAL HEALTH CARE TO IMPROVE THE QUALITY OF LIFE FOR INDIVIDUALS WITH CHILDHOOD-ONSET LUPUS

TARGETED MANIPULATION OF THE ZEBRAFISH GENOME THROUGH HOMOLOGOUS RECOMBINATION

PATIENT IPS CELLS WITH COPY NUMBER VARIATIONS TO MODEL NUROPSYCHIATRIC DSORDERS

MOLECULAR-TARGETED THERAPIES OF CHILDHOOD CHOROID PLEXUS CARCINOMA

CAMP CONTINUATION STUDY/PHASE 3

MICRO RNAS AS BIOMARKERS AND THERAPEUTIC TARGETS IN MYOTUBULAR MYOPATHY

ENZYME THERAPEUTICS FOR BIOFILM PREVENTION AND DISRUPTION

LONGITUDINAL CLINICAL AND MOLECULAR PROFILING TO IMPROVE OUTCOMES IN CHILDHOOD-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS

ELUCIDATING TOXOPLASMA INTERACTOMES CRITICAL FOR HOST CELL INVASION AND PATHOGENESIS

COMPUTATIONAL INVESTIGATION OF NEUROPATHIC CHANGES IN PRIMARY AFFERENT EXCITABILI

DISCOVERING THE TIMING AND ORIGINS OF BONE AND SOFT TISSUE CANCERS - SUMMARY SARCOMAS ARE CANCERS OF THE BONE AND CONNECTIVE TISSUE THAT AFFECT A HIGHER PROPORTION OF CHILDREN THAN ADULTS. MANY CHILDHOOD SARCOMAS ARE DIFFICULT TO DIAGNOSE, WHICH CAN LEAD TO THERAPEUTIC DELAYS. AT RELAPSE, CHILDHOOD SARCOMA PATIENTS HAVE POOR SURVIVAL, WITH LITTLE IMPROVEMENT SEEN IN 40 YEARS. WE HYPOTHESIZE THAT CHILDHOOD SARCOMAS’ TRUE BEGINNINGS – THEIR PRE-MALIGNANT MUTATIONS OR CELLS OF ORIGIN – IN FACT OCCUR MANY YEARS PRIOR TO DIAGNOSIS. WITH SUPPORT FROM THE GABRIELLA MILLER KIDS FIRST, CCDI, AND THIS R03 PROPOSAL, WE WILL DETERMINE THE TEMPORAL ORDER AND MOLECULAR PROCESSES THAT GIVE RISE TO CHILDHOOD SARCOMAS. TO DO SO, WE HAVE DRAWN ON SAMPLES AND CLINICAL DATA FROM OUR REPOSITORIES CONTAINING >6,000 SAMPLES. HIGH QUALITY SPECIMENS HAVE BEEN SELECTED TO INFORM EACH OF THE KEY TEMPORAL LANDMARKS IN THE DEVELOPMENT OF SARCOMA – FROM TUMOR INITIATION, TO THE GENERATION OF CRITICAL ONCOGENIC FUSIONS AND MALIGNANT POTENTIAL, TO POSSIBLE RELAPSE OR METASTASIS. THIS PROJECT WILL BE PURSUED IN TWO PARALLEL AIMS, USING EXISTING BIOINFORMATICS PIPELINES. FIRST, WE WILL FIND THE ORIGINATING MUTATIONS FOR CHILDHOOD SOFT TISSUE AND BONE CANCERS. THIS IS MOTIVATED BY OUR FINDING THAT CHILDHOOD EWING- AND OSTEO- SARCOMAS ARE INITIATED MULTIPLE YEARS BEFORE DIAGNOSIS, SOMETIMES STARTING IN UTERO. WE WILL RECONSTRUCT PHYLOGENETIC TREES FOR RARE SARCOMAS IN THIS COHORT. WE WILL SEE HOW OFTEN EARLY-ONSET TUMORS ARE ASSOCIATED WITH EARLY ONCOGENESIS. SECOND, WE WILL USE NON-NEOPLASTIC TUMORS OF BONE AND SOFT TISSUE AS A MODEL FOR SARCOMA INITIATION, WITHOUT PROLIFERATION. COMPLEMENTING THIS, WE WILL HAVE SEQUENCED LATE-EMERGING CHILDHOOD SARCOMAS - FROM ADULTS WHO DEVELOPED SARCOMA TYPES TYPICALLY FOUND ONLY IN CHILDREN. WE WILL LEARN WHETHER ADULT AND CHILDHOOD SARCOMAS OF THE SAME TYPE ARE DRIVEN BY THE SAME MUTAGENIC PROCESSES. WE WILL DETERMINE THE FORMATION SIGNATURES OF GENE FUSIONS, WHICH ARE MAJOR DRIVERS OF EARLY SARCOMAGENESIS. FINALLY, WE WILL USE THE SAME APPROACH TO EXAMINE SARCOMA PATIENTS AT RELAPSE, TO FIND CLINICALLY USEFUL SECONDARY MUTATIONS MISSED BY CONVENTIONAL SHORT READ APPROACHES. COLLECTIVELY, THESE DATA WILL PROVIDE A THOROUGH UNDERSTANDING OF MALIGNANT PROGRESSION IN CHILDHOOD SARCOMA. THIS WILL LAY THE FOUNDATION FOR TRIALS OF EARLY THERAPEUTIC INTERVENTION IN CHILDHOOD SARCOMA, FOR EXAMPLE BY PREDICTING THE EVOLUTIONARY TRAJECTORY OF RELAPSE BEFORE IT OCCURS. 1

CCDC78 AND THE PATHOGENESIS OF CENTRONUCLEAR MYOPATHY

DISCOVERY OF NOVEL DRUGS TO IMPROVE BONE HEALTH IN NEUROFIBROMATOSIS TYPE 1: THE WNT/BETA-CATENIN PATHWAY IN FRACTURE REPAIR AND PSEUDARTHROSIS

VALIDATION OF THE CHILDREN'S INTERNATIONAL MUCOSITIS EVALUATION SCALE (CHIMES)

DISCOVERY OF NOVEL AUTISM-ASSOCIATED VARIATION IN BRAIN MINIPROTEINS - PROJECT SUMMARY THIS R03 PROPOSAL DESCRIBES A TWO-YEAR RESEARCH PLAN FOCUSED ON THE INVESTIGATION OF PREVIOUSLY UNANNOTATED MINIPROTEINS TO THE GENETIC ETIOLOGY OF AUTISM SPECTRUM DISORDER (ASD). RARE INHERITED AND DE NOVO GENETIC VARIANTS ARE IMPORTANT CAUSES OF ASD, BUT EXPLAIN THE ETIOLOGY IN ONLY ~20% OF FAMILIES. FURTHERMORE, RARE ASD-ASSOCIATED VARIANTS HAVE BEEN IDENTIFIED IN NONCODING REGIONS OF THE GENOME, BUT THE FUNCTIONAL SIGNIFICANCE OF THOSE FOUND IS LARGELY UNKNOWN, REPRESENTING A CRITICAL KNOWLEDGE GAP IN ASD GENETICS. WE RECENTLY COMPLETED A STUDY TO PROFILE THE MRNA TRANSLATIONAL LANDSCAPE (THE “TRANSLATOME”) OF THE HUMAN BRAIN, IDENTIFYING THOUSANDS OF SMALL OPEN READING FRAMES (SORFS) ENCODING PUTATIVE MINIPROTEINS <100 AMINO ACIDS, MANY OF WHICH ARE TRANSLATED FROM ANNOTATED NONCODING REGIONS OF THE GENOME. WE HYPOTHESIZE THAT MINIPROTEINS REPRESENT AN UNAPPRECIATED CACHE OF HIDDEN GENES WHOSE ROLE IN DISEASE IS ALMOST ENTIRELY UNEXPLORED. TO ADDRESS THE POTENTIAL ROLE OF MINIPROTEINS IN ASD, WE WILL LEVERAGE THE LARGEST WHOLE-GENOME SEQUENCING (WGS) DATASET IN ASD, AS WELL AS OUR NEWLY CREATED ATLAS OF HUMAN BRAIN MINIPROTEINS, TO DISCOVER MINIPROTEIN GENES ASSOCIATED WITH ASD RISK BASED ON RARE INHERITED AND DE NOVO SEQUENCE-LEVEL AND STRUCTURAL VARIANTS (AIM 1). ADDITIONALLY, OUR PRELIMINARY DATA SUGGEST THAT MANY MINIPROTEINS LACK THREE-DIMENSIONAL STRUCTURE (INTRINSICALLY DISORDERED) AND ARE RICH IN SEQUENCE MOTIFS THAT BIND RNA. TRADITIONAL SEQUENCE-BASED ANALYSIS OF PROTEINS WILL PERFORM POORLY ON SHORT, HIGHLY DISORDERED MINIPROTEINS. THEREFORE, IN AIM 2, WE WILL BUILD PHYSICAL FEATURE-BASED ANALYSIS PARADIGMS TO PREDICT THE MOLECULAR FUNCTION OF ASD-ASSOCIATED MINIPROTEINS. THIS WORK COMBINES EXPERTISE IN DEVELOPMENTAL NEUROSCIENCE, GENOMICS, AND COMPUTATIONAL PROTEIN BIOLOGY. THE KNOWLEDGE GAINED FROM THIS R03, INCLUDING THE IDENTIFICATION OF NEW ASD-ASSOCIATED GENES, WILL FORM THE BASIS OF FUTURE STUDIES TO CHARACTERIZE THE FUNCTION, CELL TYPE-SPECIFICITY, AND DEVELOPMENTAL REGULATION OF MINIPROTEINS IN THE HUMAN BRAIN, AS WELL AS THEIR CONTRIBUTION TO ASD. OUR APPROACH TO INCORPORATING PREVIOUSLY UNANNOTATED MINIPROTEINS IN GENETIC ANALYSIS CAN BE APPLIED TO OTHER NEUROLOGIC AND NON-NEUROLOGIC CONDITIONS, THEREBY EXPANDING OUR UNDERSTANDING OF THE GENETIC ARCHITECTURE OF HUMAN DISEASE.

DEVELOPMENT OF "EVIDENTIAL" METHODOLOGY FOR THE ANALYSIS OF GENETIC DATA