Based on our hypothesis that very early brain maldevelopment in autism involves regional brain overgrowth, we propose to focus our analysis on pathways or processes where there is strong evidence for regulation of brain size. We hypothesize that three pathways regulating growth and programmed cell death could be responsible for the observed changes in brain size early in the course of autism: increased activity in the Wnt pathway;increased activity of genes important for neurogenesis;and decreased activity of genes important for apoptosis. We propose to use this hypothesis-driven approach to determine if common genetic variation in such genes may be responsible for the increased brain size seen in individuals with ASD, confirm that such variants are functional in proliferation or apoptosis assays, and use this information in cell-based small molecule screens to define potential therapeutic classes of compounds that will modulate these phenotypes. Therefore, we propose to investigate the genetic variation of specific pathways that may be responsible for brain overgrowth in autism spectrum disorders by the following Specific Aims:
Aim 1. Determine whether common variants in the Wnt/PCP pathways, neurogenesis/mitosis and apoptosis are present in typically developing infants, developmentally delayed or ASD infants.
Aim 2. Determine whether genetic variation in Aim 1 is associated with ASD or any phenotypes discovered in Projects 1 and 2 using novel hypothesis-oriented multivariate data analysis methodologies.
Aim 3. Determine the functional significance of genetic variants associated with ASD or any phenotypes discovered in Projects 1 and 2 using in vitro assays of proliferation and/or apoptosis in NSCs.
Aim 4. Screen small molecule libraries for compounds that modulate or ameliorate functionally significant proliferation and apoptotic genetic variants found using NSC assays in Aim 3.
|Bacon, Elizabeth C; Osuna, Suzanna; Courchesne, Eric et al. (2018) Naturalistic language sampling to characterize the language abilities of 3-year-olds with autism spectrum disorder. Autism :1362361318766241|
|Brandler, William M; Antaki, Danny; Gujral, Madhusudan et al. (2018) Paternally inherited cis-regulatory structural variants are associated with autism. Science 360:327-331|
|Moore, Adrienne; Wozniak, Madeline; Yousef, Andrew et al. (2018) The geometric preference subtype in ASD: identifying a consistent, early-emerging phenomenon through eye tracking. Mol Autism 9:19|
|Fingher, Noa; Dinstein, Ilan; Ben-Shachar, Michal et al. (2017) Toddlers later diagnosed with autism exhibit multiple structural abnormalities in temporal corpus callosum fibers. Cortex 97:291-305|
|Pierce, Karen; Marinero, Steven; Hazin, Roxana et al. (2016) Eye Tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an Autism Spectrum Disorder Subtype Associated With Increased Symptom Severity. Biol Psychiatry 79:657-66|
|Solso, Stephanie; Xu, Ronghui; Proudfoot, James et al. (2016) Diffusion Tensor Imaging Provides Evidence of Possible Axonal Overconnectivity in Frontal Lobes in Autism Spectrum Disorder Toddlers. Biol Psychiatry 79:676-84|
|Pramparo, Tiziano; Lombardo, Michael V; Campbell, Kathleen et al. (2015) Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers. Mol Syst Biol 11:841|
|Pramparo, Tiziano; Pierce, Karen; Lombardo, Michael V et al. (2015) Prediction of autism by translation and immune/inflammation coexpressed genes in toddlers from pediatric community practices. JAMA Psychiatry 72:386-94|
|Lombardo, Michael V; Pierce, Karen; Eyler, Lisa T et al. (2015) Different functional neural substrates for good and poor language outcome in autism. Neuron 86:567-77|
|Stoner, Rich; Chow, Maggie L; Boyle, Maureen P et al. (2014) Patches of disorganization in the neocortex of children with autism. N Engl J Med 370:1209-1219|
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