TARGETING GENETIC PATHWAYS FOR BRAIN OVERGROWTH IN AUTISM SPECTRUM DISORDERS

$289,513P50FY2008MHNIH

University Of California, San Diego, La Jolla CA

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Abstract

Based on our hypothesis that very early brain maldevelopment in autism involves regional brain overgrowth,[unreadable] we propose to focus our analysis on pathways or processes where there is strong evidence for regulation of[unreadable] brain size. We hypothesize that three pathways regulating growth and programmed cell death could be[unreadable] responsible for the observed changes in brain size early in the course of autism: increased activity in the Wnt[unreadable] pathway; increased activity of genes important for neurogenesis; and decreased activity of genes important[unreadable] for apoptosis. We propose to use this hypothesis-driven approach to determine if common genetic variation[unreadable] in such genes may be responsible for the increased brain size seen in individuals with ASD, confirm that[unreadable] such variants are functional in proliferation or apoptosis assays, and use this information in cell-based small[unreadable] molecule screens to define potential therapeutic classes of compounds that will modulate these phenotypes.[unreadable] Therefore, we propose to investigate the genetic variation of specific pathways that may be responsible for[unreadable] brain overgrowth in autism spectrum disorders by the following Specific Aims:[unreadable] Aim 1. Determine whether common variants in the Wnt/PCP pathways, neurogenesis/mitosis and apoptosis[unreadable] are present in typically developing infants, developmentally delayed or ASD infants.[unreadable] Aim 2. Determine whether genetic variation in Aim 1 is associated with ASD or any phenotypes discovered[unreadable] in Projects 1 and 2 using novel hypothesis-oriented multivariate data analysis methodologies.[unreadable] Aim 3. Determine the functional significance of genetic variants associated with ASD or any phenotypes[unreadable] discovered in Projects 1 and 2 using in vitro assays of proliferation and/or apoptosis in NSCs.[unreadable] Aim 4. Screen small molecule libraries for compounds that modulate or ameliorate functionally significant[unreadable] proliferation and apoptotic genetic variants found using NSC assays in Aim 3.

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