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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH081755-02
Application #
7681645
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2008-08-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$289,513
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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