TARGETING GENETIC PATHWAYS FOR BRAIN OVERGROWTH IN AUTISM SPECTRUM DISORDERS

针对自闭症谱系障碍中大脑过度生长的遗传途径

基本信息

批准号：
7681645
负责人：
ANTHONY J. WYNSHAW-BORIS
金额：
$ 28.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681645
关键词：
Age-Months Alleles Apoptosis Apoptotic Autistic Disorder Biological Biological Assay Biologically Based Therapy Brain Brain region Cataloging Catalogs Cells Class Classification Colony-Forming Units Assay Data Data Analyses Development Developmental Delay Disorders Disease Early identification Frequencies Gene Expression Gene Targeting Genes Genetic Genetic Heterogeneity Genetic Variation Genome Genomics Genotype Grant Growth Individual Infant Knowledge Lead Methodology Methods Mitosis Modeling Pathogenesis Pathway interactions Patients Phenotype Plant Roots Process Prospective Studies Recruitment Activity Regulation Risk Sample Size Screening procedure Symptoms Technology Therapeutic Time Variant autism spectrum disorder base brain pathway brain size expectation genetic analysis genetic variant genome wide association study genome-wide linkage in vitro Assay nerve stem cell neurogenesis novel novel therapeutics relating to nervous system size small molecule small molecule libraries

项目摘要

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.

基于我们的假设，即自闭症早期大脑发育不良涉及区域性大脑过度生长，我们建议将分析重点放在有强有力证据表明监管的途径或过程上大脑的大小。我们假设调节生长和程序性细胞死亡的三种途径可能是导致自闭症早期观察到的大脑大小变化的原因：Wnt 活动增加途径；对神经发生重要的基因活性增加；和重要基因活性降低用于细胞凋亡。我们建议使用这种假设驱动的方法来确定是否存在常见的遗传变异这些基因中的基因可能导致自闭症谱系障碍患者大脑体积增大，证实此类变体在增殖或凋亡测定中具有功能，并在基于细胞的小型实验中使用此信息分子筛选以确定调节这些表型的潜在治疗化合物类别。因此，我们建议研究可能导致的特定途径的遗传变异通过以下具体目标来治疗自闭症谱系障碍中的大脑过度生长：目标 1. 确定 Wnt/PCP 通路、神经发生/有丝分裂和细胞凋亡中是否存在常见变异存在于正常发育的婴儿、发育迟缓或 ASD 婴儿中。目标 2. 确定目标 1 中的遗传变异是否与 ASD 或任何发现的表型相关在项目 1 和 2 中使用新颖的面向假设的多元数据分析方法。目标 3. 确定与 ASD 或任何表型相关的遗传变异的功能意义项目 1 和 2 中使用 NSC 增殖和/或凋亡的体外测定发现了这一点。目标 4. 筛选小分子库中具有调节或改善功能的化合物使用目标 3 中的 NSC 检测发现增殖和凋亡遗传变异。