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

• 批准号: 8117636
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 35.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117636
• 关键词: Age-Months; Alleles; Apoptosis; Apoptotic; Autistic Disorder; Biological; Biological Assay; Biologically Based Therapy; Brain; Brain region; Cataloging; Catalogs; Cells; 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; 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; genome-wide linkage; in vitro Assay; nerve stem cell; neurogenesis; novel; novel therapeutics; relating to nervous system; small molecule; small molecule libraries

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与局部脑过度生长有关， 我们建议将我们的分析重点放在有强有力证据表明可以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条途径可能是 自闭症病程早期观察到的脑大小变化的原因：WNT中的活动增加 途径；对神经发生重要的基因活性增加；以及重要基因活性降低 用于细胞凋亡。我们建议使用这种假设驱动的方法来确定常见的遗传变异 这类基因可能是ASD患者大脑增大的原因，证实 这些变异体在增殖或凋亡分析中起作用，并在基于细胞的小细胞中使用这些信息 分子筛选，以确定潜在的治疗类化合物，将调节这些表型。 因此，我们建议调查特定途径的遗传变异，这可能是导致 自闭症谱系障碍患者大脑过度生长的具体目的如下： 目的1.确定Wnt/PCP通路中常见的变异、神经发生/有丝分裂和细胞凋亡 通常存在于发育中的婴儿、发育迟缓或自闭症婴儿中。 目标2.确定目标1的遗传变异是否与ASD或任何已发现的表型有关 在项目1和2中使用新的以假设为导向的多变量数据分析方法。 目的3.确定与ASD或任何表型相关的遗传变异的功能意义 在项目1和2中使用神经干细胞的体外增殖和/或凋亡检测发现。 目标4.筛选小分子文库，寻找调节或改善显著功能的化合物 在AIM 3中使用NSC分析发现的增殖和凋亡遗传变异。