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: 7292327
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-06 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292327
• 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

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.

根据我们的假设，自闭症的早期大脑发育不良涉及局部大脑过度生长， 我们建议将我们的分析集中在有强有力证据表明调控的途径或过程上， 脑容量我们假设，调节生长和程序性细胞死亡的三种途径可能是 负责观察到的自闭症早期大脑大小的变化：Wnt的活动增加 途径;增加对神经发生重要的基因的活性;和减少对神经发生重要的基因的活性。 for apoptosis凋亡.我们建议使用这种假设驱动的方法来确定是否共同的遗传变异 在这些基因中可能是导致ASD患者大脑体积增加的原因， 这些变体在增殖或凋亡测定中是功能性的，并且在基于细胞的小分子生物学中使用该信息。 分子筛选以确定将调节这些表型的化合物的潜在治疗类别。 因此，我们建议研究可能导致这种疾病的特定途径的遗传变异。 自闭症谱系障碍的大脑过度生长，具体目标如下： 目标1.确定Wnt/PCP通路、神经发生/有丝分裂和细胞凋亡中的常见变体是否 通常存在于发育中的婴儿、发育迟缓或ASD婴儿中。 目标2.确定Aim 1中的遗传变异是否与ASD或发现的任何表型相关 在项目1和2中使用新的面向假设的多变量数据分析方法。 目标3.确定与ASD或任何表型相关的遗传变异的功能意义 在项目1和2中使用NSC中增殖和/或凋亡的体外测定发现。 目标4。筛选小分子文库中调节或改善功能显著性的化合物 在Aim 3中使用NSC测定发现的增殖和凋亡遗传变体。