孤独症相关的CHD8新发突变调控神经元突起生长发育的作用和机制

项目名称： 孤独症相关的CHD8新发突变调控神经元突起生长发育的作用和机制

项目编号： No.81471386

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈晓钎

作者单位： 华中科技大学

项目金额： 70万元

中文摘要： 孤独症是儿童最常见的中枢神经系统发育紊乱性疾病，其病理生理基础是神经元生长发育的异常，临床表现为社会交往/交流障碍、兴趣狭窄及刻板重复行为，尚无特效治疗药物。最新的一个突破性进展是发现了许多与孤独症相关的单基因新发突变(de novo mutation，即生殖细胞基因突变)。其中，染色体结构域解旋酶DNA结合蛋白8 (CHD8)突变仅在孤独症患者出现，且突变频率最高，是一个重要的孤独症候选致病基因。过表达短片段CHD8 (类似CHD8无义突变)明显阻碍N2a细胞突起生长、同时下调脑红蛋白和p-Akt表达，提示CHD8突变通过脑红蛋白-Akt调控神经元突起生长发育。本项目拟深入研究CHD8突变在神经元突起生长发育过程中的作用及其机制，同时在大鼠和斑马鱼中确定CHD8突变与孤独症特征行为的相关性。结果将为确认CHD8突变是孤独症的病因提供实验证据，同时为孤独症药物治疗提供理论基础或药靶。

中文关键词： 孤独症；CHD8；新发突变；神经突起生长；斑马鱼

英文摘要： Autism is a neuronal growth and development disorder characterized by impaired social interaction and verbal/non-verbal communication, repetitive and stereotyped behavior. As the most common neural genetic disorder in children, there is still no drug specific for autism. The latest breakthrough of autism study is the discovery of de novo mutations of single gene. Among those mutated genes, chromodomain-helicase-DNA-binding protein 8 (CHD8) is likely one of the most important autism-causing candidates due to its specificity and highest mutation frequency in autism patients. Overexpression of the short CHD8 (similar to CHD8 nonsense mutation) suppressed neurite outgrowth and down-regulated the expression of neuroglobin and p-Akt in N2a cells, suggesting that CHD8 mutation controls neurite growth and development of neurons via neuroglobin-Akt signaling pathway. The purpose of this study is to: 1) investigate the role of CHD8 mutations in neurite outgrowth/development of neurons and its underlying mechanisms; 2) study the relationships of CHD8 mutations with autism-characterized social behaviors in rats and zebrafishes. Our results will provide strong laboratory evidences supporting for the role of CHD8 mutation as a autism-causing gene. Also, our results may provide potential therapeutic targets for drug development of autism.

英文关键词： autism;CHD8;de novo mutation;neurite outgrowth;zebrafish