CHD8与线粒体呼吸链的相互调节在神经发育及自闭症谱系障碍中的作用及其机制研究

Autism spectrum disorders (ASD) are developmental brain disorders of highest prevalence. Mitochondrial dysfunctions are known to be closely involved in the pathological mechanism of several neurological disorders. However, whether mitochondria play a direct role in the etiology of ASD remains largely unknown. By analyzing the brain transcriptome data, we unexpectedly observed a negative correlation between ASD genes and mitochondrial genes. We hypothesize that these two groups of genes antagonize each other and that mutations of ASD risk genes may lead to mitochondrial dysfunction, which, in return, may affect ASD gene expression and brain development. This project aims to explore whether CHD8, a representative ASD risk gene, suppress mitochondrial function and neuronal morphogenesis by directly binding to mitochondrial genes and suppressing their expression. We will further use neuronal culture and ASD mouse models to examine whether an appropriate dosage of mitochondrial inhibitors could mitigate defects in the gene expression, neuronal morphogenesis and animal behavior caused by CHD8 gene deficiencies. This innovative research will shed new light on the molecular and cellular etiology of ASD and will lead to the identification of new drug targets for the pharmacological intervention of ASD.

自闭症谱系障碍（ASD）是影响最广泛的神经发育性疾病之一。线粒体功能异常在多种神经系统疾病的病理机制中扮演重要的角色，然而线粒体是否直接参与到ASD的病理机制中尚不清楚。通过对人脑转录组数据进行分析，我们意外地发现ASD风险基因群的表达与线粒体基因群的表达呈现显著的负相关性。因此推测在正常脑发育过程中两组基因之间存在相互拮抗作用，ASD基因功能的缺失可能导致线粒体功能异常，而线粒体功能反馈影响ASD基因的表达，从而影响发育进程。本课题拟检验一个代表性ASD风险基因CHD8是否通过直接结合在线粒体基因上抑制其表达，从而调节线粒体功能和神经元形态发育。并将进一步探索适当剂量的线粒体功能抑制剂能否纠正CHD8基因缺陷造成的基因表达异常、神经元形态发育异常及动物行为异常。此项研究从一个崭新的视角研究ASD的分子及细胞学机理并将有助于开拓基于线粒体及代谢通路的ASD药物干预新靶点。

自闭症谱系障碍（ASD）是影响最广泛的神经发育性疾病之一。本课题原计划借助小鼠突变模型，检验一个代表性ASD风险基因CHD8是否通过直接结合在线粒体基因上抑制其表达，从而调节线粒体功能和神经元形态发育。并将进一步探索适当剂量的线粒体功能抑制剂能否纠正CHD8基因缺陷造成的基因表达异常、神经元形态发育异常及动物行为异常。在本项目支持下，我们建立了“匹配共表达分析”算法，有效预测基因组中未知的ASD风险基因及其参与的汇聚性分子通路；我们成功构建Chd8基因突变小鼠、Cdh11基因敲除小鼠及Med13l基因敲除小鼠等ASD小鼠模型，研究了这些模型鼠的行为表型并阐述了造成这些行为缺陷相关的神经发育机制，发现线粒体功能紊乱及炎症反应异常可能在Chd8及Med13l等基因变异导致的自闭症病理机制中发挥重要作用；在此基础上，还探索并揭示了动物恐高行为的神经科学基本原理。