SHANK3是突触前后复合体的核心物质和功能基础，SHANK3基因变异被确认为自闭症谱系障碍等神经精神疾病易感因素，但该基因变异增强相关疾病易感性的分子机制尚不明确。本项目拟在申请人既往关于突触结构基因NRXN1和NLGN4X的研究基础上，结合生物信息学和神经生物学研究方法，发展功能基因组学研究策略：1）靶向下调神经干细胞发育模型中SHANK3基因表达水平，模拟单基因缺失效应，2）动态监测发育过程中继发于SHANK3单基因变异的差异表达基因网络、蛋白网络和分子通路变异，3）阐释“基因变异”至“神经细胞结构与功能发育异常”的基因组学机制。本研究采用人类神经干细胞模型有利于模拟人源性神经细胞动态发育过程，转录组测序结合生物信息学分析方法具有高通量、全局性研究效能，其结果有助于明确人源性SHANK3基因变异影响神经细胞结构与功能发育的全局性动态分子机制，推动神经精神疾病分子病理机制研究进展。

The SHANK3 gene encodes one of the most important components in the synaptic complex. Genetic variants in SHANK3 have been strongly associated with the pathogenesis and neuropathology of autism spectrum disorders(ASDs), but the mechanism underlying this association has not been fully investigated, due to the lack of appropriate disease models for ASDs. We previously developed a neural stem cell based model to knockdown NRXN1 and NLGN4X and investigate the functional effects by examining cellular and molecular phenotypes. In the current proposal, we will develop functional genomics strategy by combining expertise on bioinformatics, genomics and neurobiology: 1) to model the cellular phenotypes of SHANK3 gene knockdown in neural stem cells derived from human induced Pluripotent Stem Cells (hiPSCs) by RNA interfere techniques.2) to investigate the disturbed pattern of gene expression network and protein network in the development time-course using RNA-Seq techniques. 3) to explore the mechanism of molecular pathophysiology from upstream (single gene variant) to downstream (cellular phenotypes) from the perspective of genomics. The combination of high-throughput genomics (next-generation sequencing) and the use of neural stem cell models could contribute to the process of modeling neurodevelopment in a high-throughput fashion. Successful completion of the study will enable exploration of the molecular mechanism of cellular phenotype abnormalities resulting from SHANK3 dysfunction, and contribute to improving related disease research.