家族性帕金森病的致病基因克隆与功能机制研究

帕金森病(PD）的病因及发病机制与环境因素、遗传因素和老年化相关，而遗传因素在PD发病机制中的作用是当前的研究热点。我们前期研究工作中，采用新一代测序技术、生物信息学分析及遗传学分析等方法和策略对我们收集的PD家系进行分析，遴选到两个候选新的PD致病基因（暂命名为PD-TBS1和PD-TBS2），他们分别参与网格蛋白介导的内吞及囊泡代谢、内质网应激介导的细胞凋亡途径可能在PD发病机制中起作用。本项目，在前期研究工作基础上，拟进一步收集家族性PD和散发性PD，采用新一代测序技术方法和策略定位、克隆新的PD致病基因；采用分子遗传学、分子神经生物学等实验技术，构建转基因细胞模型、Knock in/Knock out小鼠模型及携带新的PD致病基因突变的iPS细胞系，从细胞学水平、基因工程小鼠水平及诱导性多潜能干细胞（iPS）系水平探讨新的PD致病基因的分子发病机制。

Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders. Environmental factors, genetic factors and aging are contributed to the etiology of PD and the role of genetics in PD pathogenic mechanism is attracting increasing attention. During our previous work, two candidate causal genes have been identified in two families by next generation sequencing, bioinformation analysis and genetic analysis, which were temporarily named PD-TBS1 and PD-TBS2. The two genes may participate in clathrin mediated endocytosis, vesicle metabolic and endoplasmic reticulum mediated apoptosis. In this project, based on our previous large collection of familial PD resources and our successful experience in pathogenic genes cloning, we intend to clone PD pathogenic genes in Chinese population by using advanced technologies such as next generation sequencing(NGS) and single nucleotide polymorphism linkage analysis chip; Furthermore, we will generate cell model, Knock in/Knock out mice model and iPSc carrying novel pathogenetic gene mutations identified in our research, and investigate the molecular pathogenic mechanisms (especially for PD-TBS1 and PD-TBS2) in vitro and in vivo.