MicRNA107调控BACE1mRNA基因与阿尔茨海默病内质网应激病理机制研究

项目名称： MicRNA107调控BACE1mRNA基因与阿尔茨海默病内质网应激病理机制研究

项目编号： No.81201030

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 王涛

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 阿尔茨海默病（AD）是病因未明的常见神经退行性疾病，与BACE1基因及线粒体应激有关，但相互关系及调控机制未明。本课题以胎鼠海马神经元及AD患者为对象，探讨micRNA107调控BACE1mRNA基因及内质网应激在AD病理机制中的作用。应用衣霉素诱导海马神经元细胞ERS，以qPCR和Western blot检测内质网应激信号分子及基因表达，研究BACE1基因表达对内质网信号途径的影响，检测PEAK、IRE1α及Caspase的变化，观察相关凋亡蛋白表达及在不同细胞器的分布，研究BACE1诱导细胞凋亡的分子途径。通过免疫共沉淀实验研究micRNA107与BACE1mRNA及内质网应激信号分子的相互作用，研究micRNA107对BACE1mRNA表达的影响及调控内质网应激的作用机理。探索AD患者micRNA107与BACE1mRNA基因表达与脑脊液Aβ水平的关系。为AD治疗和新药研发提供依据。

中文关键词： 阿尔茨海默病；遗忘型轻度认知功能损害；微小RNA107；血浆；脑部微环境

英文摘要： Alzheimer's disease (AD) is a common neurodegenerative disease that etiology is unknown. The BACE1 gene and mitochondrial stress would be correlated to the pathogenesis of AD, but the mutual relation and regulatory mechanism between them is unknown. Subjects are the fetal rat hippocampal neurons and AD patients. Our research will explore micRNA107 control BACE1mRNA gene and internal regulation of endoplasmic reticulum stress in the AD pathological mechanisms. On the one hand, we will induce the ERS to hippocampal neurons by tunicamycin and use qPCR and Western blot to analysis of ERS signaling molecules such as PEAK, eIF2α, GSK-3, IRE1α, ASK1, JNK, Akt and gene expression of BACE1mRNA, BACE1. On the other hand, we will detect the change of PEAK, IRE1α and Caspase signals and want to discover the pathway of BACE1 inducing apoptosis. We will study the interaction of micRNA107 and BACE1mRNA by co-immunoprecipitation experiments, and study the effect and mechanism of how micRNA107 regulate BACE1mRNA. We will observe the expression of apoptotic proteins and the distribution in organelles, and research the molecular pathways of inducing apoptosis by BACE1. Last, we will explore the micRNA107 and BACE1mRNA gene expression and CSF Aβ levels of AD patients. We hope to provide the basis for AD treatment and drug discover

英文关键词： Alzheimer’s disease；amnestic mild cognitive imparment；Micro RNA107；Plasma；brain microenvironment