Copine VII在阿尔茨海默病中的作用机制研究

项目名称： Copine VII在阿尔茨海默病中的作用机制研究

项目编号： No.31500821

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 神经、认识与心理学

项目作者： 朱炳林

作者单位： 重庆医科大学

项目金额： 20万元

中文摘要： Copine VII (CPNE7)是一个62KD的蛋白质，其功能不清。我们在对经尼古丁处理过的阿尔茨海默病(Alzheimer's disease, AD)动物模型大脑转录组测序发现CPNE7基因表达显著增加。进一步发现CPNE7 mRNA和蛋白质在AD模型中都下降。细胞过表达CPNE7抑制凋亡和β样淀粉蛋白(Aβ)相关蛋白的表达，提示CPNE7可能在AD中具有重要作用。已知磷脂酸/磷脂酶D (PA/PLD)和核仁蛋白(Nucleolin)通路与AD的发生密切相关，它们都能与CPNE7相互作用。本研究拟利用离体神经元细胞和AD动物模型，通过免疫印迹、免疫组化、电生理及动物行为学等方法，研究：(1) nucleolin介导CPNE7对Aβ通路的调节；(2) PA/PLD介导CPNE7对凋亡、自噬的影响。本项目将有助于理解CPNE7在AD中的保护作用及机制，为探讨新的治疗策略提供实验基础。

中文关键词： 阿尔茨海默病；Copine；VII；β淀粉样蛋白；磷脂酸；核仁蛋白

英文摘要： Copine VII (CPNE7) is a 62KD protein, but its biological function remains unclear. Preliminary RNA-seq analysis demonstrated that in the brain of animal model of Alzheimer's disease (AD) treated with nicotine exhibited enhanced expression of CPNE7 gene. qPCR and Western Blotting results showed that the expression of both CPNE7 mRNA and protein were decreased in AD models. In cells overexpressed CPNE7 apoptosis and amyloid-β protein (Aβ) production were significantly inhibited, suggesting CPNE7 may play an important role in AD pathogenesis. Phosphatidic acid/phospholipase D (PA/PLD) and nucleolin pathway are closely related to AD, and they have been shown to interact with CPNE7. We will study that (1) if and how nucleolin might mediate the effect of CPNE7 on Aβ production; and (2) the functional role of PA/PLD in CPNE7 regulation of apoptosis and autophagy in the neuronal cell line and AD animal model by experimental methods of immunoblotting, immunohistochemistry, electrophysiology and behavior analysis. This study will help to understand the mechanisms of CPNE7 in AD pathogenesis and provide experimental basis for the search of new treatment strategies.

英文关键词： Alzheimer's disease (AD);Copine VII (CPNE7);Amyloid-β protein (Aβ);Phosphatidic acid (PA);Nucleolin