应激反应基因NDRG2在AD神经病理损伤中的保护作用与机制研究

项目名称： 应激反应基因NDRG2在AD神经病理损伤中的保护作用与机制研究

项目编号： No.81471110

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李燕

作者单位： 中国人民解放军第四军医大学

项目金额： 70万元

中文摘要： β淀粉样蛋白（Aβ）堆积是阿尔茨海默病（AD）的重要病理学特征，能促进谷氨酸等兴奋性神经递质在神经突触的堆积和毒性作用，但是具体分子机制并不清楚。已有的文献和我们近期发表的研究证明：NDRG2是一个细胞应激反应基因，在脑中特异表达于星形胶质细胞；AD病人和AD模型动物中NDRG2表达显著增高；NDRG2结合并稳定Na+/K+-ATPase；Na+/K+-ATPase驱动着星形胶质细胞通过谷氨酸转运体GLT-1摄取神经突触中的谷氨酸。上述结果提示NDRG2可能受到Aβ的刺激而反应性升高，作为一种内源性保护分子，通过调控Na+/K+-ATPase促进GLT-1摄取多余的谷氨酸。本项目拟综合利用分子生物学、细胞生物学、神经生物学和动物行为学等方法，在体外星形胶质细胞和NDRG2基因敲除鼠以及AD模型鼠水平，深入研究上述科学设想，为探索AD病程中的内源性保护机制提供新线索，为AD的诊治提供新思路。

中文关键词： 阿尔茨海默病；β-淀粉样蛋白；N-myc；下调基因2；星形胶质细胞

英文摘要： Amyloid β protein (Aβ), one of the important pathological features of Alzheimer's disease (AD), can promote the accumulation and excitotoxicity of glutamate, the main excitatory neurotransmitter in the synapses, but the specific molecular mechanism is unclear. The existing literature and our recent studies have shown that: NDRG2 was a cellular stress response gene which was specific expressed in astrocytes in the brain; NDRG2 expression significantly increased in AD patients and AD animal model; NDRG2 protein can bind and stabilize Na+/K+-ATPase; Na+/K+-ATPase drives glutamate intake in synapses through Glial glutamate transporter 1 (GLT-1) by astrocyte. These results suggest NDRG2 may be elevated response with Aβ stimulation. And as an endogenous protective molecule, NDRG2 may regulate Na+/K+-ATPase to promote redundant glutamate intake via GLT-1. This project intends to comprehensively use multiple methods, including molecular biology, cell biology, neurobiology and animal behavior, and at astrocytes, NDRG2 knockout mice and AD model mice levels to deeply study above scientific hypotheses. Our study could provide new clues on the endogenous protective mechanism in the process of AD and new insights into diagnosis and treatment for AD.

英文关键词： AD;beta-amyloid;NDRG2;astrocyte