GPER1介导的雌激素非基因组效应在脑缺血神经元损伤中的保护作用和机制研究

项目名称： GPER1介导的雌激素非基因组效应在脑缺血神经元损伤中的保护作用和机制研究

项目编号： No.81200902

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： 赵天智

作者单位： 中国人民解放军第四军医大学

项目金额： 23万元

中文摘要： 雌激素有显著脑保护作用，但其临床应用存在争议，主要原因是其脑保护机制不详。仅研究雌激素脑保护基因组机制是不全面的，因为其脑保护中也存在非基因组机制。G蛋白偶联雌激素受体-1（GPER1）是目前唯一公认的雌激素膜受体，雌激素可通过它启动非基因组生物效应。研究已证实GPER1介导的非基因效应在心肌、肝细胞缺血损伤中有明显的保护作用。我们前期发现GPER1在中枢神经系统表达，缺血损伤后脑GPER1表达增加。据此，我们推测GPER1在脑缺血神经元损伤中有保护作用。本研究拟分别建立大鼠全脑缺血和海马神经元糖氧剥离模型，借助免疫组化、免疫印迹、MTT法、 水迷宫等技术观察GPER1对脑缺血海马神经元的保护作用,并探讨"GPER1 介导雌激素通过PI3K/Akt 通路调节ASK1的活性来抑制脑缺血诱导的神经元凋亡"这一机制。本课题的完成能深化对雌激素脑保护机制的认识，也可为研究神经保护提供新靶点。

中文关键词： 缺血；神经元；G蛋白偶联雌激素受体；AKT；ASK1

英文摘要： There is still a dispute involved in the clinical application of estrogen because of the undefined mechanisms underlying its neuroprotective effects, although its significant neuroprotective activities have been identified. The simple classification of the neuroprotective mechanisms of estrogen is genomic and non-genomic processes. The identification of G protein－coupled estrogen receptor 1 has introduced an receptor potentially responsible for non-genomic estrogen signaling. Several studies have demonstrated that G protein－coupled estrogen receptor 1 may mediate protective effects of estrogen against ischemic damage in cardiac muscle and hepatocyte. Our previous research had suggested that there is G protein－coupled estrogen receptor 1 in central nervous system by immunostaining. Furthermore,we found that the expression of G protein－coupled estrogen receptor 1 is increased in the rat brain following cerebral ischemia. Thus, we presume that estrogen exerts neuroprotective effects via G protein－coupled estrogen receptor 1. In the study, the hypothesis that G protein－coupled estrogen receptor 1 has a neuroprotective effect that is achieved through the inhibition of ASK1 on PI3K/Akt signaling cascade is investigated by Immunohistochemistry, immunoblotting，gene transfection，water maze，patch clamp and so on in a rat

英文关键词： ischemia；Neuroin；G protein-coupled estrogen receptor；AKT；Apoptosis signal-regulating kinase