TRPM7在神经细胞缺血损伤中的作用及DREAM对TRPM7调控机制研究

项目名称： TRPM7在神经细胞缺血损伤中的作用及DREAM对TRPM7调控机制研究

项目编号： No.81501026

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 谈颂

作者单位： 电子科技大学

项目金额： 17.5万元

中文摘要： 神经元缺血损伤是脑卒中引起脑功能障碍的核心之一，NMDA 受体介导的“兴奋性毒性”作用是导致损伤的重要原因，但NMDA受体拮抗剂的临床试验未能显示有效。TRPM7是不依赖NMDA的通道蛋白，激活后引起细胞内Ca2+持续超载，导致恶性氧化应激。目前认为DREAM是多种通道蛋白的调控因子，相关研究和前期实验提示梗死区DREAM和TRPM7蛋白表达均显著增加。针对DREAM作为Ca2+结合蛋白的特性和TRPM7对Ca2+的通透性的特点，我们提出假说：二者可能存在一定的功能相关性，共同参与神经细胞缺血损伤过程。我们采用在体外培养神经元细胞中上调或下调TRPM7表达，同时应用TRPM7基因敲除小鼠，以阐明TRPM7在缺血损伤中的作用，在此基础上探讨DREAM与TRPM7的结合及对TRPM7通道生化功能特性的调控机制。本课题将进一步拓宽对中枢TRPM7通道功能的认识，为脑卒中治疗药物研发提供新靶点。

中文关键词： 脑卒中；缺血损伤；TRPM7；DREAM

英文摘要： Neuronal ischemia injury is a primary cause of neurological impairment in ischemic stroke patients. Cerebral ischemia injury is mainly associated with the excitotoxic action induced by glutamate excitotoxicity (NMDA receptor mediated) pathway. But pharmacological agents that disrupt the excitotoxic pathway have only led to disappointing clinical trials. TRPM7 is Ca2+-permeable divalent cation channel protein and is associated with neuronal cell death under ischemic stresses. The activation of TRPM7 is a NMDA-independent pathway that significantly contributes to the pathological Ca2+ overload. It is revealed that DREAM is a Ca2+-binding modulator of channel proteins. Our study and other studies have showed the high expressions of DREAM and TRPM7 in the central and surrounding areas of the infarction. Based on the Ca2+-binding characteristics of DREAM and the Ca2+-permeable property of TRPM7, we propose that both DREAM and TRPM7 being involved in ischemic damage together，owing to possible functional relationship between them. Therefore, we will upregulate and downregulate the expression of TRPM to study the mechanism of TRPM7-mediated neuronal damage in vitro (oxyzen-glucose deprivation fowllowed by reoxygenation cell model) and in vivo (TRPM7 knock-out mice model). Then, we will further investigate that mechanism of DREAM-mediated modulation of TRPM7 in the process of cerebral ischemic induced injury. Our study would promote the deep understanding of exact modulating mechanism of TRPM7 expression and provide a new target for further development of neuroprotection drugs on stroke.

英文关键词： Stroke;ischemia injury;Transient receptor potential melastatin 7;Downstream regulatory element antagonist modulator