阻断TRPV4受体对脑缺血再灌注损伤的作用及其分子机制

项目名称： 阻断TRPV4受体对脑缺血再灌注损伤的作用及其分子机制

项目编号： No.31271206

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 陈蕾

作者单位： 南京医科大学

项目金额： 74万元

中文摘要： 胞内钙离子（[Ca2+]i）超载和脑水肿是导致和加重脑缺血再灌注神经元死亡的重要因素。对Ca2+具有通透性的TRPV4受体可被急性脑卒中时细胞水肿等因素激活，使[Ca2+]i升高。TRPV4受体激活后能损伤星形胶质细胞，破坏血脑屏障。申请者前期研究发现激活TRPV4受体能增强NMDA电流，诱导海马神经元死亡。基于TRPV4受体阻断剂能减少缺血再灌注后脑梗死体积的预实验结果，本课题将探讨阻断TRPV4受体保护脑缺血再灌注损伤的分子机制。本课题首先确定阻断TRPV4受体保护脑缺血再灌注损伤的时间窗；并阐明阻断TRPV4受体是否通过（1）抑制[Ca2+]i升高，进而减少自由基和一氧化氮的生成或下调p38MAPK信号通路；（2）降低血脑屏障的通透性，阻止脑水肿的发生；（3）降低谷氨酸的兴奋毒作用等多靶点的调控机制对脑缺血再灌注损伤起保护作用，为开辟缺血性脑损伤临床治疗的新途径提供理论和实验依据。

中文关键词： 脑缺血再灌注；脑水肿；TRPV4 受体；神经保护；钙离子

英文摘要： Intracellular calcium overload and brain edema are important mechanisms underlying the cerebral ischemia-reperfusion injury. As its permeability to calcium ion, activation of TRPV4 receptor by the cell swelling etc. during the acute cerebral stoke, can lead to the increase in intracellular free calcium concentration ([Ca2+]i). Activation of TRPV4 receptor mediates astrocytic cell death, leading to damage of blood-brain barrier. Our previous study found that activation of TRPV4 receptor enhanced NMDA-induced current and could induce hippocampal pyramidal neuron death. Based on our previous result that intracerebroventricular injection of TRPV4 antagonist markedly decreased the volumes of cerebral infarction after 24h reperfusion in middle cerebral artery occlusion model mice, the present project will explore the molecular mechanisms underlying the neuroprotection of blocking TRPV4 receptor on ischemia-reperfusion injury. We will study, firstly, the key time window of the neuroprotection of blocking TRPV4 receptor on cerebral ischemia-reperfusion injury; secondly, whether blocking TRPV4 receptor exerts the neuroprotection through multiple mechanisms including (1) decreasing [Ca2+]i to inhibit the production of free radicals and nitric oxide or to downregulate p38MAPK signaling pathway, (2) reducing the permeabili

英文关键词： cerebral ischemia-reperfusion；brain edema；TRPV4 receptor；neuroprotection；calcium ion