GSK-3β调节的BCL-2蛋白酶体降解在脑缺血后细胞凋亡中的作用

项目名称： GSK-3β调节的BCL-2蛋白酶体降解在脑缺血后细胞凋亡中的作用

项目编号： No.81501060

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： 魏海东

作者单位： 西安交通大学

项目金额： 17.5万元

中文摘要： 中风严重威胁国民健康，由于tPA治疗时间窗限制，目前中风干预措施极为有限。细胞凋亡在脑缺血损伤的病理生理变化中发挥着关键作用。有效的干预凋亡，可挽救缺血半暗带受损的细胞，减轻脑损伤。但是在脑缺血中有关细胞凋亡的具体调节机制依然不明，难以进行针对性干预。申请者前期发现，GSK-3β抑制剂可升高半暗带组织的BCL-2含量，并抑制细胞凋亡。申请者近期还发现GSK-3β抑制剂可降低脑缺血后半暗带组织的BCL-2泛素化，结合BCL-2的可磷酸化位点及GSK-3β的激酶活性，再加上泛素蛋白酶体系统在细胞信号调节中的重要作用，我们认为GSK-3β对BCL-2的磷酸化调节以及BCL-2的泛素蛋白酶体降解可能在脑缺血损伤及凋亡调节中发挥着重要作用。本研究可能阐明BCL-2的蛋白酶体降解途径，完善BCL-2参与凋亡的调节机制，揭示脑缺血后线粒体相关细胞凋亡通路的关键环节。本研究可能提示中风干预的潜在靶点。

中文关键词： 脑缺血再灌注损伤；细胞凋亡；糖原合成激酶3beta；B淋巴瘤细胞2；蛋白酶体

英文摘要： Stroke, especially ischemic stroke is a huge threat to our people’s health, because of the limitation of the narrow time window of tissue type plasminogen activator therapy, there is very few intervening measures against stroke. The cellular apoptosis plays a very key role in the pathophysiology processing of cerebral ischemia injury. The effective intervention against apoptosis signal will rescue the injured cells in the ischemic penumbra, which leads to the alleviation of cerebral ischemic injury. However, the specific regulating mechanism of cellular apoptosis after cerebral ischemia is unclear, which hinders us to provide more direct intervention. The applicant found out that a GSK-3β inhibitor increased the BCL-2 protein level in the ischemic penumbra and prevented the cellular apoptosis through the primary study. Recently, the applicant observed that the GSK-3β inhibitor could decrease the ubiquitination of BCL-2 protein in the ischemic penumbra after cerebral ischemia reperfusion injury. In view of the phosphorylating site of BCL-2, the kinase enzyme activity of GSK-3β and the important role of ubiquitin-proteasome system in the cell signal regulation. We assumed that the phosphorylating regulation of BCL-2 by GSK-3β and the degradation of BCL-2 through ubiquitin-proteasome system are very likely to play a considerable important role in cerebral ischemia reperfusion injury and regulation of cellular apoptosis. The present study could elucidate the ubiquitin-proteasome degradation pathway of BCL-2, and in further to complete the BCL-2 involved apoptosis mechanism. Meanwhile, the present study would reveal the key regulation node of mitochondria associated cellular apoptosis pathway after cerebral ischemia reperfusion injury. Finally, the project results may indicate a potential effective target for stroke which has a wider therapy time window.

英文关键词： cerebral ischemia reperfusion injury;cellular apoptosis;glycogen synthase kinase-3 beta;B-cell lymphoma 2;proteasome