蛋白激酶Cgamma在缺血性脑卒中鼠脑皮层神经元缺血损伤中作用及其分子机制研究

项目名称： 蛋白激酶Cgamma在缺血性脑卒中鼠脑皮层神经元缺血损伤中作用及其分子机制研究

项目编号： No.31471142

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生理学与整合生物学

项目作者： 李俊发

作者单位： 首都医科大学

项目金额： 86万元

中文摘要： 脑卒中是高发病率、高致残率和致死率的脑重大疾病，但目前对占脑卒中发病60-70%的缺血性脑卒中临床治疗尚缺乏有效措施，主要原因是人们对脑内源性神经保护机制的认识不清。我们已发现参与脑低氧预适应形成的神经元特异性蛋白激酶C(cPKC)gamma及其19个相互作用蛋白可保护缺血脑组织；脑缺血损伤程度与脑内cPKCgamma表达量呈负相关。据此，本课题拟利用cPKCgamma基因敲除小鼠、脑中动脉阻塞(MCAO)缺血性脑卒中和原代培养皮层神经元氧-糖剥夺(OGD)缺血模型，借助神经行为学、细胞生物学、生物化学和分子生物学等学科技术，明确cPKCgamma及其特定相互作用蛋白在脑缺血神经细胞急性坏死、程序性坏死、凋亡和自噬中作用及其cPKCgamma信号转导机制。成果将丰富人们对脑缺血损伤机制和脑内cPKCgamma特异信号转导通路的认识，并为缺血性脑卒中的防治提供有效的干预措施或生物分子标记物。

中文关键词： 脑低氧预适应；缺血性脑卒中；蛋白激酶C；gamma；细胞凋亡；程序性坏死

英文摘要： Stroke is one of the main brain disorders with a high incidence of morbidity, disability and mortality. Ischemic stroke accounts for 60-70% of the total stroke patients. However, the current therapies for ischemic stroke are limited to symptomatic treatment such as thrombolysis, and still lack the effective therapeutic methods. We have found that classical protein kinase C (cPKC)gamma and its 19 identified interacting proteins were involved in the development of cerebral hypoxic preconditioning and protected brain against ischemic injury;and the extent of cerebral ischemic injury negatively correlated with endogenous cPKCgamma expression levels in brain. Therefore, this project will use cPKCgamma gene knockout mice, middle cerebral artery occlusion (MCAO)-induced cerebral ischemic stroke in vivo as well as oxygen-glucose deprivation (OGD)-induced ischemic injury in primary cultured cortical neurons in vitro. The role of cPKCgamma and its interacting proteins in ischemia-induced cell acute necrosis, necroptosis, apoptosis and autophagy and its cPKCgamma isoform-specific signal transduction mechanism will be systematically explored by using the techniques of behavioral test, cell biology, biochemistry and molecular biology. The achievements of this study will enrich our understanding of cPKCgamma-specific signal transduction pathway underlying cerebral ischemic injuries, and provide molecular targets or biomarkers for prevention and treatment of ischemic stroke in clinic.

英文关键词： Cerebral hypoxic preconditioning;Ischemic stroke;PKC gamma;Apoptosis;Necroptosis