细胞间Connexin43通过调节AQP4对脑缺血后损伤及对侧区域神经再生效应的研究

项目名称： 细胞间Connexin43通过调节AQP4对脑缺血后损伤及对侧区域神经再生效应的研究

项目编号： No.81500998

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： 褚鹤龄

作者单位： 复旦大学

项目金额： 17.5万元

中文摘要： 脑缺血后可诱导神经再生，但集中在侧脑室壁的脑室下区（SVZ）和海马齿状回的颗粒下层（SGZ）的神经干细胞如何增殖并迁移到梗死及对侧区域尚未明确。研究表明，细胞间缝隙连接蛋白43（Cx43）和水通道蛋白4（AQP4）都是神经再生的重要因子，Cx43可传递多种信号，包括MAPK。我们既往的研究显示，AQP4基因敲除可上调炎性因子表达，MAPK通路的激活可上调AQP4表达。故我们推测，脑缺血后的损伤信号可能通过Cx43传递，使得SVZ及SGZ中AQP4表达变化，调节炎性因子水平，促进神经干细胞增殖后向梗死及对侧区域迁移。本课题应用两种方法，即免疫双标定点观察及小动物正电子发射显像（microPET）在活体进行三维动态连续观察，更系统研究Cx43在脑缺血后梗死及对侧半球皮层、SVZ及SGZ神经再生的作用，并探讨该作用是否与调节AQP4的表达相关，同时研究Cx43调节AQP4表达可能的信号转导通路。

中文关键词： 缝隙连接蛋白43；；水通道蛋白4；脑缺血；神经再生；小动物PET

英文摘要： Neurogenesis can be induced by cerebral ischemia. However, the neural stem cells (NSCs) are predominantly concerntrated in subventricular zone (SVZ) and subgranular zone (SGZ) in adult mammalian. Mechanisms on how NSCs in these locations are proliferated and migrate to infarcted and contralateral regions still remain unknown. It is demonstrated that both intercellular connexin43 (Cx43) and aquaporin4 (AQP4) are essential for neurogenesis and there is a close relation between them. Meanwhile, Cx43 plays important roles in transduction of multiple signals, including mitogen-activated protein kinase (MAPK). Our previous studies revealed that AQP4 knock-out can increase proinflammatory cytokines expression, besides, activation of MAPK pathways induces AQP4 up-regulation. Therefore, we conclude that the damage signal pathways caused by cerebral ischemia may be transducted through Cx43, which may change AQP4 expression in SVZ and SGZ and regulate proinflammatory cytokines, resulting in proliferation of NSCs and migration to infarcted and contralateral regions to promote neural restoration. We choose two different methods: double immunofluorescence labeling is for observation at certain time points and micro-positron emission tomography (microPET) is for 3D dynamic and continuous observation in living mice, so as to comprehensively study effects of Cx43 on neurogenesis after cerebral ischemia in infarcted and contralateral cortex, SVZ and SGZ. Furthermore, we investigate whether regulation of AQP4 is involved in these effects of Cx43 and the possible signal pathways through which AQP4 expression is regulated by Cx43. The results may be helpful for development of new drugs to promote neural restoration after cerebral ischemia.

英文关键词： connexin43;aquaporin4;cerebral ischemia ;neurogenesis;microPET