Nck1在NMDA受体介导的缺血性神经损伤中的作用及其机制研究

缺血性脑卒中是致死率极高的神经系统疾病。缺血后由NMDA受体介导的兴奋性毒是神经元死亡的主要原因。然而，在脑缺血损伤过程中全面阻断NMDA受体功能来保护神经元的治疗方案迄今未获得成功。近年来，以特定NMDA受体亚型为治疗靶点的干预方案已取得了有希望的进展。因此，深入理解不同亚型的NMDA受体复合物的组成及相应介导的信号通路有助于开发特异且有效的脑缺血损伤治疗手段。我们前期的发现提示Nck1蛋白可能在NMDA受体复合物中作为支架蛋白起到征募Src激酶从而调控NMDA受体磷酸化，尤其是GluN2A酪氨酸1246位点磷酸化的功能。我们希望综合运用一系列实验技术手段，如分子生物学、细胞成像、生化、整体动物模型等全面并深入地解析Nck1作为NMDA受体复合物中的成员在脑缺血过程中的作用，同时希望这种探索有助于推进以特定亚型的NMDA受体为靶点的脑缺血治疗进展。

Stroke is a major course of death in the world as a neurological disease. Excessive activation of NMDA receptor is a primary factor of neuronal death caused by excitotoxicity after ischemia. However, inhibition of the total NMDA receptor has not been successful in treating ischemia of brain. Otherwise, it is reported that intervention of certain type of NMDA receptor and its corresponding signal pathway is succeed in rodent and primate animal model of stroke. Therefore, for developing specific and effective treatment of ischemia, more efforts are needed to better and deeply understand the roles of different subtypes of NMDA receptor complex and their mediating signal pathway in ischemia. Based on our preliminary results, we proposed that Nck1, a member of NMDA receptor complex, played a scaffolding role in recruiting Src kinase for facilitating its phohorylating NMDA receptor, especially for a novel tyrosine phosphorylation site of 1246 of GluN2A, a subunit of NMDA receptor. Combining molecular cloning, cell imaging, biochemistry and animal model, the project herein will provide comprehensive as well as in-depth illustration of the role of Nck1 as a member of NMDA receptor complex in ischemia, hoping the exploration carried out in the project will enable us to promote the advance of dealing with ischemia by targeting NMDA receptor.