p75ICD调控p35-p25/CDK5信号通路在脑出血诱导的神经元凋亡中的作用

项目名称： p75ICD调控p35-p25/CDK5信号通路在脑出血诱导的神经元凋亡中的作用

项目编号： No.81471188

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 曹茂红

作者单位： 南通大学

项目金额： 70万元

中文摘要： 脑出血后血肿周围组织继发性损伤涉及众多因素，其中兴奋性毒性、炎症反应对脑出血后神经元凋亡尤为重要。前期研究中，我们发现并证实p35-p25/CDK5信号通路在脑出血后神经元凋亡中有重要作用。p35作为CDK5主要激活因子，其裂解生成p25与钙离子内流、炎症介质释放密切相关。我们又发现神经营养因子受体p75ICD与p35相互作用，由此引出对p75ICD如何参与调节p35-p25/CDK5信号通路来介导脑出血后神经元凋亡的思考。本课题拟从ICH动物模型研究p35、p25、CDK5活性的表达；通过培养原代神经元、工具细胞检测p75ICD与p35的相互作用、作用位点，及谷氨酸盐、炎症介质刺激原代神经元分析p75ICD对p35-p25/CDK5的调控机制；最后在整体模型中靶向干预p75ICD的表达，综合分析以明确p75ICD在p35-p25/CDK5凋亡通路中的意义，从而为脑出血的治疗提供新的思路。

中文关键词： 脑出血；神经元；凋亡；p75ICD；p35-p25/CDK5

英文摘要： Multiple mechanisms, especially mediated by excitotoxity and inflammation, were involved in secondary nerve injury of perihematoma following intracerebral hemorrhage. According to our previous investigation, we acknowledged that p35-p25/CDK5 signaling pathway played an important role in neuronal apoptosis of ICH. p35, the main neuronal specific activator of CDK5, was closely associated with the influx of calcium ions as well as the release of inflammtory mediator to cleave to its more stable active p25 form. Using co-immunoprecipitation, we discovered the relationship of p35 with p75ICD, a truncated mutant of p75 neurotrophic factor receptor, in vitro and in vivo, indicating involvement of p75ICD in regulating the p35-p25/CDK5 signaling pathway upon neuronal apoptosis following ICH. Thus, further investigation of possible function of p75ICD in the process was needed. Based on this hypothesis, we aimed to study the expression of p35, p25 and CDK5 activity upon apoptosis by establishing an ICH rat model. Then, we examined the interaction between p75ICD and p35 as well as its potential action sites by incubating primary cortical neuron and HEK-293T. Furthermore, glutamate and inflammatory mediator were used to stimulus primary cortical neuron to expound the underlying mechanism of regulations. Eventually, we wanted to clarify the influence of p75ICD upon neuronal apoptosis induced by p35-p25/CDK5 following ICH through interventing the expression of p75ICD in rat. Thus，a new idea can be provided to clinical treatment of ICH.

英文关键词： ICH;neuron;apoptosis;p75ICD;p35-p25/CDK5