IRF5诱导小胶质细胞极化在脑缺血后神经元损伤中的作用及机制

项目名称： IRF5诱导小胶质细胞极化在脑缺血后神经元损伤中的作用及机制

项目编号： No.81471864

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： 尹昌林

作者单位： 中国人民解放军第三军医大学

项目金额： 69万元

中文摘要： 原发与继发神经损伤导致的功能障碍是影响脑缺血及创伤性脑损伤患者生存及生活质量的重要因素。小胶质细胞(MG)是脑炎症反应最主要的免疫细胞，脑缺血早期即被激活并释放大量炎性因子，在继发性神经损伤中发挥重要作用，但其极化调控的机制尚不清楚。我们前期研究发现：下调干扰素调节因子5（IRF5）可以减弱内毒素（LPS）诱导MG的I型极化，降低I型极化分子表达，而增强IRF5表达则MG的I型极化增强。我们推测：IRF5调控MG极化在缺血性脑损伤中发挥重要作用，其机制可能与髓样分化因子（MYD88）依赖的信号通路有关。本课题拟在前期工作的基础上，证实大鼠缺血性脑损伤模型中IRF5信号及MG极化发生变化，探讨大鼠缺血性脑损伤模型及MG与神经元共培养体系中IRF5信号调控MG极化的机制及对早期继发神经损伤的影响。本课题将深化对缺血性脑损伤后神经继发损伤机制的认识，并为其探索新的干预靶点和治疗措施。

中文关键词： IRF5；小胶质细胞；极化；神经元损伤；缺血性脑损伤

英文摘要： The dysfunction caused by primary and secondary neuron injuries is an important factor that impacts the survival and quality of life in brain ischemia and traumatic brain injury patients. As the main immune cell for inflammation in brains, microglia (MG) is activated at early stage of brain ischemia and releases a large number of inflammatory cytokines, participates in early secondary injury of neuron, but the mechanism of its polarization remains unclear. we demonstrated that interfering on interferon regulatory factor 5 (IRF5) decreased the type I polarization of MG to LPS and reduced the expression of type I polarization molecules, yet overexpression of IRF5 could enhance the type I polarization of MG. We hypothesesed that MG polarization controlled by IRF5 may play a key role in ischemic brain injury, and MYD88-dependent signaling pathway might be the molecule basis. In this study based on our previous work, changes of IRF5 signal and MG polarization in a rat ischemic brain injury model would be conformed firstly，then by using methods such as overexpression of or interference on IRF5 signaling genes, real time PCR(RT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting(WB) and immunohistochemistry (IHC), we try to demonstrate the mechanism of MG polarization controlled by IRF5 and its role on neuron injury at early stage in a rat ischemic brain injury model and a co-culture system of MG and neuron. These data might shed light on the mechanism of secondary neuron injury post brain ischemia, thus exploring novel intervention targets and therapies.

英文关键词： IRF5;microglia;polarization;neuron injury;brain ischemia