脑梗死后神经元死亡可释放有害物质激活小胶质细胞导致炎症。已知caspase-8（Cas8）介导小胶质细胞活化引起炎症及神经元毒性。我们发现Cas8主要在大鼠脑的小胶质细胞表达，并在脑缺血后表达上调，提示Cas8参与缺血后小胶质细胞活化。我们推测：脑梗死后损伤神经元释放有害物质，通过Cas8通路，激活小胶质细胞产生炎症因子。炎症因子反作用于神经元加剧其死亡并诱发脑内炎症级联反应。本项目拟采用CreLysMCas8fl/fl小鼠在小胶质细胞敲除Cas8基因，结合凋亡、程序性坏死通路阻断剂、RNA干扰抑制Cas8活化或表达，通过分子生物学、组织病理学等手段，在脑梗死动物模型上检测小胶质细胞活化，炎症因子表达，神经元死亡，脑梗死面积，血脑屏障及脑水肿等变化，从细胞及动物水平验证上述假说。本课题有望揭示Cas8在小胶质细胞活化及脑梗死后炎症级联反应中的作用及机制，为脑梗死后炎症干预治疗提供理论基础。

Microglia can be activated by the harmful factors released from dead neurons after cerebral infarction, then induced the over-expression of inflammatory factors and brain damage. Recently, several studies reported that the activation and neurotoxic effect of microglia depend on caspase-8 (Cas8). In our previous experiments, we found that Cas8 is expressed richly in microglia and up-regulates after global cerebral ischemia/reperfusion injury in the brain of rat model, suggested that Cas8 may be involved in the activation of microglia after cerebral ischemia. Based on these, we propose that, harmful factors released from dead neurons activate microglia through caspase-8 dependent manner; microglial activation leads to inflammatory cascade for the overexpression and release of inflammatory cytokines; inflammatory damage and neuronal death are enlarged by these cytokines. In this project, we tried to use kinds of technology and methods, such as signal pathway inhibitors, RNA interference to inhibit the expression of caspase-8, CreLysMCasp8fl/fl mice, to prove our hypothesis in cultured microglia and animal models of middle cerebral artery occlusion. The activation of microglia, the expression of inflammatory cytokines, neuronal death, brain infarct volume, behavior, the damage of blood brain barrier and brain edema will be detected. The implementation of the project is expected to reveal the role of caspase-8 in microglia activation and inflammatory cascade after brain infarction, thus providing a theoretical basis for the intervention of inflammatory injury after cerebral infarction.