缺血性脑卒中神经损伤和修复的炎性机制研究

With the development of aged population, stroke has become one of the major worldwide diseases with very high morbidity and mortality. Numerous efforts have been put into the investigation on the role of blood vessel cells or individual types of neurons, which partially warrants the explanation of underlying mechanism of cerebral ischemia and reperfusion injury. However, the detailed cellular and molecular mechanism needs to be further demonstrated to underpin the novel molecular mechanism of microglial activation and the role of neuro-inflammation in the neural injury and neural recovery upon stroke. Our previous studies identified that Hippo pathway plays an important role in oxidative stress-induced neuronal cell death. Most recently, we also found that Hippo signaling is critical for microglia activation and neuro-inflammation among stroke-induced neural injury. Therefore, in this proposal, we firstly aim to investigate how the innate recognition receptor (cGAS) and autophagy (Atg5) specifically influence the stroke-induced microglial activation by utilizing genetic and chemical manipulation. Secondly, we aim to define the cellular and molecular events underlying ischemia-mediated neuronal cell death upon microglial firing. Finally, we try to elucidate the function of neuro-inflammation in the neurogenesis after stroke. Together, this study will explain the novel molecular mechanism of the interplay between microglial activation and neural injury/regeneration upon ischemia/reperfusion, with a strong implication for the therapeutic avenue in the treatment of ischemia-related diseases, especially brain stroke.

脑卒中的发病率逐年增高，具有极高的致残率和致死率，严重危害人类健康。大量的研究从血管和不同类型神经细胞的角度部分揭示了脑卒中发生发展的机理。我们的工作系统地阐明了Hippo通路在氧化应激诱导下神经元死亡的作用和机制，同时发现了小胶质细胞介导的神经炎症在神经损伤中起到重要的作用，脑卒中导致神经损伤的神经炎症机制亟待深入。在前期的工作基础上，拟利用分子、细胞生物学和信号转导的研究手段，通过遗传操作和靶点药物操作的方法，结合脑卒中疾病模型，重点研究脑缺血再灌注后小胶质细胞激活过程中，先天免疫识别受体cGAS的作用及其调控机制；阐明自噬在小胶质细胞激活和神经损伤中的功能和分子机理。在脑卒中发生发展中，分别从神经炎症的产生机制，神经炎症介导神经损伤的机理，和神经炎症对于神经损伤后修复与再生的作用及其机理三个主要方面，阐明脑卒中神经损伤和修复的炎症机理，为脑卒中的临床治疗提供理论依据和潜在的治疗靶点。

脑卒中具有极高的致残率和致死率，随着社会的发展和人口老龄化的加剧，其发病率逐年增高，严重危害人类健康。本项目利用分子、细胞生物学和信号转导的研究手段，通过遗传操作和靶点药物操作的方法，结合脑卒中疾病模型，我们分别从神经炎症的产生机制，神经炎症介导神经损伤的机理，和神经炎症对于神经损伤后修复与再生的作用及其机理三个主要方面展开研究。我们发现小胶质细胞介导的神经炎症在脑卒中引起的神经损伤中起到重要的作用。主要结果包括（1）HDAC3-cGAS信号通路参与缺血性脑卒中的神经炎症和神经损伤发展过程并发挥重要作用。（2）E3泛素连接酶Mib2可以调控NF-κB信号通路的激活，并且在缺血性脑卒中引起的小胶质细胞激活中发挥重要作用。（3）小胶质细胞自噬在小胶质细胞激活中发挥关键作用。小胶质细胞中特异性敲除Atg5可以引起小胶质细胞激活，引起脑内神经炎症。以上研究详细阐明了脑卒中神经损伤和修复的炎症机理，为脑卒中的临床治疗提供理论依据和潜在的治疗靶点。