Mincle/Syk信号通路介导的小胶质细胞极性转化在蛛网膜下腔出血后炎性损伤中的作用及机制研究

Immune inflammatory response plays an important role in the second brain injury after subarachnoid hemorrhage (SAH). Microglia activation and polarization switch decide the degree of inflammatory injury and outcome。In Previous studies, there found mincle activation and expression mainly in microglia after SAH induction , which can increase the expression of inflammatory factor IL-1β. Mincle/syk signal pathway can be used as a new therapeutic target immune inflammatory response to reduce the central nervous system damage after SAH. This research is to study whether microglial activation and M1/M2 polarization can be regulated by Mincle/syk pathway activation or inhibition in BV2 cells, and explored its role in primary neuron culture.Then I want to find the rule of microglia polarization after SAH in punctured rats SAH models and the role of microglia polarization switch by Mincle/syk pathway activation or inhibition, and explore its molecular mechanisms. I also try to find the relationship between inflammatory response mediated by this pathway and the injury of neurovascular unit, such as the disruption of blood brain barrier,neuronal apoptosis and vascular inflammation in Mincle -/- mice SAH model, Through this research, I hope to make certain of the role of Mincle/syk pathway in the immune inflammatory injury after SAH，reveal mechanisms of the inflammatory injury of Mincle/syk pathway and explore a new way of prevention and treatment of second brain injury after SAH.

炎症反应在蛛网膜下腔出血（SAH）后继发性脑损伤中起着重要作用。小胶质细胞的活化及M1/M2极性转化决定着炎性损伤的程度及疾病转归。前期研究发现SAH后Mincle受体激活，主要于小胶质细胞表达，炎症因子IL-1β表达增高，Mincle可作为新的治疗靶点来减少SAH后早期脑损伤。本课题拟通过离体小胶质细胞，研究Mincle受体信号通路能否参与调控小胶质细胞的极性转化及对原代培养神经元细胞的作用。通过大鼠SAH模型研究SAH后小胶质细胞M1/M2型极性转化的规律，Mincle/Syk信号通路改变在小胶质细胞M1/M2型极性转化中的作用及调控机制。通过Mincle-/-敲基因小鼠模型研究该通路激活和抑制后在SAH后对神经血管单元中血脑屏障破坏，神经元凋亡以及血管炎症中的作用及分子机制，进一步揭示Mincle/syk通路在SAH后炎性损伤中的作用机制，为SAH后继发性脑损伤的防治提供理论依据。

自发性蛛网膜下腔出血(Subarachnoid Hemorrhage, SAH)是临床上最常见的脑血管病急诊之一，具有致残程度高，致死率高的特点，其病因 80-90%是由于颅内动脉瘤破裂所致。目前研究发现，SAH 后脑组织内微循环障碍、离子失衡、血脑屏障破坏、免疫炎症反应、细胞死亡通路激活、脑血管痉挛等多种病理机制共同导致血管神经功能障碍 ，但 SAH 后继发性脑损伤的机制至今尚未有阐明，免疫炎症反应作为最主要的损伤因素，可与其它各种机制相互作用，共同造成神经功能损伤。Mincle 介导的信号通路参与了小胶质细胞的极性转化，其激活促进了小胶质细胞由 M2 型（抗炎型）向 M1 型（促炎型）改变。为了深入研究Mincle在蛛网膜下腔出血后的作用，我们通过在体 SAH 模型观察蛛网膜下腔出血后小胶质细胞表型改变随时间的变化规律。 在体模型中，Mincle 受体激活会通过Mincle/Syk 通路调节小胶质细胞极性转化，参与 SAH 后炎症反应。通过脑室注入Mincle 小干扰 RNA和腹腔内注射Syk激酶抑制剂Piceatannol，能减少小胶质细胞向M1型转化，抑制免疫炎症反应的发生，减轻SAH 造成的神经元凋亡，血脑屏障通透性及血管内皮细胞损伤，为 SAH的药物治疗提供理论基础。