TIGAR调节磷酸戊糖途径在缺血性脑中风星形胶质细胞死亡中的作用和机制

Astrocyte death is an important mechanism in the pathophysiology of cerebral ischemia. Preventing astrocyte death may contribute to the improvement of neurological deficits induced by ischemic brain injury. The cause of astrocyte death is cell metabolic crisis and microenvironment destruction caused by ischemia hypoxia. TP53-induced glycolysis and apoptosis regulator (TIGAR) is reported to inhibit glycolysis and increase the flow of pentose phosphate pathway. In our preliminary works, we found that TIGAR was up-regulated in astrocyte after cerebral ischemia and reperfusion, and promoted the survival of astrocyte. In the present proposal we will use conditioned TIGAR knockout mice and transgenic mice, permanent middle cerebral artery occlusion, in vitro hypoxia model mediated by the oxygen-glucose deprivation to find: ① The relationship between TIGAR expression in astrocyte and brain injury induced by ischemia; ②The effects of TIGAR-regulated PPP on cell metabolic homeostasis, DNA damage and endoplasmic reticulum (ER) stress；③The effects of TIGAR-regulated PPP on cell inflammation in astrocytes. The significance of these studies will reveal the important role and underlying mechanisms of TIGAR for astrocyte survival under ischemic condition, the proposed study will also suggest a new research direction for stroke treatment.

星型胶质细胞死亡是脑缺血的重要病理机制。阻止星形胶质细胞死亡可改善缺血性脑损伤神经功能。星形胶质细胞死亡起因主要是由于缺血缺氧造成的细胞代谢危机和微环境破坏。TIGAR是p53靶基因，主要作用是抑制糖酵解和激活戊糖旁路。我们前期研究发现TIGAR在缺血后星形胶质细胞中激活，并向线粒体，内质网和细胞核定位增多，对星形胶质细胞生存有重要作用。本课题将充分利用条件性TIGAR敲除和转基因鼠，应用大脑中动脉局灶性脑缺血再灌模型和体外原代培养大脑皮层星形胶质细胞缺氧缺糖/复氧复糖模型研究：①星形胶质细胞内TIGAR表达与缺血后脑损伤的关系；②TIGAR对缺血时细胞代谢稳定、DNA损伤和内质网应激的影响；③TIGAR对缺血时细胞炎症反应的影响。本项目旨在阐明TIGAR在星形胶质细胞抗缺血损伤中的重要作用及作用机制，为缺血性脑中风提供新的研究方向。

星型胶质细胞死亡是脑缺血的重要病理机制。阻止星形胶质细胞死亡可改善缺血性脑损伤神经功能。星形胶质细胞死亡起因主要是由于缺血缺氧造成的细胞代谢危机和微环境破坏。TIGAR是p53靶基因，主要作用是抑制糖酵解和激活戊糖旁路。我们前期研究发现TIGAR在缺血后星形胶质细胞中激活，并向线粒体，内质网和细胞核定位增多，对星形胶质细胞生存有重要作用。本课题将充分利用条件性TIGAR敲除和转基因鼠，应用大脑中动脉局灶性脑缺血再灌模型和体外原代培养大脑皮层星形胶质细胞缺氧缺糖/复氧复糖模型，发现：（1）脑缺血后胶质细胞内TIGAR表达增加，过表达TIGAR减轻OGD/R诱导的胶质的死亡和减少脑缺血损伤；（2）过表达TIGAR 可以抑制缺血再灌诱导的细胞焦亡；（3）使用TIGAR-转基因（tg-TIGAR）小鼠和TIGAR-敲除（ko-TIGAR）小鼠，经过脑缺血处理后，过表达TIGAR对脑缺血损伤发挥着神经保护作用，而敲除TIGAR可加重脑缺血损伤。进一步阐明TIGAR 表达对神经细胞生存的意义，进一步了解缺血时神经细胞内源性的抗损伤机制，为寻找新的神经保护提供思路。