G6PD对脑缺血损伤的保护作用及机制研究

Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme that catalyses the irreversible reaction in the pentose phosphate pathway, generating the form of NADPH and GSH. G6PD plays an important role in cellular metabolism. TIGAR (a downstream gene of p53) can inhibit glycolysis, activate pentose pathway and reduce the production of ROS. Our recent studies have found that over-expression of TIGAR played a protective role in cerebral ischemia injury, over-expression of TIGAR could enhance the expression of G6PD and knockdown of TIGAR reduced the expression of G6PD. In this proposal, we will use the focal ischemia/reperfusion model in mice and the oxygen-glucose deprivation model in primary cortical neurons to study that (1) the roles of G6PD in ischemic damage and its neuroprotective effect. (2) the molecular mechanisms of neuronal survival affected by G6PD，and the effects of G6PD on neuron energy metabolism, DNA damage and repair. We will also clarify the significance of G6PD expression on neuronal survival, and further understand the endogenous mechanisms of neuron resistance to damage during ischemia. This proposal will provide new ideas for the treatment of stroke.

葡萄糖-6-磷酸脱氢酶(G6PD)，为磷酸戊糖途径的限速酶，催化不可逆反应，有利于促进NADPH和GSH产生。G6PD对细胞代谢有着重要影响。p53下游基因TIGAR抑制糖酵解，激活戊糖通路，能降低ROS的产生。我们近年的研究发现TIGAR过表达在脑缺血损伤中起保护作用，过表达TIGAR可增强G6PD表达，敲除TIGAR可降低G6PD表达。本研究将利用小鼠局灶缺血再灌模型和神经细胞缺糖缺氧模型研究缺血再灌时(1) G6PD在缺血性神经损伤中的作用，探索其是否发挥神经保护作用；（2）G6PD影响神经细胞生存的分子机制，探索其对神经元细胞代谢以及DNA损伤和修复的影响。本研究将阐明G6PD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，进而为治疗脑中风提供新的思路。

葡萄糖-6-磷酸脱氢酶(G6PD)，为磷酸戊糖途径的限速酶，催化不可逆反应，有利于促进NADPH和GSH产生。G6PD对细胞代谢有着重要影响。p53下游基因TIGAR抑制糖酵解，激活戊糖通路，能降低ROS的产生。我们近年的研究发现TIGAR过表达在脑缺血损伤中起保护作用，过表达TIGAR可增强G6PD表达，敲除TIGAR可降低G6PD表达。本研究将利用小鼠局灶缺血再灌模型和神经细胞缺糖缺氧模型，发现：（1）证明G6PD 在缺血再灌时快速上升，受TIGAR 调控；G6PD 的高表达增强了戊糖通路，降低ROS；G6PD 的高表达抑制4-HNE，蛋白硝基化和γH2AX 激活；G6PD的高表达发挥神经保护作用；（2）G6PD通过PPP途径在脑缺血损伤中发挥着保护作用，这种保护作用可被NADPH 模拟， NADPH也能够减轻脑缺血损伤；阐明G6PD 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。