TIGAR在脑缺血时表达的调节及对神经损伤的影响

p53 is a tumor suppressor that plays important roles in cell death and survival. Recent studies have revealed that 53 regulates expression of SCO2 and TIGAR (TP53-induced glycolysis and apoptosis regulator), two proteins involved in regulation of cell metabolism. TIGAR can decrease the levels of fructose-2,6-biphosphate, reduce glycolysis and inhibit ROS production. Overexpression of TIGAR inhibits p53-mediated apoptosis. Crisis in energy metabolism and increase levels of ROS are major pathogenic mechanisms in ischemic brain injury. However, if TIGAR is upregulated during brain ischemia and what its roles in neuronal injury induced by brain ischemia are unexplored so far. This proposal will use mouse model of brain ischemia/reperfusion to study:(1) Brain ischemia/reperfusion-induced TIGAR expression and underlying mechanism; (2) The roles of TIGAR in neuronal death/survival under ischemia/reperfusion condition, to uncover TIAGR is a pro-survival factor; (3) The molecular mechanisms by which TIGADR affects neuronal survival, to explore if TIGAR exerts neuroprotective effects through inhibiting production of ROS and protection of mitochondria. .This study will elucidate at the first time, the role of TIGAR induction in neuronal survival after ischemia/reperfusion insult. Thus, this study will advance our understanding endogenous protective mechanisms and provide new avenue for developing strategy of effective therapy for ischemia.

p53通过其下游基因SCO2和TIGAR对细胞代谢有重要影响，为p53对细胞生存的调节开辟了新的研究领域。TIGAR能降低2，6-二磷酸果糖水平，从而抑制糖酵解和ROS的产生。在过表达p53的同时过表达TIGAR可以抑制p53介导的细胞凋亡。细胞代谢应急和ROS升高在脑缺血时是最主要的神经损伤机制。在脑缺血时TIGAR的表达是否升高以及它在脑缺血损伤中的作用未见报道，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：（1）缺血再灌时TIGAR的诱导表达及调节机制，探索是否有非p53依赖的机制；（2）TIGAR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；（3）TIGAR影响神经细胞生存的分子机制，探索其对ROS产生的抑制和线粒体的保护作用。.本研究将首次阐明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。

p53通过其下游基因SCO2和TIGAR对细胞代谢有重要影响，为p53对细胞生存的调节开辟了新的研究领域。TIGAR能降低2, 6-二磷酸果糖水平，从而抑制糖酵解和ROS的产生。细胞代谢应急和ROS升高在脑缺血时是最主要的神经损伤机制。本研究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）证明缺血再灌可诱导TIGAR表达及其上调机制不依赖p53，TIGAR的表达与缺血再灌时血糖浓度的升高在时间上有相关性，可是葡萄糖对TIGAR的表达没有影响，而调节血糖的激素（胰高血糖素，肾上腺素，糖皮质激素和胰岛素）对TIGAR的表达有调节作用，转录因子sp-1可能参与TIGAR表达的调节。正常条件TIGAR主要表达在神经元，胶质细胞的表达相对较低，TIGAR表达水平与神经元对缺血损伤的敏感性相关；（2）在缺血再灌后TIGAR定位到线粒体增加，TIGAR的高表达增强了戊糖通路，线粒体ROS减少，抑制caspase3激活，TIGAR对线粒体功能有保护作用；（3）TIGAR的上调在缺血再灌损伤中对神经元起保护作用，外源性NADPH可以减少脑梗死体积和改善中风后运动功能和认知功能的恢复；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。