PHLDA3对脑缺血损伤的影响及其调节机制

脑缺血损伤严重威胁人类健康和生命，其机制尚未完全阐明。PHLDA3是一个p53下游基因，参与凋亡、炎症、细胞增殖等多种病理生理机制的调控。但是PHLDA3在脑缺血损伤中作用和机制尚未见报道。我们的预实验发现在脑缺血再灌中PHLDA3表达上调，部分向内质网和线粒体定位增加，下调PHLDA3表达可降低缺血/再灌引起的自噬水平上调和炎症因子释放，阻止神经元死亡，提示PHLDA3可能介导了缺血后神经损伤。因此，本项目将采用小鼠局灶缺血再灌模型和神经细胞缺糖缺氧模型，应用多种分子生物学方法等手段，研究：（1）PHLDA3表达在脑缺血损伤中作用；（2）PHLDA3调控内质网应激，线粒体功能及炎症反应的分子机制；（3）PHLDA3对自噬和凋亡通路的调节机制在脑缺血损伤中的作用。旨在阐明PHLDA3在脑缺血损伤中的作用及机制，提出神经损伤的新靶点，为今后脑缺血损伤防治研究提供新的思路。

Brain ischemic injury is a serious threat to human health and life, and its mechanism has not been fully elucidated. As a downstream gene of p53, phlda3 is involved in the regulation of apoptosis, inflammation, cell proliferation and other pathophysiological mechanisms. However, the role and mechanism of phlda3 in cerebral ischemic injury have not been reported. In our preliminary works, we found that the expression of phlda3 was up-regulated, and partly localized to endoplasmic reticulum and mitochondria. Down-regulated of phlda3 expression could reduce the level of autophagy and the release of inflammatory factors caused by ischemia/reperfusion, and prevent the death of neurons, suggesting that phlda3 could mediate the neuronal injury after ischemia. Therefore, in the present proposal, we will use focal ischemia-reperfusion model in mouse and in vitro hypoxia model mediated by the oxygen-glucose deprivation, and a variety of molecular biological methods to study：(1) the role of phlda3 expression in cerebral ischemia-reperfusion injury; (2) the molecular mechanism of phlda3 regulating endoplasmic reticulum stress, mitochondrial function and inflammatory response; (3) the regulatory mechanism of phlda3 on autophagy and apoptosis pathway in cerebral ischemia-reperfusion injury. The purpose of this study is to elucidate the role and mechanism of phlda3 in cerebral ischemic injury, and to propose a new target of neuronal injury, so as to provide a new research direction for the treatment of stroke.