脑缺血预处理通过p38 MAPK-mTOR信号通路调控神经元自噬诱导脑缺血耐受的机制研究

研究发现脑缺血预处理(CIP)可诱导脑缺血耐受，深入研究其机制可为脑缺血性疾病的防治研究提供新思路和线索，具有重要意义。自噬是溶酶体降解利用细胞内物质成分的过程，适度自噬发挥保护作用，但不完全或过度自噬可导致细胞死亡。mTOR是调节自噬的重要通路，且受p38 MAPK调控。我们前期研究证明，p38 MAPK在CIP诱导的脑缺血耐受中发挥作用。我们预实验结果提示氧-葡萄糖剥夺(OGD)预处理可能通过调节神经元自噬诱导OGD耐受。据此，我们提出CIP可能通过p38 MAPK-mTOR信号通路调控神经元自噬诱导脑缺血耐受。本研究将在整体水平和细胞水平，通过透射电镜、免疫组化、Western blot、siRNA等技术，首先证实CIP通过影响自噬诱导脑缺血耐受，在此基础上，进一步研究p38 MAPK-mTOR信号通路在细胞水平调控神经元自噬诱导缺血耐受的分子机制，为脑缺血疾病防治研究提供实验依据。

It has been found that cerebral ischemic preconditioning (CIP) can induce brain ischemic tolerance. It is important to study the mechanism involved in the process, because it will provide experiment fundament and new clue for the study in the prevention and treatment of brain ischemia. Autophagy is a process of bulk degradation of cytoplasmic components by lysosomes. Moderate autophagy plays protective effect, while incomplete or excessive autophagy can lead to cell death. mTOR is one of the important pathways regulating autophagy and is regulated by p38 MAPK. Our previous study has proved that p38 MAPK participates in the induction of brain ischemic tolerance induced by CIP. Our preliminary experiment results suggest that regulation of neuronal autophagy might contribute to the induction of oxygen-glucose deprivation (OGD) tolerance by OGD preconditioning. Taken together, we hypothesize that p38 MAPK-mTOR signaling pathway may participate in the regulation of neuronal autophagy for the induction of brain ischemic tolerance induced by CIP. The present project is aimed to prove the hypothesis in vivo and in vitro study by transmission electron microscope, immunohistochemistry, western blot, siRNA and other techniques. At first, we will study whether CIP induces brain ischemic tolerance by regulating autophagy. On the basis, we will further reveal the molecular mechanism of p38 MAPK-mTOR signaling pathway in regulating neuronal autophagy for the induction of brain ischemic tolerance by CIP. It will provide experiment fundament for the study in prevention and treatment of brain ischemia.