基于mTORC1-ULK1-FUNDC1信号通路介导的线粒体自噬探讨电针预处理抗小鼠脑I/R损伤机制

Ischemic stroke has been one of the three major causes of human death in recent years. The programmed death of injured neurons was important in the pathophysiologic process of cerebral ischemia and reperfusion (I/R) injury.The autophagy was activated after cerebral I/R and the autophagy levels was increased in the early reperfusion phase, subsequently resulting in excess autophagy.Previous studies found that electroacupuncture could downregulat the over-autophagy and significantly reduce cell death by autophagy via activating PI3K/Akt/mTOR signaling pathway.Our research also indicated that electroacupuncture could relieve cerebral ischemic injury through enhancing the acitivity of mitochondrial respiratory chain enzyme and inhibiting apoptosis of neurons. We hypothesized that electroacupuncture might inhibit over-mitophagy so that to relieve neuron program cell death and cerebral ischemia and reperfusion (I/R) injury via activating mTORC1-ULK1-FUNDC1 signaling pathway.Therefore, we reproduced cerebral I/R injury model in mice, to explore the effect of electroacupuncture on neuron mitophagy and mTORC1-ULK1-FUNDC1 signal transduction pathway. This study would clarify the therapeutic mechanisms of electroacupunture in reducing cerebral I/R injury and produce new target on preventing ischemic cerebral diseases.

缺血性脑卒中是目前人类疾病三大死亡原因之一。在脑缺血再灌注（I/R）损伤的病理生理过程中，受损神经元的程序性死亡是重要特征。脑缺血再灌注损伤缺血期神经元自噬被激活，再灌注早期，自噬进一步增强，并出现过度自噬。研究显示，电针预处理可通过激活PI3K-Akt-mTOR信号通路，下调细胞自噬作用，减少再灌注期神经元的自噬性死亡。研究还发现，电针能够明显增强线粒体呼吸链酶的活性，抑制细胞凋亡。我们推测，电针预处理可能通过激活mTORC1-ULK1-FUNDC1信号通路下调再灌注期过度激活的线粒体自噬，抑制神经元程序性死亡，减轻脑缺血再灌注损伤。为验证这一假说，我们将复制小鼠脑I/R模型，观察电针干预对神经元线粒体自噬及mTORC1-ULK1-FUNDC1信号传导通路的影响。本课题将从线粒体自噬的视角阐明电针预处理减轻脑I/R损伤的机制，同时为缺血性脑疾病的防治提供新的靶点。

脑缺血再灌注（I/R）损伤常发生于脑梗死的溶栓治疗和取栓治疗之后，严重影响患者的预后。在脑缺血再灌注损伤的病理生理过程中，受损神经元的程序性死亡是重要特征。脑缺血再灌注损伤缺血期神经元自噬被激活，再灌注早期，自噬进一步增强，并出现过度自噬。前期的研究显示，电针预处理可通过激活PI3K-Akt-mTOR信号通路，下调细胞自噬作用，减少再灌注期神经元的自噬性死亡。本研究希望通过动物实验验证，电针预处理可能通过激活mTORC1-ULK1-FUNDC1信号通路下调再灌注期过度激活的线粒体自噬，抑制神经元程序性死亡，减轻脑缺血再灌注损伤。为验证这一假说，我们将复制SD大鼠及ULK1 基因敲除小鼠脑I/R模型，观察电针干预对神经元线粒体自噬的影响，同时利用mTOR 蛋白抑制剂雷帕霉素进一步验证mTORC1-ULK1-FUNDC1 信号通路在电针预处理影响神经元线粒体自噬作用中的调控作用。研究结果基本证实了电针预处理可能通过mTORC1-ULK1-FUNDC1 信号通路调控神经元线粒体自噬，减轻了脑I/R 损伤。本研究从线粒体自噬的视角阐明电针预处理减轻脑I/R损伤的机制，同时为缺血性脑疾病的防治提供新的靶点。