运动通过激活自噬减轻线粒体损伤对老龄脑缺血再灌注发挥保护作用

Ischemic preconditioning is an important endogenous protective mechanism against ischemic brain injury, but it is not applicable in people. Previous researches have demonstrated that autophagy activation plays an important role in the neuroprotection for brain ischemic injury. It has been well established that physical exercise can exert neuroprotection and anti-aging effects on aged brains both in clinical settings and animal models, and physical exercise also can prevent and rehabitate stroke. It has been revealed that autophagy in brain declines with age, and exercise can induce activation of autophagy. Based on these data, we propose that exercise could exert the protective effects like IPC in aged brains by autophagy induction. To test this, we will: (1)investigate the roles of autophagic signaling pathway in brain ischemic/repurfusion injury in young and old mice; (2) investigate if exercise could induce autophagy and reduce brain inchemia/repurfusion injury in aged mice; (3) investigate how autophagy induction contribute to the neuroprotective effects of exercse by modulating autophagy activity; (4) investigate the effects of autophagy induction on mitochondria damage and apoptosis by modulating the function of permeability transition pore, determine the role of autophagy induction in this process. This study study the protective effects and mechanism of exercise and autophagy on brain ischemia/repurfusion injury in aged mice, and shed light upon the stuy of the mechanism of brain ischemia/repurfusion injufy, also the prevention and treatment of brain ischemia in aged people.

缺血预适应是缺血脑保护的重要内源性机制，但在现实中却无法应用。前期研究证实适时、适度自噬激活对脑缺血再灌损伤起保护作用。运动具有抗衰老和神经保护作用，能有效预防和康复缺血性脑中风。已知老龄脑自噬功能下降，但适宜运动能增强自噬活性。据此我们推测，适宜运动能通过提高自噬活性发挥与缺血预适应同样的效应，对老龄脑缺血再灌损伤发挥保护作用。本课题旨在：1.观察自噬信号通路在青年和老年脑缺血再灌损伤中的作用有何差异；2.观察适宜运动能否激活自噬和减轻老龄小鼠脑缺血再灌损伤；3.通过调控自噬活性研究自噬激活在运动引起的神经保护作用中的贡献；4.通过调控线粒体通透转运孔开放研究自噬活性增强对线粒体损伤及细胞凋亡的影响，证明运动发挥作用的机制。本课题首次在器官、细胞及分子水平上探讨运动、细胞自噬在老龄小鼠脑缺血再灌损伤中的保护作用及机制，为老年脑缺血再灌注损伤机制的研究和老年脑缺血疾病的防治提供新的思路。

缺血预适应是缺血脑保护的重要内源性机制，但在现实中却无法应用。前期研究证实适时、适度自噬激活对脑缺血再灌损伤起保护作用。运动具有抗衰老和神经保护作用，能有效预防和康复缺血性脑中风。已知老龄脑自噬功能下降，但适宜运动能增强自噬活性。据此我们推测，适宜运动能通过提高自噬活性发挥与缺血预适应同样的效应，对老龄脑缺血再灌损伤发挥保护作用。本课题取得如下研究成果：1.发现自噬信号通路在青年和老年脑缺血再灌损伤过程中的变化存在差异；2.发现适宜运动能激活自噬和减轻老龄小鼠脑缺血再灌损伤；3.通过调控自噬活性，发现自噬激活在运动对衰老脑的神经保护作用发挥重要作用；4.通过调控自噬活性，发现自噬活性增强对衰老线粒体功能、线粒体质量控制具有改善作用，是运动发挥神经保护作用的重要机制。本课题首次在器官、细胞及分子水平上探讨运动、细胞自噬在老龄小鼠脑缺血再灌损伤中的保护作用及机制，为老年脑缺血再灌注损伤机制的研究和老年脑缺血疾病的防治提供了新的思路。