mtUPR介导的“神经元自救”在脑动脉内靶向亚低温治疗脑梗死中的机制研究

随着急诊取栓的发展，血流再通基础上的动脉内靶向亚低温治疗缺血性脑卒中逐渐受到关注。我们既往发现亚低温促进健康线粒体跨细胞转移至缺血神经元，改善卒中预后。但是亚低温对缺血神经元内受损线粒体有何作用？通过预实验，我们发现恒河猴脑梗死周围脑组织线粒体未折叠蛋白反应（mtUPR）相关蛋白表达显著增高，且与脑损伤程度密切相关；亚低温显著减小大鼠脑梗死体积，上调ATF4/ATF5/CHOP mRNA水平。因此我们推测：血流再通基础上的动脉内靶向亚低温，通过作用于mtUPR，重塑脑缺血后线粒体稳态平衡，促进神经元自救发挥神经保护作用。本项目拟通过细胞、大鼠、恒河猴脑缺血模型，构建慢病毒载体干预整合应激反应、ATF4/ATF5/CHOP等表达，从mtUPR介导的“神经元自救”这一微观现象出发，研究亚低温神经保护机制，进一步探讨其上游调控和下游效应机制。本项目将从新的视角为亚低温用于取栓患者提供理论依据。

With the development of mechanical thrombectomy, intra-arterial targeted mild hypothermia based on blood flow recanalization has gradually attracted more attention. We have previously found that mild hypothermia promotes the transcellular transfer of healthy mitochondria to ischemic neurons and improves the prognosis of stroke. However, what is the effect of mild hypothermia on damaged mitochondria in ischemic neurons? We have found that the expression of mitochondrial unfolded protein response (mtUPR) related proteins in the brain tissue around the cerebral infarction of rhesus monkeys were significantly increased, which was related to the degree of brain injury; mild hypothermia also significantly reduced the cerebral infarction volume in rats model, and increased the mRNA level of ATF4/ATF5/chop. Therefore, we speculate that mild hypothermia exerts neuroprotective effect through the action on mtUPR, which remodels the mitochondrial homeostasis after cerebral ischemia, and promotes the "self-rescue of neuron". In this study, we will use lentivirus vector to interfere with the expression of integrated stress response and ATF4/ATF5/CHOP through cell, rat and rhesus monkey models of cerebral infarction. We will elucidate the mechanism of mild hypothermia neural protection from the microscopic phenomenon of "self-rescue of neuron" mediated by mtUPR, and further explore its upstream regulation and downstream mechanisms. Taken together, this study will provide theoretical basis for the application of mild hypothermia in mechanical thrombectomy from a new perspective.