LncRNA XIST通过内源性竞争miR-494靶向调控ACE2/Ang-(1-7)/Mas通路抑制缺血性脑损伤神经元自噬性死亡的作用机制研究

神经元自噬性死亡会加重缺血性脑损伤。新型冠状病毒肺炎（COVID-19）合并缺血性脑损伤者高发且死亡率高，高表达ACE2的脑组织可能是COVID-19的靶器官。申请人前期发现：ACE2/Ang-(1-7)/Mas通路活化可减轻缺血性脑损伤，抑制神经元凋亡；lncRNA XIST与ACE2过表达均可抑制糖氧剥夺（OGD）所致的神经元自噬激活；XIST、miR-494与ACE2之间存在结合位点。提示XIST对缺血性脑损伤神经元自噬的抑制效应可能与调控miR-494/ACE2/Ang-(1-7)/Mas通路相关，但机制尚未明确。本项目拟从细胞、动物模型及临床样本，多层次探讨XIST通过内源性竞争miR-494靶向调控ACE2/Ang-(1-7)/Mas通路，从而抑制缺血性脑损伤神经元自噬性死亡的机制，阐明XIST对缺血性脑损伤的保护作用机制，为COVID-19合并缺血性脑损伤提供新的治疗靶点。

Autophagy death of neurons can lead to aggravate ischemic brain injury. It was found that COVID-19 patients were frequently complicated with strokes, and mortality was high. Brain tissue with high expression of human ACE2 may be the target organ of COVID-19. Our team's previous findings of the applicant: ACE2/Ang-(1-7)/Mas pathway activation can reduce ischemic brain injury and inhibit neuronal apoptosis. Both lncRNA XIST and ACE2 overexpression can inhibit neuronal autophagy activation induced by OGD. There were binding sites between XIST、miR-494and ACE2. These results suggest that the inhibitory effect of XIST on neuronal autophagy in ischemic brain injury may be related to the regulation of miR-494/ ACE2/Ang-(1-7)/Mas pathway, but the mechanism has not been defined. This project is through the perspectives of cells, animals and clinical samples, to explore the mechanism of lncRNA XIST endogenous competitive miR-494 by target regulating ACE2/Ang-(1-7)/Mas pathway to inhibit neurons autophagic death with ischemic brain injury, clarify XIST protection of ischemic brain damage effect and mechanism of action. The completion of this project, especially under the current covid-19 epidemic can provide a new therapeutic intervention targe for COVID-19 complicated with ischemic brain injury.