Apelin-13通过SIRT3抑制NLRP3炎性小体介导的细胞焦亡在脑缺血再灌注损伤中的作用研究

缺血性脑卒中是成年人致死致残的主要原因之一，目前尚无有效的药物治疗手段。我们前期研究发现，apelin-13对脑缺血再灌注损伤具有神经保护作用，能够明显增加SIRT3的表达并且能够抑制NLRP3炎性小体介导的细胞焦亡。但敲除SIRT3后，apelin-13不能够抑制NLRP3炎性小体介导的细胞焦亡进而不能发挥神经保护作用。因此，我们提出“Apelin-13通过调控SIRT3抑制NLRP3炎性小体介导的细胞焦亡改善脑缺血再灌注损伤”的科学假设。本项目将在动物和细胞水平敲除和过表达SIRT3并建立脑缺血再灌注模型，应用行为学、电镜、RNA scope、western blot和免疫荧光双标等方法研究。系统阐明apelin-13通过SIRT3抑制NLRP3炎性小体介导的细胞焦亡而发挥神经保护作用及分子机制，有助于探讨apilen-13成为神经保护剂的可能性及作用靶点，为脑卒中的防治提供新策略。

Ischemic stroke is a leading cause of death and disability for adults, and there is no effective drug treatment. Our previous study found that apelin-13 has a neuroprotective effect on cerebral ischemia-reperfusion injury. Apelin-13 can significantly increase the expression of SIRT3 and inhibit the NLRP3 inflammasome-mediated pyroptosis. However, apelin-13 could not inhibit the NLRP3 inflammasome-mediated pyroptosis and thus could not exert a neuroprotective effect after knocking out SIRT3. Therefore, this project proposed the scientific hypothesis that "Apelin-13 inhibits NLRP3 inflammasome-mediated pyroptosis via SIRT3 and ameliorates cerebral ischemia/reperfusion injury". In this project, the SIRT3 will be knockout and overexpressed at the animal and cellular model and a cerebral ischemia/reperfusion model will be established. The behavioral, electron microscopy, RNA scope, western blot, and immunofluorescence double-labeling methods will be used. This project systematically clarifies that apelin-13 exerts neuroprotective effects and molecular mechanisms by inhibiting NLRP3 inflammasome-mediated pyroptosis via SIRT3. This project helps to explore the possibility and target of apelin-13 as a neuroprotective agent and provides a new strategy for the prevention and treatment of stroke.