心肌缺血再灌注损伤（MIRI）仍然是影响缺血心肌再灌注治疗获得最佳疗效的主要障碍，而钙超载是再灌注治疗心肌细胞损伤和死亡的共同通路，文献报道MIRI时钙超载引发的心肌损伤可能是通过线粒体自噬-细胞焦亡途径介导的，因此有效抑制细胞内钙超载是防治MIRI的重要举措。申请人前期发现Homer1可通过mGluR5调控细胞内钙稳态在心肌细胞氧化损伤模型中发挥保护作用，且在H/R模型的复氧阶段Homer1表达降低的同时伴有自噬小体清除能力受损，细胞焦亡水平升高。那么Homer1能否通过维持细胞内钙稳态，改善因线粒体自噬功能障碍介导的细胞焦亡，对MIRI中缺血心肌细胞发挥保护作用，尚需阐明。本研究拟以MIRI模型为基础，通过体内外实验进一步明确钙稳态对线粒体自噬-细胞焦亡途径的影响以及Homer1对这一机制的调控作用，阐明Homer1在MIRI中的保护作用及机制，为MIRI临床防治提供理论和实验依据。

Myocardial ischemia-reperfusion injury (MIRI) is still the main obstacle affecting the optimal efficacy of myocardial ischemia-reperfusion treatment, and calcium overload is a common pathway of myocardial cell injury and death in reperfusion treatment, and what's more, according to the literature, myocardial injury caused by calcium overload in MIRI may be mediated by mitophagy-pyroptosis pathway, therefore, effective inhibition of intracellular calcium overload is an important measure to prevent and cure MIRI. In our previous study, we found that Homer1 could regulate intracellular calcium homeostasis through mGluR5 and play a protective role in the oxidative damage model of cardiomyocytes, and Homer1 expression was decreased in the reoxygenation stage of H/R model, accompanied by impaired autophagosome clearance ability, and increased cell pyroptosis. Whether Homer1 can improve cell pyroptosis mediated by mitophagy by maintaining intracellular calcium homeostasis and play a protective role on ischemic cardiomyocytes in MIRI remains to be clarified. Based on the MIRI model, this study intends to further clarify the influence of calcium homeostasis on the mitophagy-pyroptosis pathway and the regulatory effect of Homer1 on this mechanism through in vivo and in vitro experiments, and clarify the protective effect and mechanism of Homer1 on MIRI, so as to provide theoretical and experimental basis for the clinical prevention and treatment of MIRI.