糖尿病心肌更易遭受缺血再灌注损伤（IRI），研究发现其与内质网应激-线粒体自噬稳态失衡密切有关，但机制不明。新近研究表明线粒体相关内质网膜(MAM)在调节内质网与线粒体功能方面具有重要作用。我们预实验发现，Caveolin-3（Cav-3）存在于心肌细胞MAM中，并与Ca2+调节蛋白VDAC1/IP3R1形成复合体；糖尿病心肌Cav-3表达下降伴随VDAC1/IP3R1表达增加，促进Cav-3表达进而下调VDAC1/IP3R1能抑制内质网应激与MAM相关蛋白表达，并能提高线粒体自噬相关蛋白表达，从而抗心肌IRI。我们推测促进Cav-3表达进而下调VDAC1/IP3R1是恢复内质网应激-MAM-线粒体自噬稳态及抗糖尿病心肌IRI的关键。本项目拟在在体心脏与离体细胞模型上探索Cav-3通过VDAC1/IP3R1调控内质网应激-MAM-线粒体自噬稳态的分子机制，为防治糖尿病心肌IRI提供新思路。

Diabetic hearts are more vulnerable to ischemia reperfusion injury (IRI) as compared to non-diabetics. Although the mechanisms governing the increased vulnerability of the diabetic heart to IRI remain unclear, the imbalance of endoplasmic reticulum stress-mitophagy hemostasis has been suggested to play a critical role in its pathology. The mitochondrial-associated endoplasmic reticulum membrane (MAM) is a recently identified regulator that plays an important role in regulating the functions of endoplasmic reticulum and mitochondria. Our preliminary study found caveolin-3 was present in MAM preparations, and caveolin-3 and VDAC1/IP3R1 have physical interaction by co-immunoprecipitation assay. Further studies showed decreased caveolin-3 expression was accompanied with increased VDAC1/IP3R1 expression in diabetic hearts. Improving caveolin-3 expression resulting in decreased VDAC1/IP3R1 expression could attenuate the related protein expression of endoplasmic reticulum stress and MAM formation, but improve the related protein expression of mitophagy, which ultimately reduce myocardial IRI in diabetes. Therefore, we hypothesize that promoting caveolin-3 expression resulting in downregulation of VDAC1/IP3R1 expression is the key pathway to restore endoplasmic reticulum stress-MAM-mitophagy homeostasis and improve the tolerance of diabetic myocardium to IRI. This project intends to use Sprague-Dawley rats, caveolin-3-/- mice, primary cardiomyocytes and H9C2 cells as the research objects to explore the molecular mechanisms of Caveolin-3 regulating endoplasmic reticulum stress-MAM-mitophagy homeostasis through VDAC1/IP3R1. The proposed studies will improve our understanding of diabetic myocardial IRI and may help facilitate the development of novel and optimal therapies in combating ischemic heart disease in diabetes.