线粒体氧化应激是导致糖尿病心房重构和房颤的重要机制。我们的前期工作显示2型糖尿病大鼠心房肌组织存在明显内质网应激和线粒体氧化应激，且线粒体相关内质网膜（MAMs）关键蛋白VDAC1、Mfn2表达上调；内质网应激激动剂处理小鼠心房肌细胞（HL-1细胞）可导致IP3R1/GRP75/VDAC1复合体蛋白表达上调。本项目拟在此基础上，构建2型糖尿病大鼠模型，探讨内质网应激通过MAMs重要结构IP3R1/GRP75/VDAC1复合体介导线粒体氧化应激及对糖尿病心房重构及房颤诱发的影响；并通过siRNA沉默HL-1细胞GRP75或Mfn2、以及GRP75条件性敲除小鼠模型抑制内质网至线粒体钙转运，拮抗线粒体氧化应激和钙超载；通过建立多尺度虚拟心脏数学模型和药物筛选模型探究内质网应激和线粒体氧化应激之间通讯的分子机制，为房颤防治提供新的思路和干预靶点。

Mitochondrial oxidative stress is an important mechanism of atrial remodeling and atrial fibrillation (AF) in the setting of diabetes. Our previous studies suggested that there were significant endoplasmic reticulum (ER) stress and mitochondrial oxidative stress in the atria of type 2 diabetic rats, and the expressions of VDAC1 and Mfn2, the key proteins of mitochondria-associated endoplasmic reticulum membrane (MAMs), were up-regulated. Use tunicamycin, an ER stress agonist in mouse atrial myocytes (HL-1 cells), resulted in up-regulation of IP3R1/GRP75/VDAC1 complex protein expressions. The aim of this project is to establish a rat model of type 2 diabetes to explore the potential role of ER stress-MAMs-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. We further silence GRP75 or Mfn2 by siRNA in HL-1 cells and GRP75 conditional knockout mouse model, to inhibit calcium transport from ER to mitochondrial and antagonizes mitochondrial oxidative stress and calcium overload. Development of multi-scale virtual heart mathematical model and drug screening model to explore the molecular mechanism of communication between ER stress and mitochondrial oxidative stress to provide new ideas and interventional targets for the prevention and treatment of AF.