MiR-513通过STAT3调控PD-L1在自身免疫性心肌炎模型中的作用机制研究

With high and annually increasing morbidity, Dilated Cardiomyopathy, which imposes great risk of sudden death upon patients, is severely jeopardizing human's health. Autoimmune myocarditis is the initial step in the development of dilated cardiomyopathy. However, how to alleviate autoimmune myocarditis and its immune regulatory mechanisms remains unclear. The study found that excessive immune response of T cells is the key to diffuse cardiac dysfunction caused by autoimmune myocarditis. This project aims at negative regulation of PD-L1 expressed by cardiac endothelial cells in T cells, as well as targeting regulation of miR-513 on PD-L1. On the basis of researches that up-regulation of PD-L1 could reduce the severity of autoimmune myocarditis and inhibited miR-513 induce PD-L1 overexpression, we attempt to verify the targeting regulation of miR-513 on PD-L1 and its protective effect on hearts in models of autoimmune myocarditis. Making further use of molecular biology methods, we strive to explore whether miR-513 regulates PD-L1 through STAT3 pathway at the level of transcription and signal pathway. This study will further explore the potential of miR-513/PD-L1 as a attractive therapeutic target of for the treatment of autoimmune myocarditis.

扩张性心肌病发病率高、猝死率高，严重危害人类健康且发病率呈逐年升高的趋势。自身免疫性心肌炎是扩张性心肌病发病机制中的起始步骤，但如何减缓自身免疫性心肌炎及免疫调控机制目前尚未完全明确。研究发现，T细胞的过度免疫应答是自身免疫性心肌炎弥漫性心功能受损的关键环节。本课题瞄准心脏内皮细胞表达PD-L1在T细胞中的负性调控作用、以及miR-513靶向调控PD-L1，在既往发现上调心脏内皮细胞表达PD-L1改善自身免疫心肌炎严重程度及抑制miR-513能上调PD-L1的基础上，在心脏内皮细胞及自身免疫性心肌炎模型水平上验证miR-513靶向PD-L1的调控作用及其心脏保护作用。并进一步分子生物学手段，在转录和信号通路水平上，研究miR-513是否通过STAT3通路调控PD-L1。为探索miR-513靶向调控PD-L1作为自身免疫性心肌炎治疗的新靶点提供理论基础。

扩张性心肌病发病率高、猝死率高，严重危害人类健康且发病率呈逐年升高的趋势。自身免疫性心肌炎是扩张性心肌病发病机制中的起始步骤，但如何减缓自身免疫性心肌炎及免疫调控机制目前尚未完全明确。研究发现，T细胞的过度免疫应答是自身免疫性心肌炎弥漫性心功能受损的关键环节。本课题瞄准心脏内皮细胞表达PD-L1在T细胞中的负性调控作用、以及miR-143靶向调控PD-L1，在既往发现上调心脏内皮细胞表达PD-L1改善自身免疫心肌炎严重程度及抑制miR-143能上调PD-L1的基础上，在心脏内皮细胞及自身免疫性心肌炎模型水平上验证miR-143靶向PD-L1的调控作用及其心脏保护作用。为探索miR-143靶向调控PD-L1作为自身免疫性心肌炎治疗的新靶点提供理论基础。