LncRNA-DACH1通过作用于抗肌萎缩蛋白（Dystrophin）调节钠通道和室性心律失常

钠通道功能降低是心力衰竭时心律失常易感性增加的重要原因。Dystrophin蛋白是调节Nav1.5心肌细胞膜分布的重要分子。LncRNA调节多种心脏疾病，但对心肌钠通道的作用未见报道。我们发现：1）心肌细胞特异性过表达lncRNA-DACH1小鼠室性心律失常的诱发率增高，峰钠电流降低，细胞膜Nav1.5和dstrophin蛋白减少；而心肌特异性敲除lncDACH1后产生的作用相反；2）lncDACH1能够与dystrophin直接结合。我们假设：“LncRNA-DACH1通过与Dystrophin蛋白结合，抑制心肌细胞Nav1.5的膜转运与分布，导致钠电流降低，传导减慢，促进室性心律失常的发生”。本项目将应用模式动物、iPS诱导分化心肌细胞以及多种分子生物学技术阐明lncDACH1对Nav1.5的调节作用与分子机制，揭示lncDACH1对心力衰竭时Nav1.5重构以及心律失常易感的影响。

The decreased expression of Nav1.5 is important for the increased susceptibility to arrhythmia in heart failure. Dystrophin protein is an important molecule that regulates the membrane distribution of Nav1.5 in cardiomyocytes. LncRNA regulates many heart diseases, but the regulation of lncRNA on sodium channels has not been reported. We found that: 1) Cardiomyocyte-specific overexpression of lncDACH1 in mice induces an increased rate of ventricular arrhythmias, a decrease in peak sodium current, and a decrease in the cell membrane distribution of Nav1.5 and dstrophin ; while cardiomyocyte specific knock-out of lncDACH1 produces the opposite effect; 2 ) LncDACH1 can be directly combined with dystrophin. Therefore, we hypothesize: "LncRNA-DACH1 inhibits the membrane transport and distribution ofNav1.5 in cardiomyocyte by binding to Dystrophin protein, resulting in a decrease in sodium current, slow conduction, and promoting the occurrence of ventricular arrhythmia." This project will employ transgenic and knockout mice models, iPS differentiated cardiomyocytes, and a variety of molecular biological techniques to clarify the regulatory role and molecular mechanism of lncDACH1 on Nav1.5, and to reveal the effect of lncDACH1 on Nav1.5 remodeling and susceptibility to arrhythmia in heart failure.