罕见致心律失常性右室心肌病OBSCN基因突变调控心肌脂肪化的致病机制

罕见致心律失常性右室心肌病（ARVC）的病理特征是心肌纤维脂肪化，可促进疾病的发生发展。申请人前期发现了新发OBSCN非桥粒基因移码突变的ARVC家系，尚无该基因突变与ARVC的相关报道。前期工作借助人类诱导多能干细胞来源的心肌细胞（hiPSC-CMs）平台，良好复现了ARVC心律失常和心肌脂肪化的表型特点，发现疾病组心肌细胞肌浆网结构异常、钙离子电流紊乱，同时脂质含量增多，部分脂肪化相关蛋白PPARγ、C /EBPα及FABP4表达增高，即证实了该OBSCN基因突变介导心肌细胞钙循环失调而导致室性心律失常，但与ARVC心肌脂肪化的致病机制尚不明确。本项目后续将利用hiPSC-CMs模型及血液样本、临床信息来系统性探索罕见致病基因OBSCN对ARVC心肌脂肪化的致病机制，以发掘重要的脂质代谢及炎症致病通路和交汇的关键靶标，以期发现新的药物干预靶点，为罕见心血管疾病的治疗提供理论依据。

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is regarded as a rare type of cardiomyopathy, featuring progressive fibrofatty and adipose tissue replacement of the right ventricle and life-threatening ventricular arrhythmias. We discovered a rare ARVC family with a frameshift mutation of the OBSCN non-desmosome gene, and there is no report about this gene mutation and ARVC. Our previous work used the cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to reproduce the phenotypic characteristics of ARVC arrhythmia and myocardial fibroadipocytic, and found that the cardiomyocytes of disease group have abnormal sarcoplasmic reticulum structure and calcium Ionic current is disturbed. At the same time, the lipid content increased, and the expression of some fat-related proteins PPARγ, C/EBPa and FABP4 increased, which confirmed that the OBSCN gene mutation mediates the ventricular arrhythmia caused by the dysregulation of calcium circulation in cardiomyocytes. However, the pathogenic mechanism of how this gene causes myocardial fibroadipocytic in ARVC is still unclear. In the follow-up of this project, hiPSC-CMs models, blood samples and clinical information will be used to systematically explore the pathogenesis of the rare disease-causing gene OBSCN on ARVC myocardial fibroadipocytic, in order to discover important lipid metabolism and inflammation pathogenesis and the key to intersection targets, so as to find new drug intervention targets and provide theoretical basis for the treatment of rare cardiovascular diseases.