ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue

人类干细胞来源的心脏组织中的 ARVD/C 功能障碍

• 批准号: 9815578
• 负责人: LESLIE TUNG
• 金额: $ 1.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815578
• 关键词: Adipocytes; Affect; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Cardiac; Cardiac Myocytes; Cell-Cell Adhesion; Cells; Characteristics; Coculture Techniques; Disease; Disease Progression; Engineering; Evaluation; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genetic Diseases; Genetic Models; Heart; Heart Diseases; Human; In Vitro; Incidence; Infiltration; Intervention; Modeling; Myocardial tissue; Myocardium; Myofibroblast; Patients; Phase; Population; Predisposition; Risk; Slice; Structural defect; Structure; Testing; Tissues; United States; Work; human stem cells; induced pluripotent stem cell; insight; parent grant; screening; sudden cardiac death; tool

PROJECT SUMMARY Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a powerful tool in investigating cardiac disease by enabling us to model genetic cardiac conditions in vitro. Those models provide unique insight into the pathophysiology of disease and allow for the screening and evaluation of potential interventions. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disease affecting cell-cell adhesion in cardiomyocytes. Arrhythmia associated with ARVC is a major cause of sudden cardiac death in the United States, especially among young, low risk populations. The parent grant, “ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue” focuses on using iPSC-CMs derived from ARVC patients to generate engineered heart slices (EHS) to study how structural defects promote arrhythmia in ARVC. While that proposal focuses primarily on the early stages of the disease, when structural changes are not manifest on a macroscopic scale, this project aims to create a late-stage model of ARVC, where fibrosis and fatty infiltrate of myocardial tissue are prominent features. Thus, the Specific Aim of the project is to simulate the late-stage, fibro-fatty disease condition of ARVC by addition of myofibroblasts and adipocytes to ARVC EHS. Phase 1 of the project will be to create a fibrosis-like model of ARVC myocardium that displays characteristic conduction slowing and increased incidence of reentrant arrhythmia by co-culturing hiPSC-CMs with myofibroblasts (fibrosis-producing cells) in EHS. Phase 2 of the project will be to incorporate fatty infiltration into the fibrotic ARVC EHS model by tri-culture of adipocytes (fat-producing cells) with hiPSC-CMs and myofibroblasts and to test for further slowing of conduction and increased susceptibility to arrhythmia.

项目摘要 人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）提供了一种强有力的工具， 研究心脏病，使我们能够在体外模拟遗传心脏病。这些模型提供了 对疾病的病理生理学有独特的见解，并允许筛选和评估潜在的 干预措施。致心律失常性右室心肌病（ARVC）是一种遗传性疾病， 心肌细胞粘附。与ARVC相关的心律失常是心脏性猝死的主要原因， 在美国，尤其是在年轻的低风险人群中。家长补助金，“ARVD/C功能障碍， 人类干细胞衍生的心脏组织”的重点是使用来自ARVC患者的iPSC-CM， 生成工程心脏切片（EHS），以研究结构缺陷如何促进ARVC中的心律失常。而 该建议主要侧重于疾病的早期阶段，此时结构变化并不明显， 在宏观尺度上，该项目旨在创建ARVC的晚期模型，其中纤维化和脂肪浸润 是心肌组织的突出特征。因此，该项目的具体目标是模拟后期， 通过将肌成纤维细胞和脂肪细胞添加到ARVC EHS中来改善ARVC的纤维脂肪疾病状况。第1阶段 该项目将创建一个ARVC心肌纤维化样模型，显示特征性传导 通过将hiPSC-CM与肌成纤维细胞共培养减缓和增加折返性心律失常的发生率 （纤维化产生细胞）在EHS中。该项目的第二阶段将是将脂肪浸润纳入纤维化组织 ARVC EHS模型通过脂肪细胞（脂肪产生细胞）与hiPSC-CM和肌成纤维细胞的三重培养， 测试进一步减缓传导和增加对心律失常的敏感性。