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 人类诱导的多能干细胞衍生的心肌细胞（HIPSC-CMS）提供了强大的工具 通过使我们能够在体外对遗传性心脏病进行建模来研究心脏病。这些模型提供 对疾病的病理生理学的独特见解，并允许对潜力进行筛查和评估 干预措施。心律失常右心肌病（ARVC）是一种影响细胞细胞的遗传疾病 心肌细胞的粘附。与ARVC相关的心律失常是造成心脏突然死亡的主要原因 美国，尤其是在年轻的低风险人群中。父母授予，“ ARVD/C功能障碍 人类干细胞衍生的心脏组织的重点是使用源自ARVC患者的IPSC-CMS 生成工程的心脏切片（EHS），以研究结构缺陷如何促进ARVC中心律不齐。尽管 该提案主要集中于疾病的早期阶段，当结构变化不显示在 宏观量表该项目旨在创建ARVC的后期模型，其中纤维化和脂肪浸润 心肌组织的重要特征。这是该项目的具体目的是模拟晚期， ARVC的纤维脂肪疾病条件通过将肌纤维细胞和脂肪细胞添加到ARVC EHS中。 1阶段的阶段 该项目将创建一种类似ARVC心肌的纤维化模型，以显示特征传导 通过与肌纤维细胞共同培养HIPSC-CMS减慢并增加了重入心律失常的事件 EHS中的（产生纤维化的细胞）。该项目的第2阶段将是将脂肪浸润纳入纤维化 通过hipsc-CM和肌纤维细胞的脂肪细胞（产生脂肪生产细胞）的三个文化的ARVC EHS模型 测试进一步放缓传导和心律不齐的敏感性。