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.

项目概要 人诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 提供了强大的工具 这些模型使我们能够在体外模拟遗传性心脏病，从而研究心脏病。 对疾病病理生理学的独特见解，并允许筛选和评估潜在的 致心律失常性右心室心肌病（ARVC）是一种影响细胞间的遗传性疾病。 与 ARVC 相关的心律失常是心脏性猝死的主要原因。 美国，尤其是年轻、低风险人群，家长授予“ARVD/C 功能障碍”。 人类干细胞衍生的心脏组织”专注于使用源自 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。 该提案主要关注疾病的早期阶段，此时结构变化尚未显现出来。 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 因此，该项目的具体目标是模拟后期， 通过在 ARVC EHS 第一阶段中添加肌成纤维细胞和脂肪细胞来治疗 ARVC 的纤维脂肪疾病。 该项目将创建一个类似纤维化的 ARVC 心肌模型，显示特征传导 通过 hiPSC-CM 与肌成纤维细胞共培养可减缓和增加折返性心律失常的发生率 该项目第二阶段的目标是将脂肪浸润纳入纤维化细胞中。 ARVC EHS 模型通过脂肪细胞（脂肪生成细胞）与 hiPSC-CM 和肌成纤维细胞的三重培养来进行 测试传导进一步减慢和心律失常的易感性增加。