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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

基本信息

批准号：
9106007
负责人：
LESLIE TUNG
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/9106007
关键词：
3-Dimensional Action Potentials Acute Adipocytes Adrenergic Agents Affect Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Athletic Behavior Biochemical Biological Models Biopsy Blood CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiomyopathies Cell Line Cell model Cells Congenital cardiomyopathy Counseling Coupling Cues D Cells Data Desmosomes Development Disease Disease Management Disease Pathway Disease Progression Electrophysiology (science)Engineering Exercise Extracellular Matrix Fibroblasts Fibrosis Functional disorder Gap Junctions Generations Genes Genetic Goals Growth Heart Heart Diseases Heart failure Hereditary Disease Histology Human Human Genetics Incidence Infiltration Laboratories Lead Left ventricular structure Light Lipids Measurement Mechanics Modeling Mutation Myocardium Outcomes Research Pathogenesis Patients Phase Predisposition Process Proteins RNA Right ventricular structure Risk Signal Transduction Skin Slice Sodium Sodium Channel Source Specificity Staging Strenuous Exercise Structural defect Sudden Death Syndrome Testing Tissue Model Tissues Training Ventricular Arrhythmia Work biophysical properties comparison group disease phenotype experience heart cell human stem cells improved induced pluripotent stem cell insight monolayer new therapeutic target non-genetic novel therapeutics proband public health relevance scaffold simulation success sudden cardiac death therapy design tissue support frame tool

项目摘要

DESCRIPTION (provided by applicant): Advances in the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have dramatically advanced the study of heritable human genetic cardiac diseases. While these advances will eventually lead to new treatment options and improved patient counseling, these cellular model systems also permit mechanistic insights and provide a platform for modeling human cardiac tissues. The latter is critically important as patients with cardiomyopathies (genetic and non-genetic forms) or heart failure often experience arrhythmias that can result in sudden death. To study the predisposition of genetic disease syndromes to cause arrhythmias in cardiac tissue, iPSC-CMs will be cultivated in engineered heart slices (EHS), developed by our team that recapitulate a natural 3D microenvironment and enable electromechanical interactions among cells and the extracellular matrix. Our EHS support the growth of engrafted iPSC-CMs; provide important topological, biochemical, and mechanical signals to the cells; manifest functional tissue behavior, including coordinated electrophysiological and contractile activity; and can sustain cardiac arrhythmias in a quantifiable manner. In this project, we propose to use EHS to investigate mechanisms underlying the manifestation and progression of arrhythmias that promote sudden death. As a genetic tool for modeling arrhythmias, we will study iPSCs generated from probands of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) that affect proteins of the cardiac desmosome. In patients, this disease is highly pro-arrhythmic and can lead to sudden cardiac death in young athletes. Hence, the goal of this project is to investigate how structural defects promote arrhythmias in EHS. Specifically we will determine if 1) mutations of desmosomal proteins operate in the early concealed phase of AC to impair intercellular mechanical coupling, resulting in abnormal electrical coupling, slowing of electrical conduction, and reentrant arrhythmia, and 2) secondary alterations in sodium channel function also result in slowing of electrical conduction and arrhythmia. The project involves three complementary and related Aims. Aim 1 will examine the importance of syncytial interactions and tissue microenvironment on the expression and progression of the disease phenotype in ARVC iPSC-CMs. Aim 2 will develop models of simulated exercise to determine increased risk of arrhythmia in EHS models of ARVC. Aim 3 will investigate the instructive cues of different native, extracellular matrices on cellular remodeling and tissue- level arrhythmia in EHS models of ARVC. The outcome of this research will shed light on mechanisms of arrhythmia and sudden cardiac death associated with abnormalities of mechanical junctions that operate not only in ARVC but also in other more common forms of cardiomyopathies. Our study on tissue microenvironment and disease progression in the cardiomyocyte represents a critical step towards the identification of primary and ancillary pro-arrhythmic disease pathways that may prove invaluable to the development of new therapies designed to treat heritable cardiac diseases.