Multi-scale modeling of inherited pediatric cardiomyopathies

遗传性儿童心肌病的多尺度建模

• 批准号: 10469046
• 负责人: KEVIN KIT PARKER
• 金额: $ 8.45万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469046
• 关键词: 3-Dimensional; 3-Methylglutaconic aciduria type 2; Address; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Bioinformatics; Biological; Biological Assay; Biological Models; Biomedical Engineering; Cardiac; Cardiac Myocytes; Cardiology; Cardiomyopathies; Catecholaminergic Polymorphic Ventricular Tachycardia; Cell Culture Techniques; Cell model; Cells; Cessation of life; Clinical; Clinical Data; Clinical Trials; Data; Disease; Disease model; Dysplasia; Electrophysiology (science); Engineering; Environment; Functional disorder; Genes; Genetic Materials; Genome engineering; Goals; Heart Diseases; Heart Transplantation; Hereditary Disease; Human; In Vitro; Individual Differences; Inherited; Laboratories; Lead; Link; Measures; Modeling; Molecular Biology; Myocardial; Myocardial Contraction; Myocardial tissue; Myocardium; Organ; Pathogenesis; Pathway interactions; Patients; Pediatric Cardiomyopathy; Phase; Phenotype; Physiological; Physiology; Process; Property; Rare Diseases; Severity of illness; Speed; Structure; System; Tachycardia; Testing; Therapeutic Trials; Tissue Engineering; Tissue Model; Tissues; Work; arrhythmogenic cardiomyopathy; base; bench to bedside; disease phenotype; disease-in-a-dish; drug development; gene therapy; genome editing; heart cell; heart rhythm; high throughput screening; human model; improved; improved outcome; in vitro Model; individual patient; induced pluripotent stem cell; insight; inter-individual variation; interdisciplinary approach; medication safety; microphysiology system; multi-scale modeling; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient variability; response; safety testing; screening; small molecule; stem cell model; targeted treatment; therapeutic candidate; therapeutic target; three-dimensional modeling; treatment response; two-dimensional

Project summary The goal of this proposal is to advance in vitro modeling of human heart disease using genome-edited and patient-derived iPSCs, to use these models to gain new insights into disease pathogenesis, and to develop new therapeutic strategies. We focus on three monogenic cardiac diseases, Barth syndrome (BTHS), cate- cholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic cardiomyopathy (ACM; also known as arrhythmogenic right ventricular cardiomyopathy/dysplasia). These disorders represent major classes of inherited heart disease, namely disorders of cardiac rhythm (CPVT; ACM) and contraction (BTHS; ACM). No targeted therapies are available for these disorders, and current management options are far from ideal, resulting in tragic deaths or cardiac transplantation. Our studies of these diseases will push the envelope of in vitro disease models in four principle ways: (1) by refining in vitro systems to better reflect the physiology of native myocardium; (2) by objectively evaluating the ability of induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models to capture inter-individual variation between patients; (3) by identifying novel therapies through either improved mechanistic understanding or unbiased screening; and (4) by performing proof-of-concept “Clinical trials in a dish”, in which responses of engineered cell and tissue models are compared to responses of mammalian models or patients. In the UG3 Phase, we will develop physiological assay systems of these three monogenic cardiac diseases (Aim 1). These assay systems will scale from cell pairs to three dimensional engineered ventricles, providing the range of systems necessary to address challenges spanning high throughput screening to disease pathogenesis to in vitro “clinical trials”. In the UH3 Phase, we will use the 2D tissues and 3D ventricles to discover novel treatments through screens and mechanistic studies (Aim 2). We will use the 3D ventricles to perform “Clinical trials in a dish” (Aim 3), to determine the extent to which iPSC-based models capture inter-individual variation and to measure the therapeutic responses of a panel of patient microphysiological models. Our vertically integrated, multidisciplinary approach will bring together cardiac biologists, bioengineers, bioinformaticians, and clinicians to advance the state of the art for in vitro cardiac disease modeling. The impact will extend well beyond the three rare diseases directly studied by improving cardiac disease models and providing data on the usefulness of iPSC-CMs for capturing individual patient phenotypes. Creation of in vitro models of normal human organs would also greatly expedite drug development, by increasing the precision and speed of drug safety testing. Our deliverables include advances in iPSC-CM differentiation; novel bioengineered systems to assay iPSC-CM physiological properties; new insights into the pathogenesis of three representative cardiac diseases; and identification of therapeutic targets and lead compounds for disease treatment.

项目总结

项目成果

Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.

• DOI: 10.1016/j.stemcr.2023.07.005
• 发表时间: 2023-09-12
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Kim, Sean L.;Trembley, Michael A.;Lee, Keel Yong;Choi, Suji;Macqueen, Luke A.;Zimmerman, John F.;Wit, Lousanne H. C. de;Shani, Kevin;Henze, Douglas E.;Drennan, Daniel J.;Saifee, Shaila A.;Loh, Li Jun;Liu, Xujie;Parker, Kevin Kit;Pu, William T.
• 通讯作者: Pu, William T.