Multi-scale modeling of inherited pediatric cardiomyopathies

遗传性儿童心肌病的多尺度建模

基本信息

批准号：
10228715
负责人：
KEVIN KIT PARKER
金额：
$ 127.09万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10228715
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

项目摘要

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.

项目摘要该提案的目的是使用基因组编辑和患者衍生的IPSC，使用这些模型来获得对疾病发病机理的新见解，并发展新理论策略。我们专注于三种单基因疾病，巴特综合征（BTHS），猫 - 胆胺能多态性心脏心动过速（CPVT）和心律失常性心肌病（ACM；也被称为心律失常右心肌病/发育不良）。这些疾病代表主要遗传性心脏病的类别，即心律（CPVT; ACM）和收缩（BTHS; ACM）。这些疾病没有针对性的疗法，当前的管理选项远非理想，导致悲惨的死亡或心脏移植。我们对这些疾病的研究将推动信封以四个原则方式的体外疾病模型：（1）通过完善体外系统以更好地反映生理本地心肌；（2）客观地评估诱导多能干细胞衍生的能力心肌细胞（IPSC-CM）模型以捕获患者之间的个体差异；（3）识别小说通过提高机械理解或公正筛查的疗法；（4）通过表演概念证明“菜肴中的临床试验”，其中工程细胞和组织模型的反应是与哺乳动物模型或患者的反应相比。在UG3阶段，我们将发展生理这三种单基因疾病的测定系统（AIM 1）。这些测定系统将从细胞中扩展将三维工程性脑室的成对，提供解决所需的系统范围跨越高通量筛查的挑战，即疾病发病机理，以进行体外“临床试验”。在UH3中阶段，我们将使用2D组织和3D心室通过屏幕和机械研究（目标2）。我们将使用3D心室进行“盘子中的临床试验”（AIM 3），确定基于IPSC的模型在多大程度上捕获个体间的变化并测量一组患者微生物生理模型的治疗反应。我们的垂直整合，多学科方法将召集心脏生物学家，生物工程师，生物信息学家和临床医生促进体外心脏病建模的艺术状态。影响将远远超出通过改善心脏病模型并提供有关有用性的数据，直接研究了三种罕见疾病 IPSC-CMS用于捕获个别患者表型。创建正常人体器官的体外模型还可以通过提高药物安全测试的精度和速度来加快药物开发。我们的可交付成果包括IPSC-CM差异化的进步；新型生物工程系统用于测定IPSC-CM 生理特性；对三种代表性心脏病的发病机理的新见解；和鉴定热靶标和铅化合物用于疾病治疗。