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：
9788685
负责人：
KEVIN KIT PARKER
金额：
$ 127.54万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788685
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 Dimensions 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 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 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.

项目概要该提案的目标是利用基因组编辑和技术推进人类心脏病的体外建模。患者来源的 iPSC，利用这些模型获得对疾病发病机制的新见解，并开发新的治疗策略我们专注于三种单基因心脏病：巴特综合征（BTHS）胆胺能多形性室性心动过速（CPVT）和致心律失常性心肌病（ACM；也称为致心律失常性右心室心肌病/发育不良）。遗传性心脏病的类别，即心律紊乱（CPVT；ACM）和收缩紊乱（BTHS；ACM） ACM）。目前还没有针对这些疾病的靶向治疗方法，而且目前的治疗方案也远非如此。理想的情况，导致悲剧性死亡或心脏移植，我们对这些疾病的研究将突破极限。体外疾病模型的构建有四个主要途径：（1）通过完善体外系统以更好地反映生理学 (2)通过客观评价诱导多能干细胞来源的能力心肌细胞（iPSC-CM）模型通过识别新的来捕获患者之间的个体差异；通过改进机制理解或公正筛选进行治疗；(4) 通过执行概念验证“培养皿中的临床试验”，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，我们将开发生理学。这三种单基因心脏病的检测系统（目标 1）。与三维工程心室配对，提供解决问题所需的一系列系统 UH3 中的挑战涵盖高通量筛查、疾病发病机制以及体外“临床试验”。阶段，我们将使用 2D 组织和 3D 心室通过屏幕和发现新的治疗方法机制研究（目标 2），我们将使用 3D 心室进行“培养皿中的临床试验”（目标 3）。确定基于 iPSC 的模型捕获个体间差异的程度并测量我们的垂直整合，多学科方法将汇集心脏生物学家、生物工程师、生物信息学家和推进体外心脏病建模的最新技术，其影响将远远超出范围。通过改进心脏病模型并提供有用数据直接研究三种罕见疾病用于捕获个体患者表型的 iPSC-CM 创建正常人体器官的体外模型。通过提高药物安全测试的精度和速度，还将大大加快药物开发。我们的成果包括 iPSC-CM 分化方面的进展；用于检测 iPSC-CM 的新型生物工程系统生理特性；对三种代表性心脏病发病机制的新见解；鉴定用于疾病治疗的治疗靶点和先导化合物。