Elucidating Electro-Mechanical Dysfunction in Heart Failure with Human Stem Cell Models

用人类干细胞模型阐明心力衰竭中的机电功能障碍

• 批准号: 10006331
• 负责人: Joseph C. Wu
• 金额: $ 236.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006331
• 关键词: Adopted; Adult; Adverse drug effect; Affect; Arrhythmia; Benign; Calcium; Cardiac Myocytes; Cardiovascular system; Complex; Computer Models; Controlled Study; Data; Development; Dilated Cardiomyopathy; Disease; Electrophysiology (science); Eye; Feedback; Functional disorder; Genes; Genetic; Genetic Heterogeneity; Goals; Heart; Heart failure; Human; Impairment; Individual; Investigation; Lead; Mechanics; Medicine; MicroRNAs; Modeling; Molecular Profiling; Morbidity - disease rate; Muscle Cells; Mutation; Oryctolagus cuniculus; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Predisposition; Program Research Project Grants; Proteins; Research Personnel; Risk; Role; Signal Transduction; Sodium; Standardization; Testing; Therapeutic; Tissues; Validation; Variant; base; calmodulin-dependent protein kinase II; economic impact; human stem cells; improved; in silico; induced pluripotent stem cell; multimodality; new therapeutic target; novel; precision medicine; prevent; stem cell model; sudden cardiac death; synergism; targeted treatment; therapeutic target; tool

PROJECT SUMMARY (OVERVIEW) The overarching goal of this Program Project Grant (PPG) is to better understand the mechanisms by which altered sodium (Na+) and calcium (Ca2+) signaling contribute to electromechanical dysfunction in heart failure (HF). Project 1 (Wu) will define the mechanism of Na+-Ca2+ dysregulation leading to arrhythmia in HF and explore the impact of genetic heterogeneity on this phenomenon in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with mutations associated with dilated cardiomyopathy (DCM), which is a major cause of heart failure. Project 2 (Bers) will do parallel mechanistic studies in adult HF rabbit myocytes and intact hearts to understand how to break the vicious cycle Na+/Ca2+ dysregulation. Importantly, quantitative mechanistic results will inform and be validated by rabbit and human computational models. Project 3 (Mercola) will advance these investigations by taking a high-throughput approach to the electrophysiological phenotypes to elucidate the role of non-ion channel proteins in the cellular dysfunction and drug-induced arrhythmia, identifying novel therapeutic targets in this pathway, and generate an in silico model to predict arrhythmia susceptibility. An Administrative Core A (Wu) will support the three projects. Computational Modeling Core B (Grandi) will support all three projects by creating multi-scale computational models of iPSC- CMs and adult myocytes and tissues that incorporate patient-specific channel and drug effects. Together, these cross-disciplinary and synergistic studies will help lead to our goal of “Precision Medicine” for preventing HF and sudden cardiac death.

项目摘要（概述） 该计划项目赠款（PPG）的总体目标是更好地了解 钠（Na+）和钙（Ca2+）信号改变导致心力衰竭的机电功能障碍 （HF）。项目1（WU）将定义Na+ -ca2+失调的机制，导致HF和 探索遗传异质性对诱导多能干细胞衍生的这种现象的影响 源自与心肌病有关的突变患者的心肌细胞（IPSC-CMS） （DCM），这是心力衰竭的主要原因。项目2（BERS）将在成人HF中进行平行的机械研究 兔心肌细胞和完整的心脏了解如何打破恶性循环Na+/Ca2+失调。 重要的是，定量机械结果将为兔子和人类计算提供信息并得到验证 型号。项目3（Mercola）将通过采取高通量方法来推进这些投资 电生理表型阐明了非离子通道蛋白在细胞功能障碍和 药物诱导的心律不齐，鉴定该途径中的新型治疗靶标，并在计算机模型中产生 预测心律不齐的敏感性。行政核心A（WU）将支持这三个项目。计算 建模Core B（Grandi）将通过创建IPSC-的多规模计算模型来支持所有三个项目 CMS和成年肌细胞和组织，结合了患者特异性通道和药物作用。在一起，这些 跨学科和协同研究将有助于我们实现“精密医学”的目标，以防止HF和 突然心脏死亡。