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

项目概要（概述） 该计划项目补助金（PPG）的首要目标是更好地了解 改变的钠（Na+）和钙（Ca 2+）信号传导有助于心力衰竭中的机电功能障碍 （HF）.项目1（Wu）将定义导致HF心律失常的Na+-Ca 2+失调机制， 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。 来源于具有与扩张型心肌病相关的突变的患者的心肌细胞（iPSC-CM） (DCM)，这是心力衰竭的主要原因。项目2（Bers）将在成人HF中进行平行机制研究 兔心肌细胞和完整的心脏，了解如何打破恶性循环Na+/Ca 2+失调。 重要的是，定量机制的结果将提供信息，并通过兔子和人类的计算验证。 模型项目3（Mercola）将通过采用高通量方法来推进这些调查， 电生理表型，以阐明非离子通道蛋白在细胞功能障碍中的作用， 药物诱导的心律失常，确定该途径中的新治疗靶点，并生成计算机模型 来预测心律失常的易感性一个行政核心A（吴）将支持这三个项目。计算 建模核心B（Grandi）将通过创建iPSC的多尺度计算模型来支持所有三个项目。 CM和成人肌细胞和组织，包括患者特异性通道和药物作用。所有这些 跨学科和协同研究将有助于实现我们预防HF的“精准医学”目标， 心源性猝死

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.