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

项目摘要(概述) 本计划项目赠款(PPG)的首要目标是更好地了解 钠(Na+)和钙(Ca+)信号变化在心力衰竭的机电功能障碍中的作用 (Hf)。项目1(Wu)将确定Na+-Ca~(2+)失衡导致心力衰竭和心律失常的机制。 探讨基因异质性对诱导多能干细胞来源的这一现象的影响 扩张型心肌病基因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中进行平行的力学研究 了解兔心肌细胞和完整心脏如何打破Na+/Ca~(2+)失衡的恶性循环。 重要的是，量化的力学结果将被兔子和人类的计算提供信息并得到验证 模特们。项目3(Mercola)将通过采用高吞吐量方法来推进这些调查 电生理表型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，在这一途径中识别新的治疗靶点，并产生电子计算机模型 以预测心律失常的易感性。一个行政核心A(吴)将为这三个项目提供支助。计算型 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- CMS和成人心肌细胞和组织，结合了患者特定的通道和药物效应。加在一起，这些 跨学科和协同研究将有助于我们实现预防和治疗心力衰竭的“精确医学”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.