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: 10677706
• 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/10677706
• 关键词: Adopted; Adult; Affect; Arrhythmia; Benign; Calcium; Calcium Signaling; Cardiac Myocytes; Cardiovascular system; Complex; Computer Models; Controlled Study; Data; Development; Dilated Cardiomyopathy; Disease; Drug Side Effects; Electrophysiology (science); 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; Persons; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Predisposition; Program Research Project Grants; Proteins; Research Personnel; Risk; Role; Signal Transduction; Sodium; Standardization; Testing; Therapeutic; Tissues; Validation; Variant; calmodulin-dependent protein kinase II; economic impact; human stem cells; improved; in silico; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; multi-scale modeling; 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.

项目概要（概述） 该计划项目拨款 (PPG) 的总体目标是更好地了解 钠 (Na+) 和钙 (Ca2+) 信号传导的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+ 失调导致心力衰竭和心律失常的机制。 探讨遗传异质性对诱导多能干细胞来源的这一现象的影响 源自携带扩张型心肌病相关突变的患者的心肌细胞 (iPSC-CM) （DCM），这是心力衰竭的一个主要原因，项目 2（Bers）将对成人心力衰竭进行平行机制研究。 兔肌细胞和完整心脏，了解如何打破 Na+/Ca2+ 失调的恶性循环。 重要的是，定量力学结果将为兔子和人类计算提供信息并得到验证 项目 3 (Mercola) 将通过采用高通量方法来推进这些研究。 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 药物引起的心律失常，识别该途径中的新治疗靶点，并生成计算机模型 预测心律失常的易感性。行政核心 A (Wu) 将支持这三个项目。 Modeling Core 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 和成体肌细胞和组织将患者特异性通道和药物作用结合在一起。 跨学科和协同研究将有助于实现我们预防心衰和心衰的“精准医学”目标 心源性猝死。

项目成果

Generation of two induced pluripotent stem cell lines from Brugada syndrome affected patients carrying SCN5A mutations.

来自 Brugada 综合征的两种诱导多能干细胞系的产生影响了携带 SCN5A 突变的患者。

• DOI: 10.1016/j.scr.2021.102605
• 发表时间: 2021-11-01
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: Nadjet Belbachir;C. Lai;J. Rhee;Y. Zhuge;Marco V. Perez;Karim Sallam;Joseph C. Wu
• 通讯作者: Joseph C. Wu