Project 2 (Bers)

项目2（Bers）

• 批准号: 10006341
• 负责人: Donald M Bers
• 金额: $ 74.77万
• 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/10006341
• 关键词: Action Potentials; Adrenergic Agents; Adult; American; Arrhythmia; Ca(2+)-Calmodulin Dependent Protein Kinase; Caffeine; Calcium; Calcium-Sensing Receptors; Cardiac Myocytes; Cells; Cessation of life; Chronic; Clinical Data; Clinical Research; Closure by clamp; Complement; Complex; Computer Models; Connexin 43; Coupling; Dantrolene; Data; Diastole; Dilated Cardiomyopathy; Drug Targeting; Etiology; Event; Feedback; Functional disorder; Gap Junctions; Genetic; Goals; Heart; Heart Diseases; Heart failure; Human; Individual; Inherited; Link; Measurement; Mechanics; Modeling; Mus; Muscle Cells; Mutation; Myocardial dysfunction; Optics; Oryctolagus cuniculus; Outcome; Pathologic; Pathway interactions; Patients; Penetrance; Phenotype; Prevention; Rattus; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sodium; Source; Testing; Tissue Model; Tissues; Translating; Update; Validation; Variant; Ventricular; calmodulin-dependent protein kinase II; familial dilated cardiomyopathy; human model; human stem cells; indium arsenide; individualized medicine; induced pluripotent stem cell; inhibitor/antagonist; insight; novel; novel therapeutics; outcome forecast; precision medicine; pressure; prevent; programs; ranolazine; stem cell model; uptake; voltage

Project 2 (Bers): Abstract Project 2 focuses on understanding Na- and Ca-dependent myocyte mechanisms contributing to cardiac dysfunction and arrhythmias in heart failure (HF). Hallmarks of Na & Ca dysfunction in HF include elevated diastolic and late Na current (INaL), increased diastolic SR Ca leak, and Na/Ca exchange. These factors reduce systolic and diastolic function and promote triggered arrhythmias in HF. Ca-Calmodulin dependent protein kinase (CaMKII) is also chronically active in HF and directly promotes INaL and diastolic SR Ca leak via the ryanodine receptor (RyR) and is a lynchpin in a newly appreciated vicious cycle where elevated INaL or SR Ca leak (that cause arrhythmias) promote CaMKII activation to further promote higher INaL and SR Ca leak that leads to both contractile dysfunction and arrhythmogenesis in HF. Our central aim is to test this working hypothesis in adult failing hearts (and computer models of human hearts) and identify how breaking the vicious cycle at different points can be functionally beneficial. Aim 1 will test in rabbit ventricular myocytes if functional and arrhythmogenic effects of overload-induced HF can be prevented by inhibiting CaMKII, INaL or RyR. Aim 2 extends these tests to the intact rabbit heart level using optical mapping of [Ca]i and voltage Vm (where whole heart arrhythmias are complicated by cell-cell coupling, source-sink mismatch and conduction/reentry issues). Aim 3 will enhance and validate computational rabbit ventricular myocyte & tissue models and extend both to human (using rabbit data from Aim 1 & 2 and incorporating patient-specific iPSC-derived myocyte and clinical data (from Projects 1 & 3). These 3 Aims will provide valuable mechanistic insight into the vicious feedback signaling, and how targeting INa, CaMKII or RyR may have benefits in acquired or inherited (Project 1) HF.

项目 2（Bers）：摘要 项目 2 侧重于了解 Na 和 Ca 依赖性心肌细胞机制有助于心脏 心力衰竭（HF）中的功能障碍和心律失常。心力衰竭中 Na 和 Ca 功能障碍的标志包括升高 舒张期和晚期 Na 电流 (INaL)、舒张期 SR Ca 泄漏增加以及 Na/Ca 交换。这些因素减少 收缩和舒张功能并促进心力衰竭引发的心律失常。 Ca-钙调蛋白依赖性蛋白 激酶 (CaMKII) 在 HF 中也具有长期活性，并通过 INaL 和舒张期 SR Ca 渗漏直接促进 兰尼碱受体 (RyR)，是新近认识到的恶性循环的关键，其中 INaL 或 SR Ca 升高 渗漏（导致心律失常）促进 CaMKII 激活，进一步促进更高的 INaL 和 SR Ca 渗漏， 导致心力衰竭的收缩功能障碍和心律失常。我们的中心目标是测试这个工作 成人衰竭心脏（以及人类心脏的计算机模型）的假设，并确定如何打破恶性循环 在不同点进行循环可能在功能上有益。目标 1 将测试兔心室肌细胞是否功能正常 抑制 CaMKII、INaL 或 RyR 可以预防过载诱发心力衰竭的心律失常效应。目标2 使用 [Ca]i 和电压 Vm 的光学映射将这些测试扩展到完整的兔心脏水平（其中整个 心律失常因细胞间耦合、源库不匹配和传导/折返问题而变得复杂。 目标 3 将增强和验证计算兔心室肌细胞和组织模型，并将两者扩展到 人类（使用来自目标 1 和 2 的兔子数据，并结合患者特异性 iPSC 衍生的肌细胞和临床 数据（来自项目 1 和 3）。这三个目标将为恶意反馈提供有价值的机制洞察 信号传导，以及靶向 INa、CaMKII 或 RyR 如何对获得性或遗传性（项目 1）心力衰竭有益。