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的重点是理解依赖NA和CA的肌细胞机制 心力衰竭（HF）的功能障碍和心律不齐。 HF中Na＆Ca功能障碍的标志包括高架 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。这些因素减少了 收缩和舒张功能，并促进HF中的心律不齐。 Ca-钙调蛋白依赖性蛋白 激酶（CAMKII）在HF中也长期活跃，直接促进通过 ryanodine受体（RYR），是新欣赏的恶性循环中的lynchpin 泄漏（导致心律不齐）促进CAMKII激活，以进一步促进更高的INAL和SR CA泄漏 导致HF的收缩功能障碍和心律失常。我们的核心目的是测试这项工作 成人失败的心（以及人类心脏的计算机模型）中的假设，并确定如何破坏恶性 在不同点上的循环在功能上可能是有益的。 AIM 1如果功能性，将在兔心室肌细胞中测试 通过抑制CAMKII，INAL或RYR，可以防止过载引起的HF的心律失常作用。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（整个地方 心脏心律失常因细胞电池耦合，源 - 链接不匹配和传导/再入问题而变得复杂。 AIM 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（使用AIM 1和2的兔子数据，并纳入患者特异性IPSC衍生的心肌和临床 数据（来自项目1和3）。这三个目标将为恶性反馈提供宝贵的机械洞察力 信号传导以及靶向INA，CAMKII或RYR如何在获得或遗传的HF中具有好处。