Project 2 (Bers)

项目2（Bers）

• 批准号: 10249148
• 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/10249148
• 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; Prognosis; 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 therapeutic intervention; 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侧重于了解钠和钙依赖的心肌细胞参与心脏疾病的机制。 心力衰竭时的功能障碍和心律失常。心力衰竭患者钠钙功能障碍的特征包括升高 舒张期和晚期钠电流(INAL)，舒张期肌浆网钙漏增加，Na/Ca交换。这些因素减少了 心衰患者的收缩和舒缩功能，并促进触发的心律失常。钙调素依赖蛋白 激酶(CaMKII)在心力衰竭中也是长期活跃的，并通过 Ryanodine受体(RyR)是新近认识到的一种恶性循环的关键，在这种恶性循环中，INT或SR Case升高 泄漏(导致心律失常)促进CaMKII激活，进一步促进更高的INT和SR Ca泄漏，从而 导致心衰患者的收缩功能障碍和心律失常。我们的中心目标是测试它的工作情况 成人心脏衰竭假说(和人类心脏的计算机模型)，并确定如何打破邪恶的 在不同的时间点进行循环可能在功能上是有益的。AIM 1将在兔心室肌细胞中测试是否具有功能 抑制CaMKII、INAL或RyR可预防超负荷心力衰竭的致心律失常效应。目标2 使用光学标测的[Ca]i和电压Vm(其中 心律失常由细胞-细胞耦合、源-汇失配和传导/折返问题而复杂化)。 AIM 3将增强和验证计算的兔心室肌细胞和组织模型，并将两者扩展到 人(使用来自Aim 1和2的兔数据，并结合患者特定的IPSC来源的心肌细胞和临床 数据(来自项目1和3)。这三个目标将提供对恶性反馈的有价值的机械性洞察 信号转导，以及如何靶向INA、CaMKII或RyR可能在后天性或遗传性心衰中受益(项目1)。