Project 2 (Bers)

项目2（Bers）：摘要 项目2的重点是了解钠和钙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。HF中Na & Ca功能障碍的标志包括升高的 舒张期和晚期Na电流（INaL），舒张期SR Ca漏和Na/Ca交换增加。这些因素降低 并促进触发性心律失常。钙调素依赖蛋白 激酶（CaMKII）在HF中也具有慢性活性，并通过心肌细胞直接促进INaL和舒张期SR Ca泄漏。 RyR是新近认识到的恶性循环的关键， 渗漏（引起心律失常）促进CaMK Ⅱ活化，进一步促进更高INaL和SR Ca渗漏， 导致HF中的收缩功能障碍和血管生成。我们的主要目标是测试这种工作 假设在成人衰竭的心脏（和人类心脏的计算机模型），并确定如何打破恶性 在不同的点循环可以在功能上是有益的。目的1将在兔心室肌细胞中测试功能是否正常 并且通过抑制CaMKII、INaL或RyR可以防止过载诱导的HF的促凋亡作用。目的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-细胞耦合、源-库失配和传导/折返问题而复杂化）。 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（使用来自Aim 1和2的兔数据，并掺入患者特异性iPSC衍生的肌细胞和临床 数据（来自项目1和3）。这3个目标将提供有价值的机制洞察到恶性反馈 信号传导，以及靶向INa、CaMKII或RyR如何在获得性或遗传性（项目1）HF中具有益处。

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.