Phosphorylation of cMyBP-C Modulates Cardiac Arrhythmias

描述(由申请人提供)：心力衰竭(HF)的一个反复出现的临床特征是心律失常的发生，这导致HF患者心源性猝死的发生率增加，反过来也可能导致心力衰竭恶化。尽管心衰和心律失常之间有明显的联系，但目前还没有针对这些电异常的适用治疗方法。PI和他的导师们最近发现，心肌肌球蛋白结合蛋白C(cMyBP-C)的磷酸化可能在调节心脏中的钙(Ca~(2+))处理方面发挥作用。这对于理解心衰期间导致心律失常的机制具有深远的意义，并可能确定新的治疗策略。事实上，cMyBP-C磷酸化在健康心脏中广泛存在，在心力衰竭、病理性肥厚、缺血性损伤和心房颤动中严重耗尽。这项计划中的研究将利用成熟的在体心脏功能评估方法，以及开发和改进新的工具，进一步将体内发现扩展到单个分离的心室肌细胞。PI和他的导师们的工作已经建立了几个转基因动物模型，这些模型对于研究cMyBP-C如何导致心律失常至关重要，并表明携带阻止cMyBP-C磷酸化的突变的小鼠在肾上腺素能应激后表现出严重的心律失常和心源性死亡。我们假设cMyBP-C的磷酸化是心肌中适当的钙处理所必需的。因此，这项建议的总体目标是：1)确定cMyBP-C基因突变(AllP-)或模拟(AllP)磷酸化突变(AllP-)小鼠发生心律失常的倾向；2)研究分离心肌细胞钙变化的分子原因。拟议工作的独特之处在于结合了深入的活体研究和在丰富的交互环境中进行的单细胞实验，并在此类工作中取得了很好的成功记录。对于PI来说，这项调查很好地支持了他进行与心功能相关的跨学科研究的长期计划，并有望拓宽我们对心力衰竭发病机制的理解。

DESCRIPTION (provided by applicant): A recurrent clinical hallmark of heart failure (HF) is the occurrence of arrhythmias, which contribute to the increased incidence of sudden cardiac death in HF patients and can in turn also lead to worsening HF. Despite the clear link between HF and arrhythmia, no applicable treatment has been identified specifically targeting these electrical abnormalities. The PI and his mentors have recently discovered that cardiac myosin binding protein c (cMyBP-C) phosphorylation might play a role in modulating calcium (Ca2+) handling in the heart. This can have profound implications in understanding the mechanism leading to arrhythmia during HF and might identify novel therapeutic strategies. Indeed, cMyBP-C phosphorylation is extensively phosphorylated in the healthy heart and severely depleted in HF, pathological hypertrophy, ischemic injury and atrial fibrillation. The planned investigation will exploit well established methods of assessing cardiac function in vivo, as well as develop and refine novel tools to further extend the in vivo findings into single isolated cardiac ventricuar myocytes. Work by the PI and his mentors has established several transgenic animal models that will be critical to study how cMyBP-C can lead to arrhythmogenesis, and show that mice harboring mutations preventing phosphorylation of cMyBP-C display severe arrhythmia and cardiac death following adrenergic stress. We hypothesize that cMyBP-C phosphorylation is necessary for proper Ca2+ handling in the myocardium. Therefore, the overall objectives of this proposal are to: 1) determine the propensity for arrhythmias in mice harboring mutations ablating (AllP-) or mimicking (AllP+) phosphorylation of cMyBP-C, 2) investigate the molecular causes of altered Ca2+ in isolated cardiomyocytes. The unique feature of the proposed work is the combination of in depth in vivo study and single cell experiments in a richly interactive environment with a strong record of success in such work. For the PI, the investigation nicely supports his long-term plan of conducting interdisciplinary research related to cardiac function, with the prospect of broadening our understanding of the pathogenesis of heart failure.