Phosphorylation of cMyBP-C Modulates Cardiac Arrhythmias

描述（由申请方提供）：心力衰竭（HF）的复发性临床标志是心律失常的发生，这导致HF患者心源性猝死的发生率增加，进而也可能导致HF恶化。尽管HF和心律失常之间存在明确的联系，但尚未确定专门针对这些电异常的适用治疗。PI和他的导师最近发现，心肌肌球蛋白结合蛋白c（cMyBP-C）磷酸化可能在调节心脏中的钙（Ca 2+）处理中发挥作用。这可能对理解HF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被广泛磷酸化，并且在HF、病理性肥大、缺血性损伤和心房纤颤中被严重耗尽。 计划中的研究将利用已建立的评估体内心脏功能的方法，以及开发和完善新的工具，以进一步将体内研究结果扩展到单个分离的心室肌细胞。PI及其导师的工作已经建立了几种转基因动物模型，这些模型对于研究cMyBP-C如何导致糖尿病至关重要，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脏死亡。我们假设cMyBP-C磷酸化对于心肌中适当的Ca 2+处理是必要的。因此，本提案的总体目标是：1）确定携带cMyBP-C的消融（AllP-）或模拟（AllP+）磷酸化突变的小鼠中心律失常的倾向，2）研究分离的心肌细胞中Ca 2+改变的分子原因。 拟议工作的独特之处是在丰富的互动环境中结合了深入的体内研究和单细胞实验，并在此类工作中取得了成功。对于PI来说，这项研究很好地支持了他进行心脏功能相关跨学科研究的长期计划，其前景是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.