Phosphorylation of cMyBP-C Modulates Cardiac Arrhythmias

cMyBP-C 磷酸化调节心律失常

基本信息

批准号：
8596465
负责人：
Ramzi J Khairallah
金额：
$ 5.39万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2015-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8596465
关键词：
Actins Action Potentials Actomyosin Adenosinetriphosphatase Adrenergic Agents Animal Model Animals Arrhythmia Atrial Fibrillation Binding Binding Proteins Caffeine Calcium Cardiac Cardiac Death Cardiac Myocytes Cardiac Myosins Cell physiology Cells Cessation of life Clinical Conscious Depressed mood Development Diagnosis Dose Electrocardiogram Environment Event Frequencies Genes Goals Heart Heart Atrium Heart failure Hypertrophic Cardiomyopathy Hypertrophy Implant Incidence Injury Interdisciplinary Study Investigation Ischemia Isometric Exercise Isoproterenol Kinetics Lead Length Link Measures Mentors Methods Microfilaments Molecular Monitor Movement Mus Muscle Cells Mutant Strains Mice Mutation Myocardial Myocardium Myosin ATPase Organ Pathogenesis Pathologic Patients Phenotype Phosphorylation Pilot Projects Play Prevalence Proteins Protocols documentation Pump Recurrence Regulation Resistance Role Sarcomeres Stress Stress Tests Structure Telemetry Thick Filament Transducers Transgenic Animals Transgenic Mice Ventricular Ventricular Dysfunction Ventricular Premature Complexes Ventricular Tachycardia Vertebral column Work adrenergic blebbistatin flexibility heart rate variability improved functioning in vivo insight myosin-binding protein C new therapeutic target novel novel strategies novel therapeutics pressure prevent public health relevance research study response skeletal subcutaneous success sudden cardiac death tool

项目摘要

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.

描述（由申请人提供）：心力衰竭的复发性临床标志是心律不齐的发生，这导致HF患者心脏猝死的发生率增加，进而导致HF恶化。尽管HF与心律不齐之间存在明确的联系，但尚未确定针对这些电气异常的适用治疗方法。 PI和他的导师最近发现，心脏肌球蛋白结合蛋白C（CMYBP-C）磷酸化可能在调节心脏中的钙（Ca2+）处理中起作用。这可能对理解导致HF期间心律不齐的机制具有深远的影响，并可能确定新颖的治疗策略。实际上，CMYBP-C磷酸化在健康心脏中被广泛磷酸化，并严重耗尽了HF，病理肥大，缺血性损伤和心房颤动。计划的研究将利用良好的评估体内心脏功能的方法，并开发和完善新颖的工具，以进一步将体内发现结果扩展到单个孤立的心室心肌细胞中。 PI和他的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如何导致心律失常，并表明具有防止CMYBP-C磷酸化的小鼠表现出严重的心律失常和肾上腺抗应激后心脏死亡。我们假设CMYBP-C磷酸化对于心肌中的CA2+处理是必需的。因此，该提案的总体目标是：1）确定含有突变消融（ALLP-）或模仿CMYBP-C的小鼠心律不齐的倾向，2）研究了分离的心肌细胞中改变Ca2+的分子原因。拟议的工作的独特特征是在体内研究深度的结合和在丰富的互动环境中进行了单个细胞实验，并在此类工作中获得了良好的成功记录。对于PI，调查很好地支持了他进行与心脏功能有关的跨学科研究的长期计划，以扩大我们对心力衰竭发病机理的理解。