Microdomain regulation of Ca2+ release in cardiac physiology and disease

心脏生理和疾病中 Ca2 释放的微域调节

• 批准号: 9513802
• 负责人: Przemyslaw Radwanski
• 金额: $ 24.81万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513802
• 关键词: Address; Adrenergic beta-Antagonists; Animal Model; Animals; Area; Arrhythmia; Atrial Fibrillation; Binding Proteins; Brain; Calsequestrin; Canis familiaris; Cardiac; Cardiac Myocytes; Catecholaminergic Polymorphic Ventricular Tachycardia; Catecholamines; Cells; Cessation of life; Complex; Couples; Coupling; Diastole; Disease; Electrophysiology (science); Event; Exercise; Functional disorder; Genetic; Genetic Predisposition to Disease; Goals; Heart; Heart Atrium; Heart Diseases; Heart failure; Heterogeneity; Homeostasis; Image; Incidence; Intervention; Link; Mechanics; Mediating; Membrane; Mentors; Methodology; Modeling; Molecular; Molecular Abnormality; Morbidity - disease rate; Mus; Muscle Cells; Mutation; Myocardial; Myocardial tissue; Neurons; Pathology; Patients; Pharmacology; Phase; Phenotype; Physiology; Process; Proteins; Refractory; Regulation; Risk; Role; Ryanodine Receptors; Sarcoplasmic Reticulum; Signal Transduction; Stress; Sudden Death; System; Testing; Therapeutic; Tissue imaging; Tissues; Translating; Ventricular; Ventricular Arrhythmia; base; channel blockers; clinically relevant; in vivo; inhibitor/antagonist; insight; mortality; mouse model; novel; response; translational study

 DESCRIPTION (provided by applicant): Project Summary Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease and is oftena result of abnormal impulse formation. Such triggered activity are associated with abnormal Ca2+ release from the sarcoplasmic reticulum (SR) and are a hallmark of catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated mutations in the ryanodine receptors (RyR2) or calsequestrin (Casq2), the major intra-SR Ca2+ binding protein render the RyR2 leaky and predispose these patients to arrhythmias. Atrial fibrillation is an another common finding in CPVT, indicating that Ca2+ mishandling in CPVT is not isolated to the ventricles. Despite high response of CPVT to Ca2+ channel- and/or beta-blockers, refractory cases often require Na+ channel inhibitor based therapy. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood. The applicant has developed an experimental system using various murine models of CPVT that integrates information of Ca2+ handling at the cellular level with the electrophysiologic phenotype in tissue. The applicant plans to investigate the hypothesis that subpopulation of Na+ channels (neuronal Na+ channels; nNav) contribute to arrhythmogenic aberrant Ca2+ release through the microdomain Na+/Ca2+ signaling. Specifically the proposal will address the following aims during the mentored phase (K99): 1) Elucidate the molecular and subcellular consequences of subdomain-specific Na+/Ca2+ signaling on aberrant Ca2+ release in the genesis of Ca2+ -dependent atrial and ventricular arrhythmias. Here we will test the hypothesis that subdomain-specific Na+/Ca2+ signaling contributes to arrhythmogenic aberrant Ca2+ release while attempting to identify the molecular determinants of local Na+/Ca2+ subdomain signaling. 2) Define the role of Na+/Ca2+ signaling in tissue wide aberrant Ca2+ release synchronization. These translational studies will test the hypothesis that subdomain-specific Na+/Ca2+ signaling facilitates myocardial synchronization of aberrant Ca2+ release and promotes subsequent ectopic activity in intact ventricular tissue. 3) Validate the applicability of Na+/Ca2+ signaling to in vivo settings. During the independent phase (R00) the proposal will: 1) Investigate the role of subdomain-specific Na+/Ca2+ signaling on aberrant Ca2+ release in the genesis of atrial arrhythmias. 2) Examine the regional heterogeneities of the subdomain-specific Na+/Ca2+ signaling in atrial aberrant Ca2+ release synchronization. 3) Validate the therapeutic potential of perturbation of Na+/Ca2+ signaling in settings of atrial arrhythmias and translate the applicability to animal models of acquired Ca2+-mediated arrhythmias. The mechanistic and pharmacological insights gained on the cellular as well as on tissue levels will offer a mechanism-based therapeutic approach that will be tested in vivo. Furthermore, these studies will determine whether such arrhythmogenic mechanism(s) is/are applicable to a clinically-relevant model of Ca2+-mediated arrhythmias. A long term goal of this study is to better understand the cellular and molecular mechanisms of Ca2+-mediated arrhythmogenesis.

 描述（申请人提供）：项目总结心律失常导致的猝死是心脏病最常见的后果，通常是异常冲动形成的结果。这种触发活动与肌浆网（SR）的异常Ca 2+释放相关，是儿茶酚胺能多形性室性心动过速（CPVT）的标志。Ryanodine受体（RyR 2）或钙螯合蛋白（Casq 2）中的CPVT相关突变，主要的SR内Ca 2+结合蛋白使RyR 2泄漏并使这些患者易患心律失常。房颤是CPVT的另一个常见发现，表明CPVT中的Ca 2+处理不当并非孤立于心室。尽管CPVT对Ca 2+通道和/或β-阻滞剂有高反应，但难治性病例通常需要基于Na+通道抑制剂的治疗。然而，在CPVT心律失常之前，Na+内流和Ca 2+处理紊乱之间的关系仍然知之甚少。申请人已经开发了一种使用各种CPVT鼠模型的实验系统，其将细胞水平的Ca 2+处理信息与组织中的电生理表型整合。申请方计划研究Na+通道亚群（神经元Na+通道; nNav）通过微域Na+/Ca 2+信号传导促进促炎性异常Ca 2+释放的假设。具体而言，该提案将在指导阶段（K99）解决以下目标：1）阐明亚结构域特异性Na+/Ca 2+信号传导对Ca 2+依赖性房性和室性心律失常发生中异常Ca 2+释放的分子和亚细胞后果。在这里，我们将测试的假设，亚结构域特异性Na+/Ca 2+信号有助于促炎异常Ca 2+释放，同时试图确定局部Na+/Ca 2+亚结构域信号的分子决定因素。2)确定Na+/Ca 2+信号在组织广泛异常Ca 2+释放同步中的作用。这些翻译研究将测试亚结构域特异性Na+/Ca 2+信号转导促进异常Ca 2+释放的心肌同步化并促进随后在完整心室组织中的异位活动的假设。3)适用于 体内环境的Na+/Ca 2+信号传导。在独立相（R 00）期间，该提议将：1）研究亚结构域特异性Na+/Ca 2+信号传导对异常Ca 2+释放在房性心律失常发生中的作用。2)检查心房异常Ca 2+释放同步化中亚结构域特异性Na+/Ca 2+信号传导的区域异质性。3)证实Na+/Ca 2+信号扰动在房性心律失常中的治疗潜力， 适用于获得性Ca 2+介导的心律失常的动物模型。在细胞和组织水平上获得的机制和药理学见解将提供一种将在体内测试的基于机制的治疗方法。此外，这些研究将确定这种致心律失常机制是否适用于Ca 2+介导的心律失常的临床相关模型。本研究的一个长期目标是更好地了解Ca 2+介导的乳腺癌发生的细胞和分子机制。