Arrhythmia Mechanisms from Inherited and Acquired Caveolin3 Dysregulation of IK1

IK1 遗传性和获得性 Caveolin3 失调引起的心律失常机制

• 批准号: 9100905
• 负责人: Lee Lochbaum Eckhardt
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100905
• 关键词: Accounting; Action Potentials; Adrenergic Agents; Agonist; Arrhythmia; Beds; Biophysical Process; Cardiac; Cardiac Myocytes; Catecholaminergic Polymorphic Ventricular Tachycardia; Cause of Death; Caveolae; Disease; Down-Regulation; Family; Functional disorder; Future; Generations; Genes; Goals; Golgi Apparatus; Health; Heart; Heart Diseases; Heart failure; Human; Individual; Inherited; Ion Channel; Knowledge; Lipids; Long QT Syndrome; Macromolecular Complexes; Membrane; Membrane Potentials; Membrane Protein Traffic; Messenger RNA; Methods; Modeling; Muscle Cells; Mutation; Outcome; Pathogenesis; Phase; Potassium; Prevention; Protein Isoforms; Proteins; Rattus; Regulation; Regulatory Element; Research; Rest; Short QT syndrome; Signal Transduction; Signaling Protein; Site; Staging; Stream; Sudden Death; Surface; Syndrome; Testing; Therapeutic; United States; Ventricular; Ventricular Arrhythmia; caveolin-3; density; heart rhythm; improved; induced pluripotent stem cell; innovation; loss of function; loss of function mutation; mutant; novel; novel therapeutics; receptor; response; structural heart disease; sudden cardiac death; therapy development; trafficking

 DESCRIPTION (provided by applicant): Ion channel dysfunction causes arrhythmic sudden death in both acquired and inherited arrhythmia syndromes. One such family of channels include potassium inward rectifier Kir2, Kir2.1, Kir2.2 and Kir2.3, and functionally make up IK1. KCNJ2 encodes the cardiac ion channel Kir2.1, the dominant component of IK1, and loss of function mutations in KNCJ2 causes LQT7 and adrenergic dependent loss of function causes CPVT3. IK1 is down-regulated in heart failure and has decreased beta-adrenergic sensitivity despite normal to increased protein and mRNA levels. The current gap in our knowledge is the detailed mechanisms causing loss of Kir2 function in both acquired and inherited arrhythmia syndromes. These mechanisms may depend on interactions with or regulation by other proteins as part of the Kir2.1 macromolecular complex, heretofore unknown. In cardiac myocytes, caveolae are characterized by the presence of Caveolin-3, encoded by CAV3, and form lipid microdomains for ion channels and receptor molecules. Mutations of CAV3 can cause ion channel dysfunction such as those associated with LQT9, leading to arrhythmia generation, and sudden cardiac death. Caveolin-3 (Cav3) is also down-regulated in heart failure as are caveolar domains. We have previously studied CAV3 LQT9 associated mutations and found that IK1 density is decreased due to decreased channel membrane expression. In this proposal we will determine the mechanism by which Cav3, either from mutations associated with LQT9 or by acquired remodeling in heart failure, causes dysregulation of IK1 and contributes to arrhythmogenesis in these conditions. We will utilize novel and innovative methods such as human induced pluripotent derived cardiac myocyte model and complementary heart failure models. The overall objective for this proposal is to identify the mechanism by which Cav3 can contribute or disrupt the macromolecular complex for Kir2.1 and the effects on IK1 function resulting in ventricular arrhythmias. Our long-term goal is to improve treatment options for individuals with inherited or acquired arrhythmias by characterizing and identifying the mechanisms involved in arrhythmogenesis related to abnormal IK1. With knowledge gained from this proposal, we will better understand the pathogenesis of arrhythmias caused by abnormal Cav3 with Kir2.1. The models developed in the proposal will also serve as a valuable test bed for therapeutics. Thus, the proposal will not only advance the field of arrhythmia research but also allow future development of treatment options and therapeutics for this and other arrhythmia syndromes.

 描述（由申请人提供）：离子通道功能障碍会导致获得性和遗传性心律失常综合征中的心律失常性猝死。这样的通道家族包括钾内向整流器 Kir2、Kir2.1、Kir2.2 和 Kir2.3，并在功能上构成 IK1。 KCNJ2 编码心脏离子通道 Kir2.1（IK1 的主要成分），KNCJ2 的功能丧失突变会导致 LQT7，肾上腺素能依赖性功能丧失会导致 CPVT3。尽管蛋白质和 mRNA 水平正常至升高，但 IK1 在心力衰竭中下调，且 β-肾上腺素能敏感性降低。目前我们的知识差距在于导致获得性和遗传性心律失常综合征中 Kir2 功能丧失的详细机制。这些机制可能依赖于作为 Kir2.1 大分子复合物一部分的其他蛋白质的相互作用或调节，这是迄今为止未知的。在心肌细胞中，小窝的特征是存在由 CAV3 编码的 Caveolin-3，并形成离子通道和受体分子的脂质微结构域。 CAV3 突变可导致离子通道功能障碍，例如与 LQT9 相关的离子通道功能障碍，导致心律失常和心源性猝死。 Caveolin-3 (Cav3) 与小凹结构域一样，在心力衰竭中也会下调。我们之前研究了CAV3 LQT9相关突变，发现IK1密度由于通道膜表达减少而降低。在本提案中，我们将确定 Cav3 的机制，无论是来自与 LQT9 相关的突变还是通过心力衰竭中的获得性重塑，导致 IK1 失调并导致这些情况下的心律失常发生。我们将利用新颖和创新的方法，例如人诱导多能心肌细胞模型和补充性心力衰竭模型。该提案的总体目标是确定 Cav3 贡献或破坏 Kir2.1 大分子复合物的机制以及对导致室性心律失常的 IK1 功能的影响。我们的长期目标是通过表征和识别与 IK1 异常相关的心律失常发生机制来改善遗传性或获得性心律失常患者的治疗选择。通过从该提案中获得的知识，我们将更好地了解由异常 Cav3 和 Kir2.1 引起的心律失常的发病机制。该提案中开发的模型也将作为治疗学的宝贵测试平台。因此，该提案不仅将推进心律失常研究领域，而且还将允许未来开发针对这种心律失常综合征和其他心律失常综合征的治疗方案和疗法。