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）：在获得性和遗传性心律失常综合征中，离子通道功能障碍会导致猝死。一个这样的通道家族包括钾内向整流器Kir 2、Kir2.1、Kir2.2和Kir2.3，并且在功能上构成IK 1。KCNJ 2编码心脏离子通道Kir2.1（IK 1的主要成分），KNCJ 2中的功能缺失突变导致LQT 7，肾上腺素能依赖性功能缺失导致CPVT 3。IK 1在心力衰竭中下调，尽管蛋白质和mRNA水平正常，但β-肾上腺素能敏感性降低。我们目前的知识差距是在获得性和遗传性心律失常综合征中导致Kir 2功能丧失的详细机制。这些机制可能取决于与其他蛋白质的相互作用或调节，作为Kir2.1大分子复合物的一部分，迄今为止未知。在心肌细胞中，小窝的特征在于存在由CAV 3编码的小窝蛋白-3，并形成用于离子通道和受体分子的脂质微区。CAV 3的突变可引起离子通道功能障碍，例如与LQT 9相关的那些，导致心律失常的产生和心源性猝死。小窝蛋白-3（Cav 3）在心力衰竭中也下调，小窝结构域也是如此。我们先前研究了CAV 3 LQT 9相关突变，发现IK 1密度降低是由于通道膜表达降低。在这项提案中，我们将确定Cav 3的机制，无论是从与LQT 9相关的突变或通过获得性重塑心力衰竭，导致IK 1的失调，并有助于在这些条件下的血管生成。我们将利用新的和创新的方法，如人诱导多能衍生心肌细胞模型和补充心力衰竭模型。该提案的总体目标是确定Cav 3可以促进或破坏Kir2.1的大分子复合物的机制以及对IK 1功能的影响，从而导致室性心律失常。我们的长期目标是通过表征和识别与异常IK 1相关的心律失常发生机制，改善遗传性或获得性心律失常患者的治疗选择。通过从该建议中获得的知识，我们将更好地了解由Kir2.1异常Cav 3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方法的有价值的测试平台。因此，该提案不仅将推进心律失常研究领域，而且还允许未来开发这种和其他心律失常综合征的治疗选择和疗法。