权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.