Caveolae and Cardiac Repolarization

小凹和心脏复极

• 批准号: 8514364
• 负责人: Ravi Chandra Balijepalli
• 金额: $ 36.53万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514364
• 关键词: Ablation; Action Potentials; Arrhythmia; Biological Assay; Cardiac; Cardiac Myocytes; Caveolae; Cell membrane; Cells; Complement; Complex; Data; Disease; Electrocardiogram; Gene Mutation; Generations; Genes; Genetic; Genetically Engineered Mouse; Goals; Health; Heart; Heart Diseases; Heart Hypertrophy; Home environment; Human; Immunoprecipitation; Inherited; Ion Channel; Ion Channel Protein; Knock-out; Knowledge; Life; Link; Long QT Syndrome; Membrane Microdomains; Methods; Modeling; Mus; Muscle; Muscle Cells; Mutation; Myocardium; Patch-Clamp Techniques; Patients; Physiology; Potassium; Potassium Channel; Predisposition; Prevention therapy; Property; Proteomics; Regulation; Regulatory Pathway; Research; Risk; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Signaling Protein; Site-Directed Mutagenesis; Surface; Techniques; Testing; Transmission Electron Microscopy; Ventricular; Ventricular Arrhythmia; Western Blotting; Work; base; caveolin-3; density; disorder control; gain of function; heart cell; induced pluripotent stem cell; insight; mouse model; novel therapeutics; sudden cardiac death; tomography; voltage

DESCRIPTION (provided by applicant): Changes in the repolarization properties of cardiac muscle frequently underlie the increased susceptibility to ventricular arrhythmias in a variety of heart diseases, but the control of cardiac repolarization is incompletely understood. Abnormalities of repolarization resulting in action potential duration prolongation or shortening can be pro-arrhythmic. Multiple different ion channels in cardiomyocytes impact action potential repolarization, and the diversity of ion channels and regulatory pathways involved in repolarization is highlighted by the association of at least 13 distinct genes with the inherited long QT syndrome which is due to delayed repolarization. For example, mutations in the caveolin-3 gene (CAV3) have been implicated as one cause of the inherited Long QT syndrome (LQTS). Cav-3 is an essential scaffolding protein required for the formation of specialized membrane microdomains in cells referred to as caveolae which are home to multiple signaling molecules and ion channel proteins. Preliminary data presented in this application show that genetic ablation of caveolin-3 in the mouse heart dramatically prolongs cardiac repolarization. The proposed research will test the hypothesis that cardiac caveolae provide integrated regulation of cardiac repolarization by controlling the density and functional properties of specifc ion channels. Using both genetically engineered mouse models with cardiac-specific regulation of Cav-3 expression as well as human iPS cell-cardiomyocyte models, the proposal will examine the role of caveolae in the regulation of cardiac repolarization in three specific aims: 1) Determine the impact of changes in the abundance of Cav-3 in cardiomyocytes on the density of caveolae and on cardiac repolarization; 2) Evaluate the impact of changes in Cav-3 abundance and LQTS-associated Cav-3 mutations on the density and biophysical properties of voltage-gated potassium currents; and 3) Determine how wild type Cav-3 and LQTS-associated mutations of Cav-3 regulate the density and properties of ICa,L. These studies will provide mechanistic new insights into the control of cardiac repolarization and abnormalities in disease which can result in arrhythmias.

描述（由申请人提供）：心肌复极特性的变化经常是各种心脏疾病中室性心律失常易感性增加的基础，但对心脏复极的控制还不完全了解。复极异常导致动作电位时程延长或缩短可为促心律失常。心肌细胞中多种不同的离子通道影响动作电位复极，并且至少13种不同基因与由于延迟复极引起的遗传性长QT综合征的关联突出了复极中涉及的离子通道和调节途径的多样性。例如，窖蛋白-3基因（CAV 3）的突变被认为是遗传性长QT综合征（LQTS）的一个原因。Cav-3是细胞中形成称为小窝的专门膜微区所需的必需支架蛋白，小窝是多种信号分子和离子通道蛋白的家园。本申请中提供的初步数据显示，小鼠心脏中小窝蛋白-3的基因消融显著地抑制心脏复极。本研究将验证心小窝通过控制特定离子通道的密度和功能特性对心脏复极化进行综合调节的假设。使用具有Cav-3表达的心脏特异性调节的基因工程小鼠模型以及人iPS细胞-心肌细胞模型，该提案将在三个特定目标中检查小窝在心脏复极调节中的作用：1） 确定心肌细胞中Cav-3丰度变化对小窝密度和心脏复极的影响; 2）评价Cav-3丰度变化和LQTS相关Cav-3突变对电压门控钾电流密度和生物物理特性的影响;和3）确定野生型Cav-3和Cav-3的LQTS相关突变如何调节伊卡，L的密度和特性。这些研究将为控制心脏复极和可导致心律失常的疾病异常提供新的机制见解。