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SCN5A mutations and dilated cardiomyopathy

SCN5A突变与扩张型心肌病

基本信息

批准号：
8651207
负责人：
DAN M RODEN
金额：
$ 39.04万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-16 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651207
关键词：
Acute Address Affect Arrhythmia Atrial Fibrillation Behavior Cardiac Cardiovascular system Contractile Proteins Cytoskeletal Proteins Data Dependence Development Diagnostic Dilated Cardiomyopathy Disease Dose Drug-sensitive Electrocardiogram Employee Strikes Etiology Exhibits Feedback Functional disorder Genes Genetic Models Health Care Costs Heart Heart Atrium Heart failure Homeostasis Human In Vitro Lateral Link Long QT Syndrome Long-Term Effects Maps Modeling Molecular Mus Muscle Cells Mutation Optics Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Proteins Public Health Role Signal Pathway Sodium Sodium Channel Sodium Channel Blockers Syndrome System Testing Therapeutic United States Ventricular Work age related base clinical phenotype design heart rhythm improved mortality mutant public health relevance research study voltage

项目摘要

SCN5A mutations and dilated cardiomyopathy ABSTRACT Opening of the primary cardiac sodium channel, encoded by SCN5A, is responsible for rapid myocyte depolarization that initiates the cardiac cycle and underlies fast conduction in the heart. Mutations in the gene have been associated with a range of phenotypes, including long QT syndrome, Brugada syndrome, conduction disease, dilated cardiomyopathy (DCM) and atrial fibrillation. Out of hundreds of mutations linked to these disease states, only a handful have been clearly associated with DCM and heart failure and the underlying mechanisms are not understood. This proposal builds on our work establishing murine models of sodium channel-related disease to test the overall hypothesis that SCN5A mutations initiate the DCM phenotype through mechanisms directly related to electrophysiologic dysfunction; notably, this distinguishes SCN5A-related DCM from other forms of the disease. In mice with D1275N, a mutation associated with human DCM, our major findings are decreased peak sodium current, near normal gating, striking conduction delay by ECG and optical mapping, decreased abundance of the channel protein especially along the lateral myocyte border, and age-dependent development of DCM. By contrast, other mouse lines with equivalent or greater decreases in peak sodium current do not display conduction abnormalities or DCM. Accordingly, in Specific Aim 1, we will test multiple competing hypotheses to explain this apparent paradox: specific experiments will address the roles of intracellular ionic homeostasis versus abnormalities in conduction, and their underlying mechanisms, as generators of the DCM phenotype. Unlike D1275N, the DCM-associated R222Q mutation displays striking gating changes in vitro and patients display very frequent drug-sensitive ventricular ectopic activity and develop DCM. In Specific Aim 2, we will contrast mechanisms whereby R222Q and D1275N cause DCM and test the hypothesis that suppression of ectopic activity improves or reverses the DCM phenotype. Heart failure affects more that 4 million people in the United States and studies to identify molecular subsets represent an important step to tailoring mechanism-based therapy.

SCN5A突变与扩张型心肌病