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突变和扩张的心肌病抽象的由SCN5A编码的主要心脏钠通道的开放是造成快速心肌细胞的去极化，启动心脏周期并构成心脏快速传导。基因突变与一系列表型有关，包括长QT综合征，Brugada综合征，传导疾病，扩张的心肌病（DCM）和心房颤动。在与之相关的数百个突变中这些疾病状态，只有少数与DCM和心力衰竭有关基本机制尚不清楚。这项建议是建立在我们的工作的基础上的钠通道相关疾病以检验SCN5A突变启动DCM的总体假设通过与电生理功能障碍直接相关的机制表型；值得注意的是，这有区别来自其他形式的疾病的SCN5A相关DCM。在具有D1275N的小鼠中，与人DCM，我们的主要发现是峰值钠电流降低，接近正常的门控，引人注目的传导 ECG和光学映射的延迟，通道蛋白的丰度降低，尤其是沿侧面心肌细胞边界和DCM的年龄依赖性发展。相比之下，其他具有等效或等效的鼠标线峰值钠电流的较大降低不显示传导异常或DCM。因此，在具体目的1，我们将测试多个竞争假设，以解释这种明显的悖论：特定的悖论实验将解决细胞内离子体内平衡与异常传导中的作用，以及它们的基本机制是DCM表型的发电机。与D1275N不同，与DCM相关 R222Q突变显示出惊人的门控变化，患者表现出非常频繁的药物敏感性心室异位活性并发展DCM。在特定目标2中，我们将对比R222Q的机制 D1275N引起DCM并检验以下假设：异位活性的抑制可改善或逆转 DCM表型。心力衰竭影响了美国400万人的更多人和研究以识别分子亚群代表了基于机制的治疗的重要步骤。