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抽象的由 SCN5A 编码的初级心脏钠通道的开放负责快速心肌细胞去极化启动心动周期并构成心脏快速传导的基础。基因突变与一系列表型相关，包括长 QT 综合征、Brugada 综合征、传导疾病、扩张型心肌病（DCM）和心房颤动。数百个突变与在这些疾病状态中，只有少数与 DCM 和心力衰竭明确相关，并且根本机制尚不清楚。该提案建立在我们建立小鼠模型的工作基础上钠通道相关疾病，以检验 SCN5A 突变引发 DCM 的总体假设通过与电生理功能障碍直接相关的机制实现表型；值得注意的是，这区分了来自其他形式疾病的 SCN5A 相关 DCM。在患有 D1275N 的小鼠中，与人类 DCM，我们的主要发现是峰值钠电流降低、门控接近正常、传导显着心电图和光学测绘延迟，通道蛋白的丰度降低，尤其是沿侧向肌细胞边界和 DCM 的年龄依赖性发展。相比之下，其他具有同等或峰值钠电流的较大下降并不显示传导异常或 DCM。因此，在具体目标 1，我们将测试多个相互竞争的假设来解释这个明显的悖论：具体实验将探讨细胞内离子稳态与传导异常的作用，以及它们的潜在机制，作为 DCM 表型的产生者。与 D1275N 不同，DCM 相关 R222Q 突变在体外表现出显着的门控变化，患者表现出非常频繁的药物敏感性心室异位活动并发展为 DCM。在具体目标 2 中，我们将对比 R222Q 的机制和 D1275N 引起 DCM，并检验抑制异位活动可改善或逆转 DCM 的假设 DCM 表型。心力衰竭影响美国超过 400 万人，研究发现分子子集代表了定制基于机制的治疗的重要一步。