SCN5A mutations and dilated cardiomyopathy

SCN5A突变与扩张型心肌病

• 批准号: 9275119
• 负责人: DAN M RODEN
• 金额: $ 39.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/9275119
• 关键词: Acute; Address; Affect; Arrhythmia; Atrial Fibrillation; Behavior; Brugada syndrome; Cardiac; Cardiovascular system; Contractile Proteins; Cytoskeletal Proteins; Data; Dependence; Development; Diagnostic; Dilated Cardiomyopathy; Disease; Dose; Drug-sensitive; Electrocardiogram; Electrophysiology (science); Employee Strikes; Etiology; Exhibits; Feedback; Functional disorder; Genes; Genetic Models; Health; Health Care Costs; Heart; Heart Atrium; Heart failure; Homeostasis; Human; In Vitro; Lateral; Link; Long QT Syndrome; Long-Term Effects; Maps; 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; molecular subtypes; mortality; mouse model; mutant; research study; voltage

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：由 SCN5A 编码的初级心脏钠通道的开放负责心肌细胞的快速去极化，从而启动心动周期并构成心脏快速传导的基础。该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。在与这些疾病状态相关的数百种突变中，只有少数与 DCM 和心力衰竭明确相关，并且其潜在机制尚不清楚。该提案建立在我们建立钠通道相关疾病小鼠模型的工作基础上，以测试 SCN5A 突变通过与电生理功能障碍直接相关的机制启动 DCM 表型的总体假设；值得注意的是，这将 SCN5A 相关 DCM 与其他形式的疾病区分开来。在患有 D1275N（一种与人类 DCM 相关的突变）的小鼠中，我们的主要发现是峰值钠电流降低、门控接近正常、心电图和光学测绘显示显着的传导延迟、通道蛋白丰度降低（特别是沿着肌细胞外侧边界）以及年龄- DCM的依赖发展。相比之下，峰值钠电流降低相当或更大的其他小鼠品系并未表现出传导异常或 DCM。因此，在具体目标 1 中，我们将测试多个相互竞争的假设来解释这一明显的悖论：具体实验将解决细胞内离子稳态与传导异常的作用，及其作为 DCM 表型生成器的潜在机制。与 D1275N 不同，DCM 相关的 R222Q 突变在体外表现出惊人的门控变化，患者表现出非常频繁的药物敏感性心室异位活动并发展为 DCM。在具体目标 2 中，我们将对比 R222Q 和 D1275N 引起 DCM 的机制，并测试异位活性抑制改善或逆转 DCM 表型的假设。在美国，心力衰竭影响着超过 400 万人，识别分子亚群的研究代表了定制基于机制的治疗的重要一步。