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编码的主要心脏钠通道的开放负责快速的肌细胞去极化，从而启动心脏周期和心脏快速传导。该基因的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，扩张心肌病（DCM）和心房颤动。在与这些疾病状态相关的数百个突变中，只有少数与DCM和心力衰竭有关，并且不了解潜在的机制。该提议建立在我们的工作基础上，建立了与钠通道相关疾病的鼠模型，以检验总体假设，即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。值得注意的是，这将与SCN5A相关的DCM与其他形式的疾病区分开。在具有与人DCM相关的突变的D1275N的小鼠中，我们的主要发现是峰值钠电流降低，接近正常的门控，ECG和光学映射引起的传导延迟，频道蛋白质的丰度降低，尤其是沿外侧心肌细胞边界，以及DCM的年龄依赖性发育。相比之下，峰值钠电流中等效降低或更大降低的其他小鼠线不显示传导异常或DCM。因此，在特定的目标1中，我们将测试多种竞争假设，以解释这种明显的悖论：特定的实验将解决细胞内离子稳态与异常传导中的作用及其基本机制，作为DCM表型的发生器。与D1275N不同，与DCM相关的R222Q突变显示出惊人的门控变化，并且患者表现出非常频繁的药物敏感心室异位活性并发展DCM。在特定目标2中，我们将对比R222Q和D1275N引起DCM并检验以下假设：异位活性抑制会改善或逆转DCM表型的假设。心力衰竭影响了美国400万人的更多，并且研究鉴定分子亚群是基于机制治疗的重要步骤。