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:
  • 金额:
    $ 39.04万
  • 依托单位:
  • 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

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.
SCN 5A突变与扩张型心肌病 摘要 由SCN 5A编码的初级心脏钠通道的开放负责快速的心肌细胞凋亡。 启动心动周期并成为心脏快速传导的基础的去极化。的基因突变 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。在数百种与 在这些疾病状态中,只有少数与DCM和心力衰竭明确相关, 根本机制还不清楚。这项建议建立在我们建立小鼠模型的基础上, 钠通道相关疾病,以检验SCN 5A突变引发DCM的总体假设 表型通过与电生理功能障碍直接相关的机制;值得注意的是, SCN 5A相关的DCM与其他形式的疾病。在携带D1275 N的小鼠中, 在人DCM中,我们的主要发现是峰值钠电流降低,接近正常门控,显著传导 ECG和光学标测延迟,通道蛋白丰度降低,尤其是沿着侧支 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 峰值钠电流的更大降低不显示传导异常或DCM。据此在 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: 实验将阐述细胞内离子稳态与传导异常的作用, 它们的潜在机制,作为DCM表型的发生器。与D1275 N不同, R222 Q突变在体外表现出显著的门控变化,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R222 Q 和D1275 N引起DCM,并测试抑制异位活性改善或逆转DCM的假设。 DCM表型。心力衰竭影响着美国400多万人, 分子亚群代表了定制基于机制的治疗的重要步骤。

项目成果

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DAN M RODEN其他文献

DAN M RODEN的其他文献

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{{ truncateString('DAN M RODEN', 18)}}的其他基金

Vanderbilt Genome-Electronic Records (VGER) Project
范德比尔特基因组电子记录 (VGER) 项目
  • 批准号:
    10771648
  • 财政年份:
    2023
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome-Electronic Records (VGER) Project
范德比尔特基因组电子记录 (VGER) 项目
  • 批准号:
    10207727
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome-Electronic Records (VGER) Project
范德比尔特基因组电子记录 (VGER) 项目
  • 批准号:
    10659136
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:
Functional Genomics of Cardiac Sodium Channel Variants
心脏钠通道变异的功能基因组学
  • 批准号:
    10538620
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome-Electronic Records (VGER) Project
范德比尔特基因组电子记录 (VGER) 项目
  • 批准号:
    10450009
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:
SCN5A mutations and dilated cardiomyopathy
SCN5A突变与扩张型心肌病
  • 批准号:
    9275119
  • 财政年份:
    2013
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome Electronic Records Project
范德比尔特基因组电子记录项目
  • 批准号:
    8332920
  • 财政年份:
    2011
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome Electronic Records Project
范德比尔特基因组电子记录项目
  • 批准号:
    8319346
  • 财政年份:
    2011
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome Electronic Records Project
范德比尔特基因组电子记录项目
  • 批准号:
    8721555
  • 财政年份:
    2011
  • 资助金额:
    $ 39.04万
  • 项目类别:
Vanderbilt Genome Electronic Records Project
范德比尔特基因组电子记录项目
  • 批准号:
    8523192
  • 财政年份:
    2011
  • 资助金额:
    $ 39.04万
  • 项目类别:

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