Molecular mechanisms underlying cardiac sodium channelopathy

项目总结： 心脏电压门控性钠通道NaV1.5在心脏功能中起着重要作用。遗传 已知NaV1.5的突变与包括长QT综合征在内的各种心律失常有关。 我们的初步结果表明，NaV1.5通道受细胞周期蛋白依赖性激酶5(CDK5)和 CDK5和NaV1.5通道参与了由基因突变引起的心律失常 CACNA1C钙通道和MYH7肌丝基因。这项研究的主要目标是揭示 心脏NaV1.5通道调节的分子机制及其病理生理机制 与钠通道病相关的心律失常的潜在机制。目标1是研究如何 CDK5利用电生理记录的人和小鼠模型调节NaV1.5通道。目标2 是阐明心脏钠通道功能障碍是如何由心肌钙通道突变引起的。 长QT综合征8型。目的3是检验CDK5和NAV1.5异常与 家族性肥厚型心肌病和心律失常是由家族性MYH7突变引起的。这个 我们的研究方法将为研究心脏钠通道的分子基础提供新的见解 钠离子通道病引起的心律失常的调节和病理生理机制。

Project Summary: The cardiac voltage-gated sodium channel, NaV1.5, plays an important role in cardiac function. Genetic mutations in NaV1.5 are known to be associated with various cardiac arrhythmias including long QT syndrome. Our preliminary results suggested that NaV1.5 channel is regulated by cyclin-dependent kinase 5 (CDK5) and that CDK5 and NaV1.5 channel are involved in cardiac arrhythmias caused by genetic mutations in the CACNA1C calcium channel and MYH7 myofilament genes. The primary goal of this study is to unveil the molecular mechanisms of cardiac NaV1.5 channel regulation and to elucidate the pathophysiological mechanisms underlying cardiac arrhythmias associated with sodium channelopathy. Aim 1 is to examine how CDK5 regulates NaV1.5 channels using human and mouse models with electrophysiological recordings. Aim 2 is to elucidate how cardiac sodium channel dysfunction results from the cardiac calcium channel mutants in long QT syndrome type 8. Aim 3 is to test the hypothesis that CDK5 and NaV1.5 abnormalities are involved in familial hypertrophic cardiomyopathy and arrhythmias that are caused by a familial MYH7 mutation. The approaches of our study would provide new insights into the molecular basis of cardiac sodium channel regulation and the pathophysiological mechanisms underlying cardiac arrhythmias with sodium channelopathy.