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Molecular mechanisms underlying cardiac sodium channelopathy

心脏钠离子通道病的分子机制

基本信息

批准号：
10199772
负责人：
Masayuki Yazawa
金额：
$ 39.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199772
关键词：
Action Potentials Address Affect Arrhythmia Biological Assay Biomedical Engineering Calcium Calcium Channel Cardiac Cardiac Myocytes Cells Chemicals Consensus Coupling Cyclin-Dependent Kinase 5 DNA Sequence Alteration Disease Disease model Electrocardiogram Electrophysiology (science)Embryo Engineering Familial Hypertrophic Cardiomyopathy Functional disorder Future Genes Goals Heart Human Hyperactivity Hypertrophic Cardiomyopathy In Vitro Investigation Knockout Mice Lidocaine Long QT Syndrome Measures Mediating Mexiletine Microfilaments Modeling Molecular Mus Muscle Cells Mutagenesis Mutant Strains Mice Mutation Myocardial dysfunction Myosin Heavy Chains Outcome Patients Phenotype Phosphorylation Site Phosphotransferases Physiological Play Property Proteins Recombinants Regulation Risk Rodent Rodent Model Role Sampling Skin Sodium Sodium Channel Sudden Death System Techniques Technology Testing Therapeutic Time United States Ventricular Vision design experimental study heart function human model in vivo induced pluripotent stem cell inhibitor/antagonist innovation insight mouse model mutant novel overexpression ranolazine small hairpin RNA stem cell model voltage

项目摘要

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.

项目概要：心脏电压门控钠通道NaV1.5在心脏功能中起重要作用。遗传已知NaV1.5中的突变与包括长QT综合征在内的各种心律失常相关。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）的调节， 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。本研究的主要目的是揭示心脏NaV1.5通道调节的分子机制，并阐明其病理生理学机制。与钠离子通道病相关的心律失常的潜在机制。目的1是研究如何 CDK5使用具有电生理记录的人类和小鼠模型调节NaV1.5通道。目的2 是为了阐明心脏钠通道功能障碍是如何导致心脏钙通道突变，长QT综合征8型。目的3是检验CDK5和NaV1.5异常参与了家族性肥厚型心肌病和由家族性MYH7突变引起的心律失常。的我们的研究方法将为心脏钠通道的分子基础提供新的见解调节和病理生理机制的基础上心律失常与钠通道病。