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
- 来源:
- 关键词:AcuteAddressAffectArrhythmiaAtrial FibrillationBehaviorCardiacCardiovascular systemContractile ProteinsCytoskeletal ProteinsDataDependenceDevelopmentDiagnosticDilated CardiomyopathyDiseaseDoseDrug-sensitiveElectrocardiogramEmployee StrikesEtiologyExhibitsFeedbackFunctional disorderGenesGenetic ModelsHealth Care CostsHeartHeart AtriumHeart failureHomeostasisHumanIn VitroLateralLinkLong QT SyndromeLong-Term EffectsMapsModelingMolecularMusMuscle CellsMutationOpticsPathway interactionsPatientsPharmaceutical PreparationsPhenotypePlayProteinsPublic HealthRoleSignal PathwaySodiumSodium ChannelSodium Channel BlockersSyndromeSystemTestingTherapeuticUnited StatesVentricularWorkage relatedbaseclinical phenotypedesignheart rhythmimprovedmortalitymutantpublic health relevanceresearch studyvoltage
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.
SCN5A突变与扩张型心肌病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DAN M RODEN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:
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