Circadian clock regulation of myocardial ion channel expression and function
心肌离子通道表达和功能的昼夜节律时钟调节
基本信息
- 批准号:10029362
- 负责人:
- 金额:$ 61.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ARNTL geneATAC-seqAction PotentialsAddressArrhythmiaBehaviorBindingBiological ModelsCardiacCardiac Electrophysiologic TechniquesCardiac MyocytesChIP-seqChromatinChronicChronic PhaseChronobiologyCircadian DysregulationCollectionCuesDataData SetDiseaseElectrophysiology (science)Environmental Risk FactorFamilyGene ExpressionGene OrderGenesGeneticGenetic TranscriptionGenomicsGoalsHeartHeart AbnormalitiesHeart AtriumHomeostasisHourHumanIndividualIon ChannelKnock-outKnowledgeLife StyleLightLinkMessenger RNAModelingMolecularMolecular TargetMusMyocardialOutcomeOutcome StudyOutputPathologicPhasePotassium ChannelPredispositionPropertyRegulationRegulator GenesRiskRisk FactorsRodentRoleSeriesTestingTimeTime-restricted feedingTissuesTranslatingVentricularcell typecircadiancircadian pacemakerdesignexperimental studyfeedingheart rhythminsightionic balancemodifiable riskmolecular clockmouse modelpatient populationprogramsresponsesudden cardiac deathsuprachiasmatic nucleustime usetranscriptome sequencingtranscriptomicsvirtual
项目摘要
Summary:
The overall objectives of this proposal are to 1) define the genomic and transcriptomic mechanisms by which
the cardiomyocyte clock regulates ion channels that contribute to cardiac excitability; and 2) disrupt the
cardiomyocyte clock to link changes in circadian-ordered gene expression with electrophysiological properties
of atrial and ventricular cardiomyocytes. The outcomes will address significant gaps in our understanding for
how the myocardial circadian clock regulates the expression of key cardiac ion channels and how abnormal
cardiac clock function contributes to arrhythmia vulnerability.
The mechanism regulating circadian timing, the molecular clock, exists in virtually all cell types in the body. A
critical function of the molecular clock is to link time of day with a large-scale transcriptional program to support
cellular homeostasis To date, our labs have used an inducible cardiomyocyte specific mouse model to knock
out the core clock gene, Bmal1 (iCSΔBmal1). These studies showed that disruption of the myocardial clock is
sufficient to decrease ventricular K+ and Na+ channel gene expression, disrupt current levels, disrupt cardiac
excitability, and increase arrhythmia susceptibility. These studies establish a critical role for the cardiomyocyte
clock, independent of the central clock, in regulating the expression of different families of ion channel genes
that impact the ionic balance needed for normal excitability. One goal of this project is to utilize large scale
genomic and transcriptomic approaches with our mouse model system to define the circadian clock dependent
control of temporal gene expression in both atrial and ventricular tissues.
To address abnormal circadian clock function, our lab has used different models of circadian disruption, such
as chronic phase advance or time restricted feeding to test links between circadian disruption and arrhythmia
vulnerability in mouse models. We have found that disrupting either light or feeding time cues is sufficient to
induce pathological changes in cardiac rhythms in normal mice and to accelerate sudden cardiac death in a
genetic mouse model of arrhythmia susceptibility. These studies support our premise that disruption of day-
night rhythms through environmental factors leads to altered myocardial clock function with outcomes that
include modified ion channel expression, cardiac excitability and arrhythmia vulnerability.
The aims of this proposal are designed to test the following hypotheses: 1) The molecular clocks in both atrial
and ventricular cardiomyocytes are necessary to direct daily chromatin accessibility and transcriptional output
including expression of key ion channel and ion channel regulatory genes. 2) Chronic disruption of the
cardiomyocyte clock using altered time of feeding is sufficient to cause dysregulation of the cardiac clock
resulting in an imbalance in cardiac ion channel expression and currents leading to altered excitability and
increased arrhythmia vulnerability.
简介:
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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Brian P Delisle其他文献
Brian P Delisle的其他文献
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{{ truncateString('Brian P Delisle', 18)}}的其他基金
Circadian clock regulation of myocardial ion channel expression and function
心肌离子通道表达和功能的昼夜节律时钟调节
- 批准号:
10247589 - 财政年份:2020
- 资助金额:
$ 61.75万 - 项目类别:
Circadian clock regulation of myocardial ion channel expression and function
心肌离子通道表达和功能的昼夜节律时钟调节
- 批准号:
10650247 - 财政年份:2020
- 资助金额:
$ 61.75万 - 项目类别:
Circadian clock regulation of myocardial ion channel expression and function
心肌离子通道表达和功能的昼夜节律时钟调节
- 批准号:
10413214 - 财政年份:2020
- 资助金额:
$ 61.75万 - 项目类别:
Administrative Supplement -Circadian Clock Regulation of Myocardial Ion Channel Expression and Function
行政补充-心肌离子通道表达和功能的昼夜节律时钟调节
- 批准号:
10800220 - 财政年份:2020
- 资助金额:
$ 61.75万 - 项目类别:
Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
长 QT 综合征模型中揭示了延迟整流 K 通道生物发生
- 批准号:
7834209 - 财政年份:2009
- 资助金额:
$ 61.75万 - 项目类别:
Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
长 QT 综合征模型中揭示了延迟整流 K 通道生物发生
- 批准号:
7612700 - 财政年份:2008
- 资助金额:
$ 61.75万 - 项目类别:
Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
长 QT 综合征模型中揭示了延迟整流 K 通道生物发生
- 批准号:
7468128 - 财政年份:2008
- 资助金额:
$ 61.75万 - 项目类别:
Delayed Rectifier K Channel Biogenesis is Unveiled in Models of Long QT Syndrome
长 QT 综合征模型中揭示了延迟整流 K 通道生物发生
- 批准号:
7844877 - 财政年份:2008
- 资助金额:
$ 61.75万 - 项目类别:
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