A Novel Role for NFATC1 in Modulating Cardiac Excitability
NFATC1 在调节心脏兴奋性中的新作用
基本信息
- 批准号:10449135
- 负责人:
- 金额:$ 72.27万
- 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:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdolescentAffinityAlgorithmsAnimal ModelAnti-Arrhythmia AgentsArrhythmiaAtrial FibrillationBindingBinding SitesBiochemicalBioinformaticsBiological AssayCardiacCardiac Electrophysiologic TechniquesCardiac ablationCardiac developmentCardiovascular DiseasesCell Culture TechniquesCell LineCellsChIP-seqCustomDNA BindingDataEconomic BurdenElectrophysiology (science)Enzyme-Linked Immunosorbent AssayEvolutionFamilial atrial fibrillationFamilyFishesFoundationsFunctional disorderFutureGene ExpressionGeneral PopulationGenesGenetic TranscriptionGenomeGoalsHealth Care CostsHeartHeart AtriumHeart HypertrophyHumanHuman GeneticsIndividualIon ChannelIsoproterenolLocationLuciferasesMass Spectrum AnalysisMeasurementMeasuresMediatingMethodologyModalityModelingMolecularMuscle CellsMutationNatureNuclear TranslocationOpticsPathogenesisPathogenicityPathologicPathway interactionsPatientsPenetrancePhenotypePlayPredispositionPropertyRecoveryRefractoryReporterRiskRoleSiblingsSignal PathwaySinusSiteSudden DeathSusceptibility GeneTachyarrhythmiasTechniquesTestingTranscriptional ActivationTransgenic OrganismsUtahVariantZebrafishbasebioinformatics toolclinical practicedesigndifferential expressiondisease phenotypeexome sequencingexperiencegene networkgenetic pedigreegenome editinggenome wide association studyhigh riskimprovedin silicoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinnovationinsightmutantmutation carriernext generation sequencingnoveloverexpressionrare variantresponserisk stratificationsingle-cell RNA sequencingstandard carestroke risktranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY / ABSTRACT
The overall goal of this proposal is to explore the molecular and electrophysiological role of NFATC1 as a novel
atrial fibrillation (AF) susceptibility gene and to define the previously unknown contribution of NFATC1 to atrial
excitability. AF, the most common sustained arrhythmia encountered in clinical practice, has an economic burden
exceeding $7 billion in annual health care costs. Emerging evidence implicates cardiac transcription factors in
the pathogenesis in both familial forms of AF and AF in the general population. We identified a mutation in the
cardiac transcription factor NFATC1 in a high-risk Utah pedigree defined by young onset AF. NFATC1 is a Ca2+-
dependent transcription factor postulated to play a role in cardiac development, but up until now has never been
associated with cardiac excitability. Our exciting preliminary data identify a novel role for NFATC1 in modulating
atrial excitability, in that nfatc1 null zebrafish develop spontaneous atrial tachyarrhythmia and juvenile sudden
death. Aim 1 seeks to define the biochemical, molecular and electrophysiological basis of the mutant NFATC1
dysfunction, using the HL-1 atrial cell line, a human cell culture model (patient-specific and genome-edited
induced pluripotent stem cell derived cardiomyocytes, iPSC-CMs), and a whole animal model (transgenic
zebrafish). Aim 2 characterizes the role of NFATC1 in modulating atrial excitability by exploring the molecular
and electrophysiological basis for the atrial tachyarrhythmia in nfatc1 null zebrafish. Aim 3 will define NFATC1-
controlled transcriptional networks and gene pathways that regulate cardiac excitability, using single-cell RNA-
Seq, ChIP-Seq and ChIP-Mass Spectroscopy in human atrium and NFATC1 null and WT iPSC-CMs.
Our proposal leverages human genetics, genome-editing techniques, state-of-the-art Next-Gen sequencing
modalities and bioinformatics, and electrophysiology to comprehensively characterize the novel role of NFATC1
in cardiac excitability and AF pathogenesis. An understanding of a key transcriptional network that regulates ion
channel gene expression and atrial excitability will provide a broader, and more comprehensive understanding
of arrhythmia susceptibility and lay the foundation for novel AF therapies.
项目摘要/摘要
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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MARTIN TRISTANI-FIROUZI其他文献
MARTIN TRISTANI-FIROUZI的其他文献
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{{ truncateString('MARTIN TRISTANI-FIROUZI', 18)}}的其他基金
A Novel Role for NFATC1 in Modulating Cardiac Excitability
NFATC1 在调节心脏兴奋性中的新作用
- 批准号:
10653775 - 财政年份:2020
- 资助金额:
$ 72.27万 - 项目类别:
A Novel Role for NFATC1 in Modulating Cardiac Excitability
NFATC1 在调节心脏兴奋性中的新作用
- 批准号:
10026527 - 财政年份:2020
- 资助金额:
$ 72.27万 - 项目类别:
Integrating Genomic and Clinical Approaches to Sudden Death in the Young
结合基因组学和临床方法治疗年轻人猝死
- 批准号:
9242064 - 财政年份:2016
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
8950472 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
10237337 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
9123653 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
9324036 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
10477466 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
Bridging the Gap between Genomics and Clinical Outcomes in CHD
缩小先心病基因组学与临床结果之间的差距
- 批准号:
10027913 - 财政年份:2015
- 资助金额:
$ 72.27万 - 项目类别:
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HEG 钾通道中的电压传感器移动
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7340392 - 财政年份:2004
- 资助金额:
$ 72.27万 - 项目类别:
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