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
这项提议的总体目标是探索NFATC1作为一种新的分子和电生理作用
心房颤动(房颤)易感基因及NFATC1在房颤中的作用
兴奋性。房颤是临床上最常见的持续性心律失常,有经济负担。
每年的医疗保健费用超过70亿美元。新出现的证据表明,心脏转录因子在
普通人群房颤和房颤两种家族性形式的发病机制。我们发现了一种突变
心脏转录因子NFATC1是由年轻发病的房颤定义的犹他州高危家系。NFATC1是一种钙离子-
依赖转录因子被认为在心脏发育中发挥作用,但到目前为止从未被认为是
与心脏兴奋性有关。我们令人兴奋的初步数据确定了NFATC1在调控中的一个新角色
心房兴奋性,在nFATc1缺失斑马鱼发生自发性房性快速性心律失常和幼年突然
死亡。目的1确定突变型NFATC1的生化、分子和电生理基础
功能障碍,使用HL-1心房细胞系,一种人类细胞培养模型(患者特定和基因组编辑)
诱导多能干细胞来源的心肌细胞(IPSC-CMS)和全动物模型(转基因
斑马鱼)。目的探讨NFATC1在调节心房兴奋性中的作用。
NFATc1基因缺失的斑马鱼发生房性快速性心律失常的电生理基础。AIM 3将定义NFATC1-
调控心脏兴奋性的转录网络和基因通路,使用单细胞RNA-
人心房中的SEQ、CHIP-SEQ和CHIP-MS以及NFATC1缺失和WT IPSC-CMS。
我们的方案利用了人类遗传学、基因组编辑技术、最先进的下一代测序技术
模式和生物信息学,以及电生理学,全面表征NFATC1的新角色
在心脏兴奋性和房颤发病机制中的作用。对调控离子的关键转录网络的理解
通道基因表达和心房兴奋性将提供更广泛、更全面的理解
降低心律失常的易感性,为房颤的新疗法奠定基础。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MARTIN TRISTANI-FIROUZI其他文献
MARTIN TRISTANI-FIROUZI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10026527 - 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:
10653775 - 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:
Voltage Sensor Movement in the HERG Potassium Channel
HEG 钾通道中的电压传感器移动
- 批准号:
7340392 - 财政年份:2004
- 资助金额:
$ 72.27万 - 项目类别:
相似海外基金
Exploring the mental health and wellbeing of adolescent parent families affected by HIV in South Africa
探讨南非受艾滋病毒影响的青少年父母家庭的心理健康和福祉
- 批准号:
ES/Y00860X/1 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Fellowship
Scaling-up co-designed adolescent mental health interventions
扩大共同设计的青少年心理健康干预措施
- 批准号:
MR/Y020286/1 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Fellowship
Shared Spaces: The How, When, and Why of Adolescent Intergroup Interactions
共享空间:青少年群体间互动的方式、时间和原因
- 批准号:
ES/T014709/2 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Research Grant
Social Media Mechanisms Affecting Adolescent Mental Health (SoMe3)
影响青少年心理健康的社交媒体机制 (SoMe3)
- 批准号:
MR/X034925/1 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Fellowship
Parent-adolescent informant discrepancies: Predicting suicide risk and treatment outcomes
父母与青少年信息差异:预测自杀风险和治疗结果
- 批准号:
10751263 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Adolescent sugar overconsumption programs food choices via altered dopamine signalling
青少年糖过度消费通过改变多巴胺信号来影响食物选择
- 批准号:
BB/Y006496/1 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Research Grant
The Impact of Online Social Interactions on Adolescent Cognition
在线社交互动对青少年认知的影响
- 批准号:
DE240101039 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Discovery Early Career Researcher Award
Resilience Factors, Pain, and Physical Activity in Adolescent Chronic Musculoskeletal Pain
青少年慢性肌肉骨骼疼痛的弹性因素、疼痛和体力活动
- 批准号:
10984668 - 财政年份:2024
- 资助金额:
$ 72.27万 - 项目类别:
Augmented Social Play (ASP): smartphone-enabled group psychotherapeutic interventions that boost adolescent mental health by supporting real-world connection and sense of belonging
增强社交游戏 (ASP):智能手机支持的团体心理治疗干预措施,通过支持现实世界的联系和归属感来促进青少年心理健康
- 批准号:
10077933 - 财政年份:2023
- 资助金额:
$ 72.27万 - 项目类别:
EU-Funded
Family-Focused Adolescent & Lifelong Health Promotion (FLOURISH)
以家庭为中心的青少年
- 批准号:
10050850 - 财政年份:2023
- 资助金额:
$ 72.27万 - 项目类别:
EU-Funded