Molecular determinants of the cardiac pacemaker automaticity
心脏起搏器自动性的分子决定因素
基本信息
- 批准号:8504543
- 负责人:
- 金额:$ 39.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-03 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAgingArchitectureArrhythmiaArtificial cardiac pacemakerBiological PacemakersBoxingCardiac MyocytesCell Culture SystemCellsClinicalCommunicationCongenital Heart DefectsDataDevelopmentDevicesDiseaseDrug FormulationsElectronicsElectrophysiology (science)Embryonic DevelopmentEngineeringGap JunctionsGene Expression RegulationGene TargetingGenerationsGenesGoldHeartHeart BlockIn VitroIon ChannelKnowledgeLeadLinkMediatingModelingModificationMolecularMorphogenesisMuscle CellsMyocardiumNeonatalNodalNorth AmericaOutcomePacemakersPathologicPathway interactionsPhenotypePhysiologyRattusRegulationRegulator GenesRegulatory PathwayRelative (related person)ShapesSignal TransductionSignaling MoleculeSinoatrial NodeSmall Interfering RNASomatic CellSourceSpecific qualifier valueStructureSystemTestingTissuesTranscription factor genesTranscriptional RegulationVentricularbasecellular transductiondesignelectronic pacemakergenome wide association studyheart rhythmin vivoinnovationinsightknockout genemonolayernodal myocytenoveloverexpressionpostnatalprogramspublic health relevanceresearch studythree dimensional structuretooltranscription factorvoltage
项目摘要
DESCRIPTION (provided by applicant): The sinoatrial node (SA node or SAN) is a finely-tuned structure that initiates and sets the rhythm of the heartbeat. Recent insights into embryonic development have pinpointed T-box (Tbx) transcription factors as key determinants of SA node development. Tbx18, in particular, has been shown to be indispensable for the specification of the SA node during development. However, little is known about Tbx-driven gene regulatory pathways which specify morphogenesis of the SA node, and how these pathways lead to automaticity in pacemaker cells. We seek to test the general hypothesis that re-expression of Tbx18 suffices to reprogram postnatal cardiomyocytes to pacemaker cells. We propose to reveal Tbx18-dictated gene regulatory pathways that give rise to de novo automaticity. In parallel, we will characterize the changes in electrophysiological pathways which confer automaticity on normally-quiescent ventricular myocytes, and compare the reprogrammed mechanisms of pacing to those which are operative in native SA nodal myocytes, as the gold standard for genuine pacemaker cells. The main impediment to understanding the gene regulatory pathways to automaticity is a lack of a system to study specific targets of SA nodal transcriptional regulatory pathways. This is because the rapid temporal and spatial changes during embryonic development make it difficult to study specific targets of transcriptional regulation. In contrast, our proposed studies in postnatal cardiomyocytes offer a milieu for relatively slow-changing (neonatal) or steady-state (adult) electrophysiology. AIMs 2 and 3 are designed to gain insights into the Tbx18-reprogrammed automaticity in single-cell, two-cell pacing unit, 2D monolayers, and 3D structures. Our cell culture systems could readily be applied for other transcription factor- or disease-mediated studies of cellular electrophysiology. Three scientific innovations are imminent from this study. One, data from AIMs 1 and 2 will provide insights into molecular determinants of automaticity as quiescent myocytes begin to beat spontaneously and autonomously upon Tbx18 re-expression. Two, outcomes of AIM 3 will provide important insights into the source-sink mismatch phenomenon in SAN physiology. Three, at the conclusion of the proposed studies, a candidate for a biological pacemaker could be identified as an alternative to electronic pacemaker devices. Furthermore, Genome wide association studies (GWAS) have identified and linked T-box transcription factor genes with congenital heart defects and conduction system abnormalities. Dysregulation of Tbx18-guided pathways may cause improper morphogenesis of conduction system and may lead to arrhythmias. Knowledge gained from AIMs 1, 2, and 3 will provide the first cause-effect explanations for clinical manifestations of these arrhythmias.
描述(由申请人提供):窦房结(SA结或SAN)是一种微调结构,可启动和设定心跳节律。最近对胚胎发育的认识已经确定了T-box(Tbx)转录因子是SA结发育的关键决定因素。特别是,TBX 18已被证明是开发期间SA节点规范不可或缺的。然而,很少有人知道Tbx驱动的基因调控途径,指定SA结的形态发生,以及这些途径如何导致起搏细胞的自律性。我们试图测试Tbx 18的重新表达足以将出生后的心肌细胞重新编程为起搏细胞的一般假设。我们建议揭示Tbx 18决定的基因调控途径,引起从头自律性。与此同时,我们将表征电生理通路的变化,赋予正常静止的心室肌细胞的自律性,并比较重新编程的起搏机制,这些机制是在本地SA结肌细胞,真正的起搏细胞的金标准。了解基因调控途径的自动性的主要障碍是缺乏一个系统来研究特定的目标SA节点转录调控途径。这是因为胚胎发育过程中快速的时间和空间变化使得研究转录调控的特定靶点变得困难。相比之下,我们提出的研究在出生后心肌细胞提供了一个相对缓慢变化(新生儿)或稳态(成人)的电生理环境。AIM 2和3旨在深入了解单细胞、双细胞起搏单元、2D单层和3D结构中的Tbx 18重编程自动性。我们的细胞培养系统可以很容易地应用于其他转录因子或疾病介导的细胞电生理学研究。这项研究有三个科学创新。第一,来自AIM 1和2的数据将提供对自律性的分子决定因素的了解,因为静止的肌细胞开始在Tbx 18重新表达时自发地和自主地搏动。第二,AIM 3的结果将为SAN生理学中的源-汇失配现象提供重要的见解。第三,在拟议的研究结束时,可以确定生物起搏器的候选者作为电子起搏器设备的替代品。此外,全基因组关联研究(GWAS)已经确定并将T-box转录因子基因与先天性心脏病和传导系统异常联系起来。Tbx 18引导的通路的失调可能导致传导系统的不适当的形态发生,并可能导致心律失常。从AIM 1、2和3中获得的知识将为这些心律失常的临床表现提供第一个因果解释。
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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Hee Cheol Cho其他文献
Hee Cheol Cho的其他文献
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{{ truncateString('Hee Cheol Cho', 18)}}的其他基金
Heart rate control with bioengineered pacemakers
使用生物工程起搏器控制心率
- 批准号:
10638779 - 财政年份:2021
- 资助金额:
$ 39.75万 - 项目类别:
Heart rate control with bioengineered pacemakers
使用生物工程起搏器控制心率
- 批准号:
10686239 - 财政年份:2021
- 资助金额:
$ 39.75万 - 项目类别:
Heart rate control with bioengineered pacemakers
使用生物工程起搏器控制心率
- 批准号:
10184339 - 财政年份:2021
- 资助金额:
$ 39.75万 - 项目类别:
Patterning myocardial specification of human pluripotent stem cells
人类多能干细胞的心肌规格模式化
- 批准号:
10638342 - 财政年份:2019
- 资助金额:
$ 39.75万 - 项目类别:
Patterning myocardial specification of human pluripotent stem cells
人类多能干细胞的心肌规格模式化
- 批准号:
9906268 - 财政年份:2019
- 资助金额:
$ 39.75万 - 项目类别:
Molecular determinants of the cardiac pacemaker automaticity
心脏起搏器自动性的分子决定因素
- 批准号:
8373469 - 财政年份:2012
- 资助金额:
$ 39.75万 - 项目类别:
Molecular determinants of the cardiac pacemaker automaticity
心脏起搏器自动性的分子决定因素
- 批准号:
8885878 - 财政年份:2012
- 资助金额:
$ 39.75万 - 项目类别:
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