Molecular Mechanisms of Atrial Development and Regeneration
心房发育和再生的分子机制
基本信息
- 批准号:10601607
- 负责人:
- 金额:$ 60.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-21 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdultAffectAffinity ChromatographyAreaArrhythmiaAtrial FunctionAtrial Heart Septal DefectsBiological AssayBuffersCRISPR/Cas technologyCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCellsCessation of lifeChildComplexCongenital AbnormalityCongenital Heart DefectsCoupledDevelopmentDiagnosisEmbryoEmbryonic AtriumEmbryonic HeartEnhancersEpicardiumEtiologyFamilyFatigueFoundationsGene Expression ProfileGenerationsGenesGenetic EpistasisGenomicsGleanGoalsHealthHeartHeart AtriumHeart InjuriesHeterogeneityHumanHypertrophyImmunoprecipitationIn VitroIndividualInfant HealthInfant MortalityInjuryInvadedKnockout MiceKnowledgeLifeMammalsMediatingMetronidazoleMolecularMonitorMutationNatural regenerationOperative Surgical ProceduresPlayPopulationProteinsRNAReagentRepressionRibosomesRight ventricular structureRoleSignal TransductionSortingSpecific qualifier valueStrokeTestingTissuesTranscriptTransgenic OrganismsTranslational RepressionTranslationsTretinoinUntranslated RNAVenousVentricularVertebratesWNT Signaling PathwayZebrafishapoAI regulatory protein-1cardiac regenerationcardiogenesiscoronary vasculaturegain of functiongenome editinghuman stem cellsimprovedin vivoinduced pluripotent stem cellinjuredinjury and repairloss of functionmalformationmutantnovelnovel therapeutic interventionnovel therapeuticspharmacologicposttranscriptionalprematurepreventprogenitorpromoterrepairedscaffoldsingle-cell RNA sequencingtargeted treatmenttranscription factorvertebrate embryos
项目摘要
Project Summary/Abstract
Congenital heart defects (CHDs) are the most common congenital malformations. However, the molecular
etiology underlying most CHDs remain poorly understood. Furthermore, CHDs even following surgery can lead
to complications later in life that result in arrhythmias, stroke, and premature death. In order to develop novel
therapies able to prevent CHDs and target therapies to specific cardiovascular tissues, it is critical to garner
understanding of fundamental mechanisms directing normal cardiac chamber development and regeneration.
Therefore, long-term goals of our lab are to understand conserved mechanisms that direct the development of
individual cardiac chambers and chamber-specific mechanisms utilized during regeneration in vertebrates.
Few signals are known to be required that specifically direct atrial development, with specific regulators of atrial
regeneration not being understood. The specific aims of this proposal are to elucidate the mechanisms by
which a syntenic long non-coding RNA (lncRNA) family limits the expression of Nr2f transcription factors and
decipher how Nr2f protein levels affect atrial heterogeneity during development and atrial regeneration in adult
zebrafish. The studies in this proposal are relevant to human health as numerous genomic analyses now
indicate that mutations in Nr2f2 are associated with CHDs, in particular ASDs in humans. While Nr2f2 knockout
mice and in vitro studies with human stem cells have revealed requirements for both Nr2f1 and Nr2f2 in atrial
development, the mechanisms by which Nr2f proteins direct proper atrial development are not completely
understood. Importantly, there is currently no understanding of lncRNA-dependent mechanisms regulating Nr2f
proteins. Our analysis of a lncRNA we call as-oca shows that in vivo it represses the translation of nr2f1a, the
functional equivalent of mammalian Nr2f2. Moreover, we find that Nr2f1a levels regulate previously
unrecognized heterogeneity of atrial cardiomyocytes in the embryonic atrium and atrial regeneration. In Aim 1,
we will examine the specific mechanism that as-oca inhibits nr2f1a translation and the conservation of this
mechanism among the NR2F-associated lncRNA family in human induced pluripotent stem cells. In Aim 2, we
will examine the requirements of Nr2f1a and canonical Wnt signaling in generating atrial cardiomyocyte
diversity and the transcriptional signature of a previously unrecognized atrial subpopulation. In Aim 3, we will
examine the requirement of the epicardium in atrial regeneration and requirement of Nr2f1a within the atrial
epicardium. Because Nr2f transcription factors play conserved roles in atrial development of all vertebrates,
these studies will dramatically improve our understanding of post-transcriptional mechanisms regulating normal
vertebrate atrial development and unique mechanisms employed during atrial regeneration. Ultimately, these
studies will garner a foundation of knowledge that can be used to improve therapies capable of preventing and
ameliorating CHDs and efficiently repairing injured hearts.
项目总结/文摘
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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Joshua Waxman其他文献
Joshua Waxman的其他文献
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{{ truncateString('Joshua Waxman', 18)}}的其他基金
Mechanisms governing the differentiation and maintenance of atrial identity
心房特性分化和维持的机制
- 批准号:
10676430 - 财政年份:2023
- 资助金额:
$ 60.19万 - 项目类别:
Molecular mechanisms of atrial development and regeneration
心房发育和再生的分子机制
- 批准号:
9363356 - 财政年份:2017
- 资助金额:
$ 60.19万 - 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
- 批准号:
8435042 - 财政年份:2013
- 资助金额:
$ 60.19万 - 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
- 批准号:
8819146 - 财政年份:2013
- 资助金额:
$ 60.19万 - 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
- 批准号:
8606886 - 财政年份:2013
- 资助金额:
$ 60.19万 - 项目类别:
Coup-tf dependent mechanisms of ventricular and hemangioblast specification
心室和成血管细胞规范的 Coup-tf 依赖性机制
- 批准号:
9031127 - 财政年份:2013
- 资助金额:
$ 60.19万 - 项目类别:
Elucidation of molecular networks required to limit cardiac cell number
阐明限制心肌细胞数量所需的分子网络
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8111233 - 财政年份:2010
- 资助金额:
$ 60.19万 - 项目类别:
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