Molecular signaling in aortic valve development and congenital aortic valve defect
主动脉瓣发育和先天性主动脉瓣缺陷的分子信号传导
基本信息
- 批准号:10364556
- 负责人:
- 金额:$ 70.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAnimal ModelAortic AneurysmAortic Valve StenosisApoptosisBirthCandidate Disease GeneCardiacCardiac MyocytesCardiac OutputCell LineageCellsCongenital Heart DefectsCoronaryCuesDNA Sequence AlterationDefectDevelopmentDevelopmental ProcessDiseaseDisease OutcomeDissectionEmbryoEmbryonic DevelopmentEnhancersEpithelial CellsEventGeneral PopulationGenesGeneticHeartHeart Valve DiseasesHeterogeneityHumanImmunofluorescence ImmunologicIn Situ HybridizationIndividualInheritedInternationalInterventionKnock-outLeftLocationMediatingMedicineMesenchymalModelingMolecularMusMutationNOTCH1 geneOperative Surgical ProceduresPDGFB genePDGFRA genePathogenesisPatientsPatternPhenotypePlant RootsPlatelet-Derived Growth FactorRoleSOX17 geneSeverity of illnessSignal TransductionSignaling MoleculeTestingTherapeuticaortic valveaortic valve disorderautocrinebasebicuspid aortic valvecalcificationclinical subtypesdesigndisorder preventioneffective therapyepithelial to mesenchymal transitionexperimental studygene networkgenetic signaturehuman modelin vivoinsightmouse modelmutantnotch proteinreceptorresponsesingle-cell RNA sequencingspatiotemporaltherapeutic targettranscription factor
项目摘要
ABSTRACT
The normal aortic valve is tricuspid with three leaflets derived from multiple cell lineages during
embryogenesis. Aortic valve patterning is genetically controlled where individual cells in the valve-
forming field refine their fates and functions in response to positional and environmental cues. Genetic
mutations that alter cell-cell and cell-environmental signals can disrupt the developmental process,
leading to anomalous aortic valve, for example, bicuspid aortic valve (BAV). Affecting ~2% of the
general population in US, BAV is the most common congenital heart defect. Fusion of two of three
leaflets or absence of one leaflet during embryogenesis results in various BAV subtypes. After birth,
over half of BAV patients develop calcific aortic valve disease with no effective medicine, while BAV subtypes
have varied cardiac complications, which decide the disease outcome. With the International Bicuspid Aortic
Valve Consortium (BAVCon) being established to identify the genetic causes of BAV in humans, animal models
of BAV are critically needed to elucidate morphogenic and cellular mechanisms of human BAV, as well as
molecular signals that control aortic valve patterning in order to identify therapeutic targets for disease
prevention. To this end, we have generated two mouse models of BAV with distinct signaling defects and
anomalous leaflets. In the first model, knocking out notch receptor 1 (Notch1) in valve endocardial cells (VECs)
recapitulates the most common human BAV subtype – fusion of left and right coronary leaflets, which are mainly
derived from VECs by epithelial to mesenchymal transformation. This model also reveals that the NOTCH1-
TNFa signaling from VECs controls apoptosis of valve mesenchymal cells (VMCs). In the second model, deleting
SRY-box transcription factor 17 (Sox17) in VECs results in a rare but more severe type of BAV – absence of
non-coronary leaflet, of which VMCs arise predominantly from the second heart field (SHF)-derived
cardiomyocytes, and the patterning defect is associated with reduced VEC-VMC PDGFB signaling. Based on
these findings, we hypothesize that coordinated VEC-VMC signals control normal aortic valve patterning and
their disruption leads to various BAV subtypes, in the context of the origin and location of affected cells. We will
test this hypothesis in two Aims. Aim 1 is planned to reveal coordinated VEC-VMC signal networks during normal
aortic valve patterning and identify signaling events that are disrupted in various BAV subtypes. Aim 2 is designed
to uncover the functions of PDGF signaling in normal aortic valve patterning as well as use it as an example to
illustrate how a disrupted signaling event can alters cell fate and function, leading to a specific BAV. Successful
accomplishment of these Aims will provide new insights into BAV pathogenesis, with a broad implication in
congenital heart valve disease.
摘要
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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BIN ZHOU其他文献
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{{ truncateString('BIN ZHOU', 18)}}的其他基金
Molecular signaling in aortic valve development and congenital aortic valve defect
主动脉瓣发育和先天性主动脉瓣缺陷的分子信号传导
- 批准号:
10544023 - 财政年份:2022
- 资助金额:
$ 70.17万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10215615 - 财政年份:2020
- 资助金额:
$ 70.17万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10052875 - 财政年份:2020
- 资助金额:
$ 70.17万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10397428 - 财政年份:2020
- 资助金额:
$ 70.17万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10604334 - 财政年份:2020
- 资助金额:
$ 70.17万 - 项目类别:
Single Cell RNA-seq to Identify Endocardial Ontogenic Factors for the Heart
单细胞 RNA-seq 鉴定心脏的心内膜个体发育因子
- 批准号:
9769109 - 财政年份:2018
- 资助金额:
$ 70.17万 - 项目类别:
Molecular and Cellular Mechanisms in Coronary Artery Development and Anomalies
冠状动脉发育和异常的分子和细胞机制
- 批准号:
10595393 - 财政年份:2016
- 资助金额:
$ 70.17万 - 项目类别:
Deciphering the roles of Nfatc1 in developmental coronary angiogenesis
解读 Nfatc1 在发育性冠状动脉血管生成中的作用
- 批准号:
9276779 - 财政年份:2016
- 资助金额:
$ 70.17万 - 项目类别:
Deciphering the roles of Nfatc1 in developmental coronary angiogenesis
解读 Nfatc1 在发育性冠状动脉血管生成中的作用
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9160568 - 财政年份:2016
- 资助金额:
$ 70.17万 - 项目类别:
Mechanisms of Coronary Ostium Formation and Coronary Artery Patterning
冠状动脉口形成和冠状动脉模式的机制
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8580415 - 财政年份:2013
- 资助金额:
$ 70.17万 - 项目类别:
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