Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
基本信息
- 批准号:9237250
- 负责人:
- 金额:$ 59.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlagille SyndromeAutomobile DrivingBone Morphogenetic ProteinsBranchial arch structureBuffersCandidate Disease GeneCleft PalateCollectionCompetenceComplexComputer AnalysisComputer SimulationCongenital AbnormalityCraniofacial AbnormalitiesDataDatabasesDefectDevelopmentDimensionsDiseaseDorsalEmbryoEndothelin-1EnhancersEnsureEtiologyEventFaceFeedbackFishesGene ExpressionGene MutationGene TargetingGenesGeneticGenetic Enhancer ElementGenetic TranscriptionGenetic studyGoalsHigh-Throughput RNA SequencingHumanInterdisciplinary StudyJawMediatingMicrognathismModelingMolecular ProfilingMorphogenesisMusMutateNoiseNotch Signaling PathwayOutcomePathway interactionsPatternPhenotypePlayPositioning AttributeRegulator GenesRegulatory ElementResistanceRoleShapesSignal PathwaySignal TransductionSignaling ProteinSiliconSkeletal DevelopmentSkeletonStructural Congenital AnomaliesSyndromeSystemTestingTimeTo specifyTransgenic MiceTransgenic OrganismsWNT Signaling PathwayWorkZebrafishbaseclinically relevantcohesioncraniofacialcraniofacial developmentgene conservationgene functiongenetic analysisimprovedin vivoin vivo imagingknock-downmalformationmathematical modelmouse modelmutantnotch proteinnoveloverexpressionprogenitorprogramspublic health relevanceresponsesimulationskeletalspatiotemporalthree dimensional structuretooltranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Much of the craniofacial skeleton arises from the pharyngeal arches, 3D structures that undergo complex changes in shape and gene expression over time. However, detailed analyses of early gene expression profiles in the arches have not been performed in vivo. Without such information, it is impossible to predict how gene expression changes will affect subsequent skeletal development. Our labs have extensively studied the endothelin1 (Edn1), bone morphogenetic protein (Bmp), Wnt and Jag/Notch signaling pathways in the arches, as these four pathways pattern the dorsal-ventral (D-V) axis of the facial skeleton. We have shown that Edn1 and Bmp signaling initially promote ventrally- expressed genes and later subdivide the arches into separate D-V sub-domains. Our preliminary data suggest that Wnt signaling controls competence to respond to Edn1/Bmp and that these three pathways are opposed by Jag/Notch signaling. The pathways regulated by these four signals are highly dynamic, containing multiple feedback loops and crosstalk that create a robust system resistant to perturbation. With a collection of mouse and zebrafish mutants in all four signals, we are in a unique position to assess conservation of gene expression across species in sufficient detail for computational modeling. Our goal is to use these models to predict in silicon facial defects observed following genetic perturbations of these signals. Our dual-species approach will identify new candidate genes and generate models that are clinically relevant to human craniofacial genetics. To address these goals we will pursue two specific aims. In Aim 1, we hypothesize that while Edn1, Bmp, Wnt and Jag/Notch signaling are all critical for establishing the initial identities of skeletal progenitor in the arches along the D-V axis, they each play distinct roles. We will address this hypothesis by using high-throughput RNA sequencing to define early changes in gene expression in mutants of all four pathways. These Early Response Profiles (ERPs) will be used to produce models that integrate gene expression changes across mutants to understand both the unique roles of each factor and crosstalk between signals. In Aim 2 we hypothesize that "core" sets of enhancers are responsible for the ERP for each signal, some of which mediate crosstalk between or feedback within a signaling pathway, as well as insulating pathways from one another. We will address this by isolating enhancers for genes identified in Aim 1 and testing their activities in both mice
and zebrafish. These will be incorporated into our mathematical models to understand enhancer sensitivity and how this regulates sharpness of gene expression boundaries. Our long-term goal is to build a comprehensive model for a craniofacial gene regulatory network that can be amended as new data are available.
描述(申请人提供):大部分头面部骨骼来自咽弓,这是一种3D结构,随着时间的推移,其形状和基因表达会发生复杂的变化。然而,对拱门早期基因表达谱的详细分析还没有在体内进行。如果没有这样的信息,就不可能预测基因表达的变化将如何影响随后的骨骼发育。我们的实验室已经广泛研究了弓部中的内皮素1(Edn1)、骨形态发生蛋白(BMP)、Wnt和JAG/Notch信号通路,因为这四条通路形成了面部骨骼的背腹(D-V)轴。我们已经证明,Edn1和BMP信号最初促进腹侧表达的基因,后来将拱门细分为单独的D-V亚域。我们的初步数据表明,Wnt信号控制着对Edn1/BMP的反应能力,而这三条途径与Jag/Notch信号相反。由这四个信号调节的路径是高度动态的,包含多个反馈环路和串扰,从而创建了一个强大的抗扰动系统。有了所有四个信号中的小鼠和斑马鱼突变体的集合,我们处于一个独特的位置,可以为计算建模提供足够的细节来评估跨物种基因表达的保守性。我们的目标是使用这些模型来预测在这些信号的遗传扰动之后观察到的硅面部缺陷。我们的双物种方法将识别新的候选基因,并产生与人类颅面遗传学临床相关的模型。为了实现这些目标,我们将追求两个具体目标。在目标1中,我们假设,虽然Edn1、BMP、Wnt和Jag/Notch信号对于确定D-V轴弓形结构中骨骼前体细胞的初始身份都是至关重要的,但它们各自扮演着不同的角色。我们将通过使用高通量RNA测序来确定所有四条途径的突变基因表达的早期变化,从而解决这一假说。这些早期反应谱(ERP)将被用来产生整合突变体之间基因表达变化的模型,以了解每个因素的独特作用和信号之间的串扰。在目标2中,我们假设增强子的“核心”集合负责每个信号的事件相关电位,其中一些负责调节信号通路之间的串扰或信号通路内的反馈,以及相互隔离通路。我们将通过分离Aim 1中确定的基因的增强子并在两只小鼠中测试它们的活性来解决这个问题。
还有斑马鱼。这些将被合并到我们的数学模型中,以了解增强子的敏感性以及这如何调节基因表达边界的锐度。我们的长期目标是为颅面基因调控网络建立一个全面的模型,该模型可以随着新数据的出现而进行修改。
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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David E. Clouthier其他文献
Hand2 loss leads to aglossia from failure to repress Dlx5/6
- DOI:
10.1016/j.ydbio.2009.05.519 - 发表时间:
2009-07-15 - 期刊:
- 影响因子:
- 作者:
David E. Clouthier;Marthe Howard;Francie Hyndman - 通讯作者:
Francie Hyndman
Transcriptional regulation of hand2 in zebrafish neural crest cells and cardiomyocytes
- DOI:
10.1016/j.ydbio.2010.05.192 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Jennifer Ikle;David E. Clouthier - 通讯作者:
David E. Clouthier
prdm genes in zebrafish craniofacial development
- DOI:
10.1016/j.ydbio.2010.05.190 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Letitia Kwok;David E. Clouthier;Kristin B. Artinger - 通讯作者:
Kristin B. Artinger
<strong>Aglossia in Hand2 conditional knockout mutants results from misregulation of Dlx5/6</strong>
- DOI:
10.1016/j.ydbio.2010.05.129 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:
- 作者:
Francie E. Hyndman;Marthe Howard;David E. Clouthier - 通讯作者:
David E. Clouthier
David E. Clouthier的其他文献
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{{ truncateString('David E. Clouthier', 18)}}的其他基金
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
- 批准号:
10057669 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
- 批准号:
10210382 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
- 批准号:
10454286 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Gene Regulatory Networks that Establish Mandible and Maxilla Patterning
建立下颌骨和上颌骨模式的基因调控网络
- 批准号:
10653143 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
- 批准号:
10175020 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
- 批准号:
10611514 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis
肺纤维化中与 MUC5B 相互作用的基因和转录本
- 批准号:
10402929 - 财政年份:2020
- 资助金额:
$ 59.45万 - 项目类别:
Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
- 批准号:
8750599 - 财政年份:2014
- 资助金额:
$ 59.45万 - 项目类别:
Defining an Integrated Signaling Network That Patterns the Craniofacial Skeleton
定义一个模拟颅面骨骼的集成信号网络
- 批准号:
8865602 - 财政年份:2014
- 资助金额:
$ 59.45万 - 项目类别:
Hand2 Function and Regulation During Craniofacial Development
Hand2 颅面发育过程中的功能和调节
- 批准号:
8401463 - 财政年份:2009
- 资助金额:
$ 59.45万 - 项目类别:
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