Mechanisms patterning the midface
中面部图案化机制
基本信息
- 批准号:10812765
- 负责人:
- 金额:$ 42.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-18 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAntibodiesBindingBinding SitesBone structureCell Differentiation processCellsChIP-seqCodeColorCongenital AbnormalityDataDevelopmentDisease modelDysmorphologyElementsEmbryonic DevelopmentEnhancersEtiologyEyeFaceFrontonasal dysplasiaGene CombinationsGene ExpressionGenesGeneticGenetic DiseasesGenetic TranscriptionGenomeGenomicsHeadHealthHi-CHumanHuman GeneticsIn Situ HybridizationJawMapsMediatingMethodsMissionModelingMolecularMutationNational Institute of Dental and Craniofacial ResearchNeural Crest CellNoseOrthologous GenePatternPhenotypePositioning AttributeProteinsPublishingReporterResearchResolutionShapesSkeletonSpecific qualifier valueStructureSystemTestingTimeTransgenesWorkZebrafishcartilaginouschromatin immunoprecipitationcraniofacialcraniofacial developmentdomain mappingexperimental studygene functionhuman diseaseimprovedin vivoinnovationmutantparalogous geneprogenitorpromotersingle-cell RNA sequencingskeletalsuccesstranscription factorvertebrate genomezebrafish development
项目摘要
PROJECT SUMMARY/ABSTRACT: The long-term objective of this proposal is to understand formation of the
midface skeleton, both during normal development, and in human genetic disease conditions. The midface
consists of the structures around the nose, the eye, and the upper jaw. Human genetic disorders, like
frontonasal dysplasia, affect these midface structures. Specifically, the ALX transcription factor encoding genes
have been implicated in multiple types of frontonasal dysplasia. Uniquely, we model these diseases in
zebrafish by using genetic mutants. We propose that the ALX genes function to specify an identity code which
patterns the vertebrate midface. Our model draws from examples like the DLX and HOX codes, which specify
identity in the dorsoventral and anteroposterior axes of the craniofacial skeleton, respectively. We propose
three specific aims to test our innovative “alx-bullseye code” hypothesis, that nested alx gene expression
directly regulates frontonasal skeletal identity. In Aim 1 we define the skeletal structures arising from the
alx-bullseye code in wild types using in situ hybridization, live cell tracking, and lineage tracing. Aim 2 will
determine whether alx gene combinations function to specify frontonasal identity. To identify these functions,
we will compare wild types to alx mutants examining gene expression, skeletal cell differentiation, and
misexpression phenotypes. Aim 3 will uncover how alx genes molecularly control cellular identity. We will
examine an in vivo Alx direct transcriptional reporter, ChIP-seq to identify Alx protein occupancy across the
genome, and Hi-C to reveal enhancer-promoter contacts mediated by Alx. Significance of this proposal is high,
the genes that we propose function in the alx bullseye code have direct human orthologs that are associated
with midface dysmorphologies. This proposal is innovative, as there has not yet been a patterning code
proposed for the vertebrate midface. Success of this proposal will enhance our understanding of midface
craniofacial development and human disease. By using the strengths of the zebrafish system to elucidate the
molecular, cellular, and genetic mechanisms underlying frontonasal dysplasia, we are fulfilling the mission of
the NIDCR to improve human health through research.
项目总结/摘要:本提案的长期目标是了解
在正常发育期间以及在人类遗传疾病条件下的面中部骨骼。面中部
包括鼻子眼睛和上颚周围的结构。人类遗传疾病,比如
额鼻发育不良影响面中部的结构具体而言,ALX转录因子编码基因
与多种类型的额鼻发育不良有关独特的是,我们将这些疾病建模为
斑马鱼的基因突变。我们认为ALX基因的功能是指定一个身份代码,
在脊椎动物的面部中部形成图案。我们的模型借鉴了DLX和HOX代码等示例,这些代码指定
在颅面骨骼的背腹和前后轴的身份,分别。我们提出
三个具体的目的是测试我们创新的“alx-靶心码”假设,即嵌套alx基因表达
直接调节额鼻骨骼的特性。在目标1中,我们定义了由
使用原位杂交、活细胞追踪和谱系追踪在野生型中发现Alx-Bullseye密码。目标2将
确定ALX基因组合是否起指定额鼻同一性的作用。为了识别这些功能,
我们将比较野生型和alx突变体的基因表达,骨骼细胞分化,
错误表达表型目标3将揭示alx基因是如何在分子水平上控制细胞特性的。我们将
检查体内Alx直接转录报告基因ChIP-seq,以确定Alx蛋白在整个细胞中的占有率。
基因组,和Hi-C揭示增强子-启动子接触介导的Alx。这一建议的意义很大,
我们提出的在alx牛眼密码中起作用的基因有直接的人类直系同源物,
面部中部畸形这个建议是创新的,因为还没有一个模式化的代码
用于脊椎动物的中面部。这项建议的成功将提高我们对中面的理解
颅面发育和人类疾病。通过使用斑马鱼系统的优势来阐明
额鼻发育不良的分子、细胞和遗传机制,我们正在完成以下使命:
NIDCR通过研究改善人类健康。
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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James Tucker Nichols其他文献
James Tucker Nichols的其他文献
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{{ truncateString('James Tucker Nichols', 18)}}的其他基金
The Molecular Genetics and Cell Biology of Jaw Joint Morphogenesis
颌关节形态发生的分子遗传学和细胞生物学
- 批准号:
8016707 - 财政年份:2009
- 资助金额:
$ 42.86万 - 项目类别:
The Molecular Genetics and Cell Biology of Jaw Joint Morphogenesis
颌关节形态发生的分子遗传学和细胞生物学
- 批准号:
7790556 - 财政年份:2009
- 资助金额:
$ 42.86万 - 项目类别:
The Molecular Genetics and Cell Biology of Jaw Joint Morphogenesis
颌关节形态发生的分子遗传学和细胞生物学
- 批准号:
7546014 - 财政年份:2009
- 资助金额:
$ 42.86万 - 项目类别:
Imaging Delta-Induced Activation of Notch
成像 Delta 诱导的 Notch 激活
- 批准号:
7386757 - 财政年份:2007
- 资助金额:
$ 42.86万 - 项目类别:
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