Genetic Regulation of Inner, Middle and Outer Ear Development
内耳、中耳和外耳发育的遗传调控
基本信息
- 批准号:10529327
- 负责人:
- 金额:$ 52.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-03-22 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAffectAllelesAuditoryBindingBiochemicalBioinformaticsBranchial arch structureCell DeathCell Differentiation processCell modelCellsCentral Nervous SystemCephalicChIP-seqChickChick EmbryoChildChromatinClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsConductive hearing lossCongenital AbnormalityDataDefectDevelopmentES Cell LineEarEar ossiclesEctodermEmbryoEmbryonic DevelopmentEndodermEpidermisEpigenetic ProcessExternal EarFGF8 geneFailureFamilyFundingGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGoalsHeadHearingHomeobox GenesHourHumanImmunoprecipitationKnock-in MouseKnockout MiceLabyrinthMapsMesenchymeModelingMolecularMolecular AnalysisMusMutagenesisMutant Strains MiceMutateMutationNeural CrestNeural Crest CellNuclear Localization SignalOtic PlacodesPathogenicityPatientsPatternPhenotypeRegulationRepressionRoleSensorineural Hearing LossSeriesSignal InductionSignal TransductionStructureSwitzerlandTestingTimeTissuesTranscription InitiationUp-RegulationVariantWorkcraniofacialcritical perioddeep sequencingear developmentembryonic stem cellexperimental studyforkhead proteingain of functiongastrulationgene functiongene repressiongenetic variantgenomic locushereditary hearing lossinner ear developmentinterestloss of functionmicrotiamiddle earmouse modelmutantneural platenoveloverexpressionprogenitorresponsesingle-cell RNA sequencingtranscription factor
项目摘要
PROJECT SUMMARY
The mammalian inner, middle and outer ears have different embryonic origins, yet the development of
each component of the auditory apparatus must be precisely synchronized in space and time. Understanding
the mechanisms that regulate and co-ordinate the development of these structures is of central importance in
understanding the basis of the many birth defects that affect hearing. We have identified a Forkhead
transcription factor, Foxi3, that is expressed at very early stages in the embryonic head. Foxi3 mouse
mutants made in our lab lack all components of the inner, middle and external ears. Our work suggests
that one of the first steps in ear induction– the formation of the otic placode – does not occur in Foxi3 mutants.
Moreover, the mesenchyme of the first and second branchial arches that generate the middle ear ossicles and
the external ear begins to form in Foxi3 mutants, but rapidly succumbs to massive cell death. Moreover, we
have recently identified human patients with Foxi3 variants that have a variety of defects in their hearing
apparatus
To our knowledge, Foxi3 is the only mammalian gene that causes a complete developmental failure of the
entire inner, middle and outer ears when mutated by itself. We are therefore extremely interested to
understand how Foxi3 orchestrates development of the auditory apparatus at both the cellular and molecular
levels. Our data suggests that Foxi3 may act as a “pioneer” transcription factor – its main function in addition to
initiating transcription is to epigenetically organize genomic loci containing ear-specific genes in a
transcriptionally competent state. Our first two aims will determine the function and mechanism of Foxi3 during
development of the inner ear using knockout mice, chick embryo manipulations and state-of-the-art ES cell
models, deep sequencing and bioinformatic analysis. Our final aim focuses on the function the Foxi3 gene in
the development of the middle and external ear – here we will both study the effects of loss of Foxi3 in mice,
but also create mouse mutants that recapitulate the genetic variants seen in some of our human patients.
项目总结
哺乳动物的内耳、中耳和外耳具有不同的胚胎起源,但
听觉装置的每个部件必须在空间和时间上精确同步。理解
调节和协调这些结构的发展的机制在
了解影响听力的许多先天缺陷的基础。我们已经确定了一个叉头堡
转录因子,foxI3,在胚胎头部非常早期表达的转录因子。狐狸I3小鼠
我们实验室制造的突变体缺少内耳、中耳和外耳的所有成分。我们的研究表明
耳朵诱导的第一步之一--耳道胎盘的形成--在foxI3突变体中没有发生。
此外,产生中耳听小骨的第一和第二鳃弓的间质
外耳开始在foxI3突变体中形成,但很快就会死于大量细胞死亡。此外,我们
最近发现了带有foxI3变异的人类患者,这些患者的听力有各种缺陷
仪器
据我们所知,foxI3是唯一一种导致大脑发育完全失败的哺乳动物基因。
当自身发生突变时,整个内耳、中耳和外耳。因此,我们非常有兴趣
了解foxI3如何在细胞和分子上协调听觉器官的发育
级别。我们的数据表明foxI3可能是一种“先驱”转录因子--它的主要功能除了
启动转录是在表观遗传上组织包含耳朵特异基因的基因组座位
转录能力强的状态。我们的前两个目标将决定foxI3的功能和机制
利用基因敲除小鼠、鸡胚胎操作和最先进的ES细胞发育内耳
模型、深度测序和生物信息学分析。我们的最终目标集中在foxI3基因在
中耳和外耳的发育-在这里,我们都将研究foxI3丢失对小鼠的影响,
但也创造了小鼠突变,概括了我们在一些人类患者中看到的遗传变异。
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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Andrew K Groves其他文献
Andrew K Groves的其他文献
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{{ truncateString('Andrew K Groves', 18)}}的其他基金
The role of the Foxi3 transcription factor in craniofacial microsomia
Foxi3转录因子在颅面微小症中的作用
- 批准号:
10666893 - 财政年份:2023
- 资助金额:
$ 52.56万 - 项目类别:
Optimizing MERFISH to allow multiplexed measurement of developmental and tonotopicgene expression gradients in the cochlea
优化 MERFISH 以允许对耳蜗中的发育和音调基因表达梯度进行多重测量
- 批准号:
10653753 - 财政年份:2023
- 资助金额:
$ 52.56万 - 项目类别:
A multi-species approach to find regulators of deafness genes
寻找耳聋基因调节因子的多物种方法
- 批准号:
10054189 - 财政年份:2016
- 资助金额:
$ 52.56万 - 项目类别:
Enhancing Atoh1 function in hair cell regeneration
增强 Atoh1 在毛细胞再生中的功能
- 批准号:
9178066 - 财政年份:2015
- 资助金额:
$ 52.56万 - 项目类别:
Enhancing Atoh1 function in hair cell regeneration
增强 Atoh1 在毛细胞再生中的功能
- 批准号:
10708943 - 财政年份:2015
- 资助金额:
$ 52.56万 - 项目类别:
Enhancing Atoh1 function in hair cell regeneration
增强 Atoh1 在毛细胞再生中的功能
- 批准号:
10888606 - 财政年份:2015
- 资助金额:
$ 52.56万 - 项目类别:
Enhancing Atoh1 function in hair cell regeneration
增强 Atoh1 在毛细胞再生中的功能
- 批准号:
10604600 - 财政年份:2015
- 资助金额:
$ 52.56万 - 项目类别:
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