Analysis of surviving math1-null hair cells in the inner ear of chimeric mice
嵌合小鼠内耳中存活的 math1-null 毛细胞的分析
基本信息
- 批准号:7588335
- 负责人:
- 金额:$ 18.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAgeBreedingCell CommunicationCell Differentiation processCellsChimera organismChimerismCochleaComplementCuesDataDevelopmentEmbryoEnvironmentFounder GenerationGalactosidaseGenerationsGenesGoalsGreen Fluorescent ProteinsHair CellsImageryIn SituIn VitroIndividualKnockout MiceLabelLabyrinthLasersLifeLiving WillsLongevityMaintenanceMediatingMicroscopyMolecularMolecular ProfilingMusNull LymphocytesPathway interactionsPlayProcessProteinsRNAReporterRoleStagingSystemTestingTimeTissuesTransgenic MiceWild Type Mousebasecell typecongenital deafnessdeafnessimmunocytochemistryin vivoinsightmRNA Expressionmembermutantmyosin VInotch proteinpostnatalpromoterprotein expressionresearch studytissue processingtranscription factor
项目摘要
DESCRIPTION (provided by applicant): Math1, a transcription factor, is one of the critical genes for the formation of hair cells (HC) in the inner ear. The importance of Math1 was first shown in Math1 knockout mice which lack HCs (Bermingham et. al., 1999) leading to the hypothesis that Math1 was essential and sufficient for the formation of HCs. However, our recent study demonstrated that Math1- null HCs are able to be generated and to properly differentiate in the Math1-null chimeric mice, in which Math1-null cells are intermingled with wild-type cells (Du et. al., 2007). The presence of Math1-null cells within the chimeric inner ear provides evidence both that 1) wild-type cells can rescue Math1-null HCs in the chimeric environment, and 2) that given the correct external cues, cells that lack Math1 remain able to differentiate as hair cells (Du et. al., 2007). These unique cells can now be used to further explore the role of Math1 in HC development by more extensively characterizing their long-term potential as well as identifying molecular candidates that may mediate this rescue. A limitation of the previous study was that the system used to mark the genotypically mutant HCs, ss-galactosidase (ss-gal) from the mutant construct, was decreasing in expression and thus examination of mutant cells could be followed only up to postnatal days 4.5. Moreover, the tissue processing needed for ss-gal visualization compromised the integrity of the RNA. In the present proposal, these limitations will be circumvented by several chimeric combinations including the use of Math1-null mice that constitutively express green fluorescent protein and the use of other marker systems in the wild-type mice (including ROSA26 transgenic mice). Specific Aim 1 will begin to examine the long-term potential of these cells by testing the hypothesis that these HCs survive a normal lifespan and appear morphologically normal at all ages. Thus, the inner ears of chimeric mice will be examined at a range of ages using immunocytochemistry for HC markers. While the mechanism of this rescue is currently unknown, we hypothesize that at the time of differentiation of HCs, wild-type cells are able to activate downstream or parallel molecular pathways, allowing rescue of genotypically mutant HCs. Specific Aim 2 will compare the expression profiles of several molecules (e.g. Delta1, Bdnf) in chimeric Math1- null cells with those from the controls to assess whether these are molecular candidates for mediating this rescue. This data will provide information about the role of Math1 in the expression of these molecules as well as provide insight into the role of other molecules in the rescue of the genotypically Math1-null cells in the chimeric environment. One of the potential means to cure congenital deafness or deafness that occurs later in life is through the generation of new hair cells in the inner ear and Math1 is one of the candidate molecules that has shown promise in being able to generate new hair cells. This proposal will provide insight into how Math1 functions in the generation of hair cells.
描述(申请人提供):Math1是一种转录因子,是内耳毛细胞(HC)形成的关键基因之一。Math1的重要性首先在缺乏hc的Math1敲除小鼠中被证明(Bermingham et. al., 1999),这导致了Math1对于hc的形成是必要和充分的假设。然而,我们最近的研究表明,Math1-null的hc能够在Math1-null嵌合小鼠中产生并正确分化,其中Math1-null细胞与野生型细胞混合(Du et. al., 2007)。嵌合内耳中Math1缺失细胞的存在提供了两个证据:1)野生型细胞可以在嵌合环境中拯救Math1缺失的hc; 2)给予正确的外部提示,缺乏Math1的细胞仍然能够分化为毛细胞(Du et. al, 2007)。这些独特的细胞现在可以用来进一步探索Math1在HC发展中的作用,更广泛地表征它们的长期潜力,并确定可能介导这种拯救的候选分子。先前研究的一个局限性是,用于标记基因典型突变hc的系统,来自突变结构的ss-半乳糖苷酶(ss-gal)表达减少,因此只能在出生后4.5天对突变细胞进行检查。此外,ss-gal可视化所需的组织处理损害了RNA的完整性。在目前的提案中,这些限制将通过几种嵌合组合来规避,包括使用Math1-null小鼠组成性地表达绿色荧光蛋白,以及在野生型小鼠(包括ROSA26转基因小鼠)中使用其他标记系统。特异性目标1将通过测试这些hcc在正常寿命和所有年龄形态正常的假设,开始检查这些细胞的长期潜力。因此,嵌合小鼠的内耳将在一定年龄范围内使用免疫细胞化学检测HC标记物。虽然这种拯救的机制目前尚不清楚,但我们假设在hcc分化时,野生型细胞能够激活下游或平行的分子途径,从而允许拯救基因典型突变的hcc。特异性目标2将比较嵌合Math1- null细胞中几种分子(如Delta1, Bdnf)的表达谱,以评估这些分子是否是介导这种拯救的候选分子。这些数据将提供有关Math1在这些分子表达中的作用的信息,并提供其他分子在嵌合环境中拯救基因典型Math1缺失细胞中的作用的见解。治疗先天性耳聋或老年耳聋的潜在方法之一是通过在内耳中产生新的毛细胞,而Math1是一种候选分子,它已经显示出能够产生新的毛细胞的希望。这一提议将提供深入了解Math1在毛细胞生成中的作用。
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)
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KRISTIN M HAMRE其他文献
KRISTIN M HAMRE的其他文献
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{{ truncateString('KRISTIN M HAMRE', 18)}}的其他基金
Gender and Genetic effects on sleep:wake parameters following ethanol exposure
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8119666 - 财政年份:2010
- 资助金额:
$ 18.43万 - 项目类别:
Gender and Genetic effects on sleep:wake parameters following ethanol exposure
性别和遗传对睡眠的影响:乙醇暴露后的唤醒参数
- 批准号:
7991274 - 财政年份:2010
- 资助金额:
$ 18.43万 - 项目类别:
Analysis of surviving math1-null hair cells in the inner ear of chimeric mice
嵌合小鼠内耳中存活的 math1-null 毛细胞的分析
- 批准号:
7901248 - 财政年份:2009
- 资助金额:
$ 18.43万 - 项目类别:
Analysis of surviving math1-null hair cells in the inner ear of chimeric mice
嵌合小鼠内耳中存活的 math1-null 毛细胞的分析
- 批准号:
7725823 - 财政年份:2008
- 资助金额:
$ 18.43万 - 项目类别:
Mapping Cerebellar Development in Time and Space
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8068050 - 财政年份:2005
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$ 18.43万 - 项目类别:
Mapping Cerebellar Development in Time and Space
绘制小脑发育的时间和空间图
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7449641 - 财政年份:2005
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Mapping Cerebellar Development in Time and Space
绘制小脑发育的时间和空间图
- 批准号:
7635905 - 财政年份:2005
- 资助金额:
$ 18.43万 - 项目类别:
Mapping Cerebellar Development in Time and Space
绘制小脑发育的时间和空间图
- 批准号:
7255420 - 财政年份:2005
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$ 18.43万 - 项目类别:
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6694113 - 财政年份:2002
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