Wnt Signaling in Hair Cell Generation from Supporting Cells

支持细胞生成毛细胞中的 Wnt 信号转导

基本信息

  • 批准号:
    9056678
  • 负责人:
  • 金额:
    $ 35.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-12-01 至 2020-11-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): We have shown that inhibition of Notch signaling leads to regeneration of hair cells and provide partial functional recovery in the adult ear with hair cells damaged by noise-exposure. We have recently discovered that Wnt signaling provides a required stimulus for pushing both embryonic progenitor cells and adult stem cells to a hair cell fate. Wnt signaling is necessary for induction of Atoh1 in cells exposed to Notch inhibition, as demonstrated by an absence of Atoh1 upregulation when Wnt signaling is blocked. This suggests that Wnt signaling is required for hair cell differentiation in the cochlea in response to Notch inhibition. Similar to Notch inhibition, gene expression controlled by Wnt stimulates hair cell dfiferentiation, but it also appears to stimulate genes that lead to the replacement of supporting cells. One of these downstream targets, Lgr5, appears to mark cochlear progenitors capable of postnatal transdifferentiation into new hair cells. Our current knowledge of signaling pathways, and our development of the models needed for their manipulation allow a crucial series of experiments to test hypotheses on the nature of the signaling pathways required to elicit hair cell regeneration and recovery of function. Although our recent work has provided an important proof-of-principle for hair cell replacement in the adult, regeneration was limited and the transdifferentiated supporting cells were not replaced. Here, we assess the response of both the newborn and adult cochlea to inhibition of Notch after hair cell damage. We hypothesize that Wnt signaling after hair cell death leads to a partial regenerative response in the newborn cochlea and that signaling through these pathways does not reach levels necessary to initiate regeneration in the adult cochlea. In Aim 1, we test our hypothesis about Wnt signaling in the newborn cochlea by both gain and loss of function studies for a role of Wnt in regeneration in response to Notch inhibition. In Aim 2 we test whether Notch inhibition or β-catenin upregulation in the damaged cochlea in adults, where we can measure hair cell regeneration, is accompanied by gene expression changes characteristic of regeneration. In Aim 3, we test our hypothesis that forced activation of Wnt in combination with Notch inhibition will drive both supporting cell proliferation and transdifferentiation of new hair cells. We further test the idea that the regeneration we see after damage and inhibition of γ-secretase can only occur if Wnt signaling is active.


项目成果

期刊论文数量(0)
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Albert Edge其他文献

Albert Edge的其他文献

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{{ truncateString('Albert Edge', 18)}}的其他基金

Determination of Hair Cell Fate from Postnatal Cochlear Supporting Cells
产后耳蜗支持细胞毛细胞命运的测定
  • 批准号:
    10617788
  • 财政年份:
    2022
  • 资助金额:
    $ 35.49万
  • 项目类别:
Determination of Hair Cell Fate from Postnatal Cochlear Supporting Cells
产后耳蜗支持细胞毛细胞命运的测定
  • 批准号:
    10435013
  • 财政年份:
    2022
  • 资助金额:
    $ 35.49万
  • 项目类别:
A cell-specific inducible model of hearing loss
听力损失的细胞特异性诱导模型
  • 批准号:
    7774210
  • 财政年份:
    2009
  • 资助金额:
    $ 35.49万
  • 项目类别:
A cell-specific inducible model of hearing loss
听力损失的细胞特异性诱导模型
  • 批准号:
    8004060
  • 财政年份:
    2009
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    7901281
  • 财政年份:
    2009
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    8233927
  • 财政年份:
    2005
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    8432824
  • 财政年份:
    2005
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    7258349
  • 财政年份:
    2005
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    8984514
  • 财政年份:
    2005
  • 资助金额:
    $ 35.49万
  • 项目类别:
Cellular therapy for the inner ear
内耳细胞疗法
  • 批准号:
    7791386
  • 财政年份:
    2005
  • 资助金额:
    $ 35.49万
  • 项目类别:

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