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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：
Albert Edge
金额：
$ 35.49万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
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

来源：
https://reporter.nih.gov/project-details/9056678
关键词：
Accounting Adult Aging Breeding Bromodeoxyuridine Cell Count Cell Death Cell Differentiation process Cell Proliferation Cell division Cells Cessation of life Characteristics Cochlea Detection Ear Embryo Exposure to Gene Expression Generations Genes Hair Cells Health Hearing problem Immunohistochemistry In Vitro Knowledge Laboratories Labyrinth Lead Measures Motion Mus Natural regeneration Nature Necrosis Neomycin Neonatal Newborn Infant Noise Pathway interactions Proteinase 3 Recovery of Function Regenerative response Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Pathway Signal Transduction Stem cells Stimulus Supporting Cell Tamoxifen Testing Toxin Up-Regulation Work adult stem cell beta catenin cell injury equilibration disorder gamma secretase hair cell regeneration immunohistochemical markers in vivo inhibitor/antagonist loss of function model development notch protein overexpression postnatal progenitor ranpirnase receptor research study response sound transdifferentiation

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.