Regulation of sensory cell specification in the developing cochlea

发育中耳蜗感觉细胞规格的调节

基本信息

批准号：
8049082
负责人：
Olivia Mary Bermingham-McDonogh
金额：
$ 34.15万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049082
关键词：
Adult Architecture Attention Binding Biological Assay Cell Differentiation process Cell Line Cells Cochlea Cochlear duct Defect Development Electroporation Epithelium Event FGF20 gene Family Fibroblast Growth Factor Fibroblast Growth Factor Receptors Gene Expression Regulation Genes Hair Cells In Situ In Vitro Investigation Labyrinth Lateral Lead Link Mediating Modeling Molecular Mus Natural regeneration Nervous system structure Noise Organ of Corti Pathway interactions Pattern Phenotype Process Proteins Regulation Regulatory Element Reverse Transcriptase Polymerase Chain Reaction Role Sensory Signal Pathway Signal Transduction Sorting - Cell Movement Specific qualifier value Staging Supporting Cell System Testing Time Tissues Work deafness design hair cell regeneration in utero in vivo inhibitor/antagonist insight member notch protein ototoxicity public health relevance regenerative repaired research study restoration sensory mechanism transcription factor

项目摘要

DESCRIPTION (provided by applicant): The development of the organ of Corti is a tightly regulated process, in which a small "prosensory" domain of the cochlear duct is sorted into various types of hair cells and support cells. While it known that intercellular signals, like Notch and FGF, are required at several steps in cochlear development, their precise roles and relationship at the stage of sensory cell specification are not clear. In the past year, we have found that FGF20 is necessary for sensory cell specification. Inhibition of FGF20 or inhibition of the FGF receptors leads to a loss in Atoh1 expression. We have also found that inhibition of Notch signaling in explant cultures at early stages of cochlear development leads to a block in sensory cell development. These findings have led to a working model in which the prosensory Notch signal leads to the expression of Fgf20, which then activates Atoh1 in the sensory cells. In this submission, we propose several lines of investigation aimed at testing specific hypotheses about the molecular mechanisms of sensory cell specification. Our proposal has the following specific aims: 1. To determine whether the prosensory action of Notch is mediated by FGF20; 2. To determine whether the action of Notch on FGF20 expression is direct; 3. To determine whether Ets domain transcription factors are necessary and/or sufficient for sensory cell specification. A better understanding of the molecular pathways regulating normal development will be critical for rational strategies for hair cell replacement and regeneration in adult onset deafness. PUBLIC HEALTH RELEVANCE: Understanding how the sensory cells of the inner ear are specified is a very important first step towards designing rational repair strategies for use after damage due to ototoxicity or noise. This proposal is geared towards elucidating the key steps in development of the sensory cells and the molecules involved. Once the molecular pathways, and the order in which they are used, are established it would allow for testing of compounds that activate or inhibit these pathways in damaged tissue to assess their influence on regeneration.

描述（由申请人提供）：柯蒂氏器的发育是一个严格调控的过程，其中耳蜗管的一个小的“前感觉”域被分类为各种类型的毛细胞和支持细胞。虽然我们知道细胞间信号，如 Notch 和 FGF，在耳蜗发育的几个步骤中是必需的，但它们在感觉细胞规范阶段的确切作用和关系尚不清楚。在过去的一年里，我们发现FGF20对于感觉细胞的规范是必需的。抑制 FGF20 或抑制 FGF 受体会导致 Atoh1 表达丧失。我们还发现，在耳蜗发育的早期阶段，外植体培养物中Notch信号传导的抑制会导致感觉细胞发育受阻。这些发现产生了一个工作模型，其中前感觉 Notch 信号导致 Fgf20 表达，然后激活感觉细胞中的 Atoh1。在本次提交中，我们提出了几项研究，旨在测试有关感觉细胞规范的分子机制的具体假设。我们的提案有以下具体目的： 1. 确定Notch的前感觉作用是否由FGF20介导； 2. 确定Notch对FGF20表达的作用是否是直接的； 3.确定Ets结构域转录因子对于感觉细胞特化是否是必要和/或充分的。更好地了解调节正常发育的分子途径对于成人发病性耳聋的毛细胞替换和再生的合理策略至关重要。公共健康相关性：了解内耳的感觉细胞是如何指定的，是设计因耳毒性或噪音造成的损伤后使用的合理修复策略的非常重要的第一步。该提案旨在阐明感觉细胞和相关分子发育的关键步骤。一旦建立了分子途径及其使用顺序，就可以测试激活或抑制受损组织中这些途径的化合物，以评估它们对再生的影响。