FGF in Sensory System Development

FGF 在感觉系统开发中的应用

基本信息

批准号：
7524959
负责人：
Olivia Mary Bermingham-McDonogh
金额：
$ 41.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524959
关键词：
Address Adult Biological Cell Differentiation process Cells Cochlea Cochlear duct Computer Systems Development Congenital Disorders Defect Development FGF20 gene FGF8 gene FGFR1 gene FGFR3 gene Failure Fibroblast Growth Factor Fibroblast Growth Factor Receptors Funding Genes Grant Hair Cells In Vitro Inner Hair Cells Investigation Knockout Mice Lateral Lead Ligands Mediating Modeling Molecular Mus Mutant Strains Mice Mutation Natural regeneration Notch Signaling Pathway Organ of Corti Outer Hair Cells Pathway interactions Pattern Phase Phenotype Pillar Cell Play Process Regulation Reporting Role Series Signal Transduction Sorting - Cell Movement Specific qualifier value Staging Supporting Cell System Techniques Testing Time Transgenic Organisms deafness homeodomain in vivo loss of function mutant notch protein research study sensory system therapy design 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. Over the past five years, a model of this process has emerged, primarily through analysis of mice with mutations in developmentally expressed genes. The prosensory region, defined by p27 expression, is specified by the Notch pathway ligand, Jagged1, FGF receptor 1, and the transcription factor Sox2. Following specification, hair cells and supporting cells are defined within this region by a process that requires Math1, a bHLH transcription factor, and the additional Notch ligands, Jagged2 and Dll1. A final stage in the process of development of the organ of Corti again requires FGF signaling, this time through FGFR3, to direct a subset of the support cells to develop as pillar cells. While this model has received strong experimental support, there are still many unanswered questions. For example, FGF signaling is known to be critical for pillar cell development, but we have recently found that mutants in Fgfr3 also have an increase in outer hair cells. Our recent results further suggest that there may be an interaction between FGF signaling and another key regulator of hair cell development, the Notch pathway, but we know almost nothing about connections between these pathways. In our screens for other FGFs and other Notch pathway components that might play a role in cochlear development, we discovered that FGF20 is expressed in a highly specific pattern that coincides with the prosensory domain from E14 to E16 and that Hes related genes, Hesr1 and Hesr2, are expressed in this same domain, from E12.5. In this proposal we address these questions in three Specific Aims. Aim 1. Determine the role of FGF signaling and FGF20 in early cochlear development. Aim 2. Determine whether Hesr1 and Hesr2 are the downstream effectors of Jagged1/Notch. Aim 3. Determine whether Prox1 directly regulates expression of Fgfr3 in support cells of the developing organ of Corti? We will use a combination of molecular biological techniques, as well as analysis of transgenic and knockout mice, to accomplish these aims. Understanding the roles of the FGF and Notch pathways in cochlear development may lead to the design of treatments for congenital disorders. Moreover, 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.

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。在过去的五年里，这一过程的模型已经出现，主要是通过对发育表达基因突变的小鼠进行分析。由 p27 表达定义的前感觉区域由 Notch 通路配体、Jagged1、FGF 受体 1 和转录因子 Sox2 指定。根据规范，毛细胞和支持细胞在该区域内通过需要 Math1（bHLH 转录因子）和其他 Notch 配体 Jagged2 和 Dll1 的过程来定义。柯蒂氏器官发育过程的最后阶段再次需要 FGF 信号传导（这次是通过 FGFR3）来指导支持细胞的子集发育为支柱细胞。尽管该模型得到了强有力的实验支持，但仍有许多未解答的问题。例如，已知 FGF 信号传导对于支柱细胞发育至关重要，但我们最近发现 Fgfr3 的突变体也导致外毛细胞增加。我们最近的结果进一步表明，FGF 信号传导与毛细胞发育的另一个关键调节因子 Notch 通路之间可能存在相互作用，但我们对这些通路之间的联系几乎一无所知。在我们对可能在耳蜗发育中发挥作用的其他 FGF 和其他 Notch 通路成分的筛选中，我们发现 FGF20 以高度特异性的模式表达，与 E14 到 E16 的前感觉域一致，并且 Hes 相关基因 Hesr1 和 Hesr2 ，在同一域中表达，来自 E12.5。在本提案中，我们通过三个具体目标解决这些问题。目标 1. 确定 FGF 信号传导和 FGF20 在早期耳蜗发育中的作用。目标 2. 确定 Hesr1 和 Hesr2 是否是 Jagged1/Notch 的下游效应器。目标 3. 确定 Prox1 是否直接调节 Corti 器官发育的支持细胞中 Fgfr3 的表达？我们将结合使用分子生物学技术以及对转基因和基因敲除小鼠的分析来实现这些目标。了解 FGF 和 Notch 通路在耳蜗发育中的作用可能有助于设计先天性疾病的治疗方法。此外，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。