Sensory Organ Formation in the Inner Ear

内耳感觉器官的形成

• 批准号: 8374113
• 负责人: Amy Kiernan
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374113
• 关键词: Adult; Afferent Neurons; Age Factors; Alleles; Area; Attention; Cell Differentiation process; Cell Survival; Cells; Data; Defect; Development; Ear; Environmental Risk Factor; Epithelium; Equilibrium; Functional disorder; Goals; Hair Cells; Human Genetics; Label; Labyrinth; Lead; Ligands; Maintenance; Mediating; Molecular; Mouse Strains; Mus; Natural regeneration; Neurons; Notch Signaling Pathway; Organ; Pathway interactions; Pattern; Phenotype; Play; Presbycusis; Research Proposals; Role; Sensorineural Hearing Loss; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Specific qualifier value; Staging; Stem cells; Supporting Cell; Technology; Testing; Time; Tissues; Work; cell type; congenital deafness; deafness; equilibration disorder; gain of function; loss of function; notch protein; otoconia; overexpression; progenitor; programs; regenerative; therapy design; Adult; Afferent Neurons; Age Factors; Alleles; Area; Attention; Cell Differentiation process; Cell Survival; Cells; Data; Defect; Development; Ear; Environmental Risk Factor; Epithelium; Equilibrium; Functional disorder; Goals; Hair Cells; Human Genetics; Label; Labyrinth; Lead; Ligands; Maintenance; Mediating; Molecular; Mouse Strains; Mus; Natural regeneration; Neurons; Notch Signaling Pathway; Organ; Pathway interactions; Pattern; Phenotype; Play; Presbycusis; Research Proposals; Role; Sensorineural Hearing Loss; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Specific qualifier value; Staging; Stem cells; Supporting Cell; Technology; Testing; Time; Tissues; Work; cell type; congenital deafness; deafness; equilibration disorder; gain of function; loss of function; notch protein; otoconia; overexpression; progenitor; programs; regenerative; therapy design

The long-term goal of this research proposal is to understand the developmental and molecular mechanisms by which the inner ear sensory epithelium (composed of hair cells and supporting cells) is generated. Dysfunction of the sensory epithelium is a major cause of congenital deafness, age-related hearing loss, and vestibular dysfunction. While there is considerable focus on hair cell development and regeneration, the supporting cells in the sensory epithelium are also essential cell types and underlie many types of deafness and balance disorders. One approach to regenerating both hair cells and supporting cells is to manipulate the cell types that give rise to both cell types, the sensory progenitors. However, little is known about the specification and development of the sensory progenitors. In this proposal we will investigate the role of the Notch signaling pathway during sensory organ formation in the mouse inner ear, focusing on the role of one of the Notch ligands, Jagged1 (JAG1). Previous work has shown that JAG1 is required for sensory progenitor development in the inner ear, although the mechanism is not known. We hypothesize that JAG1 may play a role in the survival, proliferation, or specification of the sensory progenitors as well as in the differentiation of the supporting cells. In order to test these potential roles we will use both loss-of-function (Aim 1) and gain-of- function (Aim 2) approaches in the mouse. In Aim 1 we will use a conditional loss-of-function Jag1 mouse allele and Cre/loxP technology to generate genetically-modified mouse lines. Using different Cre-expressing mouse strains that delete JAG1 during different stages of development we can define the role that JAG1- mediated Notch signaling plays in sensory progenitor specification and differentiation. In Aim 2 we will utilize several mouse lines that can be induced to express an activated form of the Notch receptor (NICD) and investigate the consequences of activating Notch at different time points and in different cell types within the inner ear. This proposal will further define the role of JAG1-mediated Notch signaling during sensory development and differentiation within the ear as well as elucidate whether Notch signaling would be an appropriate pathway to manipulate for mammalian regeneration.

该研究建议的长期目标是了解发展和分子机制 通过其中产生内耳感觉上皮（由毛细胞和支持细胞组成）。 感觉上皮功能障碍是先天性聋，与年龄相关的听力损失和 前庭功能障碍。尽管大量关注毛细胞的发育和再生，但 感觉上皮中的支撑细胞也是必需的细胞类型，并且是许多类型的耳聋的基础 和平衡疾病。再生毛细胞和支持细胞的一种方法是操纵 引起两种细胞类型的细胞类型，即感觉祖细胞。但是，关于 感觉祖细胞的规范和发展。在此提案中，我们将调查 小鼠内耳的感觉器官形成期间的凹槽信号通路，重点是其中一个的作用 Notch配体Jagged1（Jag1）。先前的工作表明，jag1是感觉祖细胞所必需的 内耳的发展，尽管该机制尚不清楚。我们假设Jag1可能会玩 在感觉祖细胞的生存，增殖或规范中的作用以及分化 支持细胞。为了测试这些潜在角色，我们将同时使用功能丧失（AIM 1）和 - 鼠标中的功能（AIM 2）方法。在AIM 1中，我们将使用有条件的功能丧失JAG1鼠标 等位基因和CRE/LOXP技术生成遗传改性的小鼠系。使用不同的表达CRE 在开发的不同阶段删除JAG1的小鼠菌株我们可以定义JAG1-的作用 介导的Notch信号在感觉祖细胞规范和分化中发挥作用。在AIM 2中，我们将使用 可以诱导的几种小鼠线表达凹槽受体（NICD）的活化形式和 研究在不同时间点和在不同的单元格中激活Notch的后果 内耳。该建议将进一步定义在感觉过程中JAG1介导的Notch信号的作用 耳朵内的发展和差异化以及阐明Notch信号是否将是 适当的操纵哺乳动物再生的途径。