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

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.

本研究提案的长期目标是了解发育和分子机制 由此产生内耳感觉上皮（由毛细胞和支持细胞组成）。 感觉上皮功能障碍是先天性耳聋、年龄相关性听力损失和 前庭功能障碍。虽然有相当多的关注毛细胞的发育和再生， 感觉上皮中的支持细胞也是必需的细胞类型，并且是许多类型的耳聋的基础 平衡失调再生毛细胞和支持细胞的一种方法是操纵毛细胞。 这两种细胞都是感觉祖细胞。然而，人们对此知之甚少。 感觉祖细胞的特化和发育。在本提案中，我们将研究 Notch信号通路在小鼠内耳感觉器官形成过程中的作用，重点关注 Notch配体Jagged 1（JAG 1）。以前的研究表明，JAG 1是感觉祖细胞所必需的， 内耳的发育，尽管机制尚不清楚。我们假设JAG 1可能发挥了 在感觉祖细胞的存活、增殖或特化中以及在感觉祖细胞的分化中的作用 支持细胞。为了测试这些潜在的作用，我们将使用功能丧失（目标1）和功能获得（目标2）。 功能（目标2）在小鼠中接近。在目标1中，我们将使用条件性功能丧失Jag 1小鼠 等位基因和Cre/loxP技术来产生遗传修饰的小鼠系。使用不同的Cre-expressing 在不同发育阶段缺失JAG 1的小鼠品系中，我们可以确定JAG 1- 介导的Notch信号传导在感觉祖细胞特化和分化中起作用。在目标2中，我们将利用 可以诱导表达Notch受体（NICD）的活化形式的几种小鼠系， 研究在不同时间点和在不同细胞类型中激活Notch的后果。 内耳这一提议将进一步明确JAG 1介导的Notch信号在感觉神经元损伤中的作用。 以及阐明Notch信号传导是否是一个重要的信号传导机制。 适当的途径来操纵哺乳动物的再生。