Sensory Organ Formation in the Inner Ear

这项研究计划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的主要原因， 前庭功能障碍。虽然毛细胞的发育和再生受到了相当大的关注，但 感觉上皮中的支持细胞也是基本的细胞类型，是许多类型耳聋的基础。 和平衡失调。再生毛细胞和支持细胞的一种方法是操纵 产生这两种细胞类型的细胞类型，即感觉祖细胞。然而，人们对此知之甚少 感觉神经前体细胞的规范和发展。在这项提案中，我们将调查 Notch信号通路在小鼠内耳感觉器官形成过程中的作用 Notch配体，Jagged1(JAG1)。先前的工作表明JAG1是感觉前体所必需的 内耳发育，尽管机制尚不清楚。我们假设JAG1可能扮演着一个 在感觉神经前体细胞的存活、增殖或特化以及分化过程中的作用 支持细胞。为了测试这些潜在的角色，我们将同时使用功能损失(目标1)和收益- 功能(目标2)接近小鼠。在目标1中，我们将使用一只条件功能丧失的Jag1小鼠 等位基因和Cre/loxP技术来产生转基因小鼠品系。使用不同的Cre表达 在不同发育阶段缺失JAG1的小鼠品系，我们可以定义JAG1- 介导的Notch信号在感觉前体的指定和分化中发挥作用。在目标2中，我们将利用 可被诱导表达一种激活形式的Notch受体(NICD)的几个小鼠品系 研究在不同时间点和不同细胞类型中激活Notch的后果 内耳。这一提议将进一步确定JAG1介导的Notch信号在感觉过程中的作用 以及阐明Notch信号是否会是一种 控制哺乳动物再生的适当途径。

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.