Sensory Organ Formation in the Inner Ear

内耳感觉器官的形成

• 批准号: 7991778
• 负责人: Amy Kiernan
• 金额: $ 36.9万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991778
• 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

DESCRIPTION (provided by applicant): 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. In humans, genetic, environmental and aging factors contribute to defects in the development, function and survival of the sensory regions within the inner ear, leading to deafness and vestibular dysfunction. The sensory regions in the ear are composed of both hair cells and supporting cells and while the molecular signaling in hair cell development is well studied, little is known about the signals that inform supporting cell development. Results from this proposal will help to define the molecular cascade that underlies the development of the progenitor cells that give rise to both hair cells and supporting cells, and elucidate appropriate pathways to target for regenerative studies in the ear.

描述（由申请人提供）：该研究建议的长期目标是了解内耳感觉上皮（由毛细胞和支持细胞组成）的发育和分子机制。感觉上皮的功能障碍是先天性耳聋，与年龄相关的听力损失和前庭功能障碍的主要原因。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不可少的细胞类型，并且是许多类型的聋和平衡疾病的基础。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知之甚少。在此提案中，我们将研究Notch信号通路在小鼠内耳中的感觉器官形成过程中的作用，重点是一种Notch配体Jagged1（JAG1）的作用。先前的工作表明，尽管该机制尚不清楚，但内耳中感觉祖细胞发育的感觉是必需的。我们假设JAG1可能在感觉祖细胞的生存，增殖或规范以及支持细胞的分化中起作用。为了测试这些潜在角色，我们将同时使用功能丧失（AIM 1）和功能获得（AIM 2）方法。在AIM 1中，我们将使用有条件的功能丧失JAG1小鼠等位基因和CRE/LOXP技术来生成遗传改性的小鼠线。使用在不同开发阶段删除JAG1的不同表达CRE的小鼠菌株，我们可以定义JAG1-介导的Notch信号在感觉祖细胞规范和分化中发挥的作用。在AIM 2中，我们将利用几种可以诱导的小鼠线来表达Notch受体（NICD）的激活形式，并研究在不同时间点和内耳内不同细胞类型中激活Notch的后果。该建议将进一步定义JAG1介导的Notch信号在耳朵内部和分化过程中的作用，并阐明Notch信号是否是操纵哺乳动物再生的合适途径。在人类中，遗传，环境和衰老因素导致内耳内部感觉区域的发展，功能和存活缺陷，导致耳聋和前庭功能障碍。耳朵中的感觉区域由毛细胞和辅助细胞组成，虽然毛细胞发育中的分子信号传导进行了充分的研究，但对于为支撑细胞发育提供信息的信号知之甚少。该提案的结果将有助于定义祖细胞开发的分子级联反应，从而引起毛细胞和支持细胞，并阐明了适当的途径，可以在耳朵中进行再生研究。