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.

这项研究计划的长期目标是了解发育和分子机制