Orphan Nuclear Receptor COUP TFI in Hearing and Balance

孤儿核受体 COUP TFI 在听力和平衡方面的作用

• 批准号: 6516266
• 负责人: Fred A Pereira
• 金额: $ 22.64万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516266
• 关键词: auditory nuclei; balance; chimeric proteins; complementary DNA; developmental genetics; developmental neurobiology; gene induction /repression; genetic library; genetically modified animals; hearing; laboratory mouse; labyrinth; neurogenetics; nuclear receptors; polymerase chain reaction; vestibular nuclei

DESCRIPTION: (Adapted from applicant's abstract): The COUP-TFs are orphan nuclear receptors proven to play important roles in controlling diverse aspects of growth, development, differendation and homeostasis m several orgarisms. The COUP-TFs are regulators of gene expression and belong to the steroid thyroid hormone receptor superfamily of ligandactivated transcription factors. The pattern and timing of expression of an orphan nuclear receptor gene defines the sphere of direct influence of a putative hgand signaling pathway within its target tissues and cells. The spatial and temporal expression pattern of COUP-TEs during inner ear organogenesis suggest that they may play a critical role in reguladug processes that lead to the formation of a fUnctionaMnner ear. Indeed, COUPTFI loss-of-function mutants are deaf, having defects in development of the cochlea and sensory maculae of the ves6bule. This suggests that COUP-TFI is an essential gene for the development of both hearing and balance functions in the monse. To better understand the role of COUP-TFI in hearing and balance this grant will focus on the followmg aims. 1. Characterize defects in COUP-TFI mutants with respect to a detailed expression analysis of COUP-TFI during development and differentiation of inner ear structures and the brainstem auditory and vestibular nuclei. 2. Determine the mechanism of COUP-TFI action usmg chimeric embryo analysis to ascertain whether COUP-TFI acts in a cell-autonomous or non-autonomous manner in the ear. 3. Identify COUP-TFI downstream targets during inner ear development by subtraction library screens of cochlea and vestibule cDNA libraries. The completion of these aims will provide substantial insight on this novel regulator of itmer ear morphogenesis and will identify genes required in its signaling pathway for development of hearmg and balance.

描述：（改编自申请人的摘要）：COUP-TF 是孤儿 核受体被证明在控制各个方面发挥着重要作用 几种生物体的生长、发育、分化和体内平衡。这 COUP-TF 是基因表达的调节因子，属于类固醇甲状腺 配体激活转录因子的激素受体超家族。这 孤儿核受体基因的表达模式和时间定义了 其内推定的配体信号通路的直接影响范围 靶组织和细胞。的空间和时间表达模式 内耳器官发生过程中的 COUP-TE 表明它们可能发挥着关键作用 在导致功能性耳朵形成的调节过程中的作用。 事实上，COUPTFI 功能丧失突变体是聋子，具有以下缺陷： 耳蜗和小泡感觉斑的发育。这表明 COUP-TFI 是听力和听力发育的重要基因 monse 中的平衡功能。为了更好地理解 COUP-TFI 在 听证会和平衡这笔赠款将重点关注以下目标。 1. 表征 COUP-TFI 突变体在详细表达分析方面的缺陷 COUP-TFI 在内耳结构的发育和分化过程中 脑干听觉核和前庭核。 2. 确定机理 COUP-TFI 作用使用嵌合胚胎分析来确定 COUP-TFI 是否 在耳中以细胞自主或非自主方式起作用。 3. 识别 通过减法文库进行内耳发育过程中的 COUP-TFI 下游目标 耳蜗和前庭 cDNA 文库的筛选。这些目标的完成 将为 itmer 耳的这种新型调节器提供深入的见解 形态发生并将识别其信号通路所需的基因 听力和平衡能力的发展。