Orphan Nuclear Receptor COUP TFI in Hearing and Balance

描述：(改编自申请者摘要)：政变组织是孤儿 核受体被证明在控制不同方面发挥重要作用 关于生长、发育、分化和动态平衡的几个有机体。这个 COUP-TF是基因表达的调节者，属于类固醇甲状腺 激素受体超家族配体激活转录因子。这个 孤儿核受体基因的表达模式和时间决定了 ITS中假定的Hgand信号通路的直接影响范围 目标组织和细胞。时间和空间的表达模式 内耳器官发生过程中的突变表明它们可能起着关键作用 在导致fUnctionaMnner耳朵形成的规则过程中发挥作用。 事实上，COUPTFI功能丧失突变体是聋人，在 卵泡内耳和感觉斑的发育。这表明 政变-TFI是听力和听力发育的重要基因 Monse中的平衡功能。为了更好地理解政变-TFI在 听证和平衡这笔拨款将集中在以下目标上。1.描述 COUP-TFI突变体在详细表达分析方面的缺陷 COUP-TFI在内耳结构发育和分化中的作用 脑干听觉核团和前庭核团。2.确定其作用机制。 用嵌合胚胎分析确定COUP-TFI的作用 在耳朵中以细胞自主或非自主的方式起作用。3.识别 利用消减文库研究内耳发育过程中的COUP-TFI下游靶点 耳蜗和前庭cdna文库的筛选。这些目标的实现 将对ITMER EAR的这种新的调节器提供实质性的见解 并将确定其信号通路中所需的基因 心智和平衡的发展。

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.