Orphan Nuclear Receptor COUP TFI in Hearing and Balance

描述：（改编自申请人摘要）：COUP-TF是孤儿药 核受体被证明在控制不同方面发挥重要作用 生长、发育、分化和体内平衡的重要性。的 COUP-TF是基因表达的调节剂，属于类固醇甲状腺激素 配体激活转录因子激素受体超家族。的 孤儿核受体基因表达的模式和时间决定了 一个假定的汞信号通路的直接影响范围， 靶组织和细胞。的时空表达模式 内耳器官发生过程中的COUP-TE表明它们可能在内耳器官发生过程中起着关键作用。 在导致功能性中耳炎形成的调节过程中起作用。 事实上，COUPTFI功能丧失突变体是耳聋的， 耳蜗和小囊感觉斑的发育。这表明 COUP-TFI是听觉和听觉发育的重要基因， 平衡功能在monse。为了更好地了解COUP-TFI在以下方面的作用， 听证会和平衡这笔赠款将集中在以下目标。1.表征 COUP-TFI突变体中的缺陷， COUP-TFI在内耳结构发育和分化过程中的作用及其在内耳发育和分化中的作用 脑干听觉和前庭核。2.确定的机制 使用嵌合胚胎分析确定COUP-TFI是否 在耳中以细胞自主或非自主方式起作用。3.识别 利用差减文库研究内耳发育过程中COUP-TFI下游靶点 筛选耳蜗和前庭cDNA文库。这些目标的实现 将提供实质性的见解，这种新的调节器itmer耳 形态发生，并将确定其信号通路所需的基因， 听力和平衡的发展。

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.