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: 6868163
• 负责人: Fred A Pereira
• 金额: $ 24.92万
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868163
• 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 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。

项目成果

Genome-wide analysis of binding sites and direct target genes of the orphan nuclear receptor NR2F1/COUP-TFI.

• DOI: 10.1371/journal.pone.0008910
• 发表时间: 2010-01-27
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Montemayor C;Montemayor OA;Ridgeway A;Lin F;Wheeler DA;Pletcher SD;Pereira FA
• 通讯作者: Pereira FA

High frequency of the IVS2-2A>G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss.

• DOI: 10.1186/1471-2350-6-30
• 发表时间: 2005-08-08
• 期刊: BMC medical genetics
• 作者: Tang HY;Xia A;Oghalai JS;Pereira FA;Alford RL
• 通讯作者: Alford RL

Altered traveling wave propagation and reduced endocochlear potential associated with cochlear dysplasia in the BETA2/NeuroD1 null mouse.

BETA2/NeuroD1 缺失小鼠中与耳蜗发育不良相关的行波传播改变和耳蜗电位降低。

• DOI: 10.1007/s10162-007-0092-9
• 发表时间: 2007
• 期刊: Journal of the Association for Research in Otolaryngology : JARO
• 作者: Xia,Anping;Visosky,AnnMarieB;Cho,Jang-Hyeon;Tsai,Ming-Jer;Pereira,FredA;Oghalai,JohnS
• 通讯作者: Oghalai,JohnS

Sensorineural hearing loss: potential therapies and gene targets for drug development.

感音神经性听力损失：药物开发的潜在疗法和基因靶点。

• DOI: 10.1080/15216540600913258
• 发表时间: 2006
• 期刊: IUBMB life
• 影响因子: 4.6
• 作者: Tang,LouisaS;Montemayor,Celina;Pereira,FredA
• 通讯作者: Pereira,FredA