Function and structure of pendrin in thyroid cells

超出提供的空间。彭德雷德综合征是一种常染色体隐性遗传病，以先天性耳聋、甲状腺肿大和甲状腺碘有机化受损为特征。它是由PDS(彭德雷德综合征)基因突变引起的。该基因的突变可能是先天性耳聋最常见的遗传原因之一，因为它们不仅与彭德雷德综合征有关，而且也构成了两种形式的非综合征性耳聋的分子基础。PDS基因编码一种阴离子转运蛋白，属于溶质载体家族26A(SCL26A4)。垂蛋白主要在甲状腺、肾脏和内耳表达。非洲爪哇卵母细胞的功能研究表明，吊环蛋白能够转运氯化物和碘化物。在甲状腺滤泡细胞中，垂垂蛋白在顶膜表达，提示它可能参与了碘向滤泡腔的运输。在肾脏中，膜蛋白存在于皮质集合管的13层细胞中，被认为具有氯/碱交换的功能。悬垂蛋白在内耳中的确切作用尚不清楚。我们的初步数据支持吊环是一种顶端碘转运蛋白的观点。研究侧翼蛋白的阴离子转运特性对于了解其在甲状腺细胞碘转运和甲状腺激素合成中的作用是至关重要的。在这一点上，还没有关于摆动蛋白介导的碘转运的动力学性质及其调节的数据。垂垂蛋白的膜拓扑结构和次级修饰尚不清楚，PDS基因表达的决定因素也尚未确定。这项提案的目标侧重于研究吊环的功能和结构。在特定目标1中的研究旨在进一步表征吊兰素的碘离子转运性质。在特定目标2中概述的实验试图表征侧翼蛋白的膜拓扑结构和二次修饰，从而有助于阐明结构-功能关系。在特定目标3的实验将确定摆蛋白启动子的细胞特异性，并研究其调控。这些研究将为这种在甲状腺、肾脏和内耳中具有重要功能的新型阴离子转运体的(病理)生理学提供基本的见解。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Pendred's syndrome is an autosomal recessive disorder defined by congenital deafness, goiter and an impaired thyroidal iodide organification. It is caused by mutations in the PDS (Pendred's syndrome) gene. Mutations in this gene may be among the most frequent genetic causes of congenital deafness since they are not only associated with Pendred's syndrome, but they also form the molecular basis of two forms of non-syndromic deafness. The PDS gene encodes pendrin, an anion transporter belonging to the Solute Carrier Family 26A (SCL26A4). Pendrin is predominantly expressed in the thyroid, the kidney and the inner ear. Functional studies in Xenopus oocytes revealed that pendrin is able to transport chloride and iodide. In thyroid follicular cells, pendrin is expressed at the apical membrane suggesting that it could be involved in the transport of iodide into the follicular lumen. In the kidney, pendrin is found in 13-intercalated cells of the cortical collecting duct and is thought to function as a chloride/base exchanger. The exact role of pendrin in the inner ear remains unknown. Our preliminary data support the concept that pendrin is an apical iodide transporter. A detailed characterization of the anion transport properties of pendrin is essential for the understanding of its role in iodide transport in thyrocytes and the synthesis of thyroid hormones. At this point, there are no data on the kinetic properties of pendrin-mediated iodide transport, and its regulation. The membrane topology and secondary modifications of pendrin are unknown, and the determinants for PDS gene expression have not been characterized. The goals of this proposal are focused on studies addressing the function and structure of pendrin. The studies in Specific Aim 1 aim at further characterizing the iodide transport properties of pendrin. The experiments outlined in Specific Aim 2 seek to characterize the membrane topology and secondary modifications of pendrin and will thus contribute to the elucidation of structure-function relationships. The experiments in Specific Aim 3 will determine the cell specificity of the pendrin promoter and study its regulation. These studies will provide fundamental insights into the (patho)physiology of this novel anion transporter that has important functions in the thyroid, the kidney and the inner ear. PERFORMANCE SITE ========================================Section End===========================================