Function and structure of pendrin in thyroid cells

Pendrin在甲状腺细胞中的功能和结构

• 批准号: 7169850
• 负责人: PETER Andreas KOPP
• 金额: $ 24.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169850
• 关键词: Address; Anions; Apical; Cells; Chloride Ion; Chlorides; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Duct (organ) structure; Family; Future; Gene Expression; Genes; Genetic; Goals; Goiter; Growth; Growth Factor; Hormones; Inorganic Sulfates; Intercalated Cell; Iodides; Kidney; Kinetics; Knockout Mice; Knowledge; Labyrinth; Lead; Mammalian Cell; Mediating; Membrane; Membrane Proteins; Modification; Molecular; Mutate; Mutation; Oocytes; Patients; Phosphorylation; Physiology; Property; Regulation; Regulatory Element; Role; Sensorineural Hearing Loss; Site; Specificity; Structure; Structure-Activity Relationship; Syndrome; System; Thinking; Thyroid Gland; Thyroid Hormones; Tissues; Unspecified or Sulfate Ion Sulfates; Variant; Xenopus oocyte; apical membrane; base; brush border membrane; cell type; chloride-base exchanger; concept; congenital deafness; deafness; gene therapy; hormone regulation; insight; interest; kidney cell; kidney cortex; mutant; novel; promoter; research study; solute; sulfate transporter

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.

彭德雷德综合征是一种常染色体隐性遗传病，由先天性耳聋、甲状腺肿大和 甲状腺碘有机化。它是由PDS(彭德雷德综合征)基因突变引起的。基因突变 该基因可能是先天性耳聋最常见的遗传原因之一，因为它们不仅是 与彭德雷德综合征有关，但它们也构成了两种形式的非综合征的分子基础 耳聋。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。功能性 对非洲爪哇卵母细胞的研究表明，吊环蛋白能够转运氯化物和碘化物。在甲状腺滤泡中 细胞顶膜上有垂垂蛋白的表达，提示它可能参与了细胞的转运。 碘化物进入滤泡腔。在肾脏中，在皮质集合部的13层细胞中发现了垂垂蛋白。 并且被认为起到了氯/碱交换器的作用。吊环在内耳中的确切作用 仍然不为人知。我们的初步数据支持吊环是一种顶端碘转运蛋白的观点。一个 详细的表征侧链的阴离子传输特性对于理解它的性质是至关重要的。 碘在甲状腺细胞转运和甲状腺激素合成中的作用。目前，还没有关于 吊环蛋白介导的碘离子转运的动力学特性及其调控。膜的拓扑结构和 垂垂蛋白的二次修饰未知，PDS基因表达的决定因素也未知 被刻画出来了。这项提案的目标侧重于解决以下问题的研究 吊坠。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膜的拓扑结构和次要的 修饰支链蛋白，从而有助于阐明结构-功能关系。这个 在特定目标3中的实验将确定垂垂蛋白启动子的细胞特异性，并研究其 监管。这些研究将为这种新型阴离子的(病理)生理学提供基本的见解。 在甲状腺、肾脏和内耳中具有重要功能的转运蛋白。

项目成果

Applications of molecular biology and genetics in endocrinology.

分子生物学和遗传学在内分泌学中的应用。

• DOI: 10.4158/ep.13.5.534
• 发表时间: 2007
• 期刊: Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
• 作者: Kopp,Peter

Analysis of the PAX8 gene in 32 children with thyroid dysgenesis and functional characterization of a promoter variant.

32 名甲状腺发育不全儿童的 PAX8 基因分析和启动子变异的功能特征。

• DOI: 10.1515/jpem-2015-0199
• 发表时间: 2016
• 期刊: Journal of pediatric endocrinology & metabolism : JPEM
• 作者: Perone,Denise;Medeiros-Neto,Geraldo;Nogueira,CéliaRegina;Chagas,AntonioJosé;AlvesDias,VeraMaria;Viana,MariaFátima;Kopp,Peter
• 通讯作者: Kopp,Peter