FUNCTIONAL AND MOLECULAR CHARACTERIZATION OF PENDRIN

描述：（改编自申请人摘要）：Pendred综合征，表现为 感音神经性听力损失和甲状腺肿是PDS突变的结果， 基因PDS编码一种标记为pendrin的蛋白质，其功能是氯化物， 甲酸盐和碘化物转运蛋白，在甲状腺、内耳和 肾Pendrin的功能类似于先前描述的 氯/甲酸盐交换器在NaCl运输中起重要作用 这表明pendrin可能起着类似的作用， 在内耳。最近的证据表明，一些突变的个体 PDS基因中的突变不会导致甲状腺异常， 非综合征性耳聋伴前庭水管扩张（DFNB 4）。的目的 这一建议将从其功能、位置、 并确定不同的PDS突变如何影响pendrin。的 为达到这些目标，将采取以下办法： 多克隆抗pendrin抗体（已由委托人生产） 研究者）将用于鉴定pendrin在其中表达的细胞类型。 表达。 将通过测定底物特异性来分析Pendrin功能， 抑制剂概况、转运和调节动力学，以及 氯化物/碳酸氢盐交换。 PDS中不同突变对蛋白质生产、加工 将检查调节和传输特性。 将使用基因敲除小鼠模型来研究离子转运的机制 在pendrin正常表达但不活跃的细胞中。 这项工作是了解pendrin生理作用的第一步 并确定pendrin的缺陷如何导致临床表现， Pendred综合征。

DESCRIPTION: (Adapted from applicant's abstract): Pendred syndrome, manifested by sensorineural hearing loss and goiter is the result of mutations in the PDS gene. PDS encodes a protein labeled pendrin that functions as a chloride, formate and iodide transporter and is expressed in the thyroid, inner ear and kidney. Pendrin's function is similar to a previously described chloride/formate exchanger that plays an important role in NaCl transport across epithelial cells, suggesting that pendrin might perform a similar role in the inner ear. Recent evidence suggests that some individuals with mutations in the PDS gene do not develop thyroid abnormalities but instead have non-syndromic deafness with dilated vestibular aqueducts (DFNB4). The aims of this proposal are to characterize pendrin in terms of its function, location and regulation and determine how different PDS mutations affect pendrin. The following approach will be taken to achieve these aims: Polyclonal anti-pendrin antibodies (already generated by the Principal Investigator) will be used to identify the cell types in which pendrin is expressed. Pendrin function will be analyzed by determining substrate specificity, inhibitor profile, kinetics of transport and regulation, and chloride/bicarbonate exchange. The effect of different mutations in PDS on protein production, processing, regulation and transport properties will be examined. A knock out mouse model will be used to study the mechanisms of ion transport in cells where pendrin is normally expressed but rendered inactive. This work is a first step towards understanding the physiologic role of pendrin and determining how defects in pendrin lead to the clinical manifestations of Pendred syndrome.