FUNCTIONAL AND MOLECULAR CHARACTERIZATION OF PENDRIN

描述：(改编自申请者摘要)：Pendred综合征，表现 感音神经性耳聋和甲状腺肿是PDS基因突变的结果 吉恩。PDS编码一种标记为Pendrin的蛋白质，其功能类似于氯化物， 甲酸盐和碘转运蛋白，在甲状腺、内耳和 肾脏。Pendrin的功能类似于前面描述的 在氯化钠转运中起重要作用的氯/甲酸盐交换器 跨上皮细胞，这表明垂垂蛋白可能起着类似的作用 在内耳。最近的证据表明，一些携带突变的个体 在PDS基因中不会发生甲状腺异常，而是 前庭导水管扩张的非综合征性耳聋(DFNB4)。的目标是 这项建议是从功能、位置等方面来描述吊环 和调控，并确定不同的PDS突变如何影响吊环蛋白。这个 为达致这些目标，我们会采取以下方法： 多克隆抗支链蛋白抗体(已由主体产生 调查员)将被用来识别吊坠蛋白所在的细胞类型 表达。 将通过确定底物特异性来分析摆动蛋白的功能， 抑制剂谱、转运和调节动力学，以及 氯化物/碳酸氢盐交换。 PDS的不同突变对蛋白质生产、加工、 监管和运输属性将被检查。 基因敲除的小鼠模型将被用来研究离子传输的机制。 在正常表达但不活跃的细胞中。 这项工作是了解吊环的生理作用的第一步 以及确定垂蛋白缺陷如何导致临床表现 彭德雷德综合征。

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.