CFTR FUNCTION IN THE THYROID

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 甲状腺激素的生成需要摄取和释放碘进入甲状腺滤泡腔。碘的顶端退出被认为是由SLC26A4基因编码的阴离子交换蛋白Pendrin介导的。SLC26A4基因突变的患者偶尔会出现甲状腺肿，但在许多情况下是正常的。此外，小鼠SLC26A4基因敲除显示甲状腺激素水平没有差异。这些观察表明，顶端碘外流的替代途径存在于甲状腺中。 我们选择更详细地研究囊性纤维化跨膜电导调节因子(CFTR)在腔内碘蓄积中的作用。从野生型和CFTR-/-猪甲状腺中培养出极化原代培养物，以便于使用短路电流(ISC)测量和碘离子通量测量来评估阴离子传输。ISC研究表明，cAMP激活的阴离子(氯化物和碘化物)的分泌在CFTR-/-猪的甲状腺培养中被取消。到目前为止，有几种可能性与我们的发现一致。第一个模型测试CFTR是否直接介导碘从甲状腺滤泡细胞腔流出并进入滤泡腔。第二个模型研究了CFTR调节的侧膜蛋白活性是否介导了碘的外流。综上所述，CFTR1或Pendrin的缺乏可能会导致甲状腺功能不佳但足够，而两者都缺乏则会导致可检测到的甲状腺功能障碍。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Thyroid hormonogenesis requires iodide uptake and release into the thyroid follicular lumen. The apical exit of iodide is thought to be mediated by Pendrin, an anion exchanger encoded by the SLC26A4 gene. Patients with mutations in the SLC26A4 gene occasionally present with goiter, but in many cases are euthyroid. Moreover, a mouse Slc26a4 knockout shows no differences in thyroid hormone levels. These observations suggest that alternative pathways for apical iodide efflux exist in the thyroid gland. We have chosen to examine in greater detail the contributions of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to luminal iodide accumulation. Polarized primary cultures were grown from wild type and CFTR -/- pig thyroids to facilitate evaluations of anion transport using short-circuit current (Isc) measurements as well as iodide flux measurements. Isc studies indicate the presence of cAMP-activated anion (chloride and iodide) secretion that is abolished in CFTR-/- pig thyroid cultures. Several possibilities are consistent with our findings to date. The first model tests whether CFTR directly mediates iodide efflux from thyroid follicular cell space and into the follicular lumen. The second model addresses whether CFTR-regulated Pendrin activity mediates iodide efflux. Taken together, it is possible that deficiency of either CFTR- or Pendrin produces suboptimal but sufficient thyroid function, whereas lack of both will engender detectable thyroid dysfunction.