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。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 甲状腺滤泡形成需要碘的吸收和释放到甲状腺滤泡腔。 碘离子的顶端排出被认为是由Pendrin介导的，Pendrin是一种由SLC 26 A4基因编码的阴离子交换剂。 SLC 26 A4基因突变的患者偶尔会出现甲状腺肿，但在许多情况下甲状腺功能正常。 此外，小鼠Slc 26 a4基因敲除显示甲状腺激素水平没有差异。 这些观察结果表明，在甲状腺中存在顶端碘流出的替代途径。 我们选择更详细地研究囊性纤维化跨膜传导调节因子（CFTR）对腔内碘积累的贡献。 从野生型和CFTR -/-猪甲状腺生长极化原代培养物，以便于使用短路电流（Isc）测量以及碘通量测量评价阴离子转运。 Isc研究表明存在cAMP激活的阴离子（氯离子和碘离子）分泌，其在CFTR-/-猪甲状腺培养物中被消除。 有几种可能性与我们迄今为止的发现一致。 第一个模型测试CFTR是否直接介导碘从甲状腺滤泡细胞间隙流出并进入滤泡腔。 第二个模型解决了CFTR调节的Pendrin活性是否介导碘外流。 总之，CFTR-或Pendrin的缺乏可能产生次优但足够的甲状腺功能，而缺乏两者将产生可检测的甲状腺功能障碍。

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.