CFTR FUNCTION IN THE THYROID

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 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。 甲状腺激素生成需要吸收碘并将其释放到甲状腺滤泡腔中。 碘化物的顶端排出被认为是由 Pendrin 介导的，Pendrin 是一种由 SLC26A4 基因编码的阴离子交换剂。 SLC26A4 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，敲除 Slc26a4 的小鼠显示甲状腺激素水平没有差异。 这些观察结果表明，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电导调节器 (CFTR) 对管腔碘化物积累的贡献。 极化原代培养物是从野生型和 CFTR -/- 猪甲状腺中培养出来的，以便于使用短路电流 (Isc) 测量和碘化物通量测量来评估阴离子传输。 Isc 研究表明存在 cAMP 激活的阴离子（氯离子和碘离子）分泌，这种分泌在 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是一致的。 第一个模型测试 CFTR 是否直接介导碘化物从甲状腺滤泡细胞间隙流出并进入滤泡腔。 第二个模型探讨 CFTR 调节的 Pendrin 活性是否介导碘离子流出。 总而言之，缺乏 CFTR- 或 Pendrin 可能会导致甲状腺功能欠佳但足够，而两者缺乏都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.