MECHANISMS OF INTESTINAL IRON ABSORPTION

说明(改编自应用程序) 未能维持适当的铁水平是人类的特征 遗传性血色素沉着症和获得性铁过载或缺乏症。 这一应用的总体目标是确定分子机制 肠道铁吸收、结构与功能的关系 对涉及的蛋白质的调节，以及关键的生理和 其正常功能或功能障碍的病理生理学意义。这个 涉及的蛋白质包括刷状缘铁转运蛋白DCT1， 刷状缘铁还原酶和推测的基底侧铁外排系统 由IREG和Hephestn组成。我们建议检验以下假设： 金属离子(Fe2+)的结合和移位 热力学耦合驱动离子(H+)可用动力学模型描述 包括一系列由配体引起的构象变化； DCT1的性质变化是由自然发生的突变引起的 (G185R)与MK小鼠和贝尔格莱德大鼠的小细胞性贫血相关； 这种突变导致的非典型电导(表示为 卵母细胞)将揭示DCT1分子机制的新方面； IREG和Hephestn共同作用形成基侧铁输出 肠道细胞中的机制；对血清铁的敏感机制是 遗传性血色沉着症患者HFE C282Y突变的基因突变 在某些患有缺铁性贫血的儿童中， (血色沉着症)或肠道铁吸收不足(贫血)； 这种异常的铁吸收可能是由于DCT1的异常调节， 铁还原酶、IREG和/或Hephestn；DCT1在消息中受到调控 IRE/IRP系统的稳定性水平，也可能在转录水平 肠道中DCT1在刷状缘膜中表达 而在非肠道组织中，DCT1定位于 在允许转铁蛋白受体介导的铁摄取的内体中。这个 这项工作的结果将使我们更好地理解铁是如何 其他过渡金属离子，被吸收，并将创造基本知识 设计治疗金属离子的治疗策略所必需的 超负荷和缺乏症。

DESCRIPTION (adapted from the application) Failure to maintain appropriate iron levels in man is characteristic of hereditary hemochromatosis and acquired iron overload or deficiency disorders. The overall goals of this application are to determine the molecular mechanisms of intestinal iron absorption, the structure-function relationships and the regulation of the proteins involved, and the key physiological and pathophysiological implications of their normal function or dysfunction. The proteins involved include the brush-border iron transporter DCT1, the brush-border ferrireductase, and a putative basolateral iron efflux system comprising Ireg and hephaestin. We propose to test the following hypotheses: That the binding and translocation of metal-ion (Fe2+) and the thermodynamically-coupled driving ion (H+) can be described by a kinetic model comprising a series of ligand-induced conformational changes; that striking changes in the properties of DCT1 result from a naturally-occurring mutation (G185R) associated with microcytic anemia in the mk mouse and the Belgrade rat; that atypical conductances that result from this mutation (expressed in oocytes) will reveal novel aspects of the molecular mechanisms of DCT1; that Ireg and hephaestin function together to form the basolateral iron export mechanism in enterocytes; that the sensing mechanism for serum iron is disrupted in hereditary hemochromatosis patients with the HFE C282Y mutation and in certain children with iron-deficiency anemia leading to excessive (hemochromatosis) or insufficient (anemia) intestinal iron absorption; that this abnormal iron absorption may be due to abnormal regulation of DCT1, ferrireductase, Ireg and/or hephaestin; that DCT1 is regulated at the message stability level by the IRE/IRP system and possibly also at the transcriptional level; and that DCT1 in the intestine is expressed in the brush border membrane of intestinal enterocytes whereas in non-intestinal tissues, DCT1 is localized in endosomes where it allows transferrin receptor mediated iron uptake. The results of this work will lead to a greater understanding of how iron, and other transition metal-ions, are absorbed, and will create the basic knowledge required for the design of therapeutic strategies for treating metal-ion overload and deficiency disorders.