MECHANISMS OF INTESTINAL IRON ABSORPTION

描述（改编自应用程序） 人体内不能维持适当的铁水平是 遗传性血色病和获得性铁过载或缺乏症。 本申请的总体目标是确定分子机制 肠铁吸收的结构-功能关系和 参与的蛋白质的调节，以及关键的生理和 其正常功能或功能障碍的病理生理学影响。的 涉及的蛋白质包括刷状缘铁转运蛋白DCT 1， 刷状缘铁还原酶和假定的基底外侧铁流出系统 包含Ireg和肝素。我们建议检验以下假设： 金属离子（Fe ~（2+））的结合和迁移以及 动力学耦合驱动离子（H+）可以用动力学模型来描述 包括一系列配体诱导的构象变化;那惊人的 DCT 1特性的变化是由一种自然发生的突变引起的， （G185 R）与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（表达在 卵母细胞）将揭示DCT 1分子机制的新方面; Ireg和Hephaestin共同作用形成基底外侧铁输出 肠上皮细胞中的机制;血清铁的传感机制是 在HFE C282 Y突变的遗传性血色病患者中被破坏 在某些患有缺铁性贫血的儿童中， （血色素沉着症）或肠铁吸收不足（贫血）; 这种异常的铁吸收可能是由于DCT 1的异常调节， 铁还原酶、Ireg和/或肝素; DCT 1在所述信息处被调节 IRE/IRP系统的稳定性水平，也可能在转录水平 水平;并且肠中的DCT 1在刷状缘膜中表达 而在非肠组织中，DCT 1定位于 在核内体中，它允许转铁蛋白受体介导的铁摄取。的 这项工作的结果将导致更好地了解铁， 其他过渡金属离子，被吸收，并将创建的基本知识 所需的治疗策略的设计，用于治疗金属离子 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.