ZIP Proteins and Iron Metabolism

描述（由申请人提供）：尽管铁代谢紊乱（如缺铁和铁过载）在人类中很常见，但我们对介导铁摄入细胞的蛋白质的了解仍不完整。在第一轮拨款中，我们建立了 跨膜蛋白ZIP 14（金属离子转运蛋白ZIP家族的成员）可以将铁转运到细胞中，并且通过肝脏和胰腺中的铁过载而上调，肝脏和胰腺是对铁相关病理特别敏感的组织。我们最近对ZIP 14基因敲除小鼠的研究揭示了ZIP 14在体内离子代谢中的直接作用，这些小鼠显示铁状态参数的改变和肝脏和胰腺对非转铁蛋白结合铁的摄取的显著损害。通过筛选其他ZIP家族成员的铁转运活性，我们最近发现ZIP 8，ZIP 14最密切相关的蛋白质，也可以转运铁，并通过细胞铁负荷上调。在下一个资助周期中，我们将确定ZIP 14和ZIP 8在铁代谢中的生理作用。我们的中心假设是ZIP 14和ZIP 8参与各种组织的铁摄取，包括在铁过载期间积累铁的组织。本研究的第一个目的是通过使用ZIP 14基因敲除小鼠与Hfe和Hlc基因敲除小鼠、人类铁过载疾病、遗传性血色素沉着症和青少年血色素沉着症的小鼠模型分别杂交来确定ZIP 14在组织铁负荷中的作用。在我们的第二个目标中，我们将通过检查非转铁蛋白结合铁和转铁蛋白结合铁的肝脏摄取来确定双敲除ZIP 14;Hfe小鼠中肝脏铁负荷受损的机制。在我们的第三个目标中，我们将阐明ZIP 8在铁代谢中的作用以及ZIP 8对铁代谢的贡献。 通过使用新的组织特异性ZIP 8基因敲除小鼠的胰腺和心脏的铁负荷。在这些目标中提出的工作将有助于缩小我们对组织如何吸收铁的机械理解的差距。这些结果预计将产生积极的影响，因为它们可以确定新的治疗靶点，用于治疗铁代谢紊乱及其相关的病理学。

DESCRIPTION (provided by applicant): Although disorders of iron metabolism such as iron deficiency and iron overload are common in humans, our understanding of the proteins that mediate iron uptake into cells remains incomplete. In the first cycle of this grant, we established that the transmembrane protein ZIP14, a member of the ZIP family of metal-ion transporters, could transport iron into cells and is up-regulated by iron overload in the liver and pancreas, tissues that are particularly susceptible to iron-related pathologies. A direct role for ZIP14 in ion metabolism in vivo has been revealed by our recent studies of ZIP14 knockout mice, which display alterations in iron status parameters and a marked impairment in the uptake of non-transferrin-bound iron by the liver and pancreas. By screening other ZIP family members for iron transport activity, we recently discovered that ZIP8, the most closely related protein to ZIP14, could also transport iron and is up-regulated by cellular iron loading. In the next funding cycle, we will define the physiologic roles of ZIP14 and ZIP8 in iron metabolism. Our central hypothesis is that ZIP14 and ZIP8 participate in iron uptake by various tissues, including those that accumulate iron during iron overload. The first aim of the proposed research will define the role of ZIP14 in tissue iron loading by using ZIP14 knockout mice intercrossed with Hfe and Hjv knockout mice, mouse models of the human iron overload disorders, hereditary hemochromatosis and juvenile hemochromatosis, respectively. In our second aim, we will determine the mechanism of impaired hepatic iron loading in double-knockout ZIP14;Hfe mice by examining hepatic uptake of non-transferrin-bound iron and transferrin-bound iron. In our third aim, we will elucidate the role(s) of ZIP8 in iron metabolism and the contribution of ZIP8 to iron loading of the pancreas and heart by using novel tissue-specific ZIP8 knockout mice. The work proposed in these aims will help to close the gap in our mechanistic understanding of how tissues take up iron. Such results are expected to have a positive impact because they may identify new therapeutic targets for treating disorders of iron metabolism and their associated pathologies.