ZIP Proteins and Iron Metabolism

描述(申请人提供)：尽管铁代谢障碍，如缺铁和铁超载在人类中很常见，但我们对介导铁吸收到细胞中的蛋白质的了解仍然不完整。在这笔赠款的第一个周期中，我们建立了 跨膜蛋白ZIP14是ZIP金属离子转运蛋白家族的成员，可以将铁转运到细胞内，并受到肝脏和胰腺铁超载的上调，这两个组织特别容易受到铁相关病理的影响。我们最近对ZIP14基因敲除小鼠的研究揭示了ZIP14在体内离子代谢中的直接作用，这些小鼠的铁状态参数发生了变化，肝脏和胰腺对非转铁蛋白结合铁的吸收明显受损。通过筛选ZIP家族其他成员的铁转运活性，我们最近发现，与ZIP14关系最密切的蛋白质ZIP8也可以转运铁，并受到细胞铁负荷的上调。在下一个资金周期中，我们将确定ZIP14和ZIP8在铁代谢中的生理作用。我们的中心假设是，ZIP14和ZIP8参与了各种组织对铁的吸收，包括那些在铁超载期间积聚铁的组织。这项研究的第一个目的是通过将ZIP14基因敲除的小鼠分别与HFE和Hjv基因敲除小鼠、人类铁超载疾病、遗传性血色病和幼年血色病的小鼠模型杂交，来确定ZIP14在组织铁负荷中的作用。在我们的第二个目标中，我们将通过检测肝脏对非转铁蛋白结合铁和转铁蛋白结合铁的摄取来确定双基因敲除ZIP14；HFe小鼠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ZIP8在铁代谢中的作用(S)以及ZIP8对 用新型组织特异性ZIP8基因敲除小鼠研究胰腺和心脏的铁负荷。在这些目标中提出的工作将有助于弥合我们对组织如何吸收铁的机械理解上的差距。预计这些结果将产生积极影响，因为它们可能确定治疗铁代谢障碍及其相关病理的新治疗靶点。

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.