ZIP Proteins and Iron Metabolism

ZIP 蛋白质和铁代谢

基本信息

批准号：
9040152
负责人：
Mitchell D Knutson
金额：
$ 31.2万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040152
关键词：
Adolescent Affect Animal Model Animals Binding Cells Coupled Cultured Cells Data Diabetes Mellitus Diet Disease Embryo Enterocytes Erythroid Cells Family Family member Funding Genes Genetic Models Grant Health Heart Heart Diseases Hemochromatosis Hepatic Hereditary hemochromatosis Human Impairment Integral Membrane Protein Ions Iron Iron Metabolism Disorders Iron Overload Knock-out Knockout Mice Knowledge Link Liver Liver diseases Mediating Metabolic Diseases Metabolism Metals Molecular Mus Organ Outcome Pancreas Pathology Pathway interactions Physiological Plasma Play Positioning Attribute Protein Import Proteins Public Health Research Role Route Testing Therapeutic Intervention Tissues Transferrin Work ZIP protein Zinc absorption cell type feeding in vivo iron deficiency iron metabolism knockout animal member molecular targeted therapies mouse model new therapeutic target novel prevent protein function protein transport screening therapeutic target uptake

项目摘要

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.

描述（由申请人提供）：尽管铁缺乏和铁超载等铁代谢紊乱在人类中很常见，但我们对介导细胞铁摄取的蛋白质的理解仍然不完整。在本次拨款的第一个周期中，我们建立了跨膜蛋白 ZIP14 是金属离子转运蛋白 ZIP 家族的成员，它可以将铁转运到细胞中，并且会因肝脏和胰腺中铁超载而上调，而肝脏和胰腺是特别容易受到铁相关病理影响的组织。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，这些小鼠显示出铁状态参数的改变以及肝脏和胰腺对非转铁蛋白结合铁的摄取明显受损。通过筛选其他 ZIP 家族成员的铁转运活性，我们最近发现与 ZIP14 最密切相关的蛋白质 ZIP8 也可以转运铁，并且通过细胞铁负荷上调。在下一个资助周期中，我们将定义 ZIP14 和 ZIP8 在铁代谢中的生理作用。我们的中心假设是 ZIP14 和 ZIP8 参与各种组织对铁的吸收，包括那些在铁过载期间积累铁的组织。该研究的第一个目标是通过使用 ZIP14 敲除小鼠与 Hfe 和 Hjv 敲除小鼠（分别是人类铁超载疾病、遗传性血色素沉着症和幼年血色素沉着症的小鼠模型）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 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 在铁代谢中的作用以及 ZIP8 对铁代谢的贡献。使用新型组织特异性 ZIP8 敲除小鼠对胰腺和心脏进行铁负荷研究。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上的差距。这些结果预计将产生积极影响，因为它们可能会确定治疗铁代谢紊乱及其相关病理的新治疗靶点。