Divalent metal-ion transporter DMT1 and its role in intestinal metal-ion uptake

二价金属离子转运蛋白 DMT1 及其在肠道金属离子摄取中的作用

基本信息

  • 批准号:
    7856326
  • 负责人:
  • 金额:
    $ 3.58万
  • 依托单位:
  • 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:
    2008-04-01 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): DMT1 is a widely-expressed iron transporter that is essential for adequate intestinal absorption of iron and for transport of iron in red blood cell precursors for the production of hemoglobin. Rare mutations in DMT1 cause severe microcytic anemia. Conversely, dysregulation of DMT1 in hereditary hemochromatosis, the most common hereditary disease in Caucasians, results in toxic iron overload in vital organs. Since there exists no regulated mechanism for its excretion, iron homeostasis is achieved by regulating intestinal iron absorption. DMT1 is the gateway for iron absorption - it is the primary or only apical transporter of nonheme iron - making it the focus of this proposal. Iron deficiency affects as much as 10% of the U.S. population and is the most prevalent micronutrient deficiency worldwide. Important for this proposal, iron deficiency is a serious risk factor for cadmium intoxication, suggesting that cadmium and iron share a common absorptive mechanism. Under investigation in this proposal is the premise that DMT1 is a complex H+-coupled and voltage-dependent ferrous-iron (Fe2+) transporter and that an acidic microclimate at the intestinal brush-border membrane provides the proton-motive force energizing DMT1. We will probe the molecular basis of H+-coupling and explore a physiological role for the significant uncoupled H+ fluxes (slippage) through DMT1 using the voltage clamp, radiotracer (55Fe) assays, and fluorescence approaches in Xenopus oocytes expressing wildtype DMT1 or mutant proteins. Next, we will examine iron transport in the mouse intestine using radiotracer and fluorescence approaches; the use of specific inhibitors of intestinal Na+/H+ exchangers (NHE3 and NHE2) and mutant mouse models lacking NHE3, NHE2, or the gastric H+/K+-ATPase will permit us to evaluate the roles of gastric acid and the intestinal brush-border acidic microclimate in providing the H+ to drive DMT1-mediated Fe2+ transport. The second premise is that DMT1 serves absorption not only of iron but also of certain other essential metals such as Co and Mn (as well as trace metals such as Ni and V) but that this promiscuity also makes it a major route of entry for the toxic heavy metal Cd. Here, we will determine the comprehensive substrate profile and metal-ion selectivity of DMT1 using our oocyte assays. Next, we will use the Belgrade anemic rat (which bears a mutation in DMT1) to examine the physiological significance of DMT1 in the absorption of each of the metals it is capable of transporting. Finally, we will identify metal-coordination sites in DMT1. Studying DMT1 in this way will lead to a better understanding of the mechanisms of nonheme iron absorption, the conditions required for efficient absorption, and the role of DMT1 in the metabolism of other transition metals. The results of this work will help drive development of new strategies for improving metal nutrition, or for treating iron overload and heavy-metal intoxication. Public Health Relevance: Iron deficiency leads to anemia and the hereditary disease hemochromatosis leads to toxic iron overload, illustrating the importance of balancing intestinal iron absorption. The gateway for dietary iron to enter the cells lining the intestine is a protein called DMT1, which can also transport the toxic metal cadmium. In this project we will study iron and cadmium transport via DMT1 at the molecular level to drive development of new strategies to improve iron nutrition and prevent the toxic effects of cadmium or iron overload.
描述(由申请人提供):DMT1是一种广泛表达的铁转运蛋白,对于充分的肠道吸收铁和用于生产血红蛋白的红细胞前体中铁的运输是必不可少的。DMT1罕见的突变会导致严重的小细胞性贫血。相反,遗传性血色素沉着症是高加索人最常见的遗传性疾病,DMT1的失调会导致重要器官中的毒性铁超载。由于它的排泄没有调节机制,铁的动态平衡是通过调节肠道铁的吸收来实现的。DMT1是铁吸收的门户--它是非血红素铁的主要或唯一的顶端转运体--使其成为本提案的焦点。铁缺乏影响多达10%的美国人口,是世界上最普遍的微量营养素缺乏症。对这项建议很重要的是,缺铁是镉中毒的一个严重危险因素,这表明镉和铁具有共同的吸收机制。该方案的研究前提是DMT1是一种复杂的H+偶联和电压依赖的亚铁(Fe2+)转运体,肠道刷状缘膜上的酸性小气候提供了为DMT1提供能量的质子动力。我们将探索H+偶联的分子基础,并利用电压钳、放射性示踪剂(55Fe)分析和荧光方法在表达野生型DMT1或突变蛋白的非洲爪哇卵母细胞中探索通过DMT1的显著解偶联H+流(滑移)的生理作用。接下来,我们将使用放射性示踪剂和荧光方法研究小鼠肠道中铁的运输;使用肠道Na+/H+交换的特定抑制剂(NHE3和NHE2)和缺乏NHE3、NHE2或胃H+/K+-ATPase的突变小鼠模型,将使我们能够评估胃酸和肠道刷状交界处的酸性小气候在提供H+以驱动DMT1介导的Fe2+运输中的作用。第二个前提是,DMT1不仅用于吸收铁,还用于吸收某些其他必需金属,如钴和锰(以及微量金属,如镍和钒),但这种混杂也使其成为有毒重金属镉的主要进入途径。在这里,我们将使用我们的卵母细胞分析来确定DMT1的全面底物分布和金属离子选择性。接下来,我们将使用贝尔格莱德贫血大鼠(它携带DMT1突变)来检查DMT1在吸收它能够运输的每一种金属方面的生理意义。最后,我们将确定DMT1中的金属配位位点。用这种方法研究DMT1将有助于更好地理解非血红素铁吸收的机制,有效吸收所需的条件,以及DMT1在其他过渡金属代谢中的作用。这项工作的结果将有助于推动改善金属营养或治疗铁超载和重金属中毒的新策略的开发。 公共卫生相关性:缺铁导致贫血,遗传性疾病血色沉着导致毒性铁超载,说明平衡肠道铁吸收的重要性。膳食铁进入肠道细胞的通道是一种名为DMT1的蛋白质,它也可以运输有毒的金属镉。在这个项目中,我们将在分子水平上研究铁和镉通过DMT1的运输,以推动新策略的发展,以改善铁的营养,防止镉或铁超载的毒性效应。

项目成果

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Bryan Mackenzie其他文献

Bryan Mackenzie的其他文献

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{{ truncateString('Bryan Mackenzie', 18)}}的其他基金

Divalent metal-ion transporter DMT1 and its role in intestinal metal-ion uptake
二价金属离子转运蛋白 DMT1 及其在肠道金属离子摄取中的作用
  • 批准号:
    8063039
  • 财政年份:
    2008
  • 资助金额:
    $ 3.58万
  • 项目类别:
Divalent metal-ion transporter DMT1 and its role in intestinal metal-ion uptake
二价金属离子转运蛋白 DMT1 及其在肠道金属离子摄取中的作用
  • 批准号:
    8237051
  • 财政年份:
    2008
  • 资助金额:
    $ 3.58万
  • 项目类别:
Divalent metal-ion transporter DMT1 and its role in intestinal metal-ion uptake
二价金属离子转运蛋白 DMT1 及其在肠道金属离子摄取中的作用
  • 批准号:
    7570670
  • 财政年份:
    2008
  • 资助金额:
    $ 3.58万
  • 项目类别:
Divalent metal-ion transporter DMT1 and its role in intestinal metal-ion uptake
二价金属离子转运蛋白 DMT1 及其在肠道金属离子摄取中的作用
  • 批准号:
    7787496
  • 财政年份:
    2008
  • 资助金额:
    $ 3.58万
  • 项目类别:

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