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Hephaestin: A Copper Protein Involved in Iron Metabolism

Hephaestin：一种参与铁代谢的铜蛋白

基本信息

批准号：
7060932
负责人：
CHRISTOPHER D VULPE
金额：
$ 28.76万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2008-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Iron deficiency adversely affects over one-third of the world's population. Conversely, iron overload disease hemochromatosis is one of the commonest genetic defects in man. In order to maintain a balance between deficiency and toxicity, multiple regulatory systems exist to optimize iron levels in the human body. The absorption of iron by the intestine is central to this regulation because no physiologic means exists to excrete excess iron. Our long-term goal is to understand how changes the body communicates its iron needs to the intestine and how the intestine controls iron absorption into the body. We previously identified, hephaestin, which oxidizes iron from ferrous to ferric iron and is required for moving iron from gut cells into the body. We are studying its function and role in intestinal iron transport and whole body iron homeostasis. Remarkable changes occur in response to iron deficiency, the expression of iron transport proteins increase and some proteins including hephaestin move from intracellular locations to the cell surface to facilitate iron transport. In systemic iron deficiency, the intestinal enterocyte is poised for maximal absorption but is also capable of buffering the uptake of iron in case of potentially toxic dietary levels. In this study, we will ask three questions. 1) How is hephaestin regulated in response to local and systemic iron status? We will independently manipulate dietary and systemic iron status in mice to define the dietary versus systemic effects on hephaestin and other iron transport proteins. We will use cell culture studies to define the regulatory mechanisms. 2) What regulates the movement of hephaestin? We will define the dietary conditions for movement and the rate at which it occurs. We will use a cell culture system to identify the parts of hephaestin that are necessary for movement. We will try to identify the proteins that play a role in the movement of hephaestin. Finally, we will ask 3) how iron oxidation by hephaestin facilitates iron transport ? Hephaestin could be directly required in order to release iron from the iron transporter or alternatively it could create a gradient of ferrous iron which would drive the transport of iron. Iron transport assays using a buffer system that allows us to very tightly control the amount of ferrous and ferric iron will allow us to distinguish between these possibilities.

描述(申请人提供)：铁缺乏对世界上超过三分之一的人口造成不利影响。相反，铁超负荷疾病血色沉着症是人类最常见的遗传缺陷之一。为了在缺乏和毒性之间保持平衡，存在着多种调节系统来优化人体内的铁水平。肠道对铁的吸收是这种调节的中心，因为不存在排泄多余铁的生理手段。我们的长期目标是了解身体如何向肠道传递其铁需求的变化，以及肠道如何控制体内的铁吸收。我们之前发现了一种名为Hephaestin的蛋白质，它能将铁从亚铁氧化为铁，是将肠道细胞中的铁转移到体内所必需的。我们正在研究它在肠道铁转运和全身铁稳态中的功能和作用。缺铁后细胞发生显著变化，铁转运蛋白的表达增加，一些蛋白质包括Hephaestin从细胞内位置移动到细胞表面，促进铁的运输。在全身性铁缺乏的情况下，肠道肠道细胞准备最大限度地吸收，但也有能力在潜在有毒饮食水平的情况下缓冲铁的吸收。在这项研究中，我们将提出三个问题。1)在局部和全身性铁状态下，Hephestn是如何调节的？我们将独立操作小鼠的饮食和全身铁状况，以确定饮食和全身对肝素和其他铁运输蛋白的影响。我们将使用细胞培养研究来确定调控机制。2)是什么调节了海星蛋白的运动？我们将定义运动的饮食条件和运动发生的速度。我们将使用细胞培养系统来鉴定运动所必需的Hephestn部分。我们将尝试确定在肝素运动中起作用的蛋白质。最后，我们将问3)由海星蛋白氧化的铁是如何促进铁的运输的？为了从铁转运体中释放铁，可以直接需要赫菲斯汀，或者，它可以产生亚铁的梯度，从而驱动铁的运输。铁转运分析使用缓冲系统，使我们能够非常严格地控制亚铁和三价铁的数量，这将使我们能够区分这些可能性。