IRON TRANSPORT IN MAMMALIAN CELLS

铁代谢紊乱是人类疾病中最常见、也最不为人所知的疾病之一。每个拟议的研究项目都涉及哺乳动物细胞中铁代谢的一个或多个方面。研究计划的范围从细胞铁摄取的研究到转移的分子动力学，并使用从蛋白质工程到激光光谱分析的技术。组成项目的主要内容是：项目1：从转铁蛋白中摄取细胞铁的机制侧重于通过不依赖受体的途径从转铁蛋白获得细胞铁，还包括转铁蛋白-转铁蛋白受体相互作用的研究(与项目2合作)以及转铁蛋白与铁结合与蛋白质构象变化的关系(与项目5合作)。项目2：转铁蛋白受体的功能结构域探讨转铁蛋白受体与转铁蛋白的相互作用(与项目1合作)以及血色素沉着症基因产物与转铁蛋白受体的功能相互作用。项目3：通过SFT摄取转铁蛋白和非转铁蛋白结合的F试图研究PI.新发现的SFT(促进铁运输)对细胞铁摄取的调节，该项目与该提案的所有其他项目相互作用。项目4：铜在铁代谢中的作用研究了哺乳动物细胞中铁和铜代谢之间早已知晓但知之甚少的联系，特别是铜依赖的铁氧化物酶在铁运输中的作用。项目5：转铁蛋白的结构、功能和动力学研究转铁蛋白对铁和其他金属的吸收和释放受生理因素调节的分子机制。

Derangements of iron metabolism are among the most common, and least understood, of human ills. Each of the proposed research projects is concerned with one or more aspects of iron metabolism in mammalian cells. Research plans range in score from studies of cellular iron uptake to molecular dynamics of transferring and employ technologies spanning protein engineering to laser spectroscopy. Major thrusts of the component projects are: Project 1: Mechanisms of cellular iron uptake from transferring focuses on cellular iron acquisition from transferrin by receptor-independent routes, and also includes studies of transferrin-transferrin receptor interactions (in collaboration with Project 2) and relationship of iron binding by transferrin to conformational changes in the protein (in collaboration with Project 5). Project 2: Functional domains of the transferring receptor inquires into the interactions of transferrin receptor with transferrin (in collaboration with Project 1) and functional interactions of the hemochromatosis gene product and the transferrin receptor. Project 3: Uptake of transferrin & non-transferrin bound F by SFT seeks to study the regulation of cellular iron uptake by SFT (stimulated of iron transport) newly discovered by the P.I., in a project interacting with all other projects of this proposal. Project 4: Role of copper in iron metabolism examines the long-known but little understood connections between iron and copper metabolism in mammalian cells, and in particular the role of copper dependent ferroxidases in iron transport. Project 5: Structure, function and dynamics in transferrin investigates the molecular mechanisms through which the uptake and release of iron and other metals by transferrin are modulated by physiological factors.