IRON TRANSPORT IN MAMMALIAN CELLS

铁代谢紊乱是最常见、也是最不为人所知的人类疾病之一。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吸收研究到转移的分子动力学研究，并采用从蛋白质工程到激光光谱学的技术。组成项目的主要重点是： 项目 1：细胞从转铁摄取铁的机制重点关注细胞通过不依赖于受体的途径从转铁蛋白获取铁，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）以及转铁蛋白结合铁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域探究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：SFT 对转铁蛋白和非转铁蛋白结合 F 的摄取旨在研究 P.I. 新发现的 SFT（刺激铁转运）对细胞铁摄取的调节，该项目与本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长期已知但知之甚少的联系，特别是铜依赖性亚铁氧化酶在铁转运中的作用。项目5：转铁蛋白的结构、功能和动力学研究转铁蛋白吸收和释放铁和其他金属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.