ZIP Proteins and Iron Metabolism

ZIP 蛋白质和铁代谢

• 批准号: 7884238
• 负责人: Mitchell D Knutson
• 金额: $ 27.47万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884238
• 关键词: Affect; Age; Applications Grants; Applied Genetics; Bacteria; Binding; Biological Process; Cell Culture Techniques; Cell membrane; Cells; Collaborations; DNA; Data; Dependence; Deposition; Diet; Dietary Iron; Dioxygen; Disease; Drug or chemical Tissue Distribution; Electron Transport; Family; Family member; Genes; Health; Hemochromatosis; Hepatic; Homeostasis; Human; Human body; Individual; Integral Membrane Protein; Intestines; Ions; Iron; Iron Metabolism Disorders; Iron Overload; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Lipids; Liver; Measures; Mediating; Metabolism; Metals; Molecular; Morbidity - disease rate; Mus; Mutate; Nature; Nutrient; Organism; Oxidation-Reduction; Pathway interactions; Physiological; Play; Prevalence; Property; Proteins; Public Health; Radiolabeled; Rattus; Reaction; Reactive Oxygen Species; Regulation; Relative (related person); Research; Role; Techniques; Testing; Tissues; Transfection; Transferrin; Transition Elements; Up-Regulation; Venous blood sampling; Woman; Work; ZIP protein; Zinc; base; cell type; hazard; in vivo; iron metabolism; member; mortality; novel; overexpression; oxidation; protein transport; radiotracer; reproductive; research study; therapeutic target; trafficking; uptake; zinc-binding protein

DESCRIPTION (provided by applicant): Disturbances of iron metabolism increase morbidity and mortality and are among the most common disorders affecting humans. Nearly 20% of women of reproductive age in the US are iron deficient, and iron overload is increasingly being recognized as a public health concern. Despite the prevalence and adverse health effects associated with these disorders, many questions remain regarding the molecular mechanisms of iron transport. The long-term objective of the proposed work is to enhance our understanding of iron homeostasis by investigating the regulation and function of ZIP14 and other ZIP family members. ZIP14 was first identified as a zinc transporter, but recent studies indicate that it transports iron as well. Its abundant expression in the liver suggests that it plays a role in hepatic iron deposition during iron overload, and its upregulation in liver by phlebotomy and iron deficiency suggests that it functions in iron uptake. The first aim of the proposed research will be to investigate more completely the iron-dependent regulation of Zip14. Rats and mice will be made iron deficient, iron normal, or iron loaded, and a variety of tissues will be examined for Zip14 expression and cellular localization. In the second aim, cell culture studies will be used to identify the subcellular localization of Zip14 and to investigate its role in the uptake of transferrin-bound iron, the most common pathway of iron uptake by cells. To better define the in vivo role of Zip14, the third aim will characterize the iron status of Zip14 knockout mice. Tissue-specific knockout mice will be used to test the hypotheses that Zip14 plays a role in the uptake of non-transferrin-bound iron by the liver and dietary iron by the intestine. In the fourth aim, the iron transport activity of all mammalian ZIP proteins will be systematically assessed by overexpressing the proteins and measuring the uptake of radiolabeled iron. We will also examine the effect of in vivo iron status on the expression of all 14 ZIP family members. We anticipate that information derived from the experiments with Zip14, and perhaps other ZIP proteins, will be relevant to disorders of iron metabolism. Identification of other ZIP proteins that are capable of transporting iron or are regulated by iron status will enhance our basic understanding of iron homeostasis and metal ion trafficking in general. Disturbances of iron metabolism increase morbidity and mortality and are among the most common disorders affecting humans. Despite the prevalence and adverse health effects associated with these disorders, many questions remain regarding the molecular mechanisms of iron transport. The research described in this proposal will enhance our knowledge of iron transport, which will ultimately help to identify therapeutic targets for treating disorders of iron metabolism. PUBLIC HEALTH RELEVANCE: Disturbances of iron metabolism increase morbidity and mortality and are among the most common disorders affecting humans. Despite the prevalence and adverse health effects associated with these disorders, many questions remain regarding the molecular mechanisms of iron transport. The research described in this proposal will enhance our knowledge of iron transport, which will ultimately help to identify therapeutic targets for treating disorders of iron metabolism.

描述（由申请人提供）：铁代谢紊乱会增加发病率和死亡率，是影响人类的最常见疾病之一。美国近 20% 的育龄妇女缺铁，铁超载日益被视为一个公共健康问题。尽管这些疾病普遍存在并且对健康产生不利影响，但关于铁转运的分子机制仍然存在许多问题。拟议工作的长期目标是通过研究 ZIP14 和其他 ZIP 家族成员的调节和功能来增强我们对铁稳态的理解。 ZIP14 最初被确定为锌转运蛋白，但最近的研究表明它也转运铁。它在肝脏中的丰富表达表明它在铁超载期间在肝脏铁沉积中发挥作用，而放血和缺铁时它在肝脏中的上调表明它在铁吸收中发挥作用。本研究的首要目标是更全面地研究 Zip14 的铁依赖性调节。大鼠和小鼠将被制成缺铁、正常铁或铁负荷状态，并检查各种组织的 Zip14 表达和细胞定位。第二个目标是，细胞培养研究将用于鉴定 Zip14 的亚细胞定位，并研究其在转铁蛋白结合铁的摄取中的作用，转铁蛋白结合的铁是细胞摄取铁的最常见途径。为了更好地确定 Zip14 的体内作用，第三个目标将表征 Zip14 敲除小鼠的铁状态。组织特异性敲除小鼠将用于测试 Zip14 在肝脏吸收非转铁蛋白结合铁和肠道吸收膳食铁中发挥作用的假设。第四个目标是通过过表达蛋白质并测量放射性标记铁的吸收来系统评估所有哺乳动物 ZIP 蛋白的铁转运活性。我们还将研究体内铁状态对所有 14 个 ZIP 家族成员表达的影响。我们预计从 Zip14 以及其他 ZIP 蛋白实验中获得的信息将与铁代谢紊乱相关。鉴定其他能够运输铁或受铁状态调节的 ZIP 蛋白将增强我们对铁稳态和金属离子运输的基本了解。铁代谢紊乱会增加发病率和死亡率，是影响人类的最常见疾病之一。尽管这些疾病普遍存在并且对健康产生不利影响，但关于铁转运的分子机制仍然存在许多问题。该提案中描述的研究将增强我们对铁转运的了解，这最终将有助于确定治疗铁代谢紊乱的治疗靶点。公共卫生相关性：铁代谢紊乱会增加发病率和死亡率，是影响人类的最常见疾病之一。尽管这些疾病普遍存在并且对健康产生不利影响，但关于铁转运的分子机制仍然存在许多问题。该提案中描述的研究将增强我们对铁转运的了解，这最终将有助于确定治疗铁代谢紊乱的治疗靶点。