ZIP Proteins and Iron Metabolism

描述(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。在美国，近20%的育龄妇女缺铁，铁超载越来越被认为是一个公共卫生问题。尽管这些疾病的患病率和对健康的不利影响，关于铁运输的分子机制仍然存在许多问题。这项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加深我们对铁稳态的理解。ZIP14最初被鉴定为锌转运蛋白，但最近的研究表明，它也可以转运铁。它在肝脏中的丰富表达提示它在铁超载时的肝脏铁沉积中起作用，它在肝脏中的表达通过放血和缺铁而上调，提示它在铁摄取中起作用。这项拟议研究的第一个目标是更全面地研究Zip14的铁依赖调控。将使大鼠和小鼠缺铁、铁正常或铁负荷，并将检查各种组织中Zip14的表达和细胞定位。在第二个目标中，将利用细胞培养研究来确定Zip14的亚细胞定位，并研究其在转铁蛋白结合铁吸收中的作用，转铁蛋白结合铁是细胞吸收铁的最常见途径。为了更好地定义Zip14在体内的作用，第三个目的将表征Zip14基因敲除小鼠的铁状态。组织特异性基因敲除小鼠将被用来检验Zip14在肝脏吸收非转铁蛋白结合的铁和肠道吸收膳食铁方面发挥作用的假设。在第四个目标中，将通过过量表达蛋白质和测量放射性标记铁的摄取来系统地评估所有哺乳动物ZIP蛋白的铁运输活性。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实验中获得的信息，可能还有其他ZIP蛋白，将与铁代谢障碍相关。其他能够转运铁或受铁状态调控的ZIP蛋白的发现，将增强我们对铁稳态和金属离子转运的基本了解。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。尽管这些疾病的患病率和对健康的不利影响，关于铁运输的分子机制仍然存在许多问题。这项建议中描述的研究将增强我们对铁运输的了解，这最终将有助于确定治疗铁代谢障碍的治疗靶点。与公共卫生相关：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。尽管这些疾病的患病率和对健康的不利影响，关于铁运输的分子机制仍然存在许多问题。这项建议中描述的研究将增强我们对铁运输的了解，这最终将有助于确定治疗铁代谢障碍的治疗靶点。

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.