Regulatory Role of Transferrin in Erythropoiesis and Iron Metabolism

摘要 我们建议的总体目标是研究铁代谢和红细胞生成活性是如何相互关联的， 以及其中一种的失调对另一种的病理生理学有贡献的机制。两人的角色 转铁蛋白受体在这些过程中是清楚的；然而，关于信号特性的了解很少。 他们的配体，转铁蛋白。长期以来，转铁蛋白一直被认为通过与受体结合来传递铁，转铁蛋白 受体1(TFR1)，存在于所有细胞上。最近，一种同源受体，TFR2，几乎被鉴定出来 仅在骨髓和肝脏细胞上，它作为铁供应的传感器和 红血球生成。我们产生了两个铁结合位点(N和C)中的一个或另一个发生突变的小鼠， 而且不能吸收铁。我们观察到在铁代谢的调节和 这些小鼠之间的红细胞生成，表明转铁蛋白的每个叶都有不同的信号 属性。在这项建议中，我们提供了新的数据，表明在小鼠模型中有显著的改善 当铁与N叶而不是C叶特异结合时，人类疾病β-地中海贫血。我们现在把我们的 注意两个转铁蛋白叶发挥作用的机制。我们还探索了潜在的 增加N叶转铁蛋白作为无效红细胞生成的潜在治疗方法。

ABSTRACT The overall goal of our proposal is to investigate how iron metabolism and erythropoietic activity are interrelated, and the mechanisms whereby dysregulation in one contributes to pathophysiology in the other. Roles for the two transferrin receptors in these processes is clear; however, little is understood regarding the signaling properties of their ligand, transferrin. Transferrin has long been recognized to deliver iron by binding to receptor, transferrin receptor 1 (TFR1), present on all cells. More recently, a homologous receptor, TFR2, has been identified almost exclusively on bone marrow and liver cells where it serves as a sensor of iron supply and a regulator of erythropoiesis. We generated mice in which one or other of the two iron binding sites (N and C) was mutated, and unable to take in iron. We observed striking differences in the regulation of iron metabolism and erythropoiesis between these mice, demonstrating that each of lobes of transferrin has distinct signaling properties. We present in this proposal new data demonstrating significant improvement in a mouse model of the human disease β-thalassemia when iron is specifically bound to the N but not C lobe. We now devote our attention to the mechanisms by which the two transferrin lobes exert their effects. We also explore the potential of increasing N lobe TF as a potential treatment approach in ineffective erythropoiesis.