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导致另一种的病理生理学的机制。两人的角色 转铁蛋白受体在这些过程中是清楚的，但是，很少有人了解有关的信号性质 它们的配体转铁蛋白长期以来，人们一直认为转铁蛋白通过与受体转铁蛋白结合来递送铁 受体1（TFR 1），存在于所有细胞上。最近，同源受体TFR 2几乎已经被鉴定为 专门作用于骨髓和肝细胞，作为铁供应的传感器和铁代谢的调节剂。 红细胞生成我们产生了两个铁结合位点（N和C）中的一个或另一个突变的小鼠， 也不能吸收铁。我们观察到在铁代谢调节方面的显著差异， 这些小鼠之间的红细胞生成，证明转铁蛋白的每个叶具有不同的信号传导 特性.我们在该提案中提出了新的数据，证明在小鼠模型中的显着改善， 当铁特异性地结合到N叶而不是C叶时的人类疾病β-地中海贫血。我们现在致力于 注意两个转铁蛋白叶发挥其作用的机制。我们还探索了 增加N叶TF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.