Regulatory Role of Transferrin in Erythropoiesis and Iron Metabolism

转铁蛋白在红细胞生成和铁代谢中的调节作用

• 批准号: 10446880
• 负责人: Robert E Fleming
• 金额: $ 73.68万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-28 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446880
• 关键词: Affect; Affinity; Anemia; Attention; BMP6 gene; Basic Science; Binding; Binding Sites; Biological Models; Blood Circulation; Bone Marrow; Cell Culture Techniques; Cells; Clinical Sciences; Collaborations; Data; Disease; Disease model; EPOR gene; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Exhibits; Functional disorder; Goals; Health; Hematological Disease; Hepatocyte; Hereditary hemochromatosis; Homeostasis; In Transferrin; Iron; Knockout Mice; Ligands; Liver; Lobe; Mediating; Molecular; Mus; Mutate; Participant; Patients; Physiological; Plasma; Plasma Proteins; Process; Production; Property; Publishing; Receptor Signaling; Regulation; Reporting; Repression; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; System; TFR2 gene; TFRC gene; Testing; Transferrin; age group; base; beta Thalassemia; blood treatment; cell type; diferric transferrin; falls; hepcidin; human disease; human model; improved; insight; iron metabolism; knock-down; lipid nanoparticle; mRNA delivery; meetings; mouse model; novel; novel therapeutics; receptor; receptor mediated endocytosis; sensor; therapeutic target; uptake

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.

抽象的 我们提案的总体目标是研究铁代谢和红细胞生成活性如何相互关联， 以及一种机制失调导致另一种病理生理学的机制。两人的角色 转铁蛋白受体在这些过程中的作用是明确的；然而，人们对信号特性知之甚少 他们的配体，转铁蛋白。长期以来，转铁蛋白一直被认为可以通过与受体转铁蛋白结合来输送铁。 受体 1 (TFR1)，存在于所有细胞上。最近，几乎已鉴定出同源受体 TFR2 专门作用于骨髓和肝细胞，作为铁供应的传感器和铁供应的调节器 红细胞生成。我们培育出两个铁结合位点（N 和 C）之一或另一个发生突变的小鼠， 并且无法吸收铁质。我们观察到铁代谢调节和 这些小鼠之间的红细胞生成，证明转铁蛋白的每个叶都有不同的信号传导 特性。我们在这项提案中提出了新数据，证明小鼠模型的显着改进 当铁与 N 叶特异性结合但不与 C 叶结合时，就会出现人类疾病 β 地中海贫血。我们现在奉献我们的 注意两个转铁蛋白叶发挥作用的机制。我们还探索潜力 增加 N 叶 TF 作为无效红细胞生成的潜在治疗方法。