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: 8728225
• 负责人: Robert E Fleming
• 金额: $ 40.93万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728225
• 关键词: Affect; Anemia; Apoptosis; Attenuated; Binding; Clinical; Complex; Data; Deposition; Development; Dietary Iron; Disease; Dysmyelopoietic Syndromes; Erythroid; Erythropoiesis; Evaluation; Functional disorder; Heart; Hemochromatosis; Hemoglobin; Hepatic; Hepatocyte; Hormones; In Transferrin; Inborn Genetic Diseases; Individual; Injury; Iron; Iron Overload; Kinetics; Knock-out; Lead; Mediating; Modeling; Molecular; Morbidity - disease rate; Mouse Cell Line; Mus; Participant; Patients; Physiology; Plasma; Production; Property; Recycling; Regulation; Relative (related person); Role; Serum; Sickle Cell Anemia; Signal Transduction; Signaling Molecule; Splenomegaly; Staging; System; Testing; Thalassemia; Therapeutic; Tissues; Transferrin; Transferrin Receptor; Transfusion; absorption; base; diferric transferrin; dyserythropoietic anemia; erythroid differentiation; hepcidin; human TFRC protein; human disease; insight; iron metabolism; liver injury; macrophage; mortality; novel; novel therapeutics; pre-clinical; response; transferrin receptor 2; uptake

DESCRIPTION (provided by applicant): Iron overload is the principal cause of morbidity and mortality in anemias characterized by ineffective erythropoiesis, including ¿-thalassemias. In recent years, unprecedented progress in elucidating the molecular participants in iron metabolism has provided novel potential therapeutic approaches. In particular, the hepatic hormone hepcidin has been identified as a central regulator of iron absorption and distribution. The iron loading dyserythropoietic anemias are characterized by inappropriately low hepcidin levels despite iron loading. We have shown that exogenous transferrin ameliorates anemia, reduces circulating non-transferrin bound iron, and increases hepcidin expression in ¿-thalassemic mice, suggesting that transferrin is an important regulator of the cross-talk between erythropoiesis and iron metabolism. We propose to further explore mechanisms by which transferrin regulates hepcidin expression via its roles in the erythron and in the hepatocyte. Recently HFE and transferrin receptor 2 (TfR2), molecules known to participate in the hepatic regulation of hepcidin, have been found to be also functionally important in erythroid precursors. However, the effects of transferrin on erythroid HFE and TfR2 expression and signaling, and how HFE and TfR2 modulate erythropoiesis remain largely uncharacterized. Preliminary data demonstrate that exogenous transferrin (Tf) increases the relative concentration of monoferric Tf and decreases iron entry into erythroid precursors. We propose a model in which increased monoferric transferrin alters HFE, TfR1, and TfR2 mediated iron uptake and signaling, in erythroid precursors and in hepatocytes. To test this model, we propose three specific aims: 1. Compare the binding kinetics and uptake of iron from monoferric and diferric transferrin via TfR1 and TfR2 in the presence or absence of HFE. 2. Examine the effects of changes in transferrin concentration on erythroid precursors during effective and ineffective erythropoiesis. 3. Examine the effects of changes in transferrin concentration on hepatocellular hepcidin expression. Genetically modified mice and cell lines will serve as experimental systems to test the following hypotheses: HFE modulates the ability of monoferric transferrin to compete with diferric transferrin for binding to transferrin receptors (Aim 1). Tf binding affects erythroid differentiaton through modulation of HFE, TfR1, and TfR2 expression and signaling (Aim 2A). Tf regulates erythropoiesis via TfR1/HFE-mediated changes in erythroid cellular iron status and mouse ferrokinetics (Aim 2B). Monoferric-Tf modulates hepcidin expression in hepatocytes via signaling through TfR2 (Aim 3A). Increased Tf mitigates the effects of non-transferrin bound iron on hepcidin expression (Aim 3B). Administration of Tf attenuates a hepcidin down-regulatory factor in serum of mice with dyserythropoiesis (Aim 3C). These studies will clarify the physiology of the cross-talk between iron metabolism and erythropoiesis, and potentially provide the basis for the development of novel therapeutic alternatives for patients with diseases of concurrent anemia and iron overload.

描述（由申请方提供）：铁超负荷是以无效红细胞生成为特征的贫血（包括地中海贫血）的发病率和死亡率的主要原因。近年来，在阐明铁代谢的分子参与者方面取得了前所未有的进展，提供了新的潜在治疗方法。特别地，肝激素铁调素已被鉴定为铁吸收和分布的中心调节剂。铁负荷红细胞生成障碍性贫血的特征在于尽管铁负荷，铁调素水平仍不适当地低。我们已经表明，外源性转铁蛋白改善贫血，减少循环非转铁蛋白结合铁，并增加铁调素表达在地中海贫血小鼠，这表明转铁蛋白是一个重要的调节红细胞生成和铁代谢之间的串扰。我们建议进一步探索转铁蛋白通过其在肝细胞和肝细胞中的作用调节铁调素表达的机制。最近，HFE和转铁蛋白受体2（TfR 2），已知参与肝调节铁调素的分子，已被发现在红系前体中也具有重要的功能。然而，转铁蛋白对红系HFE和TfR 2表达和信号传导的影响，以及HFE和TfR 2如何调节红细胞生成仍然在很大程度上未被表征。初步数据表明，外源性转铁蛋白（Tf）的单铁Tf的相对浓度增加，并减少铁进入红系前体。我们提出了一个模型，其中增加单铁转铁蛋白改变HFE，TfR 1和TfR 2介导的铁的摄取和信号，在红细胞前体和肝细胞。为了检验这个模型，我们提出了三个具体目标：1。比较在存在或不存在HFE的情况下，通过TfR 1和TfR 2从单铁和二铁转铁蛋白中吸收铁的结合动力学和吸收。2.检查在有效和无效红细胞生成过程中转铁蛋白浓度变化对红系前体细胞的影响。3.检查转铁蛋白浓度变化对肝细胞铁调素表达的影响。转基因小鼠和细胞系将作为实验系统来测试以下假设：HFE调节单铁转铁蛋白与二铁转铁蛋白竞争结合转铁蛋白受体的能力（目的1）。Tf结合通过调节HFE、TfR 1和TfR 2表达和信号传导影响红系分化（目的2A）。Tf通过TfR 1/HFE介导的红系细胞铁状态和小鼠铁动力学变化调节红细胞生成（Aim 2B）。单铁-Tf通过TfR 2信号传导调节肝细胞中的铁调素表达（Aim 3A）。增加的Tf减轻了非转铁蛋白结合的铁对铁调素表达的影响（Aim 3B）。转铁蛋白的管理减弱铁调素下调因子在血清中的红细胞生成异常（目的3C）的小鼠。这些研究将阐明铁代谢和红细胞生成之间的相互作用的生理学，并可能为并发贫血和铁超负荷疾病的患者开发新的治疗替代方案提供基础。