Regulatory role of iron transport in stress and ineffective erythropoiesis

铁转运在应激和无效红细胞生成中的调节作用

• 批准号: 9763567
• 负责人: Yelena Ginzburg
• 金额: $ 35.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763567
• 关键词: Anemia; Apoptosis; Binding; Clinical Data; Clinical Trials; Data; Development; Dietary Iron; Disease; Dysmyelopoietic Syndromes; Erythroid; Erythropoiesis; Exhibits; Fetal Liver; Functional disorder; Goals; Health; Hematology; Heme; Hemoglobin; Hepatocyte; Hormones; In Transferrin; In Vitro; Investigation; Iron; Iron Chelating Agents; Iron Overload; Knowledge; Laboratories; Liver; Membrane; Modeling; Molecular; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Protein Export Pathway; Recovery; Recycling; Regulation; Regulatory Pathway; Role; Sickle Cell Anemia; Stress; TFRC gene; Transferrin; Wild Type Mouse; beta Thalassemia; clinical development; erythroid differentiation; experimental study; hepcidin; human disease; improved; inhibitor/antagonist; insight; interest; iron absorption; iron deficiency; iron metabolism; mouse transferrin receptor 1; novel; novel therapeutics; pre-clinical; response; senescence; trafficking; uptake

ABSTRACT Our laboratory aims to understand in detail how iron transport influences erythropoiesis and how the erythron communicates iron requirements to the liver. Iron for erythropoiesis is transported by the iron transporter transferrin (Tf) and iron uptake by erythroid precursors requires Tf-Fe binding to transferrin receptor 1 (TfR1). In turn, erythroid precursors regulate iron metabolism in part by secreting factors, such as the recently identified erythroferrone (ERFE), which suppresses the hormone hepcidin, a key inhibitor of dietary iron absorption, recycling from senescent RBCs, and mobilization from iron stores. ERFE is increased in models of both stress (i.e. phlebotomized wild type mice) and ineffective erythropoiesis (i.e. β-thalassemic mice). Furthermore, erythroid precursors express iron and heme export proteins, the function of which remains unclear. We have shown that exogenous iron-free Tf ameliorates ineffective erythropoiesis in β-thalassemic mice (Li et al., Nat Med, 2010), resulting in decreased ERFE, increased hepcidin, and relative systemic iron deficiency. We hypothesize that the beneficial effect of exogenous Tf in β-thalassemic mice is a consequence of more than frank iron restriction. Specifically, our preliminary data suggests that Tf functions via an effect on TfR1, influencing enucleation through effects on membrane TfR1 as well as iron metabolism indirectly by decreasing Erfe expression and directly by decreasing soluble TfR1. Furthermore, surprisingly, hepcidin expression is not suppressed in TfR1+/- mice, despite relative iron deficient erythropoiesis and increased ERFE expression. Thus, we hypothesize that the beneficial effect of exogenous Tf on ineffective erythropoiesis is a consequence of reduced TfR1 expression or altered TfR1 trafficking from erythroid precursors. Here we propose to define in detail how changes in Tf concentration, iron uptake and efflux, and TfR1 trafficking in the erythron influence erythropoiesis and erythroid hepcidin regulation. In the proposed three specific aims, we will 1) assess the regulatory role of Tf and TfR1 in iron restricted and ineffective erythropoiesis; 2) examine the significance of TfR1 as a regulator of hepcidin; and 3) elucidate the effect of Tf and TfR1 on iron efflux from erythroid precursors and hepatocytes. Iron transport for erythropoiesis and erythroid regulation of iron metabolism are central tenets in recovery during stress erythropoiesis and are dysregulated in ineffective erythropoiesis. Thus, successful completion of these studies elucidating the role of Tf and TfR1 in these pathways is of great interest to the hematology field, provides insight into the pathophysiology of human diseases in which erythropoiesis is disturbed, extends current knowledge in iron metabolism, and adds new paradigms for further exploring erythroid regulation of hepcidin. Lastly, the successful completion of these studies interrogating mechanisms involved in stress and ineffective erythropoiesis (responsive to PAS-13-031) will facilitate the development of clinical trials using Tf in patients with β-thalassemia and possibly other iron-loading anemias.

抽象的 我们的实验室旨在详细了解铁运输如何影响红细胞生成以及如何影响 Erythron向肝脏传达铁的要求。铁的铁由铁运输 红细胞前体的转运蛋白转运蛋白（TF）和铁吸收需要TF-FE与转铁蛋白受体结合 1（TFR1）。反过来，红斑前体通过分泌因素（例如 最近确定的促红细胞铁酮（ERFE），它抑制了马酮肝素，这是饮食的关键抑制剂 铁的非洲侵蚀，感官RBC的回收以及铁存储的动员。 Erfe增加了 两种压力（即静脉植物野生型小鼠）和无效的红细胞生成模型 小鼠）。此外，红细胞前体表达铁和血红素出口蛋白，其功能仍然存在 不清楚。我们已经表明，无铁的TF可以改善β-甲库中无效的红细胞生成 小鼠（Li等，Nat Med，2010年），导致ERFE减少，肝素增加和相对全身铁 不足。我们假设外源性TF在β-丘脑血症小鼠中的有益作用是 后果不仅仅是弗兰克铁的限制。具体而言，我们的初步数据表明TF 通过对TFR1的影响的功能，通过对膜TFR1和铁的影响影响启用 通过降低ERFE表达并直接减少固体TFR1间接代谢。此外， 令人惊讶的是，在TFR1 +/-小鼠，dospite相对铁默认 红细胞生成并增加了ERFE表达。这，我们假设 无效的促红细胞生成的外源TF是TFR1表达降低或改变的结果 来自红细胞前体的TFR1运输。在这里，我们建议详细定义TF的变化 浓度，铁吸收和外排，以及Erythroc的TFR1运输会影响红细胞生成和红斑 肝素调节。在拟议的三个特定目标中，我们将1）评估TF和TFR1在 铁受限和无效的红细胞生成； 2）检查TFR1作为肝素调节剂的重要性； 3）阐明了TF和TFR1对红细胞前体和肝细胞的铁外排的影响。铁 促红细胞生成的运输和铁代谢的红斑调节是恢复期间的核心原则 压力性红细胞生成，在无效的红细胞生成中失调。这是成功完成这些的 阐明TF和TFR1在这些途径中的作用的研究对血液学领域具有极大的关注， 提供有关促红细胞生成的人类疾病的病理生理学的见解 当前有关铁代谢的知识，并添加了新的范式，以进一步探讨 肝素。最后，这些研究成功地完成了询问压力和 无效的红细胞生成（对PAS-13-031的反应）将促进使用TF在 患有β-丘脑贫血的患者，可能是其他富含铁的贫血的患者。