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MECHANISM OF ACTION OF ERYTHROFERRONE AND PATHOLOGICAL IMPLICATIONS

赤铁酮的作用机制和病理学意义

基本信息

批准号：
10654670
负责人：
TOMAS GANZ
金额：
$ 47.76万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654670
关键词：
Ablation Acute Adipose tissue Affect Amino Acids Anemia Binding Biological Assay Blood Blood Transfusion Bone Morphogenetic Proteins Bone Tissue Brain C-terminal Characteristics Chronic Development Disease Erythroblasts Erythrocytes Erythropoiesis Erythropoietin Extracellular Fluid Extramedullary Genetic Transcription Glycoproteins Growth Health Hematology Hemoglobin Hemorrhage Hepatic Hepatocyte Homeostasis Hormones Hour Human Human Biology In Vitro Inflammation Iron Iron Overload Kidney Ligands Mediator Metabolism Modeling Molecular Mus N-terminal Pathogenesis Pathologic Patients Plasma Production Protein Family Reporting Role Serum Signal Transduction Stimulus Structure TNF gene Testing Therapeutic Tissues Transgenes Transgenic Mice Transgenic Organisms Vertebrate Biology Work antagonist beta Thalassemia hepcidin in vivo insight iron absorption iron metabolism member metal transporting protein 1 mouse model neurobehavioral novel overexpression pharmacologic programs response structural determinants thalassemia intermedia

项目摘要

Project Summary This proposal aims to elucidate the mechanisms by which normal and pathological erythropoiesis exerts systemic effects on iron metabolism and other metabolic processes. Activation of erythropoiesis by erythropoietin (EPO) causes rapid suppression of hepcidin, with consequent increase in iron absorption and the release of iron from stores. We discovered erythroferrone (ERFE), a hormone produced by erythroblasts, as the principal mediator that acutely matches the iron supply to the changing requirements of erythropoiesis. ERFE is proposed to bind to and inactivate bone morphogenetic proteins (BMPs) that regulate hepcidin transcription. In anemias with ineffective erythropoiesis, increased ERFE concentrations may not only contribute to iron overload and worsen ineffective erythropoiesis but also promote other systemic manifestations. In this proposal, we will expand the study of the mechanism of action of ERFE, define the set of BMP ligands targeted by ERFE, and conduct a detailed structure-function study. Also, we constructed transgenic mouse lines that overexpress graded levels of ERFE in erythroblasts and develop proportional iron overload and other systemic manifestations of anemias with ineffective erythropoiesis. We will use these mice to analyze the hematological and non- hematological consequences of excessive ERFE. The specific aims of the proposed project are: 1. Characterize the structural determinants of ERFE bioactivity and the interaction of ERFE with BMPs. We will define all the members of the BMP family targeted by murine and human ERFE using assays for both bioactivity and direct physical interaction. We will define the bioactive segment of ERFE and perform complete structure-function analysis of the specific amino acids required for ERFE bioactivity. 2. Analyze the hematological effects of increased ERFE concentrations in vivo. In mouse models of graded ERFE overexpression, we will analyze the effect of ERFE on iron loading and erythropoiesis, and identify which effects are independent of hepcidin. To study the effects of high ERFE in β-thalassemia, we will introduce the ERFE transgene into the th3/+ model of β-thalassemia and examine erythropoiesis and iron overload. Finally, we will test the ability of a therapeutic anti-ERFE Mab to reverse the effects of ERFE. 3. Elucidate the nonhematological effects of increased ERFE concentrations in vivo. Using transgenic ERFE mice, we will define the effects of ERFE on the brain, somatic growth, bone and adipose tissues, and renal development, all of which were affected in our preliminary characterization. Successful completion of the proposed studies will answer longstanding questions about a fundamental aspect of human and vertebrate biology, the mechanism by which the supply of iron is matched to the varying iron requirements of erythropoiesis. The work will provide important insights into the pathogenesis of iron overload in β-thalassemia and other anemias with ineffective erythropoiesis, globally very common diseases, and enhance the understanding of the mechanisms that cause the debilitating systemic effects of these diseases.

项目摘要这项建议旨在阐明正常和病理性红细胞生成的机制。对铁代谢和其他代谢过程的系统性影响。促红细胞生成素对红细胞生成的激活作用促红细胞生成素(EPO)导致海普西丁的快速抑制，从而增加铁的吸收和铁的释放从商店买的。我们发现红细胞产生的一种荷尔蒙--红细胞铁酮(ERFe)是主要的使铁供应与不断变化的红细胞生成需求相匹配的调节剂。埃尔菲被提议结合和失活调节海普西丁转录的骨形态发生蛋白。在贫血中对于无效的红细胞生成，ErFe浓度的增加不仅可能导致铁超载和恶化无效的红细胞生成，但也促进其他全身症状。在这项提案中，我们将扩大Erfe作用机制的研究，确定Erfe靶向的BMP配体集合，以及进行详细的结构-功能研究。此外，我们还构建了过表达的转基因小鼠品系红细胞中ErFe的分级水平和发展成比例的铁超载和其他全身表现红血球生成无效的贫血。我们将利用这些小鼠来分析血液学和非血液学过量Erfe的血液学后果。拟议项目的具体目标是： 1.表征Erfe生物活性的结构决定因素及其与BMPs的相互作用。我们将定义BMP家族的所有成员，以小鼠和人类Erfe为靶点，使用分析包括生物活性和直接的物理相互作用。我们将定义Erfe的生物活性部分并执行对ERFe生物活性所需的特定氨基酸进行完整的结构-功能分析。 2.分析体内ErFe浓度升高对血液学的影响。在小鼠模型中分级Erfe过表达，我们将分析Erfe对铁负荷和红细胞生成的影响，以及确定哪些作用不依赖于海普西丁。为了研究高ERFe在β-地中海贫血中的作用，我们将erfe转基因引入β-地中海贫血的Th3/+模型，并检测红细胞生成和铁超载。最后，我们将测试一种治疗性抗Erfe单抗逆转Erfe效应的能力。 3.阐明体内ErFe浓度升高的非血液学效应。使用转基因技术 ERFe小鼠，我们将确定ErFe对大脑、躯体生长、骨骼和脂肪组织的影响，以及肾脏发育，所有这些都在我们的初步特征中受到影响。拟议研究的成功完成将回答长期以来关于一个基本方面的问题在人类和脊椎动物生物学中，铁的供应与变化的铁相匹配的机制红细胞生成的要求。这项工作将为铁超载的发病机制提供重要的见解在β-地中海贫血和其他红细胞生成无效的贫血中，这是全球非常常见的疾病，而且对导致这些疾病的全身性衰弱效应的机制的理解。