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：
10396384
负责人：
TOMAS GANZ
金额：
$ 1.79万
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/10396384
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 of activation protein Metabolism Modeling Molecular Mus N-terminal Pathogenesis Pathologic Patients Pharmacology Plasma Production Protein Family Reporting Role Serum Signal Transduction Stimulus Structure TNF gene Testing Therapeutic Tissues Transgenes Transgenic Mice Transgenic Organisms Vertebrate Biology Work beta Thalassemia hepcidin in vivo insight iron absorption iron metabolism member metal transporting protein 1 mouse model neurobehavioral novel overexpression programs response 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.

项目概要该提案旨在阐明正常和病理性红细胞生成发挥作用的机制对铁代谢和其他代谢过程的全身影响促红细胞生成素激活红细胞生成。 (EPO) 导致铁调素快速抑制，从而增加铁的吸收和铁的释放我们从商店发现了红细胞铁酮 (ERFE)，这是一种由成红细胞产生的激素。提出了一种使铁供应与红细胞生成的变化需求精确匹配的调节剂。结合并灭活调节铁调素转录的骨形态发生蛋白 (BMP)。由于红细胞生成无效，ERFE 浓度增加不仅可能导致铁超负荷，无效红细胞生成恶化，还会促进其他系统性表现。在本提案中，我们将。扩大ERFE作用机制的研究，定义ERFE靶向的BMP配体集，以及此外，我们构建了过度表达的转基因小鼠品系。有红细胞中 ERFE 的分级水平，并出现成比例的铁超负荷和其他全身表现我们将使用这些小鼠来分析血液学和非贫血。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以及 ERFE 与 BMP 的相互作用。我们将使用以下测定来定义小鼠和人类 ERFE 靶向的 BMP 家族的所有成员我们将定义 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 浓度增加对小鼠模型的血液学影响。分级ERFE过度表达，我们将分析ERFE对铁负荷和红细胞生成的影响，以及确定哪些效应独立于铁调素为了研究高 ERFE 对 β-地中海贫血的影响，我们进行了研究。将把 ERFE 转基因引入 β-地中海贫血 th3/+ 模型并检查红细胞生成和最后，我们将测试治疗性抗 ERFE Mab 逆转 ERFE 影响的能力。 3. 利用转基因技术阐明体内 ERFE 浓度增加的非血液学影响。 ERFE 小鼠，我们将定义 ERFE 对大脑、体细胞生长、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表征中受到影响。成功完成拟议的研究将回答有关基本方面的长期问题在人类和脊椎动物生物学中，铁的供应与不同的铁相匹配的机制这项工作将为铁超负荷的发病机制提供重要的见解。 β-地中海贫血和其他红细胞生成无效的贫血是全球非常常见的疾病，并增强了解导致这些疾病的系统性衰弱效应的机制。