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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：
10440495
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/10440495
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 antagonist 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.

项目总结