MECHANISM OF ACTION OF ERYTHROFERRONE AND PATHOLOGICAL IMPLICATIONS

赤铁酮的作用机制和病理学意义

• 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
• 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

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 该提案旨在阐明正常和病理红血病的机制 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）引起肝素的快速抑制，因此铁滥用和铁的释放 来自商店。我们发现了erythroferrone（erfe），这是由红细胞生产的果子，是主要的 将铁供应与红细胞生成不断变化的需求抗衡的调解人。提出了Erfe 与调节肝素转录的骨形态发生蛋白（BMP）结合并失活。在贫血 由于无效的红细胞生成，ERFE浓度的升高不仅可能导致铁超载和 恶化了无效的促红细胞生成，但也促进了其他系统性表现。在此提案中，我们将 扩展对ERFE作用机理的研究，定义ERFE靶向的BMP配体的集合，并 进行详细的结构功能研究。另外，我们构建了过表达的转基因小鼠线 红细胞中ERFE的分级水平，并产生比例铁超负荷和其他系统性表现 贫血无效的红细胞生成。我们将使用这些小鼠分析血液学和非 - 过量ERFE的血液学后果。拟议项目的具体目的是： 1。表征ERFE生物活性的结构决定剂以及ERFE与BMP的相互作用。 我们将使用测定法定义由Murine和Human Erfe瞄准的BMP家族的所有成员 生物活性和直接的物理互动。我们将定义ERFE的生物活性片段并执行 ERFE生物活性所需的特定氨基酸的完整结构功能分析。 2。分析体内ERFE浓度升高的血液学作用。在鼠标模型中 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 确定哪些作用与肝素无关。为了研究高ERFE对β-丘脑贫血的影响，我们 将将ERFE转换为β-硫代助理的Th3/+模型，并检查红细胞生成和 铁超负荷。最后，我们将测试治疗性抗ERFE MAB逆转ERFE影响的能力。 3。阐明体内ERFE浓度升高的非血液学效应。使用转基因 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，所有这些都受到我们的初步特征受到影响。 成功完成拟议的研究将回答有关基本方面的长期问题 人类和脊椎动物生物学，铁的供应与不同的铁相匹配的机制 红细胞生成的要求。这项工作将为铁超载的发病机理提供重要的见解 在β-丘脑贫血和其他贫血中，无效的红血病，全球非常常见的疾病和增强 对引起这些疾病的系统性影响的机制的理解。