Macrophage regulation of the erythron

巨噬细胞对红细胞的调节

• 批准号: 9771563
• 负责人: Michael Rusty Elliott
• 金额: $ 10万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9771563
• 关键词: Acute; Adult; Anemia; BFU-E; Binding; Biological Assay; Biology; Bone Marrow; Brain; CD47 gene; CFU-E; Cell Nucleus; Cells; Data; Disease; Eating; Emergency Situation; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Fetal Liver; Future; Glucocorticoids; Hematopoietic stem cells; Heterogeneity; Human body; Immunophenotyping; Intestines; Island; Liver; Lung; Mammals; Modeling; Molecular; Mus; Myeloid Cells; Organ; Phagocytes; Phagocytosis; Production; Radiation; Recovery; Red Cell Mass result; Regulation; Reticulocytes; Role; Signal Transduction; Skin; Spleen; Stress; Testing; Tissues; Venous blood sampling; Waste Products; comparative; cytokine; fetal; high dimensionality; in vitro testing; in vivo evaluation; insight; macrophage; novel; progenitor; response

Abstract The overall aim of this proposal is to bring together the respective expertise of the Elliott and Palis labs in macrophage and erythroid biology, respectively, to better understand the role of tissue-resident macrophages in the regulation red blood cell production. While great progress has been made recently in understanding macrophage heterogeneity and tissue-specific function in many organs, including brain, skin, lungs, intestines, liver, and spleen, comparatively little is known about the diversity of macrophages in the bone marrow, where macrophages provide the microenvironmental niche for maturing erythroid precursors within “erythroblastic islands”. In Aim 1, we will employ multidimensional flow cytometric approaches with functional tests to better define the identity of erythroid-associated macrophages (EA-Macs) in the bone marrow. Adult humans synthesize 2.5 million new red blood cells every second to maintain our circulating red cell mass, which constitutes >80% of all the cells in the body. Terminal erythroblasts in mammals enucleate to yield reticulocytes and pyrenocytes. An important function of EA-Macs is pyrenocyte clearance. In Aim 2 we will test the function of CD47 “don't eat me” signals in pyrenocyte clearance, as well as the role of erythropoietin, the primary regulator of red cell production, in regulating the capacity of EA-Macs to clear pyrenocytes. Erythropoietin promotes the survival of late stage erythroid progenitors and immature erythroblasts, which together constitute the erythropoietin-responsive compartment of the erythron. Our preliminary studies in two independent- radiation and phlebotomy- models of stress erythropoiesis indicate that erythropoietin expands the erythropoietin-responsive compartment in the bone marrow in a macrophage-dependent manner. In Aim 3, we will test the novel hypothesis that EA-Macs constitute a critical component of the erythropoietin-responsive compartment during the recovery from acute anemia. Taken together these studies will establish fundamental insights regarding the microenvironmental regulation of the erythron by EA-Macs in the bone marrow and will lay the groundwork for the future study of the role of EA-Macs in erythroid-intrinsic diseases.

摘要 这项提议的总体目标是将埃利奥特实验室和帕里斯实验室各自的专业知识结合在一起 巨噬细胞和红系生物学，以更好地了解组织驻留巨噬细胞的作用 在调节红细胞的产生上。虽然最近在理解上取得了很大进展 巨噬细胞在许多器官中的异质性和组织特异性功能，包括脑、皮肤、肺、肠、 肝和脾，对骨髓中巨噬细胞的多样性知之甚少。 巨噬细胞为成熟的红系前体细胞提供微环境 岛屿“。在目标1中，我们将使用多维流式细胞术方法和功能测试来更好地 确定骨髓中红系相关巨噬细胞(EA-MACs)的特性。成年人类 每秒合成250万个新的红血球以维持我们循环中的红细胞团，这 构成人体内所有细胞的80%。哺乳动物的末梢红母细胞去核以产生 网织红细胞和肾核细胞。EA-MACs的一个重要功能是清除核细胞。在目标2中，我们将测试 CD47“不要吃我”信号在核细胞清除中的作用以及促红细胞生成素、 红细胞生成的主要调节因子，在调节EA-MACs清除肾核细胞的能力中。 促红细胞生成素促进晚期红系祖细胞和未成熟红细胞的存活， 共同构成红血球的促红细胞生成素反应室。我们的初步研究分为两个阶段 应激性红细胞生成的独立辐射和静脉切开模型表明促红细胞生成素扩张 骨髓中依赖巨噬细胞的促红细胞生成素反应室。在《目标3》中， 我们将检验这一新的假设，即EA-MACs构成促红细胞生成素反应的关键成分 在从急性贫血中恢复的过程中。综上所述，这些研究将奠定基础 EA-MACs在骨髓和Will中对红细胞微环境调节的研究 为进一步研究EA-MACs在红系内源性疾病中的作用奠定了基础。