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.

抽象的 该提议的总体目的是将Elliott和Palis Labs的相对专业知识汇集在一起 巨噬细胞和红斑生物学分别可以更好地理解组织居民巨噬细胞的作用 在调节红细胞产生中。虽然最近在理解方面取得了巨大进展 巨噬细胞异质性和组织特异性功能在许多器官中，包括大脑，皮肤，肺，肠， 肝脏和脾 巨噬细胞提供微环境的利基市场，用于在“红细胞”中成熟的红细胞前体 岛屿”。在AIM 1中，我们将采用多维流式细胞仪方法进行功能测试以更好 定义骨髓中与红细胞相关的巨噬细胞（EA-MAC）的身份。成年人 每秒合成250万新的红细胞，以维持我们的循环红细胞质量，这 构成体内所有细胞的80％> 80％。哺乳动物中的末端红细胞囊泡以产生 网状细胞和肾上腺细胞。 EA-MACS的重要功能是肾上腺细胞清除率。在AIM 2中，我们将测试 CD47“不要吃我”信号在肾上腺细胞清除中以及促红细胞生成素的作用， 红细胞生产的主要调节剂，以调节EA-MAC清除肾上腺细胞的能力。 促红细胞生成素促进了晚期红细胞祖细胞和未成熟的红细胞的生存， 共同构成了erythron的红细胞生成素响应室。我们在两个方面的初步研究 独立放射和静脉造口模型 - 压力红细胞生成的模型，表明促红细胞生成素膨胀 以巨噬细胞依赖性方式在骨髓中的红细胞生成素反应室。在AIM 3中， 我们将测试新的假设，即EA-MAC构成了促红细胞生成素反应的关键组成部分 从急性贫血恢复期间的隔室。总之这些研究将建立基本 关于骨髓中EA-MACS对ERYTHRON的微环境调节的见解，并将 为未来研究EA-MAC在红系疾病中的作用的研究奠定基础。