Macrophage regulation of the erythron

巨噬细胞对红细胞的调节

• 批准号: 10653933
• 负责人: Michael Rusty Elliott
• 金额: $ 46.23万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653933
• 关键词: 3-Dimensional; Acute; Adult; Algorithms; Anemia; Anemia due to Chronic Disorder; BFU-E; Binding; Biological Assay; Biology; Bone Marrow; Brain; CD47 gene; CFU-E; Cell Nucleus; Cells; Data; Dimensions; Disease; Eating; Emergency Situation; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Fetal Liver; Future; Glucocorticoids; Hematopoietic stem cells; Heterogeneity; Human body; Immunophenotyping; In Vitro; Ingestion; Intestines; Island; Liver; Lung; Macrophage; Mammals; Mediating; Metabolic Clearance Rate; Modeling; Molecular; Mus; Myeloid Cells; Organ; Phagocytes; Phagocytosis; Phenotype; Production; Radiation; Recovery; Red Cell Mass result; Regulation; Reticulocytes; Role; Signal Transduction; Skin; Specificity; Spleen; Stress; Testing; Tissues; Venous blood sampling; Waste Products; beta Thalassemia; body system; comparative; experimental study; fetal; high dimensionality; in vivo; in vivo evaluation; insight; novel; progenitor; response; uptake

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 bone marrow-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 are key players in providing the microenvironmental niche for maturing erythroid precursors within “erythroblastic islands.” In Aim 1, we will employ functional tests of multidimensional flow cytometric data to better define the diversity 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 via phagocytosis. In Aim 2 we will test the function of CD47 “don't eat me” signals in the differential clearance of pyrenocytes but not erythroblasts. In addition, we will investigate 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 mediate recovery from acute anemia by critically regulating the erythropoietin-responsive compartment. 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 disease states of erythroid over- and under- production.

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 巨噬细胞和红细胞生物学，以更好地理解骨髓居民的作用 调节红细胞产生的巨噬细胞。虽然最近已经取得了巨大进展 了解许多器官，包括大脑，皮肤， 肺，肠，肝脏和脾 骨髓，巨噬细胞是提供微观环境生态位的主要参与者 “红细胞岛”中的前体。在AIM 1中，我们将采用多维流量的功能测试 细胞仪数据以更好地定义与骨相关巨噬细胞（EA-MAC）的多样性 骨髓。成年人每秒合成250万新的红细胞，以保持我们的循环红色 细胞肿块占体内所有细胞的80％> 80％。哺乳动物中的终末红细胞参与 产生网状细胞和肾上腺细胞。 EA-MAC的重要功能是通过 吞噬作用。在AIM 2中，我们将测试CD47“不要吃我”信号的功能 牙龈细胞，而不是红细胞。此外，我们将研究促红细胞生成素的作用，主要 红细胞生产的调节剂，控制EA-MAC清除肾上腺细胞的能力。红细胞生成素 促进后期红斑祖细胞和未成熟的红细胞的生存，共同构成 erythro的红细胞生成素响应室。我们在两个独立的初步研究 辐射和静脉切开术 - 压力红细胞生成的模型，表明促红细胞生成素扩展 骨髓中的红细胞生成素反应室以巨噬细胞依赖性方式。在AIM 3中，我们 将检验新的假设，即EA-MACS培养基通过批判性控制急性贫血的恢复 红细胞生成素响应室。总之，这些研究将建立基本见解 涉及EA-MAC在骨髓中对ERYTHRON的微环境调节，并将放置 未来研究EA-MAC在红斑过度和不足的疾病状态中的作用的基础研究 生产。