Macrophage regulation of the erythron

巨噬细胞对红细胞的调节

• 批准号: 10440460
• 负责人: Michael Rusty Elliott
• 金额: $ 46.96万
• 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/10440460
• 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; Disease; Eating; Emergency Situation; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Fetal Liver; Future; Glucocorticoids; Hematopoietic stem cells; Heterogeneity; Human body; In Vitro; Ingestion; Intestines; Island; Liver; Lung; 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; macrophage; 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.

摘要 该提案的总体目标是将Elliott和Palis实验室各自的专业知识汇集在一起， 巨噬细胞和红细胞生物学，分别，以更好地了解骨髓驻留的作用， 巨噬细胞在调节红细胞生成。虽然最近在这方面取得了很大进展， 了解巨噬细胞异质性和组织特异性功能在许多器官，包括脑，皮肤， 肺、肠、肝和脾，相对而言，对骨骼中巨噬细胞的多样性知之甚少 骨髓，其中巨噬细胞是为成熟红细胞提供微环境生态位的关键参与者 “成红细胞岛”内的前体细胞。在目标1中，我们将使用多维流的功能测试 细胞计数数据，以更好地确定骨中红细胞相关巨噬细胞（EA-Macs）的多样性 骨髓成年人每秒合成250万个新的红细胞，以维持我们的循环红细胞。 细胞团，其构成体内所有细胞的>80%。哺乳动物的终末成红细胞去核， 产生网织红细胞和蛋白核细胞。EA-Macs的一个重要功能是通过蛋白质清除蛋白质细胞。 吞噬作用在目标2中，我们将测试CD 47“不要吃我”信号在CD 47细胞的差异清除中的功能。 核浆细胞而不是成红细胞。此外，我们将研究促红细胞生成素的作用， 红细胞生成的调节剂，调节EA-Macs清除蛋白核细胞的能力。促红素 促进晚期红系祖细胞和未成熟成红细胞的存活，它们共同构成 红细胞生成素反应区我们对两个独立的- 辐射和放血-应激性红细胞生成的模型表明，促红细胞生成素扩大了 在骨髓中的促红细胞生成素反应区室中以巨噬细胞依赖性的方式。在目标3中，我们 将测试新的假设，即EA-Macs介导急性贫血的恢复， 促红细胞生成素反应区室。综合这些研究， 关于EA-Macs在骨髓中对微环境的调节， 为今后研究EA-Macs在红细胞过多和过少疾病状态中的作用奠定了基础， 生产