Macrophage regulation of the erythron

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，以更好地了解骨髓驻留的作用 巨噬细胞在调节红细胞的产生。虽然最近在以下方面取得了很大进展 了解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的红系提供微环境的关键角色 在“红母细胞岛”内的前体。在目标1中，我们将使用多维流动的功能测试 细胞学数据更好地确定骨骼中红系相关巨噬细胞(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血液循环中的红血球 细胞质量，它构成了人体所有细胞的80%。哺乳动物的末梢红母细胞去核到 产生网织红细胞和肾核细胞。EA-MACs的一个重要功能是通过 吞噬作用。在目标2中，我们将测试CD47“不要吃我”信号在脑血管内皮细胞分化清除中的作用 肾核细胞，但不是红系细胞。此外，我们将研究促红细胞生成素的作用，主要是 红细胞生成的调节剂，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系祖细胞的存活，这两者共同构成 红血球的促红细胞生成素反应室。我们的初步研究在两个独立的- 应激性红细胞生成的放射和静脉切开模型表明，促红细胞生成素扩大 骨髓中的促红细胞生成素反应室以巨噬细胞依赖的方式。在目标3中，我们 将检验新的假设，即EA-MACs通过关键地调节 促红细胞生成素反应性隔室。综上所述，这些研究将建立基本的见解 关于EA-MACs对骨髓中红细胞微环境的调节，将为 为进一步研究EA-MACs在红系上下疾病状态中的作用奠定了基础。 制作。

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.