Macrophage regulation of the erythron

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，以更好地了解组织驻留巨噬细胞的作用 调节红细胞的生成。虽然最近在理解方面取得了很大进展， 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， 肝脏和脾脏中，对骨髓中巨噬细胞的多样性知之甚少， 巨噬细胞为“成红细胞”内成熟的红细胞前体提供微环境生态位。 岛屿”。在目标1中，我们将采用多维流式细胞术方法和功能检测， 确定骨髓中红细胞相关巨噬细胞（EA-Macs）的身份。成年人 每秒合成250万个新的红细胞，以维持我们循环中的红细胞质量， 占身体所有细胞的80%以上。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的一个重要功能是蛋白核细胞清除。在目标2中，我们将测试 CD 47“不要吃我”信号在蛋白质细胞清除中的作用，以及促红细胞生成素的作用， 红细胞产生的主要调节剂，调节EA-Macs清除蛋白核细胞的能力。 促红细胞生成素促进晚期红系祖细胞和未成熟成红细胞的存活， 一起构成了红细胞生成素应答区室。我们的初步研究 应激性红细胞生成独立放射和放血模型表明促红细胞生成素 骨髓中的红细胞生成素反应区室以巨噬细胞依赖性方式。在目标3中， 我们将检验EA-Macs构成促红细胞生成素反应性细胞因子的关键组分的新假设， 在急性贫血的恢复过程中，这些研究将建立基本的 关于EA-Macs在骨髓中对微环境调节的见解， 为进一步研究EA-Macs在红系内源性疾病中的作用奠定基础。

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.