Macrophage regulation of the erythron

巨噬细胞对红细胞的调节

基本信息

批准号：
10214601
负责人：
Michael Rusty Elliott
金额：
$ 47.43万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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/10214601
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

项目摘要

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.