权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of Erythroblastic Islands in Anemia of Inflammation

成红细胞岛在炎症性贫血中的作用

基本信息

批准号：
10596568
负责人：
Lionel Blanc
金额：
$ 61.99万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10596568
关键词：
Acute Adhesives Adult Affect Anemia Anemia due to Chronic Disorder Animal Model Autoimmune Diseases Biological Assay Bone Marrow Cell Nucleus Cells Cellular Structures Characteristics Chronic Communicable Diseases Complication Coupled DNA Data Defect Discipline of Nursing Disease Dysmyelopoietic Syndromes Erythroblasts Erythrocytes Erythroid Erythropoiesis Fetal Liver Fetal Spleen Flow Cytometry Fostering Genes Genetic Goals Granulopoiesis Growth Factor Hematology Hematopoiesis Hematopoietic Hemoglobin Heterogeneity Homeostasis Human ITGAM gene In Situ In Vitro Inflammation Inflammatory Iron Island Knockout Mice Knowledge Label Macrophage Malignant - descriptor Mammals Mediator Methods Microscopy Modeling Morbidity - disease rate Mus P-Selectin Pathologic Patients Persons Phenotype Population Population Heterogeneity Process Production Proliferating Quality of life Recovery Reporting Role Sedimentation process Stress Structure Surface TFRC gene Testing Thalassemia Therapeutic Intervention Toxic effect density differential expression follow-up granulocyte hematopoietic tissue immune activation improved in vivo insight mortality mouse model neutrophil new therapeutic target novel pharmacologic physiologic model prevent reconstitution single-cell RNA sequencing spectrograph

项目摘要

Project Summary/Abstract Terminal erythropoiesis in mammals occurs within the erythroblastic islands (EBIs), niches where erythroblasts differentiate in close interaction with a central (nursing) macrophage. Although EBIs were described in 1958 by Marcel Bessis as the first hematopoietic niche, there are still many questions to be answered to improve our understanding of their structure and function. Anemia of inflammation (AoI) occurs in patients with chronic or acute immune activation (due to an infectious, malignant, or autoimmune disease) and affects the quality of life of millions of people worldwide. The overall goal of this application is to understand the structure and function of the EBI as the erythropoietic niche in normal, baseline erythropoiesis and how this is modified in conditions leading to anemia of inflammation. Our preliminary data show that F4/80, VCAM1, and CD169 are expressed heterogeneously by the central macrophages within the EBIs. In marked contrast, CD11b is low or negative on the EBI macrophage, while it is abundantly present on other cells within the islands. The CD11b+ cells within EBIs are granulocyte precursors in contact to the central macrophage (Mφ). Moreover, EBIs in the bone marrow of mice with AoI have increased number of CD11b+ cells and their central macrophages, evaluated after isolation of EBIs with gradient density sedimentation, have increased expression of P-selectin, an adhesive molecule that attracts neutrophils. We hypothesize that the central EBI Mφ provides a niche for both erythropoiesis and granulopoiesis at homeostatic (baseline) hematopoiesis through intercellular interactions, while it preferentially supports erythropoiesis in stress erythropoiesis conditions. In contrast, under conditions of inflammation, changes of the central EBI Mφs like increased P-selectin expression, favor granulopoiesis versus erythropoiesis, leading to AoI. Here, we propose to (1) define the spectrum of the central EBI macrophage identity in mouse and human BM at baseline conditions, and in mouse fetal liver and spleen as models of physiological and pathological stress erythropoiesis, (2) determine structural and functional interactions of the EBI Mφs with the granulocyte precursors co-existing within EBIs at baseline conditions, and (3) evaluate the mechanisms by which the EBI Mφs and granulocyte precursors in AoI suppress erythropoiesis and test if P-selectin blockage improves AoI in animal models. These studies will expand our knowledge on the fundamental questions regarding the identity of EBI Mφs and their role in hematopoiesis and illuminate novel therapeutic targets and strategies to manage patients with AoI, a common complication increasing morbidity in millions of patients with malignant, infectious, or autoimmune diseases, worldwide.

项目概要/摘要哺乳动物的终末红细胞生成发生在有红细胞岛 (EBI) 内，这是有红细胞的生态位与中央（护理）巨噬细胞密切相互作用而分化。尽管 EBI 于 1958 年被描述马塞尔·贝西斯（Marcel Bessis）作为第一个造血利基市场，仍有许多问题需要回答，以提高我们的水平了解它们的结构和功能。炎症性贫血 (AoI) 发生在慢性或急性免疫激活的患者中（由于传染性、恶性或自身免疫性疾病）并影响全世界数百万人的生活质量。该应用程序的总体目标是了解 EBI 作为红细胞生成素的结构和功能。正常、基线红细胞生成的利基以及在导致贫血的情况下如何改变它炎。我们的初步数据表明，F4/80、VCAM1 和 CD169 的表达异质性 EBI 内的中央巨噬细胞。与此形成鲜明对比的是，CD11b 在 EBI 上较低或为负值巨噬细胞，而它大量存在于岛内的其他细胞上。 EBI 中的 CD11b+ 细胞是粒细胞前体与中央巨噬细胞（Mφ）接触。此外，骨髓中的 EBI 分离后评估，患有 AoI 的小鼠 CD11b+ 细胞及其中央巨噬细胞数量增加梯度密度沉降的 EBI 增加了 P-选择素（一种粘附分子）的表达吸引中性粒细胞。我们假设中央 EBI Mφ 为红细胞生成和粒细胞生成提供了一个利基通过细胞间相互作用实现稳态（基线）造血，同时它优先支持应激性红细胞生成条件下的红细胞生成。相反，在炎症条件下，中枢 EBI Mφs 类似于 P-选择素表达增加，有利于粒细胞生成而不是红细胞生成，从而导致 AOI。在这里，我们建议 (1) 定义小鼠和人类中央 EBI 巨噬细胞身份的谱基线条件下的 BM 以及小鼠胎儿肝脏和脾脏作为生理和病理模型应激性红细胞生成，(2) 确定 EBI Mφ 与粒细胞的结构和功能相互作用基线条件下 EBI 中共存的前体，以及 (3) 评估 EBI 产生的机制 AoI 中的 Mφs 和粒细胞前体抑制红细胞生成，并测试 P-选择素阻断是否可以改善 AoI 动物模型。这些研究将扩展我们对有关 EBI Mφ 身份和它们在造血中的作用并阐明了治疗 AoI 患者的新治疗靶点和策略，一种常见并发症，增加了数百万恶性、传染性或自身免疫性疾病患者的发病率疾病，全世界。