Mechanisms of anemia of chronic inflammation and aging in mice.

小鼠慢性炎症和衰老贫血的机制。

基本信息

批准号：
7728049
负责人：
Cindy Norene Roy
金额：
$ 36.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728049
关键词：
5-Aminolevulinate synthase Abscess Acute Erythroblastic Leukemia Acute-Phase Reaction Age Aging Anemia Anemia due to Chronic Disorder Animal Model Area BFU-E Basophilic Erythroblast Biological Assay Biological Process Biology Blast Cell Bone Marrow Bone Marrow Suppression Cells Cellular biology Chronic Chronic Disease Clinical Communication Data Detection Development Disease Down-Regulation Elderly Erythroblasts Erythrocyte Anion Exchange Protein 1 Erythrocyte Survival Erythroid Erythropoiesis Gene Expression Gene Targeting Genes Genetic Transcription Globin Hematopoiesis Hemoglobin Heterogeneity Human Immune response Immune system In Vitro Inflammation Inflammatory Interferons Interleukin-1 Interleukin-6 Iron Knowledge Link Mediating Mediator of activation protein Methods Molecular Mus North America Pathogenesis Patients Physiological Population Study Prevention Preventive Production Proteins Regulation Research Rheumatoid Arthritis Risk Factors Role Sampling Serum Serum iron level result Signal Transduction Small Interfering RNA Spleen Staging Sterility Syndrome Systemic Lupus Erythematosus Testing Transforming Growth Factors Tumor Necrosis Factor-alpha Validation aged antimicrobial peptide cytokine disability frailty hepcidin improved insight knock-down mRNA Expression macrophage mortality mouse model progenitor public health relevance response tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Anemia of inflammation or chronic disease (AICD) is the most common form of anemia in North America outside of iron deficiency (PAS-08-019). Furthermore, the anemia associated with aging and the geriatric syndrome, frailty has recently been linked to inflammation, suggesting the molecular mechanisms underlying both of these anemias may be conserved. Though AICD can arise in diverse clinical contexts, common features of this condition include inflammation and limited erythropoiesis. Hepcidin antimicrobial peptide (Hepc) has been implicated in the pathogenesis of AICD because it is a negative regulator of macrophage iron egress. Though Hepc is sufficient to induce anemia, it is not clear that Hepc is required for the pathogenesis of AICD. Very little is known concerning the molecular regulation of erythropoiesis in the context of inflammation. The slow progress in this area of research is partly related to the heterogeneity of diseases underlying AICD and the difficulty procuring relevant patient samples. To gain insight into the anemia associated with inflammation in the context of chronic disease and aging, we propose to test the hypothesis that IL-6 down regulates hemoglobin synthesis in basophilic erythroblasts, independent of Hepc activity. Animal models provide a critically important tool to characterize the communication between the immune system and erythropoiesis. We have three relevant mouse models that will be useful for investigating the relationship between inflammation, aging, and anemia. Specifically, we aim to: 1.) Determine whether Hepc or IL-6 is required for the anemia associated with inflammation induced by sterile abscess or aging. 2.) Determine whether the expression of genes required for hemoglobin synthesis is inhibited in erythroblasts of aged mice, mice with sterile abscess, and Hepc Tg+ mice. 3.) validate IL-6-mediated inhibition of genes involved in hemoglobin synthesis in vitro. We expect to determine whether Hepc or IL-6 is required for AICD. Further, we expect to identify common regulators of erythropoiesis whose function is modified in the context of aging and inflammation. PUBLIC HEALTH RELEVANCE: This project will gain insight into how the biological processes of inflammation and aging cause anemia in mice. The results of this project will guide our search for improved methods of prevention, detection, and treatment of anemia in humans.

描述（由申请人提供）：炎症或慢性疾病贫血 (AICD) 是北美除缺铁 (PAS-08-019) 之外最常见的贫血形式。此外，与衰老和老年综合症、虚弱相关的贫血最近与炎症有关，表明这两种贫血背后的分子机制可能是保守的。尽管 AICD 可能出现在不同的临床环境中，但这种疾病的共同特征包括炎症和红细胞生成有限。铁调素抗菌肽 (Hepc) 与 AICD 的发病机制有关，因为它是巨噬细胞铁排出的负调节因子。尽管Hepc足以诱发贫血，但尚不清楚Hepc是否是AICD发病机制所必需的。关于炎症背景下红细胞生成的分子调节知之甚少。该领域研究进展缓慢部分与AICD疾病的异质性以及获取相关患者样本的困难有关。为了深入了解慢性疾病和衰老背景下与炎症相关的贫血，我们建议检验以下假设：IL-6 下调嗜碱性成红细胞中的血红蛋白合成，与 Hepc 活性无关。动物模型提供了一个极其重要的工具来表征免疫系统和红细胞生成之间的通讯。我们拥有三种相关的小鼠模型，可用于研究炎症、衰老和贫血之间的关系。具体来说，我们的目标是： 1.) 确定与无菌脓肿或衰老引起的炎症相关的贫血是否需要 Hepc 或 IL-6。 2.)确定老年小鼠、无菌脓肿小鼠和Hepc Tg+小鼠的成红细胞中血红蛋白合成所需基因的表达是否受到抑制。 3.) 在体外验证 IL-6 介导的对血红蛋白合成相关基因的抑制作用。我们期望确定 AICD 是否需要 Hepc 或 IL-6。此外，我们期望找到红细胞生成的常见调节因子，其功能在衰老和炎症的背景下发生改变。公共健康相关性：该项目将深入了解炎症和衰老的生物过程如何导致小鼠贫血。该项目的结果将指导我们寻找预防、检测和治疗人类贫血的改进方法。