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：
8536262
负责人：
Cindy Norene Roy
金额：
$ 27.22万
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/8536262
关键词：
5-Aminolevulinate synthase Abscess Acute Erythroblastic Leukemia Acute-Phase Reaction 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 Prevention strategy 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 TNF gene Testing Transforming Growth Factors Tumor Necrosis Factor-alpha Validation abstracting aged antimicrobial peptide cytokine disability frailty hepcidin improved insight iron deficiency knock-down mRNA Expression macrophage mortality mouse model progenitor response tool treatment strategy

项目摘要

Abstract: 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.

抽象的：炎症或慢性病贫血（AICD）是北美最常见的贫血形式在铁缺乏症之外（PAS-08-019）。此外，与衰老和老年人相关的贫血综合征，脆弱的疾病最近与炎症有关，表明了分子机制这两种贫血都可以保存。尽管AICD可能在各种临床环境中出现，但常见这种情况的特征包括炎症和红细胞生成有限。肝素抗菌肽（HEPC）之所以与AICD的发病机理有关，是因为它是巨噬细胞出口的负调节剂。尽管HEPC足以诱导贫血，但尚不清楚AICD发病机理所必需的HEPC。关于在炎症的背景下，关于红细胞生成的分子调节的知之甚少。这在这一研究领域的进展缓慢与AICD和AICD疾病的异质性有关采购相关患者样品的困难。为了深入了解慢性疾病和衰老的背景下与炎症相关的贫血，我们提议检验以下假设：IL-6下降调节嗜碱性红细胞中血红蛋白合成，，独立于HEPC活动。动物模型提供了一种非常重要的工具来表征免疫之间的通信系统和红细胞生成。我们有三种相关的鼠标模型，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.）确定是否需要与由炎症引起的炎症相关的贫血无菌脓肿或衰老。 2.）确定是否抑制了血红蛋白合成所需的基因的表达老年小鼠的红细胞，无菌脓肿的小鼠和HEPC TG+小鼠。 3.）验证IL-6介导的抑制在体外参与血红蛋白合成的基因。我们希望确定AICD是否需要HEPC或IL-6。此外，我们希望确定共同红细胞生成的调节剂，其功能在衰老和炎症的背景下被修饰。