Mechanisms of anemia of chronic inflammation and aging in mice.

描述（由申请方提供）：炎症性贫血或慢性疾病（AICD）是除缺铁以外北美最常见的贫血形式（PAS-08-019）。此外，与衰老相关的贫血和老年综合征，虚弱最近已被链接到炎症，这表明这些贫血的分子机制可能是保守的。虽然AICD可以出现在不同的临床背景下，这种情况的共同特征包括炎症和有限的红细胞生成。铁调素抗菌肽（Hepc）参与了AICD的发病机制，因为它是巨噬细胞铁排出的负调节剂。虽然Hepc足以诱导贫血，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控知之甚少。这一领域的研究进展缓慢，部分原因是AICD基础疾病的异质性和难以获得相关患者样本。为了深入了解慢性疾病和衰老背景下与炎症相关的贫血，我们建议测试IL-6下调嗜碱性成红细胞血红蛋白合成的假设，独立于Hepc活性。动物模型为描述免疫系统和红细胞生成之间的通讯提供了至关重要的工具。我们有三个相关的小鼠模型，将有助于研究炎症，衰老和贫血之间的关系。具体而言，我们的目标是：1.）确定Hepc或IL-6是否是与无菌脓肿或衰老引起的炎症相关的贫血所必需的。2.）确定老年小鼠、无菌性脓肿小鼠和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.）第三章在体外验证IL-6介导的对参与血红蛋白合成的基因的抑制。我们希望确定AICD是否需要Hepc或IL-6。此外，我们期望确定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被修改。公共卫生相关性：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。

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.