Mechanisms of anemia of chronic inflammation and aging in mice.

摘要： 炎症性贫血或慢性疾病（AICD）是北美最常见的贫血形式 铁缺乏症（PAS-08-019）之外。此外，与衰老和老年人相关的贫血 综合征，虚弱最近与炎症有关，表明了潜在的分子机制 这两种贫血可能是保守的。虽然AICD可能出现在不同的临床背景下，但常见的 这种病症的特征包括炎症和有限的红细胞生成。Hepcidin抗菌肽 因为它是巨噬细胞铁排出的负调节剂，所以与AICD的发病机制有关。 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。的 这一研究领域进展缓慢，部分原因是AICD基础疾病的异质性， 获取相关患者样本的困难。 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 提出检验IL-6下调嗜碱性成红细胞中血红蛋白合成的假设， 独立于Hepc活性。 动物模型提供了一个非常重要的工具来表征免疫系统之间的通信。 系统和红细胞生成。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.）的人。确定Hepc或IL-6是否是与炎症相关的贫血所必需的， 无菌脓肿或老化。 2.）确定血红蛋白合成所需的基因表达是否受到抑制， 老年小鼠、无菌脓肿小鼠和Hepc Tg+小鼠的成红细胞。 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，我们希望确定共同的 红细胞生成的调节剂，其功能在衰老和炎症的情况下被改变。

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.