Mechanisms of anemia of chronic inflammation and aging in mice.

摘要： 炎症性或慢性病贫血(AICD)是北美最常见的贫血形式 除缺铁外(PAS-08-019)。此外，与衰老和老年人相关的贫血 最近，虚弱与炎症有关，这表明了 这两种贫血都可能是保守的。尽管AICD可以出现在不同的临床环境中，但常见的 这种情况的特征包括炎症和有限的红细胞生成。海普西丁抗菌肽(HepC) 由于AICD是巨噬细胞铁外流的负性调节因子，因此与AICD的发病机制有关。 虽然丙型肝炎足以引起贫血，但尚不清楚丙型肝炎在AICD的发病机制中是否必需。 在炎症的背景下，关于红细胞生成的分子调控知之甚少。这个 这一研究领域进展缓慢的部分原因是AICD基础疾病的异质性和 获取相关患者样本的困难。 为了深入了解在慢性病和老龄化的背景下与炎症相关的贫血，我们 建议测试IL-6下调嗜碱性红细胞中血红蛋白合成的假设， 与丙型肝炎病毒的活性无关。 动物模型提供了一个至关重要的工具来描述免疫之间的联系 系统和红细胞生成。我们有三个相关的鼠标模型，它们将有助于研究 炎症、衰老和贫血之间的关系。具体来说，我们的目标是： 1)确定与炎症相关的贫血是否需要HepC或IL-6 无菌脓肿或老化。 2.)确定血红蛋白合成所需基因的表达是否受到抑制 老年小鼠、无菌脓肿小鼠和丙型肝炎小鼠的红细胞。 3.)体外验证IL-6对血红蛋白合成相关基因的抑制作用。 我们希望确定AICD是否需要HepC或IL-6。此外，我们希望找出共同的 红血球生成的调节剂，其功能在衰老和炎症的背景下被改变。

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.