Mechanisms of anemia of chronic inflammation and aging in mice.

描述(由申请人提供)：炎症性或慢性病贫血(AICD)是除缺铁之外北美最常见的贫血形式(PAS-08-019)。此外，与衰老和老年综合征、虚弱相关的贫血最近被认为与炎症有关，这表明这两种贫血的分子机制可能是保守的。虽然AICD可以在不同的临床情况下发生，但这种情况的共同特征包括炎症和有限的红细胞生成。海普西丁抗菌肽(HEPC)是巨噬细胞铁外流的负性调节因子，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。这一研究领域进展缓慢的部分原因是AICD基础疾病的异质性，以及难以获得相关的患者样本。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下调嗜碱性红细胞中血红蛋白合成的假设，这与HepC的活性无关。动物模型为研究免疫系统和红细胞生成之间的联系提供了一个至关重要的工具。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+小鼠的红细胞中合成血红蛋白所需基因的表达是否受到抑制。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改变。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更好的预防、检测和治疗人类贫血的方法。

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.