The Hepcidin-Ferroportin Axis in Anemia of Inflammation: Mechanisms and Targets

描述（由申请人提供）：炎症性贫血（AI，也称为慢性病贫血）与多种感染性和炎症性疾病相关，并导致其发病。AI的发病机制尚不完全清楚，治疗选择有限。促红细胞生成素、静脉铁剂或它们的组合越来越多地用于治疗这种病症，但该疗法仅部分有效，并且经常需要高剂量的这些药剂，副作用的风险增加。因此，非常需要新的、更具体的治疗方式。最近的外地住房准备金（PAS-08 - 019）确认了这一领域的重要性和及时性。铁调素是全身铁稳态的关键调节剂和急性期反应物。最近的研究表明，在炎症条件下增加的铁调素产生是AI发展的主要贡献者，并且可能是对促红细胞生成素耐药的原因。因此，拮抗铁调素活性是改善AI治疗的有希望的方法。然而，介导铁调素对膜铁转运蛋白的作用的特定分子途径知之甚少。我们建议全面定义铁调素与其受体ferroportin的相互作用激活的途径，并确定拮抗这些途径的化合物。具体而言，我们将：1）通过使用小分子抑制剂和siRNA的高通量筛选（HTS）系统地发现铁调素拮抗剂2）使用鉴定的铁调素拮抗剂，表征细胞模型中的Fpn内化途径3）在AI的动物模型中，确定所选拮抗剂的功效和铁调素-膜铁转运蛋白轴对疾病过程的贡献。所提出的方法将回答关于AI的发病机制和对红细胞生成刺激剂的抗性的相关问题的基本问题。它还可以提供先导化合物，用于进一步开发作为治疗剂。总的来说，这项建议有效和全面地解决了一个重要和及时的科学和医学问题。公共卫生相关性：拟议的项目将有助于了解和治疗一种常见的贫血，这种贫血是在感染和炎症性疾病中发展起来的。

DESCRIPTION (provided by applicant): Anemia of inflammation (AI, also called anemia of chronic disease) is associated with a wide variety of infectious and inflammatory conditions and contributes to their morbidity. The pathogenesis of AI is incompletely understood and treatment options are limited. Erythropoietin, intravenous iron or their combination are increasingly used to treat this condition but the therapy is only partially effective and frequently requires high doses of these agents with increasing risk of side effects. Thus new, more specific therapeutic modalities are greatly needed. The significance and timeliness of this area was recognized by a recent RFA (PAS-08-019). Hepcidin is the key regulator of systemic iron homeostasis and an acute phase reactant. Recent studies indicate that increased hepcidin production in inflammatory conditions is a principal contributor to the development of AI and is a likely cause of resistance to erythropoietin. Therefore, antagonizing hepcidin activity is a promising approach for improving therapies for AI. However, the specific molecular pathways that mediate the effect of hepcidin on ferroportin are poorly understood. We propose to define comprehensively the pathways activated by the interaction of hepcidin with its receptor ferroportin and identify compounds that antagonize these pathways. Specifically, we will: 1) Systematically discover hepcidin antagonists by high-throughput screening (HTS) with small molecule inhibitors and siRNA 2) Using identified hepcidin antagonists, characterize Fpn internalization pathways in cellular models 3) In animal models of AI, define the efficacy of selected antagonists and the contribution of the hepcidin- ferroportin axis to the disease process. The proposed approach will answer fundamental questions about the pathogenesis of AI and the related problem of resistance to erythropoiesis-stimulating agents. It may also provide lead compounds for further development as therapeutics. In the aggregate, this proposal effectively and comprehensively addresses an important and timely scientific and medical problem. PUBLIS HEALTH RELEVANCE: The proposed project will help understand and treat a common form of anemia which develops in infections and inflammatory disorders.