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，也称为慢性疾病性贫血）与多种感染性和炎症性疾病相关，并导致其发病率。人工智能的发病机制尚不完全清楚，治疗方案也有限。促红细胞生成素、静脉注射铁或它们的组合越来越多地用于治疗这种疾病，但这种治疗只是部分有效，而且往往需要高剂量的这些药物，副作用的风险也在增加。因此，迫切需要新的、更具体的治疗方式。最近的RFA （PAS-08-019）承认了这一领域的重要性和及时性。Hepcidin是全身铁稳态的关键调节因子，也是急性相反应物。最近的研究表明，炎症条件下hepcidin产生的增加是AI发展的主要因素，也是对促红细胞生成素产生耐药性的可能原因。因此，拮抗hepcidin活性是改善AI治疗的一种有希望的方法。然而，介导hepcidin对铁转运蛋白影响的特定分子途径尚不清楚。我们建议全面定义hepcidin与其受体铁转运蛋白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)通过小分子抑制剂和siRNA的高通量筛选（HTS）系统地发现hepcidin拮抗剂；2)利用已鉴定的hepcidin拮抗剂，在细胞模型中表征Fpn内化途径；3)在AI动物模型中，确定所选拮抗剂的疗效以及hepcidin-铁转运蛋白轴对疾病过程的贡献。提出的方法将回答关于AI的发病机制和对促红细胞生成素的抗性的相关问题的基本问题。它也可能为进一步开发治疗药物提供先导化合物。总而言之，这一建议有效而全面地解决了一个重要而及时的科学和医学问题。与publicis健康相关：拟议的项目将有助于了解和治疗一种常见的贫血，这种贫血是由感染和炎症性疾病引起的。

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.