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

描述(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有关，并导致其发病率。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、静脉补铁或它们的组合越来越多地被用于治疗这种疾病，但这种治疗只有部分有效，而且经常需要高剂量的这些药物，副作用的风险增加。因此，迫切需要新的、更具体的治疗方式。这一领域的重要性和及时性得到了最近的一份区域评估报告(PAS-08-019)的承认。海普西丁是全身铁稳态的关键调节剂，也是一种急性时相反应物。最近的研究表明，炎症条件下海普西丁的产生增加是AI发生的主要原因，也可能是对促红细胞生成素产生抵抗的原因。因此，拮抗海普西丁活性是改善AI治疗的一条很有前途的途径。然而，介导海普西丁对铁蛋白作用的具体分子途径却知之甚少。我们建议全面定义海普西丁与其受体铁蛋白相互作用所激活的通路，并确定拮抗这些通路的化合物。具体地说，我们将：1)通过使用小分子抑制剂和siRNA的高通量筛选(HTS)系统地发现海普西丁拮抗剂；2)使用已鉴定的海普西丁拮抗剂，表征FPN在细胞模型中的内化途径；3)在AI的动物模型中，确定所选拮抗剂的疗效以及海普西丁-铁门蛋白轴在疾病过程中的贡献。所提出的方法将回答有关AI发病机制的基本问题以及与红细胞生成刺激剂耐药相关的问题。它还可能为进一步开发治疗药物提供先导化合物。总体而言，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形式的贫血，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.