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

Public Health Relevance

The proposed project will help understand and treat a common form of anemia which develops in infections and inflammatory disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Wright, Daniel G
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Ruchala, Piotr; Nemeth, Elizabeta (2014) The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci 35:155-61
Fung, Eileen; Sugianto, Priscilla; Hsu, Jason et al. (2013) High-throughput screening of small molecules identifies hepcidin antagonists. Mol Pharmacol 83:681-90
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Preza, Gloria C; Ruchala, Piotr; Pinon, Rogelio et al. (2011) Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 121:4880-8
Clark, Richard J; Tan, Chia Chia; Preza, Gloria C et al. (2011) Understanding the structure/activity relationships of the iron regulatory peptide hepcidin. Chem Biol 18:336-43
Ramos, Emilio; Kautz, Leon; Rodriguez, Richard et al. (2011) Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 53:1333-41
Gardenghi, Sara; Ramos, Pedro; Marongiu, Maria Franca et al. (2010) Hepcidin as a therapeutic tool to limit iron overload and improve anemia in ýý-thalassemic mice. J Clin Invest 120:4466-77

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