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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082717-05
Application #
8322327
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Wright, Daniel G
Project Start
2008-09-30
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$320,737
Indirect Cost
$112,466
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kim, Airie; Nemeth, Elizabeta (2015) New insights into iron regulation and erythropoiesis. Curr Opin Hematol 22:199-205
Ruchala, Piotr; Nemeth, Elizabeta (2014) The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci 35:155-61
Rodriguez, Richard; Jung, Chun-Ling; Gabayan, Victoria et al. (2014) Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun 82:745-52
Preza, Gloria Cuevas; Pinon, Rogelio; Ganz, Tomas et al. (2013) Cellular catabolism of the iron-regulatory peptide hormone hepcidin. PLoS One 8:e58934
Fung, Eileen; Sugianto, Priscilla; Hsu, Jason et al. (2013) High-throughput screening of small molecules identifies hepcidin antagonists. Mol Pharmacol 83:681-90
Tussing-Humphreys, Lisa; Pusatcioglu, Cenk; Pustacioglu, Cenk et al. (2012) Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin. J Acad Nutr Diet 112:391-400
Goodnough, Julia B; Ramos, Emilio; Nemeth, Elizabeta et al. (2012) Inhibition of hepcidin transcription by growth factors. Hepatology 56:291-9
Qiao, Bo; Sugianto, Priscilla; Fung, Eileen et al. (2012) Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 15:918-24
Ravasi, Giulia; Pelucchi, Sara; Trombini, Paola et al. (2012) Hepcidin expression in iron overload diseases is variably modulated by circulating factors. PLoS One 7:e36425
Ganz, Tomas; Nemeth, Elizabeta (2012) Hepcidin and iron homeostasis. Biochim Biophys Acta 1823:1434-43

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