The pathogenesis of anemia of inflammation and the homeostatic regulation of iron absorption and distribution rank among the major unsolved problems in classical hematology. We identified and characterized human hepcidin, a new 25 amino acid peptide made in the liver and excreted in urine. Remarkably, the production of this peptide was strongly induced by infection, inflammation and iron overload. Others have shown that hepcidin inhibits iron absorption in the small intestine and placental iron import, and induces the sequestration of iron in macrophages. Hepcidin may thus be the iron stores regulator and the key mediator of anemia of inflammation. We now propose to explore the role of hepcidin in the pathogenesis of anemia of inflammation by elucidating the regulation of hepcidin production by inflammation, infection, and iron status, and its counter-regulation by anemia. We will test the hypothesis that interleukin-6 is the key mediator of hepcidin regulation. Specifically, we will: 1. Characterize the regulation of hepcidin synthesis by cytokines and pathogen-associated molecules; 2. Analyze the counter-regulation of cytokine-induced hepcidin synthesis by erythropoietin and hypoxia; 3. Elucidate the regulation of hepcidin synthesis by iron; 4. Analyze the regulation of hepcidin synthesis by iron and inflammation in healthy volunteers, in patients with classical and non-classical hemochromatosis, and in patients with anemia of inflammation. To maximize the applicability of the work to human patients, we will study the regulation of hepcidin excretion in healthy volunteers and patients with various types of hemochromatosis. This work is important both for the fundamental understanding of iron metabolism and for its exciting translational potential in the treatment of anemia of inflammation and some forms of hemochromatosis. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Wright, Daniel G
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
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Stefanova, Deborah; Raychev, Antoan; Deville, Jaime et al. (2018) Hepcidin Protects against Lethal Escherichia coli Sepsis in Mice Inoculated with Isolates from Septic Patients. Infect Immun 86:
Ganz, Tomas (2018) Erythropoietic regulators of iron metabolism. Free Radic Biol Med :
Coffey, Richard; Ganz, Tomas (2017) Iron homeostasis: An anthropocentric perspective. J Biol Chem 292:12727-12734
Latour, ChloƩ; Wlodarczyk, Myriam F; Jung, Grace et al. (2017) Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia. Haematologica 102:60-68
Aschemeyer, Sharraya; Gabayan, Victoria; Ganz, Tomas et al. (2017) Erythroferrone and matriptase-2 independently regulate hepcidin expression. Am J Hematol 92:E61-E63
Ganz, Tomas; Jung, Grace; Naeim, Arash et al. (2017) Immunoassay for human serum erythroferrone. Blood 130:1243-1246
Ganz, Tomas; Nemeth, Elizabeta (2016) Iron Balance and the Role of Hepcidin in Chronic Kidney Disease. Semin Nephrol 36:87-93
Hanudel, Mark R; Chua, Kristine; Rappaport, Maxime et al. (2016) Effects of dietary iron intake and chronic kidney disease on fibroblast growth factor 23 metabolism in wild-type and hepcidin knockout mice. Am J Physiol Renal Physiol 311:F1369-F1377
Kim, Airie; Nemeth, Elizabeta (2015) New insights into iron regulation and erythropoiesis. Curr Opin Hematol 22:199-205
Drakesmith, Hal; Nemeth, Elizabeta; Ganz, Tomas (2015) Ironing out Ferroportin. Cell Metab 22:777-87

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