Disorders of iron metabolism are among the most prevalent diseases in humans. Iron deficiency is thought to affect greater than one billion people worldwide, particularly women and children. The anemia of chronic inflammation, resulting from disordered systemic iron distribution, is the most common form of anemia in hospitalized patients as well as patients with common chronic diseases such as heart failure, rheumatoid arthritis, renal disease, and cancer. The inherited iron overload disorders collectively known as hereditary hemochromatosis are similarly common;the prevalence of a single mutant allele, HFE, that confers a risk for iron overload is as much as 10% in individuals of Northern European descent. The transmembrane transport of iron and copper, another essential micronutrient, are substantially dependent upon protein reductases to maintain the metals in the oxidation state required by the predominant cell surface and endosomal metal importers. For example, erythroid cells are uniquely dependent upon the transferrin cycle for iron acquisition. Transferrin binds ferric (Fe3+), whereas ferrous (Fe2+) iron is the species that is transported across the endosomal membrane. This necessitates an intra-endosomal reduction step. We recently identified the major erythroid transferrin cycle endosomal ferrireductase, Steap3, by positionally cloning the mouse iron deficiency anemia mutant nm1054. Steap3 is one of a family of four homologous proteins in mammalian genomes, three of which we have recently demonstrated have not only ferrireductase, but also cuprireductase, activity. In this grant we will investigate the roles of the Steap proteins in metal metabolism through gene expression, cross-complementation, murine deficiency phenotypic analyses, and protein association studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080011-08
Application #
7917342
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Wright, Daniel G
Project Start
2003-07-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
8
Fiscal Year
2010
Total Cost
$348,422
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Bartnikas, Thomas B; Steinbicker, Andrea U; Campagna, Dean R et al. (2013) Identification and characterization of a novel murine allele of Tmprss6. Haematologica 98:854-61
Bartnikas, Thomas B; Wildt, Sheryl J; Wineinger, Amy E et al. (2013) A novel rat model of hereditary hemochromatosis due to a mutation in transferrin receptor 2. Comp Med 63:143-55
Anderson, Sheila A; Nizzi, Christopher P; Chang, Yuan-I et al. (2013) The IRP1-HIF-2? axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab 17:282-90
White, Carine; Yuan, Xiaojing; Schmidt, Paul J et al. (2013) HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17:261-70
Bartnikas, Thomas B; Parker, Clarissa C; Cheng, Riyan et al. (2012) QTLs for murine red blood cell parameters in LG/J and SM/J F(2) and advanced intercross lines. Mamm Genome 23:356-66
Bartnikas, Thomas B; Fleming, Mark D (2012) Hemojuvelin is essential for transferrin-dependent and transferrin-independent hepcidin expression in mice. Haematologica 97:189-92
Schmidt, Paul J; Fleming, Mark D (2012) Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2. Am J Hematol 87:588-95
Bartnikas, Thomas B; Andrews, Nancy C; Fleming, Mark D (2011) Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood 117:630-7
Bartnikas, Thomas B; Fleming, Mark D (2010) A tincture of hepcidin cures all: the potential for hepcidin therapeutics. J Clin Invest 120:4187-90
Schmidt, Paul J; Andrews, Nancy C; Fleming, Mark D (2010) Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin. Blood 116:5679-87

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