HEPHAESTIN--A COPPER PROTEIN INVOLVED IN IRON METABOLISM

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Disturbances of iron metabolism significantly impact human health. Over 1.5 billion people suffer from iron-deficiency anemia and the associated increased risk of impaired cognitive development, increased susceptibility to infection, and increased mortality. At particular risk are women of child-bearing age and infants. Iron excess due to the inherited iron-overload disorder hemochromatosis is relatively common in certain populations and causes hepatic cirrhosis, diabetes, arthritis and cardiac disease. Despite the clinical prevalence of iron deficiency and iron overload, dietary iron uptake is poorly understood. The investigation of a unique mammalian model of iron deficiency anemia, the sla mouse, has revealed a fundamental component of intestinal iron transport. Sla mice take up iron from the intestinal lumen but have greatly diminished export of iron out of transmembrane-bound ceruloplasmin homologue highly expressed in the mature absorptive cells of the small intestine, the primary site of iron uptake in gastrointestinal tract. We have named this protein "Hephaestin" and hypothesize that it is a ferroxidase necessary for iron export from the intestine. First, we will determine the cellular location of the hephaestin protein and, second, determine the spatial and temporal expression pattern of the hephaestin mRNA and protein as compared to the related protein ceruloplasmin. Thirdly, we will ask whether the expression of hephaestin is regulated by the copper or iron status of the body. Finally, we will develop a functional assay for the hephaestin protein and determine its role in intestinal iron export. Understanding of the basic systems of iron transport by the mammalian organism is necessary to understand the etiology of iron deficiency anemia and iron overload in humans and devise effective therapies.