application) The broad long-term objectives of this project are to gain a greater understanding of the biology of iron absorption (uptake and transfer) with a view to the development of novel therapeutic approaches to iron overload diseases. Recent exciting discoveries including the hemochromatosis gene HFE and the metal transporters DMT1, hephaestin and SFT have provided the opportunity to study the steps in the pathway of iron uptake and transport across the intestinal cell as well as intracellular signaling pathways involved. In the first instance it is proposed to examine the distribution of both HFE mRNA and proteins in normal individuals, patients with hemochromatosis, other forms of iron overload and iron deficiency as well as in several animal models. In addition, this project will investigate the distribution and expression of DMT1, hephaestin, Ireg1 and SFT in these human subjects and animal models. These studies will be integrated with a more detailed analysis of HFE trafficking and processing, including the precise nature of the assembly, localization, transport and degradation of the HFE molecule. This knowledge will provide an avenue for the development of therapeutics aimed at increasing the secretion and transport of the mutated form of HFE to the compartment where it is active. The experiments in the various animal models should allow the elucidation of the relative contributions of brush border uptake and basolateral transfer in normal and abnormal iron homeostasis and the responses to various stimuli known to modulate iron absorption. A novel aspect of the experimental protocol involves hepatocyte transplantation to examine the role of the liver in regulating iron absorption. A major aspect of this study is the determination of the three dimensional structure of hephaestin and DMT1 and to use these in structure based design studies to develop novel therapeutic agents that inhibit intestinal iron absorption. Such agents will be particularly applicable to the treatment of disorders in which iron absorption is elevated, such as hemochromatosis and thalassemia. In the former this should reduce or even abolish the requirement for prolonged phlebotomy therapy which is time-consuming, expensive and often poorly tolerated by patients. The approach is a multidisciplinary one combining the expertise of members of the Clinical Sciences Unit of QIMR in iron metabolism with that of x-ray crystallography and structure-based drug design studies at the Centre for Drug Design and Development in the University of Queensland.
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