Human conditions with disrupted iron homeostasis are very common and most centre around the inappropriate production of the peptide hormone hepcidin, which regulates body iron metabolism. Hepcidin is produced by the liver and secreted into the bloodstream where it acts as a negative regulator of intestinal iron absorption and storage iron release. Prominent examples of conditions associated with altered hepcidin production are hereditary haemochromatosis, the anaemia of inflammation and b-thalassaemia.
To investigate the pathways by which hepcidin production is regulated by the body and to investigate ways to manipulate these pathways with the aim of treating diseases of iron homeostasis.
A range of techniques and models will be used to examine the regulation of hepatic hepcidin expression. The in vivo role of soluble forms of Hfe and Tfr2 will be determined using adenovirus-mediated overexpression in mice, as each of these molecules has the potential to modulate hepcidin production. Knockdown of hepatocyte Smad6 and Smad7 will be achieved using siRNA in mouse models of haemochromatosis and b-thalassaemia to determine whether inhibition of these molecules can modulate disease progression. Studies will also be carried out in cells in culture. Analysis of the BMP6 promoter will be carried out in cultured stellate cells and sinusoidal endothelial cells to seek regulatory elements that might provide targets for future pharmacological interventions. In addition, potential small molecule modulators of BMP6 induced hepcidin expression will be investigated by screening hepatocyte cells in culture with a panel of molecules from the Scaffold Collection available at Compounds Australia, Eskitis Institute for Drug Discovery.
Techniques to be used include mouse breeding and dietary manipulation, tissue culture, drug screening, microscopy and immunohistochemistry, gene and protein expression studies, in vivo viral-mediated gene manipulation and trace element analysis.