- A/Prof David Frazer
Iron overload diseases represent one of the largest groups of inherited disorders worldwide. The primary iron overload disorder HFE-related haemochromatosis is the most common autosomal recessive disease in humans, affecting 1 in 180 Australians and leading to liver cancer, dementia, diabetes and arthritis if untreated. Iron loading anaemias such as beta-thalassaemia have equally devastating effects and are prominent in southern European, Middle Eastern and southeast Asian populations.
These two forms of iron loading share the common features of increased dietary iron absorption and macrophage iron recycling, both of which are secondary to reduced levels of the iron regulatory hormone hepcidin. Hepcidin acts by binding to the iron export protein ferroportin, reducing the amount of iron it delivers to the plasma. Ferroportin in turn requires a copper-dependent ferroxidase to export iron efficiently. It is this hepcidin/ferroportin/ferroxidase axis that is critical for body iron intake and distribution. While both hepcidin and ferroportin are being investigated as potential therapeutic targets for iron loading disorders, the essential ferroxidase component of this pathway has received little, if any, attention.
The goal of this project is to test the hypothesis that disrupting the activity of hephaestin, the main ferroxidase involved in dietary iron absorption will alleviate the iron loading that occurs in haemochromatosis and beta-thalassaemia.
This will be investigated using the following specific aims:
- To use knockout mice to examine the effect of disrupting hephaestin activity in mouse models of haemochromatosis and beta-thalassaemia
- To examine the effect of tetrathiomolybdate, a known inhibitor of hephaestin activity, on iron loading in mouse models of haemochromatosis and beta-thalassaemia
- To establish a high throughput assay using cultured cells to screen for novel compounds able to inhibit the activity of hephaestin.
- Mouse handling and experimental manipulation, including genotyping, use of knockout mice and crossing of genetic line
- Gene and protein expression analysis
- Biochemical analysis of iron levels
- Enzyme assays
- Cell culture, including maintenance of cells, establishment of screening assays and screening of compound libraries.
This project should determine whether the ferroxidase hephaestin is a viable pharmacological target for treating the iron loading conditions haemochromatosis and beta-thalassaemia.
You may be eligible to apply for a research scholarship.
A/Prof David Frazer
Phone: 0413 160 569
Affiliation: Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute