The regulation of body iron homeostasis

Projects can be adapted to suit Honours or PhD student.

BACKGROUND

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.

AIMS

To investigate the pathways by which hepcidin production is regulated and to investigate ways to manipulate these pathways with the aim of treating diseases of iron homeostasis.

APPROACH

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 TFR1 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, including an in-depth analysis of the binding of soluble TFR1 to membrane bound HFE and factors affecting this interaction.