In this research proposal we hypothesise that the paracrine release of tissue ferritin by damaged liver cells in chronic liver disease, causes an inflammatory response via ferritin endocytotic and signalling receptors on hepatic stellate cells (HSCs – liver fibroblasts), which drives hepatic fibrogenesis and cirrhosis, which may ultimately be associated with the development of hepatocellular carcinoma. While the association between inflammation and circulating ferritin in chronic liver injury is well established, we propose that rather than simply being a consequence of inflammation, elevated tissue-derived ferritin plays a role in mediating processes associated with hepatic injury.
This study is designed to determine the identity of the HSC ferritin signalling and endocytotic receptors and thus the pathways which facilitate upregulated inflammation in hepatic fibrogenesis. We have identified a number of highly novel ferritin-binding proteins with signalling potential in HSCs. In this study we will characterise theses candidates and other potential cell surface/intracellular binding proteins using confocal/live microscopy and proteomic analysis coupled with bioinformatic platforms. We propose that HSCs are exposed to ferritin released from iron-damaged hepatocytes or following Kupffer cell phagocytosis of hepatocyte remnants/apoptotic bodies. This study will assess the paracrine role of released hepatocellular ferritin in regulating HSC activation via ferritin receptor candidates.
Physiological relevance will be demonstrated in animal models of injury/inflammation. Clinical significance will be demonstrated in human chronic liver disease by assessing the association between serum/liver ferritins and their receptors, and inflammation and hepatic fibrosis severity. These are highly novel and innovative studies which will identify proinflammatory ferritin-induced signalling pathways in HSC. Strategies designed to reduce the impact of liver disease in the future will have to rely on new treatments targeting such regulatory pathways. Our proposal will provide an important cornerstone for such advances.
- PhD project but may also be considered for a Honours project.