Dr Ermanno Gherardi
Based: MRC Centre, Cambridge
Donor: Frank Litchfield Charitable Trust
Amount: £88,044 (payable over 3 years)
Start date: October 2000
Title of study: Engineered forms of HGF/SF in liver disease
This was a three year research project.
Download: Gherardi final report.pdf
"The behaviour of liver cells is controlled by signals that instruct them to divide or perform functions that are specific to the liver. One of these signals is HGF/SF, a protein essential for liver development and that may play an important role in liver regeneration after injury.
Our laboratory, which is based at the MRC Centre in Cambridge, aims to harness the therapeutic potential of HGF/SF for treating acute and chronic liver disease and is using genetic engineering in order to make the protein more suitable for clinical applications.
The natural form of HGF/SF is very potent in promoting the growth of liver cells in culture but, when introduced in the circulation, it only reaches a fraction of the target cells because it is trapped in the intercellular space (the so-called extracellular matrix).
It demonstrated that it is possible to alter HGF/SF by genetic engineering in order to diminish trapping in the tissue and increase therapeutic activity. We have also demonstrated that the engineered proteins are very active in promoting the survival of mice treated with lethal doses of N-Acetyl-p-aminophenol (APAP) or by Ą-amanitin, two experimental models of acute liver damage.
These results indicate that engineered forms of HGF/SF or NK1 (the receptor binding fragment of HGF/SF) may be useful in acute liver failure and open the prospect of specific clinical studies. They also imply that these molecules may have potential therapeutic activity in chronic liver disease, a point that will be addressed in the third year of the project."
Dr E Gheradi, 2000
Reference:
Lietha D, Chirgadze DY, Mulloy B, Blundell TL and Gherardi E; Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor; EMBO J , 2001; 20: 5543-5555