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Molecular Hepatology

The Molecular Hepatology team is focused on understanding the roles played by a key enzyme family in chronic liver diseases. We have clear indications from following successful targeting for type 2 diabetes therapy that related approaches may also combat fatty liver diseases.

We are working to understanding what makes chronic liver diseases wax and wane. Chronic liver disease often causes inflammation, high blood pressure and cancer.

Current Projects:

  1. 1  Circulating dipeptidyl peptidase 4 activity correlates with NAFLD severity in type 2 diabetes and obesity.
  2.  Dipeptidyl peptidase 4 is a driver of fatty liver and liver fibrosis.
  3.  Dipeptidyl peptidase 4 slows anti-tumour T cells getting into a tumour.
  4. Fibroblast activation protein in humans: Circulating levels rise with liver fibrosis and cirrhosis but not Rheumatoid Arthritis or Systemic Sclerosis.
  5. Fibroblast activation protein functions: what are the important substrates.
  6.  Dipeptidyl Peptidase 9 functions: Targeted inactivation of Dipeptidyl Peptidase 9 enzyme activity as a cause of death in newborn mice and immune dysfunction in adult mice.
  7.  Homology modeling of human Kynurenine Aminotransferase III and binding by its inhibitors using molecular docking.

Associate Professor Mark Gorrell

Head of Molecular Hepatology Laboratory

Phone: +61 2 9565 6152
Mobile: +61 419 933 474
Email: m.gorrell@centenary.org.au

Associate Professor Mark Gorrell heads the Molecular Hepatology Laboratory in the Liver Injury and Cancer Program. He trained in cell biology, virology, immunology and protein biochemistry at Australian National University, University of Melbourne and Johns Hopkins University. His research is focussed upon liver cancer prevention and treatment, chronic liver disease pathogenesis, diabetes, protein and enzyme biochemistry and cell biology related to the proteases DPP4, DPP9 and fibroblast activation protein (FAP). He has authored over 130 publications attracting H index 40, i10 index 81 and > 5,000 citations. His research experience also includes small RNA viruses, transcriptomics, proteomics and cell biology. His research was important in the development of DPP4-targetted therapies for type 2 diabetes, which are now used to treat millions of patients. Inside Centenary Institute, he chairs the postgraduate research and equipment grants committees, is Sub-Dean for postgraduate research and a Commercialisation Committee member. Outside Centenary Institute, he is active in the International Proteolysis Society, the Gastroenterological Society of Australia, NHMRC grant reviews, and editorial boards of Journals including Scientific Reports.

Research:
With colleagues, he discovered that DPP4 modifies the activities of several chemokines [1997 J Exp Med]. He discovered DPP8, DPP9 and DPP10 (2000 FEBS J; 2004 BBA; 2006 BBA) allowing the development of DPP4 selective inhibitors. His work on DPP4 function in human T cells and on DPP9 provided key insights into the safety of DPP4 inhibitors in clinical use [2011 Scand J Immunol; 2013 PlosOne]. He also discovered novel substrate recognition sites in DPPs used in drug development, ligand binding sites on DPP4 that are binding sites of MERS virus, and constructed the first DPP4 protein structure prediction [1999 FEBS J; 1999 FEBS Lett].

His team showed that DPP4, FAP and DPP9 amplify cell death signals and alter cell adhesion [2006 FEBS J; 2005 Hepatology; 2011 Mol Cancer Res; 2015 BBA-MCR], identified several chemokines cut by DPP8 [2008 FEBS Letters], and identified most of the known substrates of FAP [2011 FEBS J] and DPP9 [2015 FEBS J]. Using novel 2-photon microscopy, showed that harmful collagen is near FAP in cirrhotic liver [2003 J Struct Biol]. He found that the levels of FAP in human blood specifically correspond to the presence of liver fibrosis [2015 Diabetes Research].

He found that mice lacking DPP9 die soon after birth and that these mice have metabolism defects [2013 PlosOne; 2016 Expl Cell Res]. He found that DPP9 influences growth factor signaling [2011 Mol Cancer Res].

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