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Centenary Institute - Medical Research
Centenary Institute - Medical Research

Liver Enzymes in Metabolism and Inflammation Program

The increase in all forms of liver disease is a burden for our healthcare system. Furthermore the rise of fatty liver disease in conjunction with diabetes is of particular concern. Our focus in liver disease research is understanding the roles played by a key enzyme family.

We have discovered that the genes for encoding the for enzymes of this family are an important factor in influencing the disease. Also, enzymes make excellent drug targets to design. Our liver disease research has indicated that type 2 diabetes therapy may also combat fatty liver diseases.

We are working to understanding what makes chronic liver diseases wax and wane. When left untreated it often goes on to cause inflammation, high blood pressure and cancer. As a result we are learning about the tumour microenvironment to discover new treatment options.

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.

Professor Mark Gorrell heads the Liver Enzymes in Metabolism and Inflammation Program. He trained in cell biology, virology, immunology and protein biochemistry at the Australian National University, University of Melbourne and Johns Hopkins University in the USA.

His research is focussed upon liver scarring and 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 150 publications attracting H index 45, i10 index 100 and > 7,100 citations. His research was important in the development of DPP4-targeted therapies for type 2 diabetes, which are now used to treat millions of patients. His research experience also includes small RNA viruses, transcriptomics, proteomics and cell biology.

Professor Gorrell has supervised more than 16 PhD and M Phil students, was the 2018 Supervisor of the Year of Sydney Research and is an Academic Leader in Research Education in The University of Sydney Faculty of Medicine and Health, for which he received the 2019 SUPRA Award. He is active in the International Proteolysis Society, the Gastroenterological Society of Australia, NHMRC grant reviews, and is a senior editorial board member for Scientific Reports.

Research:
With colleagues, Professor Gorrell discovered that DPP4 and DPP8 modify the activities of several chemokines (1997 J Exp Med; 2008 FEBS Letters), and 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 insights into the safety of DPP4 inhibitors in clinical use (2011 SJI; 2013 PlosOne; 2018 ICB). He also discovered novel substrate recognition sites in DPPs used in drug development and protein-protein binding sites on DPP4, 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), and identified most of the known natural substrates of FAP (2011 FEBS J; 2016 Peptides; 2019 MCP) and DPP9 (2015 FEBS J).

Professor Gorrell was first to image collagen in human liver by second harmonics (2003 J Struct Biol). He also developed the first specific enzyme assay for FAP (2014 FEBS), which he used to map the bodily distribution of FAP and discover that measuring FAP in human blood is a useful biomarker for liver fibrosis (2015 Diabetes Research).

The team found that DPP9 is essential for the survival of mice (2013 PlosOne; 2016 Expl Cell Res) and that DPP9 influences growth factor dependent cellular proliferation (2011 Mol Cancer Res).

Professor Gorrell has a keen interest in models of disease (2011 J Hepatol). His 2017 paper showing the importance of DPP4 in liver fibrosis is the best on that topic (Immunol Cell Biol). The team recently created a new model of primary liver cancer, which better resembles the current human situation of over-nutrition (2018 Scientific Reports) and better ways to examine tumour growth (2019 Cancers).