Biology of Dipeptidyl Peptidase IV and related proteins

Summary

Research projects centre on mouse models of liver disease and obesity and on the delineation of inhibitors, substrates, biochemistry and in vivo expression and function of the Dipeptidyl Peptidase IV [DPP-IV / DPP4] family that consists of DPP-IV, Fibroblast activation protein, DPP8 and DPP9.

Supervisor(s)

Associate Professor Mark Gorrell

Research Location

Camperdown - Centenary Institute

Program Type

Masters/PHD

Synopsis

The Dipeptidyl Peptidase (DPP) IV gene family contains four enzymes. Two of these enzymes, DP8 and DPP9, were first cloned in our lab. Some of the enzymatic functions of DPP8 and DPP9 overlap with those of DPPIV and the fourth enzyme of the family, fibroblast activation protein (FAP). DPPIV has roles in tumour growth, diabetes, arthritis, modulation of T cell proliferation and fat and glucose metabolism. Inhibitors are in clinical use to treat type II diabetes patients. DPP8 and DPP9 are expressed by lymphocytes and gut and liver cells and may also have a role in tumors. Fibroblast activation protein (FAP) has roles in tumour growth, fat and glucose metabolism, and in chronic liver disease. We have found that FAP expression strongly correlates with fibrosis score in patient biopsies, that human liver derived FAP is a gelatinase, that hepatic stellate cells made to overexpress FAP develop a more pro-fibrotic phenotype, and less fibrosis and less fatty liver develop in mice deficient in FAP gene expression. These data strongly implicate FAP in the tissue remodelling process that is a key feature of the pathogenesis of liver fibrosis and cirrhosis. Thus, FAP is a potential therapeutic target. FAP will be compared with DPPIV and DPP9 in some projects. Key questions to be addressed in future graduate research projects include in vitro and in vivo inhibitor studies, delineation of substrates, biochemistry and in vivo expression and function of these enzymes using gene knockout mice and by studying patient sera.

Additional Information

Current and recent postgraduate research student projects:

  • 2003-2007       PhD: Expression deficiency of Dipeptidyl Peptidase 8 and 9.
  • 2003-2008       PhD:. Role of discoidin domain receptor 1 in the molecular pathogenesis of fibrosis.
  • 2003-2007       PhD: Biology of fibroblast activation protein elucidated in gene knockout mice.
  • 2004-2007       PhD: Dipeptidyl Peptidase 9 expression and action.
  • 2005-2010       MMed: Roles of profibrotic cytokines in liver fibrosis in diabetes.
  • 2007-2011       PhD: Epitope tags in structural biology.
  • 2007-2010       PhD: Fibroblast activation protein ligands.
  • 2009-                PhD: DPP9 in cancer signalling
  • 2011-                PhD: protease substrates

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Keywords

Liver cirrhosis, Cancer, Fibrosis, Protein biochemistry, Cell imaging, enzymes, molecular biology, diabetes, Obesity, inflammation

Opportunity ID

The opportunity ID for this research opportunity is: 185