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Liver Cell Biology

Lab head: Dr Nicholas Shackel
Location: Centenary Institute of Cancer Medicine and Cell Biology

 

To understand the molecular mechanisms regulating liver fibrosis aiming to developed novel therapeutic agents as well as developing new diagnostic investigations.

 

The current focus of the research group is to further understand the role of the glycoprotein CD147 in mediating basic and fundamental aspects of tissue inflammatory responses and carcinogenesis. Our group has made the fundamental discovery that CD147 mediates a process of inflammatory cell aggregation, which was previously not recognised that mediates inflammatory responses and carcinogenesis. Taking this novel discovery from the bench through to high impact papers is the current focus of the group.

To understand the molecular mechanisms regulating liver fibrosis aiming to developed novel therapeutic agents as well as developing new diagnostic investigations.
 
The current focus of the research group is to further understand the role of the glycoprotein CD147 in mediating basic and fundamental aspects of tissue inflammatory responses and carcinogenesis. Our group has made the fundamental discovery that CD147 mediates a process of inflammatory cell aggregation, which was previously not recognised, that mediates inflammatory responses and carcinogenesis. Taking this novel discovery from the bench through to high impact papers is the current focus of the group.

Website: http://www.centenary.org.au/p/ourresearch/liver/liverimmunobiology/LiverCellBiology/
Lab members: Dr Nicholas Shackel Dr Fiona Warner A/Prof Susan McLennnan Dr Annette Maczurek (Post-doctoral scientist) Aimei Lee (PhD Student) William d'Avigdor (PhD Student) Dr Emilia Prakoso (PhD Student) 1 new post-doctoral scientist starting in Nov 2012 2 new PhD students starting in 2013
Funding: In excess of $500,000
Research approach equipment: We use a range of techniques includes genomics analysis, confocal fluorescence, flow cytometry, Immunohistochemistry, quantitative PCR and Western blot analysis. Our group runs the facility for Gene Array Analysis with thin the Centenary Institute using both the latest Affymetrix Platform and Nimblegen
Publications:

 

1.         Rahman W, Huang P, Belov L, Chrisp JS, Christopherson RI, Stapelberg PM, Warner FJ, et al. Cluster of Differentiation (CD) Antibody Array Analysis of Human Liver Disease. Liver International 2012.

2.         McCaughan GW, Gorrell MD, Bishop GA, Abbott CA, Shackel NA, McGuinness PH, Levy MT, et al. Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance. Immunological reviews 2000;174:172-191.

3.         Yin JL, Shackel NA, Zekry A, McGuinness PH, Richards C, Putten KV, McCaughan GW, et al. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for measurement of cytokine and growth factor mRNA expression with fluorogenic probes or SYBR Green I. Immunology and cell biology 2001;79:213-221.

4.         McGaughan GW, Shackel NA, Gorrell MD. Discussion on differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 2001;121:1263-1264.

5.         Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. The American journal of pathology 2002;160:641-654.

6.         Shackel NA, Gorrell MD, McCaughan GW. Gene array analysis and the liver. Hepatology 2002;36:1313-1325.

7.         Shackel NA, Rockey DC. Intrahepatic gene silencing by RNA interference. Gastroenterology 2004;126:356-358; discussion 358-359.

8.         Shackel NA, Rockey DC. Stem cells and liver disease: promise laced with confusion and intrigue. Gastroenterology 2004;127:346-348.

9.         Shackel N, Rockey D. In pursuit of the "Holy Grail"--stem cells, hepatic injury, fibrogenesis and repair. Hepatology 2005;41:16-18.

10.      Shackel NA, Seth D, Haber PS, Gorrell MD, McCaughan GW. The hepatic transcriptome in human liver disease. Comparative hepatology 2006;5:6.

11.      Shackel NA, McCaughan GW, Warner FJ. Hepatocellular carcinoma development requires hepatic stem cells with altered transforming growth factor and interleukin-6 signaling. Hepatology 2008;47:2134-2136.

12.      McCaughan GW, Shackel NA, Bertolino P, Bowen DG. Molecular and cellular aspects of hepatitis C virus reinfection after liver transplantation: how the early phase impacts on outcomes. Transplantation 2009;87:1105-1111.

13.      Rauch A, James I, Pfafferott K, Nolan D, Klenerman P, Cheng W, Mollison L, et al. Divergent adaptation of hepatitis C virus genotypes 1 and 3 to human leukocyte antigen-restricted immune pressure. Hepatology 2009;50:1017-1029.

14.      Eckersley-Maslin MA, Warner FJ, Grzelak CA, McCaughan GW, Shackel NA. Bone marrow stem cells and the liver: are they relevant? Journal of gastroenterology and hepatology 2009;24:1608-1616.

15.      Song S, Shackel NA, Wang XM, Ajami K, McCaughan GW, Gorrell MD. Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic human liver. The American journal of pathology 2011;178:1134-1144.

16.      McCaughan GW, Shackel NA, Bowen DG. Liver transplantation and hepatitis C: will understanding the interleukin-28B polymorphisms improve outcomes? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2011;17:219-221.

17.      Bao W, Min D, Twigg SM, Shackel NA, Warner FJ, Yue DK, McLennan SV. Monocyte CD147 is induced by advanced glycation end products and high glucose concentration: possible role in diabetic complications. American journal of physiology. Cell physiology 2010;299:C1212-1219.

18.      Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Insights into the Pathobiology of Hepatitis C Virus Associated Cirrhosis: Analysis of Intrahepatic Differential Gene Expression. American Journal of Pathology 2002;160:641-654.


Glycosylation of Extracellular Matrix Metalloproteinase inducer (EMMPRIN) in human liver disease and the development of cirrhosis and hepatic carcinoma

Primary supervisor: Nicholas Shackel

 

Glycosylation of Extracellular Matrix Metalloproteinase inducer (EMMPRIN) in human liver disease and the development of cirrhosis and hepatic carcinoma

 

Supervisors:  Dr Nick Shackel and A/Prof Sue McLennan

 

Liver Cell Biology                            Centenary Institute http://www.centenary.org.au/p/ourresearch/liver/liverimmunobiology/LiverCellBiology/

Dr. Nick Shackel                      n.shackel@centenary.usyd.edu.au                   9565-6286

A/Prof. Sue McLennan             sue.mclennan@sydney.edu.au                        9515-5185

 

Background: Liver disease resulting from persistent hepatic injury by alcohol abuse or chronic hepatitis infections is an increasing cause of mortality in our community. Liver injury is characterised by remodeling of the extracellular matrix (ECM) or scar formation within the liver that gives rise to fibrosis, cirrhosis and eventually hepatic carcinoma (HCC).

 

Extracellular Matrix Metalloproteinase inducer(EMMPRIN) is an abundant glycoprotein and a potent inducer of matrix metalloproteinases (MMPs) in cells. MMPs play an important role in the natural occurring ECM turnover, and an imbalance in MMPs expression has a major impact on the composition of the ECM, leading to fibrosis and subsequently cirrhosis. Following gene array analysis of human liver samples from healthy and cirrhosis affected individuals, we identified increased expression of EMMPRIN in primary biliary cirrhosis (PBC) and hepatitis C virus (HCV) associated cirrhosis (1, 2). In addition to its role in induction of MMPs, EMMPRIN has been shown to enhance angiogenesis and invasion potential of tumor cells. There are three N-glycosylation sites on the protein EMMPRIN. It has been shown that glycosylation of EMMPRIN affects its MMP stimulating activity. Therefore EMMPRIN glycosylation is likely to determine extracellular matrix remodeling and progression of liver disease.

 

 

Hypothesis and aims: We hypothesize that the glycosylation pattern of EMMPRIN plays a role in liver injury and the development of cirrhosis and hepatic carcinoma. Our aim with this project is to identify and characterise the glycosylation pattern of EMMPRIN in liver injury.

1.     Glycosylation of EMMPRIN will be analysed in livers of patients that developed cirrhosis and HCC following chronic liver injury compared to donor livers.

2.     Mutant EMMPRIN proteins with mutations at three known N-glycosylation sites (independently and combined) will bepurified and analysed.

 

 

Skills:This project will utilise confocal microscopy, mammalian cell culture, transfection, animal models, primary cell isolation and flow cytometry as well as immunohistochemistry techniques. It is envisaged that the student who undertakes this project will become proficient in all of these methods whilst being exposed to a number of other general laboratory techniques.

Conclusion and significance: This project will answer important questions about the functional significance of glycosylation of EMMPRIN in development of liver disease and cancer progression whilst exposing the student to a broad range of laboratory skills.

 

 

Contacts:For further information and to arrange a time to discuss the project details please contact Dr N. Shackel on 0434603129 or email n.shackel@centenary.usyd.edu.au. 

 

Selected references:

1. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 2001;49:565‐576.

2. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Insights into the pathobiology of hepatitis C virus‐associated cirrhosis: analysis of intrahepatic differential gene expression. Am J Pathol 2002;160:641‐654.


Discipline: Infectious diseases and Immunology
Co-supervisors: Susan McLennan
Keywords: Cancer, Liver Cancer, Liver fibrosis
Contact: Email Nicholas Shackel