Liver Cell Biology Lab

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

 

Ultimately we aim 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 cancer. Our group has made the fundamental discovery that CD147 alters immune cell function and aggregation, which was previously not recognised and this is important in driving liver injury and potential the development of cancer. 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 Thomas Tu (Post-doctoral scientist), Dr Annette Maczurek (Post-doctoral scientist), Magdalena Budzinska (Research Assistant), Christine Yee (Research Assistant), Aimei Lee (PhD Student), William d'Avigdor (PhD Student) and Robert Cheng (PhD Student)
Funding: Sydney Medical Research Foundation, Cancer Council NSW
Research approach equipment: We use a range of techniques includes genomics analysis, confocal fluorescence microscopy, flow cytometry, immunohistochemistry, quantitative PCR and Western blot analysis. Our group runs the facility for Gene Array Analysis within 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.         Shackel NA, Gorrell MD, McCaughan GW. Gene array analysis and the liver. Hepatology 2002;36:1313-1325.

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

4.      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.


The role of CD147 mediated cell aggregation in the development of human liver injury and liver cancer.

Primary supervisor: Nicholas Shackel

Supervisors:  Dr. Nick Shackel and A/Prof. Sue McLennan

 

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: Chronic liver injury is typically characterised by inflammation, progressive fibrosis and cirrhosis. The sequelae of cirrhosis include liver failure and hepatocellular carcinoma (HCC). The global health burden from liver disease is immense.

Our group has identified the glycoprotein CD147 as being highly expressed in liver injury and it now also has been found as upregulated in a variety of tumours, including HCC. CD147 not only induces matrix metalloproteinases (MMP) that participate in ECM remodelling, but also induces angiogenesis and plays a role in tumour energy metabolism through its interaction with monocarboxylate transporter 1 (MCT1). Clinical trials with LICARTIN (a 131Iconjugated mAB against CD147) for the prevention of HCC recurrence are currently underway and very promising.

We have made the novel discovery that CD147 mediates a process of inflammatory cell aggregation within the injured liver, which mediates further inflammatory responses and carcinogenesis.  When blocking CD147 by either using a monoclonal antibody or in our genetic CD147-/- knockout model we find significantly less liver injury which coincidences with a reduction in intrahepatic leukocyte aggregates.

Unfortunately, CD147 is expressed on hepatocytes and leukocytes, and while we see that blocking CD147 function shows a reduction in liver injury we cannot tell whether it is the leukocyte or hepatocyte CD147 expression which is responsible.

We are planning to specifically knockout CD147 in hepatocytes and leukocytes and have access to floxed CD147 mice and Alb-Cre and Vav-cre animals, within our research institute. Crossing those animals allows us to delete CD147 in either the hematopoietic system or hepatocytes.

Hypothesis:

CD147 on leukocytes or hepatocytes plays an important role in inflammation associated liver injury and progression to HCC.

Aims:

1.     Characterization liver injury in animals with hepatocyte-specific CD147 deletion.

2.     Characterization liver injury in animals with leukocyte-specific CD147 deletion.

 

Skills: This project will utilise confocal microscopy, real-time RT-PCR, 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.

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.

 

Relevant References:

1.      Xu J, Shen ZY, Chen XG, Zhang Q, Bian HJ, Zhu P, Xu HY, Song F, Yang XM, Mi L,
Zhao QC, Tian R, Feng Q, Zhang SH, Li Y, Jiang JL, Li L, Yu XL, Zhang Z, Chen ZN. A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 2007. 45(2):269-76

2.         Shackel, N.A., et al., Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut, 2001. 49(4): 565-76.


Discipline: Infectious diseases and Immunology
Co-supervisors: Assoc Prof Sue McLennan
Keywords: Liver Disease, Liver fibrosis, Liver Cancer
Contact: