The Role of Extracellular Matrix Metalloprotease Inducer (EMMPRIN) in Liver Disease

Summary

The role of the hepatocyte in progressive liver injury.

Supervisor(s)

Dr Nicholas Shackel

Research Location

Camperdown - Centenary Institute

Program Type

Masters/PHD

Synopsis

Background: Liver injury has many diverse causes which result in a common progression of injury characterised by hepatocyte damage, hepatocyte regeneration, loss of hepatic architecture and bridging fibrosis in what is known pathologically as cirrhosis1. The sequelae of cirrhosis include liver failure and hepatocellular carcinoma (HCC). The global health burden from liver disease is immense with in excess of 450 million individuals infected with viral hepatitis and HCC being the fifth most common human malignancy2,3. Therefore, a better understanding of the pathophysiology of fibrogenesis is essential. The hepatocyte has classically been regarded as a “bystander” in the evolution of intrahepatic fibrogenesis. However, it is now clear that hepatocytes produce matrix metalloproteinases (MMPs) involved in extracellular matrix (ECM) remodelling4 (see preliminary results). Following gene array analysis of human liver disease we have identified increased hepatocyte expression of number of molecules including EMMPRIN, a known regulator of MMPs. Further, we have demonstrated that hepatocyte EMMPRIN regulates MMP production. Our results are the only description of molecules expressed on hepatocytes that are capable of ECM remodelling in fibrotic liver disease. 
Project Aims: This project proposal will study the role of hepatocytes in ECM remodelling. Further, we plan to focus on the role of the hedgehog pathway in progressive liver injury as well as using functional genomics approaches, including gene arrays and microRNA arrays, to better understand the molecular pathways pivotal to the progression of liver fibrosis. Achieving the aims of this project will lead to a new understanding of hepatic fibrogenesis and ultimately lead to better therapeutic interventions targeting the progression of liver fibrosis.

  1. Sancho-Bru, P., R. Bataller, X. Gasull et al., J Hepatol, 2005. 43(2): p. 272-82.
  2. Lai, C.L., V. Ratziu, M.F. Yuen, and T. Poynard, Lancet, 2003. 362(9401): p. 2089-94.
  3. Poynard, T., J. McHutchison, M. Manns, R.P. Myers, and J. Albrecht, Hepatology, 2003. 38(2): p. 481-92.
  4. Garciade Leon Mdel, C., I. Montfort, E. Tello Montes et al., Exp Mol Pathol, 2006. 80(1): p. 97-108.

Additional Information

Techniques:

  • Molecular Biology
  • Cell biology
  • Flow cytometry
  • Microarrays (gene and microRNAs)
  • Protein Biochemistry (Western blotting, target protein silencing protein-protein interactions studies)
  • Cell Culture
  •  Microscopy (light and confocal)
  • Animal model of liver injury
Possible research area for PhD topics:
  1. The role of hepatocyte in liver injury: A novel regulator of matrix remodeling?
  2. The role of EMMPRIN in the development of liver fibrosis and its progression to hepatocellular cancer.
  3. Genes regulating the development of progressive liver fibrosis.
  4. The role of the Hedgehog pathway in liver fibrosis and its progression to hepatocellular cancer.

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Keywords

Liver disease, Liver fibrosis, Liver cancer, Gene microarray, RNA silencing, Micro RNA, Hedgehog pathway, Liver & hormonal disorders, Cell biology, Human body

Opportunity ID

The opportunity ID for this research opportunity is: 134

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