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ECRU Biotechnology Group

Staff Members

Head: Dr Anthony Dear

Post-Doctoral Research Scientist

Dr Hong Bin-Liu

BSc (hons) Student

Mr David Martin

Post Doctoral Fellow

Dr Yunshan Hu

Research Activities

The matrix biology group was established in 2001 with a view to exploring the therapeutic regulation of extracellular matrix (ECM) degrading enzyme systems, principally the plasminogen activating (PA) and matrix metalloproteinase (MMP) enzyme cascades, in the setting of cancer and vascular disease.

The PA and MMP enzyme systems have classically been associated with cell surface mediated degradation of the ECM, facilitating cellular migration in the setting of physiological conditions such as wound healing and inflammation. Aberrant, excessive expression of PA and MMP members is thought to contribute to the metastatic phenotype by facilitating malignant cell migration through natural barriers, dissemination into blood and lymphatic vessels, and subsequent formation of distant tumour foci. The PA and MMP systems are also thought to contribute to malignant tumour growth and development via facilitation of proteolytic events associated with tumour derived endothelial cell migration in the process of angiogenesis.

In the setting of vascular disease, elevated expression levels of PA and MMP system members have recently been identified as contributing to enhanced ECM turnover seen in conditions such as atherosclerosis, neointimal hyperplasia and the progression of abdominal aortic aneurism dilatation.

In conjunction with mediating pericellular proteolysis in both health and disease recent evidence identifies additional functional roles, for members of the PA and MMP systems including propagation of transmembrane signalling events and regulation of gene expression. These observations suggest a pleiotropic role for both PA and MMP family members, beyond that originally identified, which may contribute to their functional involvement in both physiological and pathological processes.

Research is being conducted into the regulation, by small molecule inhibitors, of PA and MMP family members, which may be of benefit in the treatment of metastatic cancer and vascular disease. Identification and assessment of non-proteolytic events mediated by the PA and MMP family members and the functional contribution of these effects to cellular processes such as migration are also a focus of research activities undertaken by the group.

Current Research Projects

  1. In vitro and In vivo Assessment of Small Molecule Inhibitors of Extracellular Matrix Degradation in Metastatic Malignancy.
  2. Assessment of Inhibition of Extracellular Matrix Turnover in In vitro and In vivo models of Vascular Disease.

Publications

  1. Dear A.E, Medcalf R.L. “Molecular and Cellular Biology of Plasminogen Activator Inhibitor Type- 2 (PAI-2)”. Invited review: Fibrinolysis 9: 321-30 (1995).

  2. Dear A.E, Ruegg M, Shen Y, Medcalf R.L. “Molecular mechanisms governing TNF mediated regulation of plasminogen activator inhibitor type-2 (PAI-2)”. Eur. J. Biochem 241:93-100 (1996).

  3. Dear A.E, Costa M, Medcalf R.L. “Urokinase mediated transactivation of the Plasminogen activator inhibitor type 2 (PAI-2) gene promoter in HT-1080 cells utilises AP-1 binding sites and potentiates phorbol ester-mediated induction of PAI-2 mRNA”. FEBS Lett 402:265-272 (1997).

  4. Dear A.E, Medcalf RL. (1998). “The urokinase type plasminogen activator receptor (u-PAR) (CD 87): A pleiotropic Molecule”. Eur.J.Biochem 252:185-193 (1998).

  5. Dear A.E, Medcalf R.L. “The Novel Anti-Tumour Agent Oxamflatin Differentially Regulates and Urokinase and Plasminogen Activator Inhibitor Type 2 expression and inhibits urokinase-mediated proteolytic activity”. Biochim Biophys Acta 1492:15-22 (2000).

  6. Kuan YM, Dear AE, Grigg MJ Homocysteine: An aetiological contributor to peripheral vascular arterial disease. ANZ J Surg 72:668-671 (2002)

  7. Peart MJ, Dear AE, Tainton KM, Ruefli AA, Sedelies K, Trapani JA, Smyth MJ, Johnstone RW. “Novel Mechanisms of Apoptosis Induced by Histone Deacetylase Inhibitors“. Cancer Res. Aug 1;63(15):4460-71 (2003).

  8. Cakarovski K, Leung J, Restall C, Carin-Carlsson A, Yang E, Perlmutter P, Anderson R, Medcalf RL and Dear AE. “Novel Inhibitors or Urokinase Type Plasminogen Activator and Matrix Metalloproteinase Expression and Activity in Metastatic Cancer Cell Lines”. Int.J.Cancer 110:610-616 (2004).

  9. Liu HB, Dear AE, Medcalf RL and Simpson RW. “Rosiglitazone and Pioglitazone-Mediated Inhibition of Plasmonogen Activator Inhibitor Type 1 (PAI-1) Expression in C11-STH Human Vascular Endothelial Cells. A Possible Mechanism for Thiazolidinedione-Mediated Attentuation of Atherosclerosis” Cardiovascular Pathology, 13:3 Suppl 1:99-100 (2004).