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Dr Robert L Medcalf
Department of Medicine
Monash University
Box Hill Hospital, Box Hill 3128, Victoria
Email: Robert.medcalf@med.monash.edu.au
Tel: +61-3-9895 0318
Fax: +61-3-9895 0332
Homepage: http://www.med.monash.edu.au/medicine/box_hill/research/fibrinolysis.html

We are interested in the cellular and molecular biology of proteases and inhibitors associated with the plasminogen activating enzyme system. We have a particular interest in the role and regulation of tissue-type plasminogen activator (t-PA) in endothelial cells and neuronal cells. t-PA is known for its role as a fibrinolytic agent but also plays a role within the CNS where it has been shown to mediate excitotoxic injury. We have been studying t-PA-mediated neurotoxicity in animal models and using primary culture of cortical neurons. We have also been assessing the neurotoxic effects of a related protease derived from the saliva of the vampire bat. This protease (DSPA) does not display this neurotoxic effect, despite the fact that it is as equipotent as t-PA as a plasminogen activator.
We are also investigating the regulation of plasminogen activator inhibitor type 2 (PAI-2) and prothrombin. PAI-2 inhibits urokinase but is located intracellularly suggesting additional functions for this protease inhibitor. We have been exploring the regulation of the PAI-2 gene at the post-transcriptional level and also its functional role in monocytes. Our efforts on prothrombin are focused on a G to A polymorphism that occurs at the last residue of its mRNA. This polymorphism (G20210A) is associated with an increase in the plasma levels of prothrombin and an increase in the incidence of venous thrombosis. We have shown that this single nucleotide substitution influences the expression level of prothrombin in vitro by altering the stability of prothrombin mRNA.
Peter J. Grant, Professor of Molecular Vascular Medicine, Leeds University, UK (Prothrombin and von Willebrand factor gene polymorphism projects).

Associate Professor Paul Bohjanen, Minneapolis, USA (PAI-2 project).

Professor Phil Beart, Monash University Department of Pharmacology. (Project assessing the regulation of the t-PA gene in cultures of primary cortical neurons).

Dr David Howells, Austin Hospital, Department of Medicine and Neurology, Austin Hospital, University of Melbourne (neurotoxicity of t-PA in vivo project)

Professor Christina Jern. Clinical Experimental Research Laboratory, Goteborg University, Sweden. Collaborative project assessing the functional significance of the –7351 polymorphism in the human t-PA gene promoter.
Yu, H., Schleuning, W.-D., Michl, M., Liberatore, G., Tan, S.S., and Medcalf, R.L (2001). Control elements between –9.5 and –3.0 kb in the human tissue-type plasminogen activator gene promoter direct spatial and inducible expression to the murine brain. Eur. J. Neurosci. 14:799-808.

Yu, H., Maurer, F., and Medcalf R. L. (2002) Plasminogen activator inhibitor-2: a regulator of monocyte proliferation and differentiation. Blood 99:2810-2818.

Carter, A.M., Sachchithananthan, M., Stasinopoulos, S., Maurer, F., and Medcalf, R.L (2002). Prothrombin G20210A is a bifunctional gene polymorphism Thromb. Haemost. 87:846-853.

Liberatore, G.T., Samson, A., Bladin, C., Schleuning, W.D., and Medcalf, R.L. (2003). Vampire bat salivary plasminogen activator (desmoteplase) – a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke 34:537-543.

Yu, H., Stasinopoulos, S., Leedman, P, and Medcalf, R.L. (2003). Inherent instability of plasminogen activator inhibitor type 2 mRNA is regulated by tristetraprolin. J. Biol. Chem. 278:13912-13918.

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