Molecular Neurotrauma and Haemostasis Laboratory
Key terms: Fibrinolysis, stroke, traumatic brain injury (TBI)
Fibrinolysis is the enzymatic removal of a blood clot via the breakdown of its structural component, fibrin. Tissue-type plasminogen activator (t-PA) is a key enzyme component of the fibrinolytic system that converts plasminogen into its active form, plasmin, which in turn degrades fibrin. Although it is generally accepted that this is the primary role of the plasminogen activating system, there is now clear evidence that t-PA plays an important role in the central nervous system. In the brain under normal conditions, t-PA is highly expressed and plays a positive role in neuronal plasticity and memory formation. However, under conditions of brain injury, t-PA can increase blood brain permeability and modulate neuronal function. Our research aims to provide a better understanding of the biology and pathophysiology of the plasminogen activating system in the central nervous system, particularly in relation to neurotrauma, ischaemic stroke and in multiple sclerosis.
Astrocytes in culture at 40x magnification under nontreated conditions
(left) or after addition of t-PA. Note the profound morphological changes
mediated by t-PA. This image was selected for the cover of Blood (Niego et al 2012)
Projects and Opportunities
- Determine how fibrinolytic enzyme modulate blood brain barrier permeability
- Identify and characterise factors released from platelets during clot formation that modulate neuronal function
- Explore the mechanism by which plasminogen activators and matrix metalloproteinases modulate neurovascular permeability following brain trauma
- Determine the role of tissue-type plasminogen activator in the pathogenesis of multiple sclerosis
- Determine the role of protein aggregation in neurotoxic plasmin formation, and the sequence of events triggered by t-PA following the accumulation
of misfolded proteins in acute brain injury
For current project opportunity descriptions please visit our honours page
Medcalf, R.L., 2015, The traumatic side of fibrinolysis, Blood [P], vol 125, issue 15, American Society of Hematology, Washington USA, pp. 2457-2458.
Draxler, D., Medcalf R.L. (2015). The fibrinolytic system: more than fibrinolysis? Transfus Med Rev. 29:102-9.
Borg, R.J., Samson, A.L*., Au, A E-L., Scholzen, A., Fuchsberger, M., Kong, Y.Y., Freeman, R., Mifsud, N.A., Plebanski, M*., and Medcalf, R.L.* (2015). Tolerogenic phagocytosis by human and mouse dendritic cells is promoted by plasmin formation. PLoS One Jul 1;10(7):e0131216. doi: 10.1371/journal.pone.0131216. eCollection 2015 (*joint senior authors).
Boyd, B.J., Galle, A., Daglas, M., Rosenfeld, J.V., and Medcalf, R.L. (2015). Traumatic brain injury opens blood brain barrier to stealth liposomes via EPR-like effect. J Drug Targeting. June 16; 1-7 In press
Au, A.E., Sashindranath, M., Borg, R.J., Kleifeld, O., Andrews, R.K., Gardiner, E.E., Medcalf, R.L., Samson, A.L., 2014, Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase, Cell Death & Disease [E], vol 5, Nature Publishing Group, United Kingdom, pp. 1-13.
Samson, A.L., Knaupp, A.S., Kass, I., Kleifeld, O., Marijanovic, E.M., Hughes, V.A., Lupton, C.J., Buckle, A.M., Bottomley, S.P., Medcalf, R.L., 2014, Oxidation of an exposed methionine instigates the aggregation of glyceraldehyde-3-phosphate dehydrogenase, Journal Of Biological Chemistry [P], vol 289, issue 39, American Society for Biochemistry and Molecular Biology Inc., USA, pp. 26922-26936.
Niego, B., Medcalf, R.L., 2014, Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tPA-induced thrombolysis?, Journal of Cerebral Blood Flow and Metabolism [P], vol 34, issue 8, Nature Publishing Group (NPG), United States, pp. 1283-1296.
Freeman, R., Niego, B., Croucher, D.R., Pederson, L.O., Medcalf, R.L., 2014, t-PA, but not desmoteplase, induces plasmin-dependent opening of a blood-brain barrier model under normoxic and ischaemic conditions, Brain Research [P], vol 1565, Elsevier, Netherlands, pp. 63-73.
Niego, B., Medcalf, R.L., 2013, Improved method for the preparation of a human cell-based, contact model of the blood-brain barrier, Journal of Visualized Experiments [E], vol 2013, issue 81, Journal of Visualized Experiments, United States, p. 1.
Cops, E., Sashindranath, M., Daglas, M., Short, K.M., Pereira, C.d.F., Pang, T., Lijnen, R., Smyth, I.M., Hannan, A.J., Samson, A.L., Medcalf, R.L., 2013, Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait, Experimental Neurology [P], vol 249C, Academic Press, United States, pp. 8-19.
Medcalf, R., 2012, Desmoteplase: Discovery, insights and opportunities for ischaemic stroke, British Journal of Pharmacology [P], vol 165, issue 1, John Wiley & Sons, United Kingdom, pp. 75-89.
Samson, A.L., Knaupp, A.S., Sashindranath, M., Borg, R.J., Au, A.E., Cops, E.J., Saunders, H.M., Cody, S.H., McLean, C.A., Nowell, C.J., Hughes, V.A., Bottomley, S.P., Medcalf, R.L., 2012, Nucleocytoplasmic coagulation: an injury-induced aggregation event that disulfide crosslinks proteins and facilitates their removal by plasmin, Cell Reports [E], vol 2, issue 4, Cell Press, USA, pp. 889-901.
Sashindranath, M., Sales, E., Daglas, M., Freeman, R., Samson, A.L., Cops, E., Beckham, S.A., Galle, A.A., McLean, C.A., Morganti-Kossmann, M.C., Rosenfeld, J.V., Madani, R., Vassalli, J., Su, E.J., Lawrence, D.A., Medcalf, R.L., 2012, The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans, Brain [P], vol 135, issue 11, Oxford University Press, United Kingdom, pp. 3251-3264.
Wu, F., Wu, J., Nicholson, A., Echeverry, R., Haile, W., Catano, M., An, J., Lee, A., Duong, D., Dammer, E., Seyfried, N.T., Tong, F.C., Votaw, J.R., Medcalf, R.L., Yepes, M., 2012, Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain, Journal Of Neuroscience [P], vol 32, issue 29, Society for Neuroscience, United States, pp. 9848-9858.