Medcalf Group - Molecular Neurotrauma, Haemostasis
Key terms: Fibrinolysis, stroke, traumatic brain injury (TBI)
2022 group L-R: Back row - Zikou (Oscar) Liu, Ahnaf Hossain, Sayan Thuraisamy, Rob Medcalf, Front row - Fiona McCutcheon, Joanne Chia, Heidi Ho, Charithani (Cherry) Keragala; Yunxin (Cindy) Xiao, Rachel Waring
Group Leader - Prof Robert Medcalf
Prof Robert Medcalf is deeply interested in fibrinolysis - the process our bodies implement to remove blood clots. He is investigating how we can use our natural clot busting mechanisms to help treat stroke victims. His interest is in the chemicals in our bodies that can help reduce the long-term damage of stroke and also in other diseases of the brain including traumatic brain injury.
Find out more about Prof Robert Medcalf
Ms Heidi Ho
Dr Joanne Chia
Dr Zikou Liu
Ms Cindy Xiao (PhD pending)
Dr Charithani Keragala
Ms Fiona McCutcheon
Mr Ahnaf Amer Hossain
Mr Sayan Thuraisamy
Ms Rachel Waring
Ms Fei Wu
Visiting clinician-scientist on Sabbatical
Dr Stuart Hastings (Anaesthetist)
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)
- Determine how fibrinolytic enzymes modulate blood brain barrier permeability and the immune response in patients with acute ischaemic stroke and patients with traumatic brain injury.
- To understand the role and importance of the fibrinolytic system in Alzheimer’s Disease and in patients with Cerebral Amyloid Angiopathy (CAA).
- To determine the extent to which antifibrinolytic agents (i.e. tranexamic acid) modulates the immune response in trauma (PATCH trial; https://www.patchtrauma.org/), reduces postoperative infection rates (TRIGS trial; https://www.trigs.org.au/), and postoperative delirium (TRIGS-D trial; https://www.anzca.edu.au/profiles/ctn-trials/underway/trigs-trial).
For current project opportunity descriptions please visit Professor Rob Medcalf's projects listed in SupervisorConnect.
- 2013: Professor Roger Lijnen, Department Cardiovascular Sciences , Center for Molecular and Vascular Biology, KU Leuven , Leuven , Belgium
- 2018: Peter J Grant, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, UK.
The Medcalf laboratory has also had success in gaining contractual research projects with Biotech firms
In relation to Acute Ischaemic Stroke:
1. PAION GmbH (Germany, 2002). Forest Research Institute, USA (2006-2007); Lundbeck (Denmark, 2012-2013): All three firms were involved with the development of desmoteplase and contractual projects were awarded to explore the potential use of Desmoteplase (vampire bat derived plasminogen activator) for patients with Acute Ischaemic stroke.
2. PAION Deutschland GmbH: 2/06/06 → 1/11/06. Optimised plasminogen activator (OPA) Neurotoxicity Project. Effects of OPA-1 on excitotoxicity in cultured neuronal cells
3. Forest Research Institute (USA). 23/03/06 → 31/12/07. Desmoteplase, tranexamic acid and annexin A2 study
4. Lundbeck (Copenhagen, Denmark) 1/09/12 → 1/04/13
To investigate effects of desmoteplase and recombinant tissue plasminogen activator (rt-PA), on their ability to modulate permeability across the blood brain barrier using an in vivo mouse model.
In relation to new drugs to improve endogenous fibrinolysis
5.Cereno Biotech, Gothenburg, Sweden 29/09/17 → 31/07/18. To investigate the effect of valproic acid and anticoagulants on haemostasis and fibrinolysis in vivo and in vitro
In relation to Flow cytometric profiling to evaluate new drugs for cancer
6. INmuneBio (USA) (2018-2019); INmuneBio Australia: 1/05/18 → 30/04/19. To test the effects of XPro1595 on the cellular immune profile in a phase I study for InmuneBio
1993-1997 NH&MRC R.D. Wright Fellowship (#937703) Medcalf, R.L. Amount $225,680; Title: Molecular and cellular biology of t-PA and PAI-2 gene expression.
2003-2007 NH&MRC Senior Research Fellowship Level A (#236860) Medcalf, R.L. Amount $614,750
2008-2012 NH&MRC Senior Research Fellowship Level A (#491088). Medcalf, R.L. Amount $623,553.
2013-2017. NH&MRC Principle Research Fellowship (PRF) APP1044152. Medcalf RL (CI-A). Amount: $714,745
Previous NHMRC project Grants
1994-1996: NH&MRC (#940415). Investigator Medcalf, R.L. (CI-A) Amount: $172,140; Title: Regulation of plasminogen activator and plasminogen activator inhibitor gene expression.
1994-1996: NH&MRC Investigators: Salem, H (CI-A). Medcalf, R.L. (CI-B). Coughlin P, Bird, P. Amount: $181,200; Title: Characterisation and molecular biology of a novel proteinase inhibitor.
1997-1999 NH&MRC #970419 Investigators: Medcalf, R.L (CI-A). Shen, Y. Amount:$197,700; Title: Transcriptional regulation of the fibrinolytic system
1999-2001 NH&MRC #980862 Investigators: Medcalf, R.L (CI-A). Maurer, F. Amount/yr: $345,000; Title: Regulation of the PAI-2 gene.
1999-2001 NH&MRC #990219. Investigators: Medcalf, R.L (CI-A). Costa, M. Amount: $390,000; Title: Molecular control of fibrinolysis
2000-2002 NH&MRC #124316. Investigators: Medcalf, R.L. (CI-A) Amount/yr: $240,000; Title: Regulation of tissue-type plasminogen activator gene expression in endothelial cells and in transgenic mice.
2000-2002 NH&MRC #124315. Investigators: Medcalf, R.L. (CI-A). Carter, A. Amount: $210,000; Title: The molecular basis for the increased incidence of thrombosis associated with the prothrombin G20210A gene polymorphism
2001-2003. NH&MRC #143615. Investigators: Medcalf, R.L (CI-A). Yu, H. Amount: $241,527; Title: Post-transcriptional regulation of the plasminogen activator inhibitor type 2 gene.
2003-2005 NH&MRC #236862. Investigators: Medcalf, R.L. (CI-A), Costa M. Amount/yr: $490,500; Title: Molecular Mechanisms for the cell-type specific regulation of the tissue-type plasminogen activator gene.
2004-2006 NH&MRC #248250. Investigators: Medcalf, R.L. (CI-A), Yu, H. Amount: $318,000; Title: Post-transcriptional regulation of plasminogen activator inhibitor type 2 gene expression.
2008-2010 NH&MRC #491152 Investigators: Medcalf, R.L. (CI-A). Amount: $504,098; Title: Role and regulation of tissue-type plasminogen activator in the central nervous system.
2008-2010 NH&MRC #491151. Investigators: Medcalf, R.L. (CI-A) Stasinopoulos S, Nagamine Y. Amount: $508,838; Title: Post-transcriptional regulation of plasminogen activator inhibitor type 2.
2009-2011 NH&MRC #566776 Investigators: Stewart, A.G., Medcalf, RL (CIB), Hughes, R.A., Banwell, M.G. Amount: $368,025; Title: 2-Methoxyestradiol analogues: prototype modulators of annexin II-dependent plasminogen activation. Total: $390,000
2010-2012 NH&MRC #APP606658 Investigators: Medcalf, RL (CI-A), Lawrence DA. Title: “To determine the means by which plasminogen activators modulate integrity of the blood brain barrier”. Total: $514,018
2010-2012 NH&MRC #APP606659 Investigators: Medcalf, RL (CI-A), Bottomley, S., Samson, A. Title: “To investigate how the aggregation of proteins during neuronal injury promotes neurotoxic plasmin formation”. Total: $576,250
2010-2012 NH&MRC #APP606660 Investigators: Medcalf, RL (CI-A). Title: “To understand the role of the plasminogen activating and matrix metalloproteinase systems in traumatic brain injury”. Amount $490,644
2013-2015. NHMRC #APP1045755 Investigators: Medcalf, R.L. (CI-A), Lawrence DL (CI-B). Title: How enzymes and enzyme inhibitors effect the brain after traumatic brain injury. Amount: $592,143.
2013-2015. NHMRC# APP1045756 Investigators: Medcalf, R.L. (CI-A), Michell, A. (CI-B). Title: How can we improve the way blood clots are removed in ischaemic stroke? Amount: $565,847
2013-2016 (extended to 2017) NHMRC #APP1044894. Investigators: Gruen, R.,(CI-A), Mitra, B. (CI-B), Bernard, S (CI-C), Jacobs, I (CI-D), Medcalf, R.L. (CI-E), Reade, M (CI-F), Tran, H (CI-G). Title: Pre-hospital Antifibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study). Amount $1,668,152.
2017-2020 NHMRC #APP1126636 Investigators: Medcalf, R.L., (CI-A), Plebanski, M., Boyd, B,. Gruen, R., Roberts, I., and Tran, H. Title: The effect of anti-fibrinolytic drugs on blood-brain barrier integrity and the immune response in traumatic brain injury. Amount $870,476.
2018-2021 NHMRC #APP1141046. Investigators: Nandurkar, H., Medcalf, R.L (CI-B) and Robson, S. Targeted delivery of CD39 to the ischaemic brain improves outcomes in stroke. Amount $895,780
Total previous NHMRC funding: $10,349,338
Currently held NHMRC grants:
2019-2022 NHMRC #APP1156506. Investigators: Medcalf, R.L., (CI-A), Boyd, B, Cloud, G. Title: Improving the safety and efficacy of thrombolytic therapy in acute ischaemic stroke. Amount $1,371,900.
2020-2024, NHMRC #APP1185145. Investigators: Myles, P., Medcalf, R.L (CI-B), Brown, W., Peel, T., and Kasza, J. Title: Tranexamic acid to Reduce Infection after Gastrointestinal Surgery – the TRIGS Trial. Budget $5.196m.
Currently held MRFF grants:
2022-2026. MRF2014406 MRFF - Rare Cancers, Rare Diseases and Unmet Need (RCRDUN). Title: “Accelerating clot lysis in ischemic stroke with dornase alfa in an Umbrella Bayesian Optimised Phase 2 trial”. Campbell, B. C. V. (CI-A), Churilov, L., Medcalf, R (CI-C)., Alemseged, F., Kleinig, T., Dewey, H., Delcourt, C., Mitchell, P., Donnan, G. & Davis, S. M. $1.453m
- Medcalf publication accolade
- Editorial by Prof Medcalf on "Fibrinolysis and Trauma Outcomes" published in Anesthesiology, Jan 2022
- Mutimer, C., Keragala, C. B., Markus, H.S., Werring, D.J., Cloud, G.C., and Medcalf, R.L. (2021) Cerebral amyloid angiopathy and the fibrinolytic system: is plasmin a therapeutic target? Stroke 52(8):2707-2714. doi: 10.1161/STROKEAHA.120.033107
- Medcalf, R.L. Keragala, C.B., and Myles, P.S. (2020). Fibrinolysis and COVID-19: A plasmin paradox. J Thromb Haemost. Sep;18(9):2118-2122. doi: 10.1111/jth.14960
- Daglas, M, Galle, A., Draxler, D.F., Sashindranath, M., and Medcalf, R.L. (2020). Sex-dependent effects of tranexamic acid on blood-brain barrier permeability and the immune response following traumatic brain injury in mice. J Thromb Haemost Oct;18(10):2658-2671. doi: 10.1111/jth.15015.
- Draxler, D.F., Yep, K., Hanafi, G., Winton, A., Daglas, M., Ho, H., Sashindranath, M., Wutzlhofer, L.M., Forbes, A., Goncalves, I., Tran, H., Wallace, S., Plebanski, M., Myles, P.S., Medcalf, R.L. (2019). Tranexamic acid modulates the immune response and reduces post-surgical infection rates. Blood Advances, 28;3(10):1598-1609. doi: 10.1182/bloodadvances.2019000092.
- Daglas, M, Draxler, D.F., Ho, H., McCutcheon, F., Galle, A, Au, A-E, Larsson, P., Gregory, J., Alderuccio, F., Sashindranath, M, Medcalf, R.L. (2019). Activated CD8+ T cells cause long-term neurological dysfunction following traumatic brain injury. Cell Reports, Oct 29;29(5):1178-1191.e6. doi: 10.1016/j.celrep.2019.09.046
- Draxler, D.F., Lee, F., Ho, H., Keragala, C.B., Medcalf, R.L., Niego, B. (2019). t-PA suppresses the immune response and aggravates neurological deficit in a murine model of ischemic stroke. Frontiers Immunol. 10:591. doi: 10.3389/fimmu.2019.00591. eCollection 2019.
- Draxler, D.F., Daglas, M., Fernando, A., Hanafi, G., McCutcheon, F., Ho, H., Galle, A., Au, A.-E., Niego, B., Wilson, K., Plebanski, M., Sashindranath, M., Medcalf, R.L. (2019). Tranexamic Acid Modulates the Cellular Immune Profile after Traumatic Brain Injury in Mice without Hyperfibrinolysis. J Thromb Haemost. 17(12):2174-2187 doi:10.1111/jth.14603.