Medcalf Group - Molecular Neurotrauma, Haemostasis
Key terms: Fibrinolysis, stroke, traumatic brain injury (TBI)
2023 group L-R: Back row - Georgia Fitzpatrick, Rob Medcalf, Zikou Liu. Front row - Isabel Tippett, Orr Zaacs, Heidi Ho, Fiona McCutcheon, Fei Wu, Charithani Keragala Wu. Absent - Joanne Chia, Suhani Sharma.
Meet the team
Ms Heidi Ho
Dr Joanne Chia
Dr Zikou Liu
Dr Charithani Keragala
Ms Fiona McCutcheon
Ms Suhani Sharma
Ms Georgia Fitzpatrick
Ms Isabel Tippett
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 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.
Sabbatical visits by international scientists
- 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.
Contractual research with biotech firms
The Medcalf laboratory has also had success in gaining contractual research projects with Biotech firms
- In relation to Acute Ischaemic Stroke:
- 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.
- 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
- Forest Research Institute (USA). 23/03/06 → 31/12/07. Desmoteplase, tranexamic acid and annexin A2 study
- 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
- 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
- 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
Fellowship and grant awards
- Monash Institute of Medical Engineering (MIME) Seed fund
- 2022-2023 Investigators: A/Prof Corrie (CI-A), Prof Robert Medcalf (CI-B), Prof Geoffrey Cloud (I-C) Title: "Predicting stroke thrombolysis outcome". Amount $50,000
- NHMRC grants
- 2019-2023 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.
- MRFF grant
- 2023-2024: MRFF Cardiovascular Health Mission (ID: 2016377). “Targeting no-reflow to augment tissue salvage in stroke”. Ng, F. (CI-A), Sutherland B (CI-B), Campbell B (CI-C), Medcalf RL (CI-D), Desmond, P (CI-E), Turner, R (CI-F), Thijs, V (CI-G), Johns, H (CI-H), Donnan, G (CI-J), Davis, S (CI-K). Total budget: $1m
- Clinical Trials and Cohort Study grant
- 2022-2026. (ID: 2015100). 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. (CI-B), Medcalf, R (CI-C)., Alemseged, F. (CI-D), Kleinig, T. (CI-E), Dewey, H. (CI-F), Delcourt, C. (CI-G), Mitchell, P. (CI-H), Donnan, G. (CI-I), Davis, S. M. (CI-J). Budget: $1.453m
Previous grants and fellowships
- NHMRC Fellowships
- 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
- 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
Dean's Awards for Excellence in Research and Supervision
Prof Robert Medcalf won the 2019 Dean's Award for Excellence in Research (Postgraduate Research Supervision)
Prof Robert Medcalf won the 2020 Dean's Award for Excellence in Education - Honours Supervision.
YouTube video presentation (3:28 min): Prof Robert Medcalf won the 2020 Dean's Award for Excellence in Education - Honours Supervision
- Medcalf publication accolade
- Editorial by Prof Medcalf on "Fibrinolysis and Trauma Outcomes" published in Anesthesiology, Jan 2022
For Improved Method for the Preparation of a Human Cell-based, Contact Model of the Blood-Brain Barrier video please click here
- McQuilten, Z.K., Venkatesh, B et al…, Medcalf, R.L et al Tong, S.Y.C. (100 co-authors) (2022). Anticoagulation strategies in Non-Critically ill patients with COVID-19. NEJM Evidence. EVIDoa2200293. doi.org/10.1056/EVIDoa2200293.
- Smart, C., Mitchell, A., McCutcheon, F., Medcalf, R.L, Thiele, A. (2023). Tissue-type plasminogen activator induces conditioned receptive field plasticity in the mouse auditory cortex. iScience. 26, 105947 https://www.cell.com/iscience/pdf/S2589-0042(23)00024-X.pdf.
- Coupland, L.A., Rabbolini, D., Crispin, P.J., Schoenecker, J.G., Miller, J.J., Ghent, T., Medcalf, R.L., Aneman, E.A. (2023). Point-of-care Diagnosis and Monitoring of Fibrinolysis Resistance in the Critically Ill: Results from a Feasibility Study. Critical Care 27:55 https://doi.org/10.1186/s13054-023-04329-5 .
- 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.