Medcalf Group - Molecular Neurotrauma, Haemostasis

Key terms: Fibrinolysis, stroke, traumatic brain injury (TBI)

2017 Medcalf lab
2017 group Back row L-R: Prof Robert Medcalf, Mr Dominik Draxler, Dr Be'eri Niegro, Mr Felix Lee Front row L-R: Ms Fiona McCutcheon, Ms Li Chow, Ms Saffanah Zhara, Ms Maria Daglas, Dr Charithani Keragala, Ms Stevi Harman Absent: Ms Sofia Vorontzov, Ms Heidi Ho, Ms Anna Mitchell, Ms Nicola Sandler.

Research Overview

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.

figure2figure1

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

Selected Publications

For Improved Method for the Preparation of a Human Cell-based, Contact Model of the Blood-Brain Barrier video please click here

Kwaan, H, Lisman, T, Medcalf, R.L. Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential. Seminars in Thrombosis and Hemostasis. 2017:43(2), 113-114.

Draxler D.F, Sashindranath M, Medcalf  R.L. Plasmin: A modulator of immune function. Seminars in Thrombosis and Hemostasis. 2017:43(2) 143-153

Draxler D.F, Madonto M.T, Hanafi G, Medcalf R.L. A flowcytometric analysis to efficiently quantify multiple innate immune cells and T Cell subsets in human blood. Cytometry Part A. 2017:91(4) 336-350

Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse. Journal of Thrombosis and Haemostasis. 2016:14(12) 2496-2508

Szabo R, Samson A.L, Lawrence D.A, Medcalf R.L, Bugge, T.H. Passenger mutations and aberrant gene expression in congenic tissue plasminogen activator-deficient mouse strains. Journal of Thrombosis and Haemostasis. 2016:14(8)1618-1628

Dahl L.C.M, Nasa Z, Chung J, Niego B, Tarlac V, Ho H, Galle A, Petratos S, Lee J.Y, Alderuccio F, Medcalf R.L. The influence of differentially expressed tissue-type plasminogen activator in experimental autoimmune encephalomyelitis: Implications for multiple sclerosis. PLoS One. 2016:11(7), Article number e0158653.

Samson A.L, Ho B, Au A.E, Schoenwaelder S.M, Smyth M.J, Bottomley S.P, Kleifeld O, Medcalf R.L. Physicochemical properties that control protein aggregation also determine whether a protein is retained or released from necrotic cells. Open Biology. 2016:6(11), Article number 160098  

Szydzik C, Niego B, Dalzell G, Knoerzer M, Ball F, Nesbitt W.S, Medcalf R.L, Khoshmanesh K, Mitchell A. Fabrication of complex PDMS microfluidic structures and embedded functional substrates by one-step injection moulding. RSC Advances. 2016:6(91) 87988-87994

Karve I.P, Zhang M, Habgood M, Frugier T, Brody K.M, Sashindranath M, Joakim Ek, C, Chappaz S, Kile B.T, Wright D, Wang H, Johnston L, Daglas M, Ates R.C, Medcalf, R.L, Taylor J.M, Crack P.J, Ablation of type-1 IFN signaling in hematopoietic cells confers protection following traumatic brain injury. eNeuro. 2016:3(1)89-93