Thrombosis and Vascular Diseases Research Group

Thrombosis and Vascular Diseases Research Group

Thrombosis and Vascular Diseases Research Group members.

Research in the Thrombosis and Vascular Diseases Research Group aims to understand the cellular mechanisms of how blood clots are formed and what leads to stabilisation of blood clots. The research of Professor Jackson and her team ranges from work on the cellular, molecular, physiological and biochemical aspects of thrombosis, to small animal models of in vivo thrombus formation and ischaemic stroke. In addition, research of this team examines the importance of cell surface receptors known as immunoreceptors in infection and immunity, with a particular emphasis on bacterial pathogens.

Research objectives

  • To study mechanisms that regulate platelet thrombus formation in mouse models.
  • To study immunoreceptors in the immune system in our established models.
  • Develop a new understanding on how immunoreceptors recognise and process bacterial pathogens to regulate immunity.
  • To gain knowledge on the importance of tetraspanins and immunoreceptors in regulating blood clots.
  • To study mechanisms of signaling and compartmentalisation in platelet responsiveness.
  • To understand the role of platelet activation in modulating inflammatory phenotype and contribution to atherogenesis.
  • To obtain crystal structures of immunoreceptors and use this information to design drugs.

The team

Collaborators

  • Prof. Leonie Ashman, University of Newcastle
  • Assoc. Prof. Mark Wright, Monash University
  • Prof. Nicole Beauchemin, McGill University
  • Assoc. Prof. Heyu Ni, St. Michael's Hospital
  • Prof. Sonia Najjar, University of Toledo
  • Dr. Odilia Wijburg, University of Melbourne
  • Prof. Karin Przyklenk, Wayne State University
  • Prof. Paul Monagle, Royal Children's Hospital Melbourne
  • Dr. Ralph Audehm, Diabetes Australia (Victoria)
  • Profs. A.D. Michelson and A.L. Frelinger III, Harvard University

Current funding

2011

  • Diabetes Australi8a. $50,000 Linden, M. Aspirin r5esistance

2010

  • Carlton Football Club $28,000 "Markers of inflammation and immune function during training and competition for AFL football" Coffey V, Linden MD (2010)
  • Carlton Football Club $28,000 "Markers of inflammation and immune function during training and competition for AFL football" Coffey V, Linden MD (2010)
  • Sir Edward Dunlop Medical Research Foundation $15,000. “Understanding platelet immunoreceptors in contact-dependent events that modulate platelet thrombus formation”. Jackson DE. (2011)
  • NHMRC Project Grant APP1010939 Fraser J, Fung YL, Jackson DE, Semple J, Bidstrup B and Schibler A. “The unholy alliance between extracorporeal circuitry and transfusion medicine: characterising inflammation and injury. (2011-2013)$926,299/3 years

2009

  • NHMRC Project Grant (#603812) Jackson DE, Wright MD and Ashman LK. $568,500 for 3 years. "Tetraspanins serve as molecular facilitators to regulate platelet thrombus formation". (2010-2012).
  • NHF Grant-in-Aid (#603813) (G09M 4360) Jackson DE, Beauchemin N. $129,000 for 2 years. "Contact-dependent control of thrombogenesis mediated by immunoreceptors". (2010-2011).
  • Rebecca Cooper Medical Research Foundation: $20,000. "Stabilisation of blood clots-Implications for cerebral ischaemic stroke". Jackson DE. (2010).
  • William Angliss (Victoria) Charitable Trust $1,000. "Thrombosis and Vascular Diseases". Jackson DE (2010).
  • Ian Potter Foundation $100,000. "Establishment of a Clinical Flow Cytometry Core Facility" Linden MD.

2008

  • National Heart Foundation Grant-in-Aid G 08M 3768 Jackson DE (CIA). $130,000/2 years. "Signaling mechanisms that regulate platelet thrombus formation and growth". (2009-2010).

Research projects

Understanding platelet immunoreceptors in contact-dependent events that modulate platelet thrombus formation

Receptors that invoke opposing intracellular signaling effects are considered essential for maintaining a balance between activation and quiescence of the immune system. This conceptual model may also be involved in the regulation of haemostasis and thrombosis. While the ITAM and ITIM signaling as a major means of activating and inhibiting platelets has been established by studies on GPVI-FcR gamma-chain collagen receptor and PECAM-1, our understanding of immunoreceptor signaling in the context of haemostasis and thrombosis is at an early stage. Prof. Jackson's team demonstrated a novel role for CEACAM1 serving as a negative regulator of platelet-collagen interactions involving GPVI receptor and thrombus growth in vitro and in vivo.

Tetraspanins serve as molecular facilitators to regulate platelet thrombus formation

Tetraspanin superfamily members, CD151 and TSSC6 act by augmenting 'outside-in' (ligand-occupied) integrin alphaIIbbeta3 signaling but not agonist-induced activation of 'inside-out' integrin alphaIIbbeta3 signaling. The presence of tetraspanins, CD151 and TSSC6 in tetraspanin-integrin alphaIIbbeta3 complexes may be important for maintaining stable platelet adhesive interactions in platelet thrombus formation in vivo. Our study was designed to determine the role of CD151 in platelet thrombus formation in vivo and define the contribution of platelet versus endothelial CD151 in regulating platelet thrombus formation in vivo. Our data provides evidence for a pivotal involvement of platelet CD151 in the regulation of thrombus stability in vivo in the context of microvascular and arteriolar thrombosis.

The role of immunoreceptors in infection and immunity

The Ig-ITIM superfamily member, PECAM-1 negatively regulates haematopoietic cell function, leukocyte transmigration, immune homeostasis and vascular permeability. However, whether PECAM-1 plays a role in controlling bacterial infections in vivo remains unknown. Ingestion of S. enterica var Typhimurium, results in localised infections of the small intestine that range from mild gastroenteritis to severe systemic illness in humans, contributing to global morbidity and mortality. This study was designed to determine the functional role of PECAM-1 in controlling a primary infection of S. Typhimurium in mouse models in vivo and in peritoneal macrophage processing of S. Typhimurium in vitro. Our data shows that PECAM-1 serves to control Salmonella Typhimurium infection in vivo.

Plaque stability and atherothrombosis-role of cell surface receptors

Atherothrombosis is a major cause of cardiovascular events. Animal models are now available to study acute thrombus formation by plaque rupture to study atherothrombosis by intravital fluorescence microscopy. What factors are important in plaque stability in atherosclerosis is still poorly defined. In this project, we will examine the importance of cell-contact dependent events in the modulation of plaque stability in atherothrombosis using a mouse model.

The role of platelet activation in atherogenesis

Beyond their role in the late thrombotic complications of atherosclerosis, there is increasing evidence to suggest that platelet activation plays an important role in atherogenesis. In this project we will chronically introduce activated platelets in an animal model of accelerated atherogenesis and monitor cell destiny, cellular interactions and the phenotypic impact of interaction with activated platelets, and the impact of inflammatory phenotype and rate of atherogenesis.

Characterization of novel antiplatelet agents

The Thrombosis and Vascular Biology Laboratory has many active collaborations with both academic research groups and with industry to characterize the antiplatelet potential and mechanism of novel and emerging therapeutic agents. These include the highly active marine fish oil Lyprinol, novel synthetic flavanoids, and a gaseous mediator hydrogen sulphide. For inquiries about academic or commercial collaboration please contact Denise Jackson or Matthew Linden.

Recent publications

  • Moheimani F and Jackson DE. P2Y12 and atherosclerosis. International Journal of Haematology 2012. “In press”
  • Mosawy S, Jackson DE, Woodman, OL and Linden MD. Quercetin and 3’,4’-dihydroxyflavanol selectively inhibit human platelet dense granules but notalpha ranules and improve arterial blood flow in a model of acute arterial thrombosis. J. Thromb. Haemost. 2012; ‘Submitted”.
  • Jones CI, Barrett NE, Moraes LA, Gibbins JM and Jackson DE. Endogenous inhibitory mechanims and the regulation of platelet function. Platelets and Megakaryocytes, Humana Press, Methods in Molecular Biology 2012; 788:342-366.
  • Moheimani F and Jackson DE. Venous Thromboembolism: classificatio, risk factors, diagnosis and management. ISRN Haematology 2011: 124610. 10.08.2011
  • Przyklenk K, Frelinger AL 3rd, Linden MD, Whittaker P, Li Y, Barnard MR, Adams J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of the serotonin 5HT(2A) receptor improves coronary patency in an in vivo model of recurrent thrombosis. J Thromb Haemost 2010; 8(2):331-40.
  • Vucinic L, Singh I, Spargo FJ, Hawley JA, Linden MD. Gamma tocopherol supplementation prevents exercise induced coagulation and platelet aggregation Thromb Res 2010;125(2);196-9
  • Linden MD and Jackson DE. The role of platelets in atherogenesis. Intl J Biochem Cell Biol 2010; "In press". (Cells In Focus review).
  • Linden MD and Jackson DE. Platelets: Pleiotropic roles in atherogenesis and atherothrombosis. Int. Journal Biochem. Cell Biology 2010;42:1762-1766. (In focus review). Impact factor: 4.9.
  • Frelinger AL 3rd, Li Y, Linden MD, Barnard MR, Fox ML, Christie DJ, Furman MI, Michelson AD Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009; 120(25):2586-96. [Impact Factor 14.5].
  • Orlowski E, Chand R, Yip J, Wong C, Goschnick MW, Wright MD, Ashman LK and Jackson DE. A platelet tetraspanin superfamily member, CD151, is required for thrombus growth and stability in vivo. J Thromb. Haemost. 2009; Sept 9:7(12):2074-2084. [Impact factor: 6.29].
  • Harris K and Jackson DE. Unravelling the complicated networks of integrin αIIbβ3 signalling in platelets. Current Signal Transduction Therapy 2008;3(3);158-167.
  • Frelinger AL III, Li Y, Linden MD, Tarnow I, Barnard MR, Fox ML, Michelson AD. Aspirin "resistance": role of pre-existent platelet reactivity and correlation between tests. J Thromb Haemost 2008 6(12):2035-44.
  • Frelinger AL III, Jakubowski JA, Li Y, Barnard MA, Linden MD, Tarnow I, Fox ML, Sugidichi A, Winters KJ, Furman MI, Michelson AD. The active metabolite of prasugrel inhibits adenosine diphosphate- and collagen-stimulated platelet procoagulant activities. J Thromb Haemost 2008;6(2):359-65.
  • Jackson DE. Affairs of the heart. IMPACT Bulletin, Macpharlane Burnet Institute, 2008.
  • Linden MD, Barnard MR, Frelinger AL III, Michelson AD, Przyklenk K. Effect of adenosine A(2) receptor stimulation on platelet activation-aggregation: Differences between canine and human models. Thromb Res. 2008;121(5):689-98
  • Wong C, Liu Y, Yip J, Chand R, Wee JL, Oates L, Nieswandt B, Rehemann A, Ni H, Beauchemin N and Jackson DE. CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo. Blood 2009;113:1818-1828. [Impact factor: 10.80]. Blood First Edition Paper, prepublished online November 13, 2008; DOI 10.1182/blood-2008-06-165043
  • Wong MX, Hayball JD and Jackson DE. PECAM-1-regulated signaling thresholds control tolerance in anergic transgenic B cells. Mol. Immunol. 2008;45:1767-1781. [Impact factor: 4.768].
  • Linden MD, Furman MI, Frelinger AL III, Fox ML, Barnard MR, Li Y, Przyklenk K, Michelson AD. Indices of platelet activation and the stability of coronary artery disease. J Thromb Hemost 2007 5(4):761-5.
  • Goschnick MW and Jackson DE. Tetraspanins-Structural and signaling scaffolds that regulate platelet function. Minireviews in Medicinal Chemistry 2007;7:1236-1247. [Impact factor: 3.15].
  • Sardjono CT, Harbour SN, Yip JC, Paddock C, Tridandapani S, Newman PJ and Jackson DE. Palmitoylation at Cys595 is essential for PECAM-1 localisation into membrane microdomains and for efficient PECAM-1-mediated cytoprotection. Thromb. Haemost. 2006;96(6):756-766.
  • Wee JL and Jackson DE. Phosphotyrosine signalling in platelets-Lessons for vascular thrombosis. Current Drug Targets 2006;7(10):1265-1273. (Citations: 2).
  • Goschnick M, Lau LM, Wee JL, Hogarth PM, Robb LM, Wright MD and Jackson DE. Impaired 'outside-in' integrin αIIbβ3 signalling and thrombus stability in TSSC6-deficient mice. Blood 2006;Sept 15 108(6):1911-1918. [Impact factor: 10.37]. (Citations: 9).
  • Wong XM, Hayball JD, Hogarth PM and Jackson DE. The inhibitory co-receptor, PECAM-1 provides a protective effect in the suppression of collagen-induced arthritis. Journal of Clinical Immunology 2005;25(1):19-28. [Impact factor: 3.442]. (Citations: 5).
  • Wee JL and Jackson DE. The Ig-ITIM superfamily member, PECAM-1 regulates the 'outside-in' signalling properties of integrin αIIbβ3 in platelets. Blood 2005;106:3816-3823. [Impact factor: 10.131]. (Citations: 8).
  • Lau LM, Wee JL, Wright MD, Moseley GW, Hogarth PM, Ashman LK and Jackson DE. The tetraspanin family member, CD151 regulates the outside-in integrin αIIbβ3 signalling and platelet function. Blood 2004;104(8):2368-2375. [Impact factor: 10.131]. (Citations: 19).
  • Wright MD, Geary SM, Fitter S, Moseley GW, Lau LM, Sheng KC, Apostolopolous V, Stanley E, Jackson DE and Ashman LK. Characterisation of mice lacking the tetraspanin superfamily member CD151. Mol. Cell. Biol. 2004;24(13):5978-5988. [Impact factor: 9.836]. (Citations: 28).
  • Moseley GW and Jackson DE. The multiple functions of PECAM-1. Australian Biochemist. Magazine of the Australian Society for Biochemistry and Molecular Biology Inc. August 2004;35(2):9-12.

Why not join us?

All enquiries about joining the group as Honours and Postgraduate students or as Post-doctoral Fellows should be directed to Denise Jackson or Matthew Linden.