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Platelet Signalling LaboratoryStaff Members :Unit Head - Dr Simone M Schoenwaelder ( NHMRC RD Wright and Monash University Logan Fellow) Research Assistant - Mr Shannon Turnbull, B.BioMed.Sci. (Hons) Honours Student - Ms Akiko Ono, B.BioMed.Sci. Research ActivitiesThe organs and tissues that make up the human body rely on a continual supply of blood, which is circulated throughout the body via a complex series of arteries, veins, and capillaries. This blood not only carries vital oxygen and nutrients to the tissues, as well as removing carbon dioxide and other waste products, but it is also a vehicle for various blood cells, including important clotting cells known as platelets . Platelets are small blood cells produced by megakaryocytes. In the event of blood vessel injury, these tiny blood cells are rapidly recruited to the area of damage, where they effectively seal off the injured site to prevent blood loss. This is achieved through the execution of a series of functional events beginning with adhesion, followed by spreading and aggregation, leading to thrombus (clot) formation.
Figure 1. Disruption of the endothelial lining of a blood vessel, due to injury ( All platelet functional responses must be tightly regulated to ensure that the formation a blood clot is of sufficient size to seal off the damaged area, whilst not disrupting blood flow to vital organs by causing vessel occlusion (blockage). Unfortunately, the consequences of abnormal platelet regulation are seen all too frequently in the clinical setting, with the incidence of cardiovascular related diseases such as heart attack and stroke, remaining some of the major causes of death in the western world today.
Within the Platelet Signalling Unit, current research interests include:
Investigation of Signalling Enzymes thatRegulate Platelet Adhesive Function.Many normal and pathological processes in the human body depend on the ability of cells to attach firmly to a biological surface (adhesion). A classic example of this is the adhesion of platelets to an injured blood vessel, in order to prevent blood loss. Our laboratory is investigating the regulation of an important attachment protein (or receptor), called integrin (Figure 1, The adhesive properties of this major platelet integrin aIIbb3 must be tightly regulated to ensure efficient haemostasis and avoid pathological thrombosis. Recent evidence from our laboratory and others has implicated members of the Ras family of small G-proteins, Rap1b and RhoA, as critical enzymes controlling integrin adhesion. Our studies have demonstrated for the first time that the activation of RhoA downstream of integrin aIIbb3 is responsible for maintaining stable adhesion of platelets, particularly under conditions of blood flow. This effect is achieved through modulation of integrin stability itself, rather than regulation of the platelet interaction with vWf, or initial activation of the integrin (Schoenwaelder et al, 2002). In further studies that are ongoing, we are investigating preliminary evidence demonstrating the existence of distinct yet cooperative roles for both RhoA, and another Ras family member, Rap1b, in regulating integrin aIIbb3 adhesive function (Chrzanowska-Wodnicka et al, 2003; manuscript submitted ) Related PublicationsSchoenwaelder SM , Hughan SC, Boniface K, Fernando S, Holdsworth M, Thompson PE, Salem HH, Jackson SP. RhoA sustains integrin aIIbb3 adhesion contacts under high shear. J Biol Chem. 2002 277 (17):14738-46 Chrzanowska-Wodnicka M, Schoenwaelder SM and White GC (2003) Rap1b regulates Integrin aIIbb3 activity and platelet function – lessons from a knockout. Blood, 102(11):773a.
Investigation of signalling factors that regulateblood clot consolidation or “clot retraction”.One of the mechanisms utilised by platelets to regulate the size of the blood clot is known as “platelet-mediated clot retraction”. This process describes the ability of platelets to consolidate or shrink the size of the blood clot once it has formed, through actomyosin contractile forces. This process is thought to be important for both maintenance of the vasculature and also the subsequent manner in which the blood clot is removed once wound healing has finished. Although this process is of critical importance to the over maintenance of blood vessels, our understanding of the signalling events regulating this process is limited. Our previous studies have highlighted important roles for several signalling proteins in platelet mediated clot retraction, inlcuidng the Src family tyrosine kinases (Schoenwaelder et al, 1994), and the protease calpain (Schoenwaelder et al, 1997a, 1997b). We have recently set up a novel confocal-based imaging assay in the laboratory to study the process of clot retraction, that allows us to directly monitor platelet dynamics within a retracting blood clot, through the use of fluorescence markers, monitoring both biochemical and physical changes. By gaining more insight into the signalling mechanisms regulating clot retraction and ultimately thrombus consolidation, it is hoped that these studies will identify new targets for therapeutic intervention.
Related PublicationsSchoenwaelder SM , Jackson SP, Yuan Y, Teasdale MS, Schoenwaelder SM,Yuan Y, Salem HH and Jackson SP (1997a) Calpain cleavage of focal adhesion proteins regulates the cytoskeletal attachment of Integrin aIIbb3 (Glycoprotein IIb/IIIa) and the cellular retraction of fibrin clots. J. Biol. Chem., 272 (3), 1694-1702. Schoenwaelder SM, Kulkarni S,HH, Imajoh-Ohmi S, Yamao-Harigaya W, Saido TC and Jackson SP (1997b) Distinct substrate specifities and functional roles for the 78- and 76-kDa forms of m-calpain in human platelets. J. Biol. Chem., 272 (40), 24876-24884. Other publications and Achievements fromthe Platelet Signalling Group2000 Schoenwaelder SM. Awarded joint NHMRC R Douglas Wright Fellowship and Monash Univeristy Logan Fellowship Schoenwaelder SM. Awarded Faculty of Medicine Research Initiatives Fund. Investigation into the regulation and function of the small GTPase RhoA in platelets ($17,000) Schoenwaelder SM , Yuan Y and Jackson SP (2000) Calpain regulation of integrin aIIbb3 signalling in human platelets. Platelets, 11(4), 189-198. Schoenwaelder SM , Petch LA, Williamson D, Shen R, Feng GS and Burridge K (2000) The protein-tyrosine phosphatase Shp-2 regulates the activity of RhoA. Curr. Biol., 10 :1523-1526. 2001 Schoenwelder SM. Awarded an Ipsen Medal Coomendation. Australasian Society of thrombosis and Haemostasis. Schoenwaelder SM and 2002 Lawrenson I, Kleikamp S, Lock P, Schoenwaelder SM , Alewood P, Down M, Reed C, Boyd A and Lackman M (2002) Ephrin-A5 induces cell rounding and deadhesion of EphA3 expressing 293T cells and melanoma cell lines: Evidence for a Crk-mediated signalling mechanism. J. Cell Sci.,115:1059-1072. Schoenwaelder SM , Hughan S, Boniface K, Holdsworth M, Phillip Thompson and Jackson SP (2002). RhoA sustains integrin aIIbb3-adhesion contacts under high shear. J. Biol. Chem .,277(17):14738-14746. Jackson SP, Robertson A, Kenche V, Goncalves I, Nesbitt WS, Yuan Y, Anderson KE andSchoenwaelder SM . Inhibition of Phosphoinositide 3-kinase Beta. Patent specification. Filed Ono A. Awarded one of 3 inaugural Firkin Awards, designed to encourage pursuit of postgraduate studies in the cardiovascular disciplines. Schoenwaelder SM.Awarded National Heart Foundation Grant-In-Aid, G 01M 0330, for investigations into a Role for RhoA in platelet integrin aIIbb3 signalling and thrombus growth. SM Schoenwaelder ($92, 561) Schoenwaelder SM ,Awarded (but not accepted) Anti-Cancer Council of Victoria Research Grant-in-Aid, to elucidate the signalling pathways that activate the small GTPase RhoA, and regulate cell adhesion and motility. Schoenwaelder SM. Awarded NHMRC Project Grant – New Investigator Grant to investigate Signalling Enzymes Regulating the Small GTPase RhoA ($225,000). 2003 Schoenwaelder SM.Awarded International Young Investigator Award – XIX Congress of the International Society on Haemostasis and Thrombosis, Birmingham, UK Schoenwaelder SM. Invited to act as Symposium Chair, ISTH XIX Congress, Platelet Signalling II Session, Birmingham ,UK Jackson SP and Schoenwaelder SM (2003) Anti-Platelet Therapy – In Search of the ‘Magic Bullet’. Nature Reviews Drug Discovery, October, 2 (10): 775-789. Goncalves I*,Hughan SC*, Schoenwaelder SM,. Yap CL, Yuan Y and Jackson SP (2003).Integrin aIIbb3-dependent calcium signals regulate platelet-fibrinogen interactions under flow: Involvementof PLCg2. * Denotes equal first author. J. Biol. Chem., 278 (37): 34812-34822. Chrzanowska-Wodnicka M, Schoenwaelder SM and White GC (2003) Rap1b regulates Integrin aIIbb3 activity and platelet function – lessons from a knockout. Blood, 102 (11):773a. 2004 Schoenwaelder SM. Awarded a National Heart Foundation Grant-In-Aid, to Investigate integrin aIIbb3 outside-in signalling events regulating fibrin clot retraction. |
), leads to exposure of subendothelial proteins ( 
). Platelets adhere and spread over these subendothelial proteins, in an effort to seal off the site of injury and prevent blood loss.
) which is critical for platelet adhesion. This receptor is fundamental for the physiological process of haemostasis, as evidenced by patients who suffer from severe bleeding complications due to a lack of this receptor. Integrin 