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Platelet and Leukocyte Biology LaboratoryMembers of StaffUnit HeadAssoc. Prof. Shaun Jackson Post-doctoral Research Scientists
Research Assistants
Ph.D studentsIsaac Goncalves 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 platelets and leukocytes, which play key roles in the maintenance of blood vessel integrity. The main focus of the Platelet and Leukocyte Biology Laboratories is to identify the mechanisms regulating blood vessel injury and repair, with particular emphasis on the role of blood platelets and leukocytes in these processes. 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.
Leukocytes are nucleated white blood cells (WBCs) that are formed from stem cells in the bone marrow, and defend the body against infecting organisms and foreign agents. The interaction of these WBCs with platelets at sites of vascular injury has been found to play a critical role in the inflammatory responses associated with vascular diseases such as atherosclerosis. The recruitment of leukocytes (in particular monocytes) to vessels is a key step in the initiation of atherosclerosis, and circulating activated platelets and platelet-monocyte aggregates have also been shown to promote the formation of the atherosclerotic lesion. Monocyte-platelet interaction have also been associated with vascular lesions that re-develop as a consequence of mechanical injury from balloon angioplasty and stenting, which are both currently used for the treatment of vascular disease and vessel occlusion. Therefore, a better understanding of the leukocyte-platelet interaction, and the consequence of this interaction to vessel maintenance, is fundamental in order to better understand the progression of vascular disease. Our laboratories have established state-of-the-art in vitro and in vivo models to examine interactions of circulating blood cells with vessel wall components during hemostasis and inflammation. There are numerous projects utilising transgenic mouse models to examine signalling pathways regulating platelet and leukocyte function. Current Research Projects
Recent Publications from the Blood Platelet Laboratory2004Kulkarni S, Jackson SP. (2004) Platelet Factor XIII and Calpain Negatively Regulate Integrin aIIbb3 Adhesive Function and Thrombus Growth. J Biol Chem. 279(29):30697-30706. Mangin, P., David, T., Lavaud, V., Cranmer, S.L, Pikovski, I., Jackson, S.P., Berndt, M.C., Cazenave, J., Gachet, C., and Lanza, F. (2004) Identification of a novel 14-3-3 binding site within the cytoplasmic tail of platelet glycoprotein Ib. Blood 104: 420 - 427. Kulkarni S, Nesbitt WS, Dopheide SM, Maxwell MJ, Yuan Y, Anderson KE, Hibbs ML, Salem HH, Jackson SP. (2004) SHIP1 and Lyn kinase negatively regulate integrin aIIbb3 signaling in platelets.J Biol Chem . 279(31): 32196–32204. Jackson SP, Yap CL, Anderson KE. (2004) Phosphoinositide 3-kinases and the regulation of platelet function. Biochem Soc Trans .32(2):387-92. 2003 Nesbitt, W.S., Giuliano, S., Kulkarni, S., Dopheide, C.L., Harper, I.S., and Mangin P, Yuan Y, Goncalves I, Eckly A, Freund M, Cazenave JP, Gachet C, Jackson SP, and Lanza F. (2003) Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA. J Biol Chem .278(35):32880-91. Cranmer, S.L. and Commentaries: LeBrasseur N. Calcium for strong clotting. J. Cell Biol ., 160:980, 2003 Schubert C. Platelet attraction. Nature Med., News & Views, 9:511, 2003 Goncalves I*, Jackson SP, Nesbitt WS, Kulkarni S. (2003) Signaling events underlying thrombus formation. J Thromb Haemost .1(7):1602-12. Review. Jackson SP, Schoenwaelder SM. (2003) Antiplatelet therapy: in search of the 'magic bullet'.Nat Rev Drug Discov .2(10):775-89. Review. Giuliano S, Nesbitt WS, Rooney M, Jackson SP. (2003) Bidirectional integrin alphaIIbbeta3 signalling regulating platelet adhesion under flow: contribution of protein kinase C. Biochem J. 372(1):163-72. Perrault C, Mangin P, Santer M, Baas MJ, Moog S, Cranmer SL, Pikovski I, Williamson D, Jackson SP, Cazenave JP and Lanza F. (2003) Role of the intracellular domains of GPIb in controlling the adhesive properties of the platelet GPIb/V/IX complex. Blood 101(9):3477-84. 2002 Nesbitt WS, Kulkarni S, Giuliano S, Goncalves I, Dopheide SM, Yap CL, Harper IS, Salem HH, Jackson SP. Distinct glycoprotein Ib/V/IX and integrin alpha IIbbeta 3-dependent calcium signals cooperatively regulate platelet adhesion under flow. J Biol Chem . 2002 Jan 25;277(4):2965-72. Yap CL, Anderson KE, Hughan SC, Dopheide SM, Salem HH, Jackson SP. Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3). Blood . 2002 Jan 1;99(1):151-8. Schoenwaelder 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. Dopheide SM, Maxwell MJ, Jackson SP. Shear-dependent tether formation during platelet translocation on von Willebrand factor. Blood . 2002 99(1):159-67. Williamson D, Pikovski I, Cranmer SL, Mangin P, Mistry N, Domagala T, Chehab S, Lanza F, Salem HH, Jackson SP.Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear. J Biol Chem . 2002 Jan 18;277(3):2151-9.. Selected Publications (1999-2000)Cranmer SL, Ulsemer P, Cooke BM, Salem HH, de la Salle C, Lanza F and Jackson SP. Glycoprotein Ib/IX-transfected cells roll on a von Willebrand factor matrix under flow. Importance of the GPIb-Actin Binding Protein Interaction in Maintaining Adhesion under High Shear. J. Biol. Chem . 274:6097-6106, 1999 Williamson D, Giuliano S and Jackson SP. Platelet adhesion receptors: Novel targets for antithrombotic drugs. Aust NZ J Med 29:452-461, 1999 Yuan Y, Kulkarni, S, Ulsemer P, Cranmer SL, Yap CL, Mistry N, Nesbitt, WS, Harper, IS, Williamson, D, Dopheide SM, de la Salle C, Lanza F and Jackson SP. The von Willebrand factor—glycoprotein Ib/V/IX interaction induces actin polymerisation and cytoskeletal reorganisation in rolling platelets and glycoprotein Ib/V/IX-transfected cells. J. Biol. Chem . 274:36241-36251, 1999 Kulkarni S, Dopheide SM, Yap CL, Ravanat C, Freund M, Mangin P, Heel KA, Street A, Harper IS, Lanza F and Jackson SP. A Revised Model of Platelet Aggregation. J. Clin. Inv . 105:783-791, 2000 Commentary: Ruggeri ZM. Old concepts and new developments in the study of platelet aggregation. J. Clin. Inv . 105:699-701,2000. Hinde J. Sticking point: There may be more to blood clots than meets the eye. New Scientist p18, April 1, 2000 Schoenwaelder SM, Yuan Y and Jackson SP. Calpain regulation of integrin aIIbb3 (GP IIb/IIIa) signalling in human platelets. Platelets , 11:189-198, 2000 Ulsemer P, Lanza F, Baas MJ, Schzartz A, Ravanat C, Briquel ME, Cranmer S, Jackson SP, Cazenave C, de la Salle C. Role of the leucine-rich domain of platelet GPIb-alpha for efficient processing and importance of the macroglycopeptide for normal adhesive function. The Bernard-Soulier Nancy 1 mutation reproduced in CHO cells. Thromb. Haemost . 84:104-111, 2000<< /> Dopheide SM, Yap CL and Jackson SP. Dynamic aspects of platelet adhesion under flow. Clinical and Experimental Pharmacology and Physiology (In press), 2000 Mistry N, Cranmer SL, Yuan Y, Dopheide SM, Guiliano S, Harper IS, Dunstan D, De la Salle C, Lanza F, Salem HH and Jackson SP. Cytoskeletal regulation of the platelet GPIb/IX-von Willebrand factor interaction. Blood (In press), 2000 Yap CL, Hughan SC, Cranmer SL, Rooney MM, Dopheide SM, Kulkarni S, Yuan Y and Jackson SP. Synergistic adhesive interactions and signalling mechanisms operating between platelet glycoprotein Ib/IX and integrin IIb3 . Studies in human platelets and transfected CHO cells. J. Biol. Chem . (In press), 2000 Jackson SP, Nayna Mistry and Yuan Y. Platelets and the injured vessel wall —"Rolling into Action" — Focus on Glycoprotein Ib/V/IX and the Platelet Cytoskeleton. Trends. Cardiovasc. Med . (In press), 2000 Tait AS, Cranmer SL, Jackson SP, Dawes IW and Chong BH. Phenotype changes resulting in high—affinity binding of vWf to recombinant GPIb-IX: Analysis of the platelet-type von Willebrand disease mutations. Blood (Under revision), 2000 |
), 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.