TEAM 1 (Director: François Lanza)
The research theme of the group concerns the mechanisms of adhesion and activation of platelets at the surface of injured blood vessels.
The activities of the team focus on the receptors for von Willebrand factor (glycoprotein complex GPIb-V-IX), collagen (integrin a 2 b 1 and GPVI) and fibrinogen (integrin a IIb b 3). These receptors, some of which are restricted to the platelet line (GPIb-V-IX, GPVI, integrin a IIb b 3), play a key role in the arrest of bleeding (haemostasis) and in the occurrence of thrombosis after rupture of an atherosclerotic plaque.
The work of the last few years has involved study of the normal and pathological biosynthesis of the GPIb-V-IX complex, of the signalling triggered by binding of von Willebrand factor (vWf) to GPIb-V-IX and of collagen to GPVI and integrin a 2 b 1 and of the functional roles of the GPIb b and GPV sub-units. An early intracellular signalling pathway entirely dependent on the GPIb-V-IX complex and triggered by its interaction with immobilized vWf has been characterized.
The biosynthesis and function of this receptor has been studied in CHO cells transfected with the normal complex or mutant complexes encountered in the Bernard-Soulier bleeding diathesis.
The involvement of the intracellular domain of the GPIb a sub-unit in interaction with the cytoskeleton and in the step involving activation of integrin aIIbß3 has been demonstrated using progressive deletions.
A modulatory role of the GPIbß sub-unit in cell adhesion and also in the signalling step involving its intracellular domain has likewise been revealed.
An unexpected function of GPV as a collagen receptor has been documented in vitro and in vivo using a model of arterial thrombosis in KO mice.
 IMAGE: PLATELETS |
The objective of the coming years will be to study the signalling induced by the GPIb-V-IX complex and to determine the functions of the GPIb b and GPV sub-units. One priority will be to define the part played by platelet adhesion receptors and notably by GPIb-V-IX in the occurrence and extension of thrombosis, with a view to the development of new antithrombotic strategies. The role of the signalling crossroads of adhesion receptors and receptors for soluble agonists (tyrosine kinases of the src family, phospholipase C, PI3-K) will be explored in platelet activation and arterial thrombosis. Proteome analysis will be used to identify new partners and second messengers capable of interacting with the intracellular face of the GPIb-V-IX complex. The role of GPIb b in platelet adhesion and activation and in thrombopoiesis will be studied in transfected cell lines and after inactivation or deletion of the intracellular domain in mice. This latter approach will permit us to study the functions of platelets in vivo in models of thrombosis, to elucidate the mechanisms leading to the production of giant platelets in Bernard-Soulier syndrome and likewise to evaluate the part played by the GPIb-vWf pathway in complex physiological or pathological processes involving platelets like angiogenesis or atherosclerosis.
