A major challenge in the field of cardiovascular research is:
a) the understanding of the molecular mechanisms underlying blood platelet interactions with the vasculature and (b) the development of cell-type and receptor specific antagonists to prevent uncontrolled platelet adhesion events leading to cardiovascular diseases. The deposition of platelets on thrombogenic surfaces such as ruptured arthero-sclerotic plaques may provoke acute vascular occlusion resulting in myocardial infarction, transienti schemic attacks or stroke, together the first cause of death in our Western society. Within the damaged vessel wall, collagens are the most abundant thrombogenic substances. Platelet adhesion to collagen occurs both directly, through binding to the integ in receptor a2b1, and indirectly via von Wille brand Factor (vWF) forming the bridge between collagen and the vWF platelet receptor, glycoprotein (GP) Ib. The latter interaction only occurs following a conformational change in vWF, e.g. as a consequence of the shear stress exerted by the flowing blood on vWF immobilised onto collagen. As a result of these interactions, platelets become activated and GPIIb/IIIa (or integrinaIIbb3) becomes competent to bind fibrinogen and vWF. Both are able to cross link adjacent platelets, finally resulting in a platelet plug. In the present project it is our intention to develop compounds that will interfere with the very first stages of thrombus formation, e.g. adhesion of platelets to the damaged vessel.
To this end we want to use a set of complementary approaches including the generation of recombinant binding domains of the different ligands/receptors, monoclonal antibodies and peptides, selected based on PEPSCAN analysis, phage display technology and crystal structure information. In addition, we will look for inhibitory proteins to be found in some hematophagous parasites secretingnon-immunogenic anti-haemostatic agents. Inhibition of platelet collagen interaction by these peptides and proteins will be analysed in static and dynamic adhesion experiments as well as in platelet activation (signal transduction) experiments. It is expected that such compounds by acting at the very first stages of platelet-dependent thrombus formation, will be superior to currently available antiplatelet drugs that only act at later stages of the process. The present consortium brings together a broad spectrum of complementary experience and know-how needed for the successful outcome of the present project: technology on platelet receptors (GPIb, alpha 2 bˆta 1,alpha IIb bˆta 3,alpha v bˆta 3); on vWF (clinical, molecular biology, functional analysis) is widely available. Phage display technology isoperative (using complementary libraries) in a number of groups as is signal transduction analysis. A further interdisciplinary approach is foreseen by the participation of a group involved in parasitology of hematophagous parasites. The linking of this broad expertise should enable us to progress in a significantly more efficient manner and to open up new lines of research.
Funding SchemeCSC - Cost-sharing contracts