This application seeks to develop the recently studied concept of """"""""outside-in"""""""" signalling during platelet activation. Thus, it is hypothesized that receptors on the platelet surface serve as transducers of receptor-specific signals which will result in platelet activation. Platelet adhesion is induced by vessel proteins exposed by vascular damage and platelet proteins exposed during platelet activation. Specific proteins on the platelet surface are classified as """"""""adhesion receptors"""""""". The """"""""outside-in"""""""" signalling referred to above is mediated by vessel matrix proteins and the adhesion receptor on platelets which are in a complex. Platelet adhesion, culminating in aggregation, is mediated by fibrinogen and von Willebrand Factor (VWF). Adhesion of platelets to fibrinogen as mediated by the platelet adhesion receptor GP Iib-IIIa promotes induction of tyrosine-phosphorylation of a number of proteins in the platelet. However, this interaction does not promote platelet secretion or production of thromboxane A2 (i.e. on immobilized fibrinogen). This has led Dr.
H aim ovich to propose that the interaction between immobilized fibrinogen and GP Iib-IIIa specifically activates a subset of signalling reactions. The application will examine three facets of the mechanism of platelet activation during the adhesion step with fibrinogen and/or VWF.
