Platelet Membrane Proteins in Thrombosis

At the site of vascular injury, platelet adhesion, activation, and aggregation culminate in thrombus fomation, the principle event underlying most acute arterial thrombooeculsive disorders. Given that thrombosis is the leading cause of death worldwide, understanding the contribution of platelets to the process is of particular importance. Our novel observation of altered platelet thrombus fomation in mice deficient in P-selectin serves as the basis of this proposal. Until recently, the primary function of P-sc\ectin on activated platelets and endothelial cells was thought to be promotion of the initial interaction of these cells with leukocytes. P-selectin on activated endothelial cells has been implicated in recruitment of platelets, and our observations suggest that the protein may also playa role in promoting platelet-platelet interactions. Thus, P-selectin and its ligand may be involved in promoting the interactions of platelets with leukocytes, endothelial cells, and with other platelets, This proposal will detennine the role of platelet P-selectin in platelet-platelet interactions in vitro and platelet thrombus formation in vivo. The hypothesis to be tested in this proposal is that P-selectin on activated platelets interacts with a specific platelet counterreceptor and that this interactiun affects platelet signalling and influences platelet-platelet interactions mediated bv allbf33. The Specific Aims arc to: (I) establish an in vitro assay of platelet adhesion to P-seleetin to be used to identify the platelet counterreceptor( s) for P- selectin, (2) detemline the role of P-selcctin in platelet-platelet interactions in vitro, (3) detennine the role of P- seleetin in models of thrombosis, and (4) to delineate the contribution of platelet and endothelial P-selectin to thrombosis and the arterial response to injury. This work will identify a novel target for future anti thrombotic strategies and calls into question previous results \vith P-selectin antagonists as being related exclusively to inhibition of leukocyte/platelet interactions.