The long term objective of this Academic Research Enhancement Award proposal is to elucidate the mechanism of outside-in signal transduction mediated by the platelet fibrinogen receptor, the integrin alphaIIb-beta3. Elucidation of the mechanism of outside- in signal transduction in human platelets is important basic research. This research is important not only because of the central role of platelets in cardiovascular disease but also because insight into the mechanism of outside-in signal transduction is of central importance to cell biology in general. Gaining insight into the molecular details of outside-in signal transduction in platelets may provide a rationale for the design of a pharmaceutical agent able to control at least some of the platelet behavior which contributes to development and progression of cardiovascular disease. The long-term objective of this proposal will be accomplished by characterizing the effects of a unique receptor activating peptide on platelet function. This receptor activating peptide appears to cause platelet aggregation by binding to alphaIIb and thereby eliciting a conformation change in the fibrinogen receptor which initiates a platelet activation signal transduction cascade that culminates in """"""""irreversible"""""""" platelet aggregation. The experiments described in this proposal are designed to reveal how binding of the receptor activating peptide to the receptor enables the previously inactive receptor to be able to bind fibrinogen and to determine if fibrinogen binding is necessary for subsequent signal transduction by the receptor or if subsequent signal transduction can occur in the absence of receptor crosslinking by fibrinogen or ligands. Hopefully, these experiments will reveal the type of intra-receptor subunit or inter-receptor interactions which initiate the outside-in signal transduction response in platelets.
