Regulation of Integrin alphaIIbbetaIII Function bu Scavenger Receptor-B1

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The number of known novel platelet receptors/ligands that regulate the platelet activation cascade is growing. Recent studies demonstrated that scavengejr receptor class B, type I (SR-BI) is expressed on human and murine platelets. Importantly, reduced levels of platelet SR-BI expression are associated with increased platelet aggregation in patients. Total SR-Bl deficiency in mice on an apoE null background results in spontaneous myocardial infarction and premature death. Our preliminary studies showed that deficiency of SR-BI in murine platelets is also associated with remarkably increased platelet activation and aggregation in response to selected physiological agonists. In addition, we recently identified specific ligands for SR-BI that are potent inhibitors of integriri allbps activation andplatelet aggregation in vitro. Mechanisms linking SR-BI and allbB33 activation areniknown. Control of platelet reactivity is regarded as critical for prevention of acute cardiovascular events, thus the elucidation of mechanisms by which SR-BI may regulate integrin activation and whether it contributes to thrombotic events in vivo is important. It has been established that SR-BI may participate in signa ing events in several cell types. Moreover, CD36, a close relative of SR-BI, is associated in platelets wit i several protein-tyrosine kinases of theSrc family, Thus, we hypothesized that SR-BI-mediated signaling in platelets controls platelet integrin allbpS activation and, therefore, platelet aggregation and thrombosis. T ie long-term goal of this proposal is to determine the role platelet SR-BI is playing in thrombosis and to eluc date the exact molecular and cellular mechanisms of its contribution. The specific Aims are: Aim 1.To characterize the role cif SR-BI in integrin allb(33 activation andplatelet function in vitro. Aim II. Toidentify the molecular signaling mechanisms linking SR-BI and activation of integrin allbft3 in platelets. Aim III. Wewillseek to obtain evidence that platelet SR-BIplays a significant role in the regulation of platelet activation and thrombosis in vivo.