The purpose of this new proposal is to identify the functional interplay of different constituents responsible for the variable thrombogenicity of extracellular matrices and cell surfaces exposed to flowing blood, and define the mechanisms that regulate the response of platelets to such diverse stimuli.
Our specific aims are: 1) To characterize the different extracellular matrix (ECM) components that induce platelet thrombus formation at sites of vascular lesions. We will use the ECM deposited by relevant vascular cells, purified ECM constituents and platelets with targeted genetic mutations or functional inhibition of relevant receptors to elucidate the integration of the individual contributions that mediate platelet interactions at the vessel wall. 2) To characterize the distinct pathways of platelet activation induced by different ECM components. We propose to use ex vivo flow models and mice with targeted genetic mutations to understand the interplay of different signaling pathways in platelet activation and thrombus formation on selected ECM substrates. 3) To elucidate the regulation of platelet reactivity with the surface of endothelial cells and other cells of the vessel wall and the potential contribution of such mechanisms to thrombus formation. 4) To evaluate the effects of targeted alterations of ECM, cellular and platelet components on the process of thrombus formation and stabilization following a vascular lesion in vivo. The ultimate goal of our research is to couple ex vivo studies of cells and cell products with in vivo models of vascular injury to arrive at an understanding of the mechanisms that govern the interaction of platelets with injured vessels. The results of the studies outlined in this application are likely to have an impact on public health by providing novel information on processes that are central to normal hemostasis and pathological arterial thrombosis. These findings will provide a better definition and characterization of several potential targets for antithrombotic intervention that may yield new treatments for patients at risk of cardiovascular and cerebrovascular events.
