The purpose of this application is to study the role played by van Willebrand factor (VWF) in initiating platelet deposition at sites of vascular injury, particularly in areas of the circulation characterized by rapid blood flow. The goal is to elucidate the mechanisms of adhesive interactions and cellular responses that are relevant to the arrest of bleeding from wounded tissues but also to the development of common and serious diseases caused by arterial thrombosis, such as myocardial infarction and stroke.
The first aim i s to define the biomechanical characteristics of the bonds formed between the VWF A1 domain and the platelet ilycoprotein (GP) Ib-alpha in relation to specific structural aspects of the A1 domain.
The second aim i s to define the mechanisms through which soluble VWF multimers and membrane tethers contribute to stabilizing platelet adhesion mediated by GP Ib-alpha.
The third aim i s based on structural evidence that alpha-thrombin may stabilize the VWF A1 domain-GP Ib-alpha interaction, and may thus play an unexpected role in modulating the initial adhesion of platelets to a thrombogenic surface through a mechanism that is independent of platelet activation. The proposed studies will clarify the biological significance and mechanism of this novel athrombin function.
The fourth aim i s to characterize the signaling events related to the interaction between the VWF A1 domain and GP Ib-alpha, and obtain a more definitive definition of the mechanisms through which the interaction contributes to platelet activation. The fifth aim is to define how VWF binds to extracellular matrix components, in particular to define the potential biological significance of the interactions with collagen type VI and the oligosaccharides that are present in proteoglycans. Extensive interactions with all the other projects in the program and with a core A will facilitate the development of these aims. The results of the proposed studies will have an impact on public health by providing novel mechanistic information on processes that are central to normal hemostasis and pathological arterial thrombosis.
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