Platelet-Leukocyte Switch in Vascular Disease: Project 2 of Burridge P01 HL080166

  • Smyth, Susan (PI)

Grants and Contracts Details


Platelet-leukocyte interactions occupy a central role in the interface between thrombosis and inflammation. At sites of vascular damage, adherent platelets physically and functionally interact with circulating leukocytes. We and others have shown that these interactions may contribute to intimal hyperplasia, atherosclerosis, and microvascular occlusion. The initial interactions of platelets and leukocytes are mediated by P-select-independent tethering, which is followed by firm leukocyte adhesion promoted by §~2 integrins. Analogous to the signaling events described for leukocyte interactions with endothelial cells that results in leukocyte-extravasation, we and others have demonstrated that the engagement of platelet P-selection triggers a signaling cascade in leukocytes that activates leukocyte §~2 integrins and may be required for leukocyte-transplatelet migration and infiltration at sites of vascular damage. However, the nature of platelet-mediated signaling pathway and its impact on leukocyte function and vascular disease progress is unknown. Our long-term goal is to determine the role that platelet-leukocyte interactions play in the response to vascular injury, and then, through creative and innovative approaches, apply that knowledge to improve the diagnosis and therapy of human cardiovascular disease. The objective of this application is to define the unique molecular events that are initiated in leukocytes upon binding platelets at sites of vascular injury and to determine their contribution(s) to the injury response. The central hypothesis for the proposed research is that the recruitment of leukocytes by platelets results in a crucial switch in the injury response that converts the dominant biology to inflammation with leukocyte infiltration into the vessel wall and initiation of a local and systemic inflammatory response. To test our hypothesis, we will identify platelet-initiated signaling pathways in leukocytes that are required for transmigration of leukocytes through a layer of adherent platelets using in vitro and in vivo models. We will define the pathophysiologic contribution of these pathways to the arterial injury response and the development of intimal hyperplasia. Finally, we will compare the contribution of these signaling systems to leukocyte transmigration through endothelium in models of vascular inflammation. We are particularly well-prepared to undertake the proposed research because of the well-defined animal models that we have established and the synergy provided by the PPG environment.
Effective start/end date8/1/066/30/07


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