? During inflammation leukocytes are recruited from the circulation into tissues. In order to leave the bloodstream leukocytes must adhere to and migrate across the endothelial lining of blood vessels. This proposal is aimed at understanding the complex series of adhesive and migratory events in this process. The first project will investigate the signals generated in endothelial cells as they respond to adhering leukocytes. We will investigate the roles of Rho GTPases in the assembly of leukocyte-induced endothelial cups. How leukocytes manipulate the integrity of endothelial cell-cell junctions to allow leukocyte passage will be studied. The roles of the Rapt, RhoA and Rac1 GTPases will be investigated in this process. Additionally, the role of tyrosine phosphorylation of endothelial junctional proteins will be determined during leukocyte transendothelial migration. The second project will focus on leukocyte-platelet interactions in the context of vascular injury where endothelial cells are lost and platelets provide the cellular layer lining damaged blood vessels. The roles of Rap1 isoforms and the tyrosine kinase Pyk2 will be studied in leukocytes interacting with platelets. The work will be extended to in vivo mouse models of arterial injury and inflammation. Filopodia are slender actin-based protrusions that mediate the initial contacts between leukocytes and endothelial cells during inflammation. The third project will investigate myosin X in filopodial function and endothelial cup assembly. All of the projects will take advantage of an imaging and biosensor core that will permit state of the art live cell imaging with special emphasis on the visualization of active signaling molecules by fluorescence resonance energy transfer (FRET). The long term goal of this program project proposal is to elucidate critical signaling events during inflammation that may lead to the development of novel therapies for cardiovascular disease and other inflammatory disorders.
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