"During the inflammatory response, leukocytes accumulate in the vascular lumen and undergo a morphological and molecular polarization characterized by the formation of discrete domains (a leading edge and an uropod) that allows their directional migration. We aim to understand how and when this polarization originates, as well as the endothelial signals that induce it under physiological conditions. We propose to use a novel intravital microscopy system to image these domains in real-time. Recent observations have shown that leukocytes that are adherent on the endothelium interact with other blood components, including platelets, and that these interactions contribute to the vascular and tissue injuries associated to inflammatory processes. We therefore propose to characterize the subcellular domains and receptors present in polarized leukocytes and platelets that mediate these interactions. We will also investigate the contribution of the interactions mediated by each leukocyte domain (leading edge or uropod) in the normal and pathogenic inflammatory response, using various transgenic mouse lines and different models of inflammation. These studies will allow a better understanding of the inflammatory response at the cellular and molecular levels, and may lead to the rational design of therapies targeting this group of complications that so overwhelmingly threat our quality of life."