Cells in the immune system rely on regulated adhesion to support a variety of important functions. Among them are pathogen recognition, leukocyte emigration into inflamed tissues, and lymphocyte recirculation between the primary circulation and the lymphatics. In pathological inflammation, adhesion permits inappropriately activated tissues to recruit immune cells to the inflammatory focus. This proposal is directed at understanding the leukocyte molecules which participate in adhesion reactions underlying vascular emigration, and at elucidating the role that a new class of molecule plays in the intracellular regulation of adhesion, a process sometimes turned """"""""inside-out"""""""" signalling. The principal tools to be used are biochemical and genetic. The application relies on the use of transgenic and knockout models to establish the participation of candidate enzymes and proteins which are thought to mediate the initial phases of inflammatory adhesion. A detailed analysis of the mechanism whereby P-selectin recognizes its composite target structure will be carried out, and the participation of a candidate fucosyltansferase in the formation of neutrophil ligands for E- and P-selectin will be explored. Identification of the mechanism by which cytohesins activate leukocyte integrins and their roles in other integrin adhesion events will also be examined.
