In the previous funding period, we have made important progress in this field. First, we discovered that 6-sulfo sialyl Lewis X plays a major role in lymphocyte homing by generating mutant mice deficient with two sulfotransferases GlcNAc6ST-1 and GlcNAc6ST-2. Second, we discovered that 6-sulfo sialyl Lewis X on /V-glycans, as well as on O-glycans play a substantial role as lymphocyte recruitment in inflammatory response and lymphocyte homing. Third, we discovered that natural killer (NK) cells are recruited to suppress tumor formation in draining lymph nodes and this NK cell recruitment requires interaction between L-selectin on NK cells and L-selectin ligands on lymph node HEV. Fourth, we discovered that by generating mutant mice deficient in EXT1 heparan sulfate synthase, heparan sulfate plays an essential role in embryonic development on various glycans and store chemokines necessary for lymphocyte activation. Based on these findings, two major areas of study are proposed: 1. Roles of 6-sulfo sialyl Lewis X-capping structures and O-glycans carrying 6-sulfo sialyl Lewis X in lymphocyte recruitment in inflammatory response. These studies will utilize two doubly deficient mouse models, GlcNAc6ST-1/GlcNAc6ST-2, and Corel-|33GlcNAcT/Core2GlcNAc6ST-1 to determine the function of sulfation and A/-glycan-based L-selectin ligands in chronic inflammation. 2. Roles of heparan sulfate in chemokine presentation during lymphocyte recruitment and growth factor presentation during tumor angiogenesis. The studies will utilize Tie2-directed inducible EXT1 deficient mice, which we just established, to determine the function of heparan sulfate in lymphocyte rolling and activation, and tumor progression through angiogenesis. These studies will be greatly facilitated by collaboration with Drs. Michiko Fukuda, John Lowe, Peter Seeberger, and Ulrich von Andrian. These studies will help us understand the structure and function of cell surface carbohydrates in inflammatory response and tumor progression and metastasis.
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