The primary objective of this proposal is to determine the roles of core 2 branched O-glycans in cell adhesion, development, and cancer progression. In the past few years, we have made critical progress in this field. First, we have shown that core 2 branched O-glycans play a major role in lymphocyte adhesion and tumor metastasis. Second, we have cloned cDNAs encoding two novel core 2 branching beta1,6-N-acetylglucosaminyltransferases (Core2GlcNAcT-2 and Core2GlcNAcT-3), which have different substrate specificity and tissue distribution from Core 2GlcNAcT-1 originally cloned. Third, we have demonstrated that alpha 1,4-GlcNAc on core 2 O-glycans inhibits Helicobacter pylori colonization while 6-sulfosialyl Lewis X on core 2 O-glycans facilitates H. pylori-induced inflammation. Based on these findings, three major studies are proposed as follows: 1) Identifying core 2 beta1,6-N -acetylglucosaminyltransferases that play major roles in the biosynthesis of mucin-type O-glycans in the stomach. We will determine which Core2GlcNAcTs play a major role in providing backbone structures for alpha 1,4-GlcNAc-capping structure and Lewis b blood group antigen. 2) Determining the roles of Core2GlcNAcTs in cell adhesion. We will determine the roles of Core2GlcNAcT-2 and Core2GlcNAcT-3 in selectin-mediated adhesion by utilizing mice deficient in Core2GlcNAcT-2 and Core2GlcNAcT-3. 3) Determining the roles of core 2 branched O-glycans in inflammation and tumor formation initiated by H. pylori infection. We will determine if inactivation of one of Core2GlcNAcTs leads to increased H. pylori colonization, thus early onset of gastric cancer and if inactivation of another Core2GlcNAcTs leads to attenuated lymphocyte recruitment, thus impairing inflammation and delaying the onset of gastric cancer.
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