This program project examines the structure, biosynthesis, and roles of selectin ligands in cell-cell communication. It also aims at elucidating the roles of the selectin-carbohydrate interaction in tumor cell metastasis. This program project is a close collaboration among investigators whose expertise range from carbohydrate synthetic chemistry, carbohydrate chemistry, carbohydrate biosynthesis, to cellular and molecular biology. The work centers around the sialyl Lex and related oligosaccharide structures originally discovered by the participants in this grant as E- selectin ligands. Structure and biosynthesis of E-, P- and L-selectin ligands in human and mice will be investigated. In particular, the roles of specific fucosyltransferase(s) in the formation of selectin ligands and those of N-glycans presenting selectin ligands will be determined by using knock-out mice. In addition, the structure and biosynthesis of the oligosaccharide L-selectin ligand(s) will be elucidated by cloning an enzyme that forms the ligand(s). The regulation of selectin ligand biosynthesis will be investigated in relation to subcellular localization of the enzymes involved in the biosynthesis of selectin ligands. This program project also aims at determining the roles of selectin-mediated adhesion in tumor cell dissemination. These studies will provide new information on selectin-carbohydrate interactions and may help in the design of improved therapeutic intervention in malignancies and other diseases.
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