This program project examines the structure, biosynthesis, and roles of selectin ligands in cell-cell communication. It also aims at elucidating the roles of carbohydrate binding protein-carbohydrate interactions in tumor cell dissemination and inflammation. This program project is a close collaboration among investigations whose expertise ranges from carbohydrate synthetic chemistry, carbohydrate chemistry, carbohydrate biosynthesis, to cellular and molecular biology. This work centers around the sialyl Le/x and related oligosaccharide structures originally discovered by the participants in this grant as E- selectin ligands. The structure and biosynthesis of E-, P-, and L-selectin ligands in humans and mice will be investigated. In particular, the roles of specific fucosyltransferase(s) and sulfotransferase(s) in the formation of selectin ligands will be determined by using knockout mice. Interactions of selectin or selectin-related molecules with sialyl Le/x on tumor cells will be characterized. In particular, the roles of tumor cell carbohydrates in nature killer (NK) cell-mediated cytolysis will be elucidated. Concurrently, the roles of NK cell carbohydrates and adhesion molecules will be determined in tumor cell targeting. These studies will provide new information on selectin-carbohydrate and selectin-related molecule-carbohydrate interactions under normal and pathological conditions. The knowledge obtained in these studies may help in the design of improved therapeutic interventions against malignancies and other diseases.
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