Several fucosylated oligosaccharides function as essential components of ligands for human E-, P-, and L-selection. Selectin-dependent leukocyte- endothelial cell adhesion is dependent upon these specific fucosylated, sialylated and/or sulfated moieties, represented by the sialyl-LeX molecule (sLeX) and its structural isomers. These fucosylated charged oligosaccharides, and the alpha(1,3)fucosyltransferases (alpha(1,3)FTs) that can regulate their synthesis, represent pivotal targets for therapeutic intervention in circumstances involving selectin-dependent cell adhesion, in malignancy and in inflammation. Studies in this Project will focus on defining the oligosaccharide products of two Fuc-Ts (Fuc-TIV and Fuc-TVII) that direct expression of leukocytic and endothelial cell selectin ligands, on three other Fuc-Ts (Fuc-TIII, V, and VI) that can direct expression of selectin ligands on cancer cells, and on the role of these enzymes and their products in the pathogenesis of leukocytic malignancy.
Specific Aims are as follows: (1) To define the sulfated and/or sialylated oligosaccharide acceptor substrate specificities of Fuc-TIV and Fuc-pTVII relevant to selectin ligands. (2) To determine the structures and functions of oligosaccharides directed by Fuc=TIV and Fuc-TVII utilizing mouse null mutant cells generated by gene knock-out and transfected cell lines. (3) To determine the roles of selectin ligands in the pathogenesis of leukocyte malignancy utilizing Fuc-TVII with null mutant mice and alpha- mannosidase IIx deficient mice. These studies will allow us to understand the roles of two fucosyltransferases in selectin ligand presentation, development of an organism, and hematopoietic cell malignancy.
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