The overall goals of this work are to determine mechanisms that regulate expression of mammalian oligosaccharide molecules. Fucosylated oligosaccharides were chosen as an experimental model because their fucose linkages, and the cognate fucosyltransferases responsible for their biosynthesis, are expressed with temporal and spatial precision during mammalian differentiation, and are frequently altered in association with malignant transformation. These properties suggested important functions for these molecules; this has been born out recently by studies demonstrating that one or more members of a specific set of fucosylated oligosaccharides, expressed by cells of the myeloid lineage, adhesion of these leukocytes to endothelial leukocyte adhesion molecule I during inflammation. To address the regulation of expression of such molecules, we have isolated genes and cDNAs that encode three distinct alpha(1,3)fucosyltransferases. These represent tools with which to examine transcriptional, post-transcriptional, and structure-function considerations that determine the types and relative amounts of distinct alpha(1,3)fucosylated glycoconjugates made by cells and tissues.
The SPECIFIC AIMS of this proposal are: 1. To analyze the structure and function of a novel human DNA sequence that may encode an alpha(1.3)fucosyltransferase. 2. To isolate cloned, myeloid-lineage cDNAs that participate in the biosynthesis of cell surface sialyl Lewis x and VIM-2 determinants. 3. To define the biosynthesis and structure of each alpha(1,3)FT, using biochemical, molecular genetic, and morphologic approaches. 4. To investigate the relationship between alpha(1,3)FT acceptor substrate specificity and primary sequence determinants within alpha(1,3)FTs via the creation and testing of chimeric, mutant alpha(1,3)FTs. 5. To define expression patterns of alpha(1,3)FT genes in normal human tissues.
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