An impressive array of proteins with covalently linked carbohydrate is produced by eukaryotic cells as components of secretions, membranes and extracellular matrices (ECM) and their structurally diverse saccharide units have been implicated in a number of recognition phenomena which regulate the interaction of cells with other cells, matrix constituents and circulating molecules. Our objective is to continue and expand our research which is predicated on the belief that an understanding of the biological function and alteration in disease of the carbohydrate-containing proteins depends on a structural definition of their saccharide chains and peptide core. Our broadly based investigations will focus on the structure and functional properties of several groups of glycoconjugates (glycoproteins and proteoglycans) including those from basement membranes and related ECM, mitochondria and thyroid cell surfaces; proteins with sulfated Asn-linked oligosaccharides will also be studied and we will continue to explore the macromolecular derangements of the glomerular ECM responsible for the renal filtration defect of diabetes. More specifically, our investigations will include an assessment of the biological role of heparan sulfate (HS) chains of glomerular basement membrane (GBM) proteoglycan (PC), with their novel 3- 0-sulfated ClcN-containing sequences recently described in this laboratory, in regard to antithrombin binding and antiproliferative activity; characterization of the saccharide sequences and of the core proteins of the HSPG's produced by glomerular cells (mesangial, epithelial and endothelial); polarity studies with the latter two cells to determine why their ECM's have PC's with only HS chains and not chondroitin (CS) and dermatan (DS) sulfate; analyses of diabetic glomerular ECK's for CS and DS as an index of mesangial expansion; characterization of Asn-linked oligosaccharides of type VI collagen which in the glomerulus is mesangially located. Studies on the I-antigenic major thyroid surface glycoprotein (CP-3) in regard to its lipid-glycan anchor cell surface distribution will be continued; the branch and site locations of sulfate capping groups on Asn-linked carbohydrate units of thyroglobulins will be investigated as will be the structure of the sulfated N-linked oligosaccharides of prolactins. A recently initiated study of mitochondrial glycoproteins will be pursued to permit the definition of these molecules in various compartments of this organelle as well as determination of the structure of their carbohydrate units.
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