Enzymes that transfer sialic acids to glycoproteins and glycolipids are termed sialyltransferases. Sialic acid addition generally terminates further oligosaccharide biosynthesis and thereby can generate as well as mask biologically relevant glycan structures. Among vertebrates, a highly conserved sialyltransferase gene family exists that contains at least eighteen members. These genes exhibit expression profiles that are commonly developmentally restricted and cell- or tissue-type specific. From limited studies thus far, sialic acid linkages have been found to regulate cell trafficking, adhesion, glycoprotein half-life in plasma, and signal transduction involving multi-subunit receptor complexes. In determining sialyltransferase gene function in vivo, mouse germline mutations are produced using Cre-loxP site-directed recombination in embryonic stem cells and adult mice. Subsequently, physiologic parameters are assessed by the use of specific phenotyping Core facilities provided by this Program Project Grant. In this manner, our previous findings have established critical hemostatic and immunologic roles for specific sialyltransferase genes. For example, ST3Gal-I and ST3Gal-IV promote platelet homeostasis, while ST3Gal-IV deficiency specifically results in an autosomal dominant yon Willebrand disease-like syndrome in mice. The goal of this project is to further elucidate the vascular and innate immune functions of sialyltransferases ST3Gal-I, ST3Gal-IV, and the recently identified ST3Gal-VI. Their roles in masking specific asialoglycoprotein receptor ligands, and the possible involvement of ST3Gal-IV as a modifier of human VWD will be explored. Our studies of ST3Gal sialyltransferase mutants have further resulted in the hypothesis that ST3Gal-VI will be found essential for selectin ligand formation and thus innate immune function during inflammation. This hypothesis will be investigated by generating mice deficient in ST3Gal-VI gene function and subjecting them to phenotypic analyses with PPG Core facilities, that involve determining vascular and innate immune parameters as well as selectin ligand formation and selectin-based physiologic responses. The vascular and innate immune functions of these ST3Gal sialyltransferases are also hypothesized to affect wound healing and bacterial invasion. These putative protective roles of ST3Gal-I, ST3Gal-IV and ST3Gal-VI will be investigated with the PPG Core facility. These studies will define the mechanisms by which alpha2-3 linked sialic acids function in modulating vascular and immune systems, and will likely establish important roles that may lead to new insights in human disease.
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