Our long-range goal is the development of artificial salivas for the treatment of salivary dysfunction. This Program Project Grant (PPG) will study a potentially important ingredient of artificial salivas, namely mucins. The research objectives of the PPG are two-fold. The first is to understand on a molecular level the structure-function relationships of human salivary mucins (higher molecular weight MG1 and lower molecular weight MG2) and how these molecules are made in situ. The second is to enhance these mechanisms through selective endogenous or exogenous molecular manipulation of the host. These goals are being pursued in three integrated projects: (A) Conformation/Bioactivity of Human Salivary Mucin Glycans (Dr. Michael J. Levine, Director); (B) Structure/Regulation of Human Salivary Apo-Mucin Genes (Dr. Libuse A. Bobek, Director); and (C) Regulation of Human Salivary Mucin Glycosylation (DR. Joseph T. Y Lau, Director). Project A will use a biochemical/biophysical approach to synthesize MG2 glycopeptides with varying levels of O-linked units. The bioactivity of these glycopeptides will be compared to native MG2 to assess the role of glycosylation patterns on biological function. In subsequent studies, the data obtained will be used to design mucin peptides (e.g. glycomimetics) that mimic the conformation and biological properties of bioactive glycopeptides. Project B will use a molecular biology approach to study MG2 (MUC7) gene expression and characterize the protein structure of the apo-MG1 monomeric biology approach to examine the molecular and cellular factors that dictate glycan composition in human salivary mucins. Studies will focus on the biosynthesis of the sialylated- and fucosylated-Core 1 oligosaccharides on MG2. Knowledge obtained in all 3 projects could eventually provide a template for the design of bioactive glycomimetics and recombinant mucin analogs for use in artificial salivas and gene therapy protocols for augmenting mucin expression.
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