This Program Project Grant proposal employs an interdisciplinary approach to study the functions of protein glycan interactions in the vascular system. The three thematically related projects are led by investigators with complementary expertise and a strong published record of collaborative research. Project 1 uses gene targeted mice to study the interplay of adhesion and signaling molecules in the vasculature. The emphasis is on processes that regulate the interactions of selectins with their glycoconjugate ligands, a critical early response during inflammation and thrombosis. Mice with altered expression of selectins, selectin ligands, or glycosyltransferases will be studied. Project 2 studies the interactions of galectins, another class of lectins, with neutrophils. The galectins, some of which are expressed in vascular endothelial cells, induce exposure of phosphatidylserine on activated neutrophils without causing apoptosis. This represents a novel mechanism for clearing activated neutrophils at sites of inflammation that will be explored further in the proposal. Project 3 studies how core 1-derived O-glycans contribute to angiogenesis. Major tools are mice with tissue-specific or inducible deletions of the gene encoding T-synthase, a glycosyltransferase that constructs the precursor for all core 1 O-glycans. There is unusually high synergy among the projects that results from the intellectually overlapping themes and the sharing of reagents and methods. An administrative core cements the interactions, in particular through maintenance of a server for data exchange among the projects and through computer support for processing images and other complex data. The data obtained will enhance our understanding of the functions of lectins and glycoconjugates in the vascular system during inflammation, thrombosis, and angiogenesis. This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders.
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