Leukocyte C2GIcNAcT-I in atherosclerosis

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DESCRIPTION (provided by applicant): Atherosclerosis and its complications are the most common causes of morbidity and mortality. These vascular diseases result from adhesive and signaling interactions among leukocytes, platelets and the vessel wall cells. These cellular interactions are mediated by adhesion molecules, including P, E, L-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), CD43, CD44, integrin CD18, VLA-4, and others. The cellular interactions mediated by these molecules broadly participate in various events in atherosclerosis. To obtain optimal activities, molecules including PSGL-1, CD43 and CD44 need to be modified by the addition of branched O-glycans to their protein structures. These reactions are catalyzed by core 2 1-6-N- glucosaminyltransferase-l (C2GlcNAcT-l), which is a Golgi enzyme in leukocytes. This project is designed to investigate whether C2GlcNAcT-l is crucial for cellular interactions involved in the development of atherosclerosis and its complications. In aim 1, we will investigate the rote of C2GlcNAcT-l in the interactions of mononuclear cells with atherosclerotic arteries. In aim 2, we will investigate the role of C2GlcNAcT-l in the contribution of activated platelets to atherosclerosis. In aim 3, we will investigate the role of C2GlcNAcT-l in the development, progression and regression of atherosclerotic lesions. We will also evaluate the influence of C2GlcNAcT-l in the stability of atherosclerotic lesions. In aim 4, we will investigate the role of C2GlcNAcT-l in the interactions of leukocytes and platelets with injured arteries and in the formation of arterial neointima using an established mouse carotid artery wire injury model. These studies will have significant implications for the inhibition of leukocyte C2GlcNAcT-l in the prevention and treatment of atherosclerosis and its complications.