The supplementation of glycosylation pathways with exogenously-supplied monosaccharide has potential therapeutic value for human diseases ranging from rare congenital disorders (CDGs) to cancer. In particular, N-acetylmannosamine (ManNAc) analogs that modulate cell surface sialic acid display are promising candidates for addressing glycosylation defects found in a wide range of cancers. The transition of sugar analogs from their current status as laboratory tools to clinical applications has recently been given a boost by our laboratory's recent finding that sugar analog-induced toxicity observed upon modification of monosaccharide with hydroxyl-protecting groups designed to improve their pharmacological properties is due to apoptosis. This observation, combined with the emergence of apoptosis stimulators as key targets for the control of cancer, support enhanced efforts to investigate the connections between sialic acid and apoptosis:
Specific Aim #1 is to characterize the role of ManNAc analogs in apoptosis in human cancer cells, with a focus on the effects of the N-acyl """"""""R1"""""""" group. This goal will be pursued by (A) testing the impact of the analogs on O-GlcNAc protein modification; (B) performing a step by step evaluation of the response of the various cellular pathways that execute apoptosis to analogs; (C) testing the effects of analogs on the 'biosynthetic machinery' used by cells to construct a set of the sialoglycoconjugates involved in apoptosis that include Fas, TNFalphaR2, IGF, and CD43; and (D) evaluating whether inhibition of metabolic flux through the sialic acid biosynthetic pathway is the cause, or a downstream response, to analog-induced apoptosis. The set of experiments outlined in Aim #1 are designed to comprehensively evaluate the effects of ManNAc analogs on sialic acid metabolism and link these responses to apoptosis. These compounds also elicit cell-wide responses by virtue of O-hydroxyl """"""""R2"""""""" group modifications. In this project, cellular responses of R2-groups, which deliver short chain fatty acids (SCFAs) to a cell upon intake, will be tested in Aim #2:
Specific Aim #2 is to characterize the role of R2-groups in apoptosis by (A) analyzing cellular response to analog-supplied SCFAs, (B) characterizing the effects of the SCFA 'carrier' molecule, (C) analyzing ceramide and ganglioside metabolism in analog-treated cells and (D) testing metabolic 'carry-through' of R2-groups.
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