Developing an understanding of the molecular mechanisms that underlie neuronal communication, and hence form the basis of learning and memory, stands as one of the central challenges of modern science. In this proposal, the focus is on two carbohydrate modifications that play a central role in this process, fucosylation and O-GlcNAc (O-linked N-acetyglucosamine) glycosylation. Protein fucosylation is enriched at neuronal synapses and has been implicated in long-term memory consolidation. O-GlcNAc glycosylation is a dynamic, intracellular modification found on neuronal proteins involved in gene expression, cell signaling, and synaptic plasticity. A major goal of our work is to develop an understanding of the molecular mechanisms by which these sugars influence neuronal communication and information storage. What proteins are modified in the brain, and how do specific carbohydrates regulate the structure and function of neuronal proteins? Are there common themes in the way Nature uses carbohydrate structures to encode functional information? Addressing these questions will be critical for understanding the structure-activity relationships of carbohydrates and their roles in complex brain processes. As our program takes a chemical approach, this work may reveal novel proteins and pathways for therapeutic intervention and aid in the development of new Pharmaceuticals designed to improve cognition deficits associated with aging and neurodegenerative disease. Unlike nucleic acids and proteins, carbohydrate structures are not template-encoded and thus are challenging to detect and manipulate in vivo. As such, new tools are needed to complement the traditional approaches of biochemistry and genetics to advance our understanding of carbohydrates. This work focuses on the development of chemical tools to accelerate the discovery and study of fucosyl and OGlcNAc sugars and their associated proteins. When combined with the power of biochemistry, genetics and neurobiology, these tools will provide new insights into the physiological roles of carbohydrates in the nervous system and uncover novel mechanisms of neuronal communication, learning and memory formation. The major goal of this work is to understand how carbohydrates contribute to the molecular mechanisms that underlie neuronal communication and hence form the basis of learning and memory. Ultimately, our studies should reveal novel targets for therapeutic intervention and may aid in developing new Pharmaceuticals for improving cognition deficits associated with aging and neurodegenerative disease.
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