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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084724-08
Application #
7917994
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Marino, Pamela
Project Start
2002-12-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
8
Fiscal Year
2010
Total Cost
$368,874
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Darabedian, Narek; Thompson, John W; Chuh, Kelly N et al. (2018) Optimization of Chemoenzymatic Mass Tagging by Strain-Promoted Cycloaddition (SPAAC) for the Determination of O-GlcNAc Stoichiometry by Western Blotting. Biochemistry 57:5769-5774
Thompson, John W; Griffin, Matthew E; Hsieh-Wilson, Linda C (2018) Methods for the Detection, Study, and Dynamic Profiling of O-GlcNAc Glycosylation. Methods Enzymol 598:101-135
Thompson, John W; Sorum, Alexander W; Hsieh-Wilson, Linda C (2018) Deciphering the Functions of O-GlcNAc Glycosylation in the Brain: The Role of Site-Specific Quantitative O-GlcNAcomics. Biochemistry 57:4010-4018
Griffith, Adam R; Rogers, Claude J; Miller, Gregory M et al. (2017) Predicting glycosaminoglycan surface protein interactions and implications for studying axonal growth. Proc Natl Acad Sci U S A 114:13697-13702
Wang, Andrew C; Jensen, Elizabeth H; Rexach, Jessica E et al. (2016) Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. Proc Natl Acad Sci U S A 113:15120-15125
Griffin, Matthew E; Jensen, Elizabeth H; Mason, Daniel E et al. (2016) Comprehensive mapping of O-GlcNAc modification sites using a chemically cleavable tag. Mol Biosyst 12:1756-9
Griffin, Matthew E; Hsieh-Wilson, Linda C (2016) Glycan Engineering for Cell and Developmental Biology. Cell Chem Biol 23:108-121
Wibowo, Arif; Peters, Eric C; Hsieh-Wilson, Linda C (2014) Photoactivatable glycopolymers for the proteome-wide identification of fucose-?(1-2)-galactose binding proteins. J Am Chem Soc 136:9528-31
Ramakrishnan, Parameswaran; Clark, Peter M; Mason, Daniel E et al. (2013) Activation of the transcriptional function of the NF-?B protein c-Rel by O-GlcNAc glycosylation. Sci Signal 6:ra75
Clark, Peter M; Rexach, Jessica E; Hsieh-Wilson, Linda C (2013) Visualization of O-GlcNAc glycosylation stoichiometry and dynamics using resolvable poly(ethylene glycol) mass tags. Curr Protoc Chem Biol 5:281-302

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