This project will focus on chondroitin sulfate (CS) glycosaminoglycans, a class of polysaccharides that play important roles in development, viral invasion, cancer, and spinal cord injury. CS polysaccharides display diverse sulfation patterns that are spatiotemporally regulated in vivo. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS and a lack of tools. For instance, well-defined CS molecules cannot be purified from natural sources, and as a consequence, the field has been limited to working with heterogeneously sulfated mixtures of compounds. Genetic deletion of one of the sulfotransferase genes responsible for CS biosynthesis can propagate global changes throughout the carbohydrate chain, making it difficult to pinpoint the role of specific sulfation motifs. In this grant, we will combine the tools of organic chemistry and biology to overcome these challenges. We will exploit synthetic chemistry to assemble defined CS structures (both natural and non-natural) to obtain fundamentally new information about the structure- function relationships of CS. When combined with the power of biochemistry, genetics, cell biology, and neurobiology, these molecules will provide new insights into the physiological roles of carbohydrates in the nervous system and uncover novel mechanisms of neuronal growth and repair. As our project takes a distinctly chemical approach, this work may reveal novel proteins and pathways for therapeutic intervention and aid in the development of new pharmaceuticals to stimulate regeneration after injury, aging or disease.

Public Health Relevance

This research seeks to understand how the structure of chondroitin sulfate glycosaminoglycans regulates fundamental biological processes, such as protein recognition and regulation, cell-cell communication, development, and regeneration after injury. Through the discovery of novel small molecules, proteins and pathways involved in these processes, this work may aid ultimately in the development of new therapeutic approaches to a broad range of disease states, such as cancer, infectious and neurodegenerative diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Marino, Pamela
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California Institute of Technology
Schools of Engineering
United States
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Matho, Michael H; Schlossman, Andrew; Gilchuk, Iuliia M et al. (2018) Structure-function characterization of three human antibodies targeting the vaccinia virus adhesion molecule D8. J Biol Chem 293:390-401
Cheung, Sheldon T; Miller, Michelle S; Pacoma, Reynand et al. (2017) Discovery of a Small-Molecule Modulator of Glycosaminoglycan Sulfation. ACS Chem Biol 12:3126-3133
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
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Miller, Gregory M; Hsieh-Wilson, Linda C (2015) Sugar-dependent modulation of neuronal development, regeneration, and plasticity by chondroitin sulfate proteoglycans. Exp Neurol 274:115-25
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Pulsipher, Abigail; Griffin, Matthew E; Stone, Shannon E et al. (2014) Directing neuronal signaling through cell-surface glycan engineering. J Am Chem Soc 136:6794-7
Matho, Michael H; de Val, Natalia; Miller, Gregory M et al. (2014) Murine anti-vaccinia virus D8 antibodies target different epitopes and differ in their ability to block D8 binding to CS-E. PLoS Pathog 10:e1004495
Oh, Young In; Sheng, Gloria J; Chang, Shuh-Kuen et al. (2013) Tailored glycopolymers as anticoagulant heparin mimetics. Angew Chem Int Ed Engl 52:11796-9
Griffin, Matthew E; Hsieh-Wilson, Linda C (2013) Synthetic probes of glycosaminoglycan function. Curr Opin Chem Biol 17:1014-22

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