COMPLEX CARBOHYDRATES IN NEURONAL CELL FUNCTION

Johns Hopkins University, Baltimore MD

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Abstract

This project explores the functions of neuronal complex carbohydrates-major molecular determinants on all nerve cells. Recent research provides strong evidence of the specific roles of these molecules in nerve cell regulation, and new tools with which to explore those roles. In particular, an essential role for gangliosides, major nerve cell sialoglycoconjugates, in axon-myelin interactions was recently demonstrated in vitro and in vivo. Specific gangliosides are required for long-term axon-myelin stability and may act as nerve cell receptors for myelin-mediated inhibition of nerve regeneration, a major mechanism limiting nerve repair after ventral nervous system (e.g., spinal cord) injury. This project will capitalize on recent findings, using new experimental tools to investigate the relationship between ganglioside expression and nerve egeneration, to study the effect of targeted sialic acid modification in enhancing nerve regeneration, and to probe the molecular basis for ganglioside-mediated nerve cell regulation. Cell surface carbohydrates regulate nerve regeneration. The nature central nervous system is inhibitory to nerve regeneration, due in part to myelin inhibitor proteins which bind to the nerve cell surface and halt axon outgrowth. One of these proteins, myelin-associated glycoproteins (MAG) is a sialic acid-dependent lectin (carbohydrate binding protein) which targets endogenous nerve cell gangliosides. This project will probe the function of gangliosides in the inhibition of nerve regeneration by modifying ganglioside expression, genetically and biochemically, and testing for enhanced nerve regeneration in vitro and in vivo. Molecular mechanisms of ganglioside-mediated neuronal regulation. Gangliosides reside on the cell membrane in dynamic membrane "rafts"-lateral associations of gangliosides, other sphingolipids, and membrane-associated signaling molecules. This project will use MAG chimeras, anti-ganglioside monoclonal antibodies, and synthetic photoaffinity ganglioside derivatives to search for transmembrane signaling cascades initiated with MAG binds to its target gangliosides to regulate nerve function.