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Research Summary Inhibitors of axonal regeneration in the adult nervous system The mammalian adult CNS does not regenerate after injury. One of the major obstacles to regeneration are inhibitors of regeneration that are present in myelin. Therefore to encourage axonal regeneration these inhibitors must be identified and neutralized. We identified one of these inhibitors of regeneration as myelin-associated glycoprotein (MAG). We are interested in how MAG exerts its inhibitory effects. We are characterizing the signal transduction cascade is initiated when MAG interacts with a growth cone. In addition, we have shown that MAG is a sialic acid binding protein and have mapped the sialic acid binding site to Arg118 in the extracellular domain of MAG. However, sialic acid binding alone is insufficient to inhibit axonal growth. Consequently we are now mapping the site on MAG responsible for inhibition. Coupled to this line of study we are also adopting a variety of strategies to identify the functional MAG receptor on neurons. Finally, rather than identify and neutralize inhibitors of axonal regeneration in myelin individually we have found that if the neuron’s endogenous levels of cAMP are raised, its intrinsic growth state changes such that inhibitors are all overcome simultaneously. We are now characterizing the signaling involved in this cAMP effect and testing this effect in vivo. In the long term, the results of these investigations may contribute to the treatment of spinal cord injury.
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