The adult mammalian CNS does not regenerate. Immediately after injury, inhibitors in myelin, such as myelin-associated glycoprotein (MAG), are responsible for this lack of regeneration. Therefore, there is a """"""""window of opportunity"""""""" for regeneration before the glial scar forms. At this time, for regeneration to occur, myelin inhibitors must be blocked. In culture, if neuronal cAMP levels are elevated, MAG and myelin no longer inhibit growth. In addition, endogenous cAMP levels are high in young neurons that regenerate and that are not inhibited by MAG/myelin. These high levels of cAMP drop spontaneously with development. Furthermore, when central dorsal column axons are encouraged to regenerate in vivo, by a conditioning lesion to the peripheral branch of the same dorsal root ganglion (DRG) neuron, cAMP is strongly implicated in this effect. The cAMP effect is transcription-dependent and one protein that is up regulated in response to cAMP is the enzyme Arginase I (Arg I), which is key in the synthesis of polyamines. Over-expression of Arg I or polyamines, in the absenceof elevated cAMP, are each sufficient to overcome inhibition by MAG/myelin. The effect of Arg I and polyamines on regeneration in vivo will be characterized. First, expression of Arg I and polyamines will becharacterized in those systems that regenerate. Second, polyamines will be delivered and Arg I will be over-expressed inDRG neurons in vivo, in the absence of a conditioning lesion, and a) the effect on the ability to grow on MAG/myelin assessed and b) the effects on regeneration of subsequently lesioned dorsal column axons will also be assessed. Second, the mechanism of how polyamines overcome inhibition byMAG/myelin will be addressed and involvement of transcription, glutamate receptors, potassium channels and the cytoskeleton will be assessed. Third, in a high-through-put-screen, a combinatorial drug library will be screened for small molecules that activate the Arg I promoter. Small molecules so identified will thenbe delivered to DRGs in vivo and the ability of these neurons to grow on MAG/myelin and of their central axons to regenerate in vivo will be assessed. Through these studies a molecular insight will be gained into encouraging axons to regenerate in vivo and possible therapies may be identified.
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