The lack of regeneration in the adult mammalian central nervous system can be attributed, at least in part, to inhibitors of regeneration in myelin. To date 3 inhibitors have been identified and all 3 interact with the same receptor complex to effect inhibition. However, if neuronal cAMP is elevated, inhibition by myelin is blocked and regeneration is promoted in vivo. This cAMP effect is transcription-dependent and two genes that are up regulated are metallothionein-l/ll (MT-I/II) and secretory leukocyte protease inhibitor (SLPI). If added to neurons in culture, either of these two proteins allows neurons to grow on myelin. The immediate goals of the studies in this proposal are to a) Characterize and optimize the ability of MT-1/2 and SLPI to overcome myelin inhibitors in culture, b) Begin to address their mechanism of action by asking if they block the signal transduction pathway initiated by myelin inhibitors, c) Optimize conditions for in vivo delivery by assessing if neurons from animals treated with MT-1/2 or SLPI can grow in an inhibitory environment when cultured, and d) Determine if either MT-1/2 or SLPI can encourage dorsal column regeneration in vivo. The long-term objective is to determine if either MT-1/2 or SLPI can be developed as a therapy for patients with spinal cord injury.
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