Under normal circumstances, mature retinal ganglion cells (RGCs) cannot regenerate their axons after optic nerve damage and soon begin to die. However, it was shown in the prior grant period that if macrophages become activated in the eye, many RGCs survive axotomy and regenerate their axons through the inhibitory environment of the optic nerve. A protein from macrophages was identified that may mediate these effects. Aim 1 will investigate whether this macrophage-derived protein is sufficient to stimulate optic nerve regeneration in vivo, determine whether this protein is normally present in the developing visual system, and identify its receptor. Aim 2 will test the hypothesis that the macrophage-derived protein and certain ancillary factors induce distinct molecular changes required for axon regeneration, and investigate the functional significance of some of the gene products that are induced. This work will capitalize on studies done in the prior grant period which used fluorescence-activated cell sorting to purify RGCs, followed by microarray analysis, to investigate the program of gene expression associated with successful axon regeneration. Aim 3 will test the hypothesis that a purine-sensitive kinase that was isolated in the prior funding period is part of a signal transduction pathway linking growth factor stimulation to the changes in gene expression required for axon regeneration. This research will add significantly to our understanding of optic nerve regeneration, and may provide novel targets for therapeutic interventions in glaucoma and other degenerative or traumatic disorders of the nervous system.