NGF effects on axonal growth in CNS white matter

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DESCRIPTION (provided by applicant): Axonal regeneration has now been demonstrated to occur in regions of the CNS where it was formerly thought to be impossible. These dramatic examples of successful regrowth have come from studies in which the influence of both inhibitors and promoters of neurite growth have been examined. The importance of neuronal growth state on regeneration success has recently been demonstrated in studies of optic nerve regeneration. Collectively, these results point to the importance of factors that normally stimulate growth in overcoming the non-permissive features of CNS white matter. The work proposed here will take advantage of techniques that have been developed in this laboratory over several years that permit assessment of the role of NGF in stimulating axonal growth within the CNS. Transgenic mice in which NGF is over-expressed under the control of an astrocyte-specific promoter (GFAP), will be used for both in vitro and in vivo studies of axonal growth in CNS white matter. In vivo studies of sympathetic axonal growth within CNS regions of such mice will be carried out to determine the extent to which ectopic expression of NGF modifies the growth of these aberrant fibers. In addition, tissue section culture studies will be carried out to determine whether NGF, either applied exogenously or expressed transgenically, will modify the generally non-permissive nature of CNS white matter in supporting axonal growth. Finally, the role of p75, the low-affinity NGF receptor, in modifying axonal growth of NGF-responsive neurons in CNS white matter will be studied through a series of transplant and tissue culture approaches using transgenic mice in which p75 is deficient in the presence of NGF overexpression. The primary goal is to study the role of neurotrophic factors in stimulating axonal regeneration within CNS white matter.