NGF effects on axonal growth in CNS white matter

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EXCEED THE SPACE PROVIDED. Axonal regenerationhas nowbeen demonstratedto occurin regionsof the CNS where it was formerly thoughtto be impossible. These dramaticexamplesof successfulregrowthhavecome from studiesin whichthe influenceof bothinhibitorsand promotersof neuritegrowthhave been examined. The importance of neuronalgrowthstate on regenerationsuccesshas recentlybeen demonstratedinstudiesof opticnerve regeneration. Collectively,these resultspointto the importanceof factorsthat normallystimulategrowthin overcomingthe non-permissivefeatures of CNS whitematter. The work proposedhere willtake advantage of techniquesthat have been developedinthis laboratoryover severalyears that permitassessmentof the role of NGF in stimulatingaxonalgrowthwithinthe CNS. Transgenicmice inwhich NGF is overexpressed underthe controlof an astrocyte-specificpromoter(GFAP), will be usedfor bothinvitroand invivo studies of axonalgrowth inCNS white matter. Invivostudiesof sympatheticaxonalgrowthwithinCNS regionsof such mice willbe carried outto determinethe extentto whichectopicexpressionof NGF modifiesthe growth of these aberrant fibers. In addition,tissuesectionculturestudieswillbe carriedoutto determinewhether NGF, either appliedexogenouslyor expressedtransgenically,willmodifythe generallynon-permissive natureof CNS white matterin supportingaxonalgrowth. Finally,the role of p75, the low-affinityNGF receptor,inmodifyingaxonalgrowthof NGF-responsiveneuronsinCNS white matterwillbe studiedthrough a seriesof transplantand tissuecultureapproachesusingtransgenicmiceinwhich p75 is deficientinthe presenceof NGF overexpression.The primarygoalis to studythe roleof neurotrophicfactorsin stimulating axonalregenerationwithinCNS white matter. PERFORMANCE SITE ========================================Section End===========================================