MS and its animal model, EAE, are diseases in which the immune system damages CMS myelin and axons. The hypothesis underlying this proposal is that regenerating gene (Reg) proteins exert protective and regenerative actions in the CMS during EAE. Aim 1 will quantitate endogenous expression of Reg genes in the CNS of EAE-affected mice by real-time PCR and will compare expression of each Reg gene in two different EAE models - a relapsing-remitting and a chronic, non-remitting EAE model. We expect an increased expression of Reg in the remitting EAE model. Aim 2 will test therapeutic effects of Reg proteins in the two EAE models. Treatment will be initiated both prior to and after development of clinical EAE, the latter more relevant to MS. Aim 3 will test the hypothesis that Reg proteins promote proliferation of cultured primary oligodendrocytes and protect them from the known oligodendrocyte toxins, tumor necrosis factor alpha and nitric oxide. These factors are expressed in MS CNS lesions. Overall, this combination of in vivo and in vitro studies will determine the molecular and cellular effects of Reg, perhaps identifying a potential therapy to aid in remyelination and axon protection in diseases such as MS.