John Guy, Ph.D.
The overall aim of this proposal is to test the hypothesis that reactive oxygen species play a major role in the pathogenesis of disruption of the BBB and demyelination of the optic nerve. We will pursue the following specific aims: (1) Assessment of the response of cell-specific endogenous antioxidant and free radical scavenger enzyme defenses in the optic nerve to reactive oxygen species in guinea pigs with EAE. The specific cellular expression in endothelia, axons, astroglia and oligodendroglia of the superoxide dismutases (Cu/Zn, MnSOD and ECSOD), catalase and glutathione peroxidase will be visualized by immunohistochemistry and in situ mRNA hybridization. (2) Determination of the best strategy for the suppression of demyelination and BBB disruption by genetic amplification of specific free radical scavenger defenses in mice transgenic for the superoxide dismutases (ECSOD and MnSOD). (3) Development of a clinically useful treatment strategy for prolonged suppression of demyelination and BBB disruption by amplification of beneficial defenses with viral-mediated transfer of cDNAs for the superoxide dismutases (MnSOD, Cu/Zn and ECSOD) and catalase. Using AAV mediated gene therapy we hope to markedly increase endothelial, axonal and oligodendroglial levels of the SODs and catalase. Continued overexpression of these enzyme defenses may also prevent the relapses of optic neuritis and progression to MS. Both the HAL and GCRC ward will be essential for vector production and delivery. The OCI will provide needed research nurses and patient registry facilities.
- Guy J, McGorray S, Fitzsimmons J, Beck B, Rao MA. Disruption of the BBB in experimental optic neuritis: Immunocytochemical co-localization of H2O2 and extravesated serum albumin. Invest Ophthalmol Vis Sci 35:1114-1123, 1994.
- Guy J, McGorray S, Qi X, Fitzsimmons J, Mancuso A, Rao NA. Conjugated deferoxamine reduces blood-brain barrier disruption in experimental optic neuritis. Ophthal Res. in press.