Programmed cell death, or apoptosis, is a naturally occurring process of cellular suicide that occurs in virtually all issues during normal development. The misregulation of this process is implicated a number of disease states, including neurodegenerative disorders. Ectopic activation of the apoptotic program also in association with various types of cellular injury and in diverse types of degenerative disease. It is not known, however, whether primary lesions in the apoptotic program actually cause associated pathophysiologies of whether excessive apoptosis observed in these disorders is secondarily triggered as a consequence of metabolic disturbance. Our broad goals are to directly determine: 1) the extent to which misregulated apoptotic components play a role in the onset of neurodegenerative diseases and 2) whether blocking misregulated apoptosis can alleviate associated disease symptoms. To begin an exploration of these issues, we will produce transgenic strains of mice that direct p35 expression to the retina. p35 is a potent suppressor of apoptosis that prevents cells death by inactivating several member of the death protease family (Caspases). We will directly test whether p35 expression alleviates disease symptoms in murine models of retinitis pigmentosa, a collection of human disorders associated with degeneration of retinal tissue. Transgenic mice will be established whereby the opsin promoter is used to drive high levels p35 in the adult retina. The transgene will then be introduced into genetic backgrounds such as retinal degeneration slow (rds) and other murine models of retinitis pigmentosa. If a block to the apoptosis program can mitigate disease symptoms, we can expect to observe a suppression of retinal degeneration in p35 expressing rds mice.
