PROGRESSIVE ROD-CONE DEGENERATION--SYNTHESIS & RENEWAL

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The progressive rod-cone degeneration (prcd) dog mutant has a progressive retinal degenerative disorder that serves as a model for retinitis pigmentosa in man. The disease is topographically defined and is characterized by a decreased rod outer segment (ROS) renewal rate. The studies proposed in this application examine the association between retinal protein synthesis and/or transport, renewal rate, disease and degeneration. Work with collaborators will correlate regional retinal lipid and protein synthesis as well as examining the composition of the different ROS phospholipid classes. The studies will test the hypothesis that perturbations wither in synthesis, transport or renewal compromise the visual cell and result in disease and degeneration. The protein and lipid studies will utilize both in vivo and in vitro approaches. Using single or double label combinations of various radioactively tagged precursors, it will be possible to examine the synthesis, transport or turnover of newly synthesized proteins or lipids. These studies are based on our ability to maintain the retina structurally intact and metabolically active under organ culture conditions. By using a sampling method that preserves disease, quadrant and area relationships, the biochemical, morphologic and/or autoradiographic studies will establish the causal relationship between disease and the observed abnormalities. Studies are also proposed to examine the variation in retinal degeneration phenotype that exists at the prcd locus. The prcd- slow mutant will be used to establish the temporal association between the renewal rate abnormality and disease. Since this mutant has a milder and slowly progressive disease, the proposed experiments will determine if this results from a renewal rate defect that is expressed at a later age and/ or to a lesser extent. On the other hand, the prcd mutant will be used to examine whether local factors modulate disease an can be used to experimentally manipulate disease progression. Based on our recent findings that the tissue distribution of vitamin E parallels the disease topography in the prcd retina, nutritional experiments will examine the effect of vitamin E (marginal, adequate, excess) levels on disease severity and progression. These studies will determine the association between tissue vitamin E levels, disease and degeneration and establish if the disease phenotype can be modulated (accelerated, retarded) nutritionally.