Retinal Circadian Rhythms and Photoreceptors Viability

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 DESCRIPTION (provided by applicant): Experimental evidence has shown that the mammalian retina contains a complete circadian clock system - a biochemical machinery that generate temperature-compensated 24 hour oscillation, an input pathway by which light synchronizes the cycling of the retinal clock to the environmental light/dark cycle, and neurochemical output pathways that transmit the clock's influence through-out the retina and into the rest of the brain. Emerging experimental data suggests that dysfunctions of the retinal circadian clock system may contribute to retina disease and pathology, as well as normal visual function. For example, mice lacking Period1 and Period2 (two clock genes) show significant alteration in the distribution of cone photoreceptors. Furthermore, the mammalian retinal clock influences cell survival and growth processes in the eye including the susceptibility of photoreceptors to degeneration from light damage. Bmal1 gene (Arntl) is a key component of the mammalian circadian clock. Bmal1 knock-out mice do not show any circadian rhythmicity and develop several pathologies. Preliminary data generated in our laboratory indicate that lack of a functional circadian clock induces a significant decrease in the number of cells in the outer nuclear layer of Bmal1 KOs. In this application we will test the hypothesis that genetic disruption of retinal Bmal1 accelerates photoreceptor cell death during aging (Specific Aim 1) by using Chx10-Cre-ArntlloxP/loxP mice. We have selected this mouse model since Bmal1 is only removed from the neural retina and thus the lifespan of these mice is normal, as opposed the global Bmal1 KO which has a short life span. Then, we will test the hypothesis that genetic disruption of retinal Bmal1 affects the NAD+ salvage pathway in the photoreceptors (Specific Aim 2) and thus photoreceptors viability during aging. The data that will be obtained in the proposed studies will provide a definitive answer on the role that the circadian clock plays in the modulation of photoreceptor viability and whether circadian clock dysfunction affects equally rods and cone viability during aging.