Circadian clocks control fundamental pathways in the retina, such as photoreceptor outer segment turnover. This has led to the suggestion that altered circadian regulation could contribute to age related macular degeneration (AMD) and other retinal diseases. However, this suggestion has never been tested. This proposal addresses the question of retinal circadian organization through use of targeted mutations in three """"""""central clock genes"""""""" (Per1, Per2, and Per3) and one clock-regulated gene (mNoc). Mice lacking all 3 Pers are expected to lack endogenous clock activity, while the single Per or mNoc deletions are expected to partially disrupt retinal circadian output.
Specific Aim 1 tests the hypothesis that targeted mutations in Per1, Per2, Per3, and mNoc (or their combinations) will cause functional deficits that lead to photoreceptor loss.
Specific Aim 2 analyzes alterations in previously characterized retinal circadian rhythms in Per- and mNoc-deficient mice to identify clock-regulated pathways relevant to photoreceptor health.
Specific Aim 3 tests the hypothesis that the mouse retina contains multiple clock systems that include photoreceptors, dopaminergic amacrine cells, retinal pigment epithelial cells by analyzing circadian expression of central clock genes. This project fills specific gaps in our knowledge of retinal circadian organization at the cellular level in a mammalian system, and assesses the potential effects of circadian gene disruption on retinal health.
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