Disk Renewal in Retinal Visual Cells

描述（由申请人提供）：生物钟控制视网膜的基本通路，如光感受器外段的更新。这表明昼夜节律的改变可能导致年龄相关性黄斑变性（AMD）和其他视网膜疾病。然而，这个建议从未被验证过。该建议通过使用三个“中心时钟基因”（Per1、Per2和Per3）和一个时钟调节基因（mNoc）的靶向突变来解决视网膜昼夜节律组织的问题。缺乏所有3种Pers的小鼠预计缺乏内源性时钟活动，而单个Per或mNoc缺失预计会部分破坏视网膜昼夜节律输出。Specific Aim 1验证了Per1、Per2、Per3和mNoc（或其组合）的靶向突变会导致功能缺陷导致光感受器丧失的假设。Specific Aim 2分析了先前表征的Per-和mnoc缺陷小鼠视网膜昼夜节律的变化，以确定与光感受器健康相关的时钟调节通路。特异性Aim 3通过分析中央时钟基因的昼夜节律表达，验证了小鼠视网膜包含多个时钟系统的假设，包括光感受器、多巴胺能无分泌细胞、视网膜色素上皮细胞。该项目填补了我们在哺乳动物系统细胞水平上视网膜昼夜节律组织知识的具体空白，并评估了昼夜节律基因破坏对视网膜健康的潜在影响。

DESCRIPTION (provided by applicant): 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.