Disk Renewal in Retinal Visual Cells

描述（由申请人提供）：昼夜节律钟控制视网膜中的基本通路，例如感光细胞外段更新。这导致了昼夜节律调节改变可能导致年龄相关性黄斑变性（AMD）和其他视网膜疾病的建议。然而，这一建议从未得到验证。该提案通过使用三个“中央时钟基因”（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。预期缺乏所有3种Per的小鼠缺乏内源性时钟活性，而预期单个Per或mNoc缺失部分破坏视网膜昼夜节律输出。具体目标1测试Per1，Per2，Per3和mNoc（或其组合）中的靶向突变将导致导致感光细胞丧失的功能缺陷的假设。特定目标2分析了Per和mNoc缺陷小鼠先前表征的视网膜昼夜节律的改变，以确定与感光细胞健康相关的时钟调节途径。具体目标3通过分析中心时钟基因的昼夜表达来检验小鼠视网膜包含多个时钟系统的假设，所述多个时钟系统包括光感受器、多巴胺能无长突细胞、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对视网膜昼夜节律组织的知识的具体空白，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.