Retinal Circadian Rhythms and Photoreceptors Viability

视网膜昼夜节律和感光细胞活力

• 批准号: 9208784
• 负责人: Kenkichi Baba
• 金额: $ 14.2万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208784
• 关键词: ARNTL gene; Affect; Aging; Alpha Rhythm; Biochemical; Brain; Cell Count; Cell Death; Cell Growth Processes; Cell Survival; Chickens; Circadian Rhythms; Darkness; Data; Development; Disease; Dopamine; Down-Regulation; Environment; Excision; Eye; Functional disorder; Gene Expression; Genes; Genetic; Growth; Hour; Knockout Mice; Laboratories; Light; Longevity; Melatonin; Messenger RNA; Metabolism; Molecular; Mus; Neural Retina; Nuclear; Ocular Physiology; Organism; Output; Pathology; Pathway interactions; Periodicity; Photoreceptors; Play; Predisposition; Premature aging syndrome; Proteins; Refractive Errors; Regulation; Rest; Retina; Retinal; Retinal Cone; Retinal Diseases; Role; SIRT1 gene; Signal Transduction; System; Temperature; Testing; Vertebrate Photoreceptors; Vision; age related; cell type; circadian pacemaker; experimental study; ganglion cell; mouse model; neurochemistry; photoreceptor degeneration; public health relevance

 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.

 描述（由申请人提供）：实验证据表明，哺乳动物的视网膜包含一个完整的生物钟系统——一种产生温度补偿的 24 小时振荡的生化机器，是光将视网膜时钟的周期与环境同步的输入途径。光/暗循环以及将时钟的影响传递到视网膜并进入大脑其他部分的神经化学输出途径。视网膜生物钟系统可能会导致视网膜疾病和病理以及正常视觉功能，例如，缺乏Period1和Period2（两个时钟基因）的小鼠的视锥细胞光感受器的分布会发生显着改变。 Bmal1 基因 (Arntl) 是哺乳动物生物钟的关键组成部分。敲除小鼠没有表现出任何昼夜节律性，并且我们实验室产生的一些病理学数据表明，缺乏功能性昼夜节律时钟会导致 Bmal1 KO 外核层细胞数量显着减少。我们将检验遗传破坏的假设 通过使用 Chx10-Cre-ArntlloxP/loxP 小鼠，视网膜 Bmal1 加速衰老过程中的感光细胞死亡（具体目标 1）。我们选择了这种小鼠模型，因为 Bmal1 仅从神经视网膜中去除，因此这些小鼠的寿命是正常的，与寿命较短的整体 Bmal1 KO 相反，我们将检验视网膜 Bmal1 的基因破坏影响 NAD+ 挽救的假设。光感受器中的通路​​（具体目标 2）以及光感受器在衰老过程中的活力。拟议研究中获得的数据将为生物钟在衰老过程中所扮演的角色提供明确的答案。 光感受器活力的调节以及生物钟功能障碍是否在衰老过程中同样影响视杆细胞和视锥细胞的活力。