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(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--一个产生温度补偿的24小时振荡的生化机械，一个光使视网膜时钟的周期与环境明/暗周期同步的输入路径，以及将时钟的影响通过视网膜传递到大脑其余部分的神经化学输出路径。新出现的实验数据表明，视网膜生物钟系统的功能障碍可能导致视网膜疾病和病理，以及正常的视觉功能。例如，缺乏周期1和周期2(两个时钟基因)的小鼠，视锥感光细胞的分布发生了显著的变化。此外，哺乳动物的视网膜时钟影响眼睛中细胞的生存和生长过程，包括光感受器对光损伤退化的敏感性。BMal1基因(ARNTL)是哺乳动物生物钟的重要组成部分。BMal1基因敲除小鼠没有表现出任何昼夜节律，并会发展成几种病理。我们实验室产生的初步数据表明，缺乏功能的生物钟导致BMal1 KO外核层的细胞数量显着减少。在本应用程序中，我们将检验这样一个假设，即基因破坏 通过使用Chx10-Cre-ArntlloxP/loxP小鼠，视网膜BMal1的研究加速了衰老过程中光感受器细胞的死亡(特定目标1)。我们之所以选择这个小鼠模型，是因为BMal1只从神经视网膜中移除，因此这些小鼠的寿命是正常的，而全球BMal1 KO的寿命很短。然后，我们将检验这一假设，即视网膜BMal1的基因破坏影响光感受器中的NAD+挽救途径(特定目标2)，从而影响光感受器在衰老过程中的活性。在拟议的研究中将获得的数据将提供关于生物钟在人类生活中的作用的明确答案 光感受器活性的调节以及在衰老过程中生物钟功能障碍是否同样影响视杆细胞和视锥细胞的活性。