Retinal Circadian Rhythms and Photoreceptors Viability

 描述（申请人提供）：实验证据已经表明，哺乳动物视网膜包含完整的昼夜节律钟系统-产生温度补偿的24小时振荡的生物化学机制，光将视网膜时钟的循环转换为环境光/暗循环的输入途径，以及神经化学输出通路，将生物钟的影响从视网膜传递到大脑的其他部分。新兴的实验数据表明，视网膜昼夜节律钟系统的功能障碍可能会导致视网膜疾病和病理，以及正常的视觉功能。例如，缺乏Period 1和Period 2（两个时钟基因）的小鼠在视锥光感受器的分布上显示出显着的变化。此外，哺乳动物视网膜时钟影响眼睛中的细胞存活和生长过程，包括光感受器对光损伤退化的敏感性。Bmal 1基因（Arntl）是哺乳动物生物钟的重要组成部分。Bmal 1基因敲除小鼠没有表现出任何昼夜节律，并发展出几种病理。在我们的实验室中产生的初步数据表明，缺乏一个功能性的生物钟诱导Bmal 1科斯的外核层中的细胞数量显着减少。在这个应用程序中，我们将测试的假设，遗传中断， 视网膜Bmal 1加速老化过程中感光细胞死亡（具体目标1）。我们选择了这种小鼠模型，因为Bmal 1仅从神经视网膜中去除，因此这些小鼠的寿命是正常的，而全球Bmal 1 KO的寿命很短。然后，我们将测试视网膜Bmal 1的遗传破坏影响光感受器中的NAD+补救途径（特异性目的2）并因此影响老化期间光感受器活力的假设。在拟议的研究中将获得的数据将提供关于生物钟在人体内所起作用的明确答案。 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。

 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.