Circadian Organization of the Retina

视网膜的昼夜节律组织

• 批准号: 8048065
• 负责人: DOUGLAS G MCMAHON
• 金额: $ 37.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048065
• 关键词: Address; Alleles; Award; Biological Clocks; Biological Models; Biological Preservation; Brain; Cells; Circadian Rhythms; Communication; Coupled; Critical Pathways; Darkness; Development; Disease; Dopamine; Elements; Exhibits; Gene Expression; Generations; Genes; Goals; Human; In Vitro; Individual; Knock-out; Light; Measures; Melatonin; Metabolism; Methods; Modeling; Molecular; Molecular Genetics; Mus; Myopia; Neurotransmitters; Optic Nerve; Organ; Organism; Periodicity; Physiology; Population; Reading; Reporter Genes; Research; Rest; Retina; Retinal; Retinitis Pigmentosa; Role; Sensory; Shapes; Signal Transduction; Sleep; Stimulus; Synapses; System; Testing; Time; Tissues; Vision; Visual; Work; cellular imaging; circadian pacemaker; clinically relevant; dopaminergic neuron; insight; light entrainment; luminescence; macular edema; neural model; neuromechanism; photoreceptor degeneration; public health relevance; recombinase; relating to nervous system; response; retinal neuron

DESCRIPTION (provided by applicant): The retina is both a sensory organ and a self-sustained neural circadian clock. As the primary sensory organ for vision, the retina performs the initial steps of transduction and encoding of physical light stimuli into neural signals, and then transmits visual and photic information to the rest of the brain via the optic nerve. The intrinsic retinal circadian clock shapes overall retinal sensory function into high acuity "day" and high sensitivity "night" states by modulating retinal neurons and reconfiguring retinal circuits through rhythmic gene expression and rhythmic of release of modulatory neurotransmitters such as dopamine and melatonin. Although the retinal circadian clock exerts extensive influence over retinal physiology and metabolism, the underlying cellular and molecular mechanisms of the retinal circadian clock are not well understood. The long-term goal of the research proposed here is to elucidate the fundamental mechanisms of the mammalian retinal circadian clock and its control of retinal sensory function. For the upcoming award period we propose to examine the functional role of specific circadian clock genes and cell populations in the retinal circadian clock, as well as the mechanisms by which the retinal clock modulates retinal sensitivity. Specifically, we propose to examine the following issues: Specific Aim I: Molecular Organization of the Retinal Circadian Clock. Using mouse lines in which the core circadian clock genes Per1, Per2, Cry1, Cry2, Clock and NPAS2 are knocked out we will test the functional role of each of these genes in the mouse retinal circadian clock. Specific Aim II. Cellular Organization of the Retinal Circadian Clock. Using single-cell luminescence imaging and cell- specific manipulation of molecular circadian clock function via mouse lines carrying floxed alleles of the core clock gene Bmal1 and cell-specific expression of Cre recombinase, we will seek to determine which cell populations in the retina are circadian pacemakers. Specific Aim III. Circadian Clock Control of Retinal Function. Using molecular genetic approaches, we will test which cells and transmitter pathways are critical for: (1) circadian control of retinal sensitivity using the ERG, and (2) light entrainment of the retinal clock. Completion of these aims will provide insight into the underlying mechanisms by which visual function and sensitivity is modulated according to time of day in many organisms, including humans. These findings will be fundamental for understanding normal retinal function, the retina as a model biological clock system, and contribute to our understanding of clinically relevant circadian and dopaminergic retinal mechanisms associated with photoreceptor degeneration and myopia. PUBLIC HEALTH RELEVANCE: Our vision is different at different times of day because our retina works differently at different times of day. These functional daily rhythms are not simple responses to the daily light-dark cycle, but, as demonstrated by their persistence in constant darkness, they are the overt expression of an endogenous, self-sustained circadian clock in the retina that drives many rhythms in retinal physiology and metabolism. The retinal circadian clock adjusts retinal function, biasing it appropriately for day or night vision. In addition, the retinal clock imparts differential vulnerability to retinal light damage at different times of day, is altered in the blinding disease retinitis pigmentosa, and influences macular edema and the development of myopia. Increased understanding of the retinal circadian clock is important to understanding human vision and its preservation and to elucidating the mechanisms of this model neural circadian pacemaker.

描述（由申请人提供）：视网膜既是感觉器官，也是自我维持的神经生物钟。作为视觉的主要感觉器官，视网膜执行将物理光刺激转导和编码为神经信号的初始步骤，然后通过视神经将视觉和光学信息传输到大脑的其他部分。内在的视网膜生物钟通过节律性基因表达和调节性神经递质（如多巴胺和褪黑激素）的节律性释放来调节视网膜神经元和重新配置视网膜回路，从而将整体视网膜感觉功能塑造为高敏锐度“白天”和高灵敏度“夜间”状态。尽管视网膜生物钟对视网膜生理和代谢产生广泛影响，但视网膜生物钟的潜在细胞和分子机制尚不清楚。这里提出的研究的长期目标是阐明哺乳动物视网膜生物钟的基本机制及其对视网膜感觉功能的控制。在即将到来的奖励期内，我们建议研究特定生物钟基因和细胞群在视网膜生物钟中的功能作用，以及视网膜生物钟调节视网膜敏感性的机制。具体来说，我们建议研究以下问题：具体目标一：视网膜昼夜节律钟的分子组织。使用核心生物钟基因 Per1、Per2、Cry1、Cry2、Clock 和 NPAS2 被敲除的小鼠品系，我们将测试这些基因中的每一个在小鼠视网膜生物钟中的功能作用。具体目标二。视网膜昼夜节律钟的细胞组织。利用单细胞发光成像和通过携带核心时钟基因 Bmal1 的 floxed 等位基因和 Cre 重组酶的细胞特异性表达的小鼠品系对分子生物钟功能进行细胞特异性操作，我们将寻求确定视网膜中的哪些细胞群是昼夜节律起搏器。具体目标 III.视网膜功能的昼夜节律时钟控制。使用分子遗传学方法，我们将测试哪些细胞和递质通路对于以下方面至关重要：(1) 使用 ERG 控制视网膜敏感性的昼夜节律，以及 (2) 视网膜时钟的光夹带。完成这些目标将有助于深入了解包括人类在内的许多生物体根据一天中的时间调节视觉功能和敏感性的潜在机制。这些发现对于理解正常视网膜功能、视网膜作为生物钟系统模型至关重要，并有助于我们理解与感光器变性和近视相关的临床相关昼夜节律和多巴胺能视网膜机制。 公共卫生相关性：我们的视力在一天中的不同时间是不同的，因为我们的视网膜在一天中的不同时间工作不同。这些功能性日常节律并不是对日常明暗周期的简单反应，而是，正如它们在持续黑暗中的持续存在所证明的那样，它们是视网膜中内源性、自我维持的生物钟的明显表达，驱动着视网膜生理和新陈代谢中的许多节律。视网膜生物钟调节视网膜功能，使其适当地偏向日间或夜间视力。此外，视网膜时钟在一天中的不同时间对视网膜光损伤的脆弱性不同，在致盲疾病视网膜色素变性中发生改变，并影响黄斑水肿和近视的发展。增加对视网膜生物钟的了解对于理解人类视觉及其保存以及阐明该模型神经昼夜节律起搏器的机制非常重要。