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）：视网膜既是感官器官，又是自我维持的神经昼夜节律钟。作为视觉的主要感觉器官，视网膜执行了将物理光刺激转导和编码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余部分。内在的视网膜昼夜节律时钟通过调节视网膜神经元并通过节奏基因表达和调节性神经释放剂的释放节律来调节视网膜神经元并重新配置视网膜电路，从而将整体视网膜感觉函数塑造为高敏锐的“天”和高灵敏度“夜间”状态。尽管视网膜昼夜节律对视网膜生理和代谢产生了广泛的影响，但视网膜昼夜节律时钟的基本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昼夜节律时钟的基本机制及其对视网膜感觉功能的控制。在即将到来的奖项期间，我们建议检查视网膜昼夜节律时钟中特定的昼夜节律基因和细胞种群的功能作用，以及视网膜时钟调节视网膜灵敏度的机制。具体来说，我们建议检查以下问题：特定目的I：视网膜昼夜节律的分子组织。使用核心昼夜节律基因PER1，PER2，CRY1，CRY2，CHILC和NPAS2的小鼠线，我们将测试这些基因在小鼠视网膜昼夜节律时钟中的功能作用。具体目标II。视网膜昼夜节律的蜂窝组织。使用携带核心时钟基因BMAL1的floxe虫等位基因的小鼠系和CRE重新组合酶的细胞特异性表达的小鼠线对分子昼夜节律函数的单细胞发光成像和细胞特异性操纵，我们将寻求确定视网膜中哪些细胞群是昼夜节律动物制作者。特定目标III。昼夜节律对视网膜功能的控制。使用分子遗传方法，我们将测试哪些细胞和发射器途径对于：（1）使用ERG控制视网膜灵敏度的昼夜节律，以及（2）视网膜时钟的光夹带。这些目的的完成将提供有关根据许多生物（包括人类）在包括人类的时间中的时间来调节视觉功能和灵敏度的潜在机制的洞察力。这些发现将是理解正常视网膜功能，视网膜作为模型生物钟系统的基础，并有助于我们理解与光感受器变性和近视相关的临床相关的昼夜节律和多巴胺能视网膜机制。 公共卫生相关性：在一天中的不同时间，我们的愿景有所不同，因为我们的视网膜在一天中的不同时间的工作方式有所不同。这些功能性的每日节奏不是对日常光黑暗周期的简单响应，但是，如它们在恒定的黑暗中的持久性所证明的那样，它们是视网膜中内源性，自我维持的昼夜节律的公开表达，它在视网膜生理学和代谢中驱动了许多节奏。视网膜昼夜节律时钟调节视网膜功能，对白天或夜间视觉适当偏见。此外，视网膜钟在一天中的不同时间赋予视网膜光损伤的差异脆弱性，在盲目的疾病性视网膜炎色素炎中会改变，并影响黄斑水肿和近视的发展。对视网膜昼夜节律钟的了解对于理解人类的视力及其保存以及阐明该模型神经昼夜节律起搏器的机制至关重要。