Methoxyindoles in Retina: Function and Regulation

视网膜中的甲氧基吲哚：功能和调节

• 批准号: 7927637
• 负责人: P Michael Iuvone
• 金额: $ 17.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7927637
• 关键词: Adenylate Cyclase; Affect; Age; Age related macular degeneration; Anabolism; Biochemical; Biological; Biological Rhythm; Blindness; Boxing; Calmodulin; Cell Culture Techniques; Cell physiology; Cells; Chickens; Circadian Rhythms; Cyclic AMP; Data; Development; Dopamine; Environment; Enzymes; Epithelial Cells; Feedback; Figs - dietary; Ganglia; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Lead; Light; Mediating; Mediator of activation protein; Melatonin; Messenger RNA; Metabolism; Methodology; Molecular; Mus; Myxoid cyst; Ocular Pathology; Organism; Output; Oxidative Stress; Pathologic Processes; Pathology; Phosphorylation; Photoperiod; Photoreceptors; Physiology; Pigments; Play; Premature aging syndrome; Principal Investigator; Process; Regulation; Research; Retina; Retinal; Retinal Cone; Role; Signal Transduction; System; Testing; Time; Transactivation; Visual; age related; cell type; circadian pacemaker; cryptochrome; dopaminergic neuron; in vivo; light intensity; methoxyindole; novel; oxidative damage; photoreceptor degeneration; prevent; programs; promoter; retinal neuron; transcription factor

DESCRIPTION (provided by applicant): Circadian clocks generate daily biological rhythms that provide adaptive advantage to organisms by allowing them to anticipate and prepare for regular daily changes in their environment, such as changes of light intensity between day and night. Melatonin and N-acetylserotonin (NAS) are circadian modulators synthesized in retina, primarily in photoreceptor cells. Circadian rhythms of NAS and melatonin synthesis, with peak levels at night, are directly controlled by clocks located in retinal cells. Melatonin affects cellular functions of photoreceptors, pigment epithelial cells, and dopamine neurons, and regulates circadian physiology in the retina. Together with dopamine, melatonin plays a pivotal role in the modulation of visual sensitivity and adaptation by photoperiod and circadian clocks. Melatonin also protects retinal cells from oxidative damage. Our long-term goal is to understand the control of retinal circadian clocks and their output signals - NAS, metatonin and dopamine. In this application, we propose to test the hypotheses that a light-evoked surge in dopamine release at dawn resets and synchronizes the circadian clocks throughout the retina, serving as a master regulator of circadian physiology, and that a clock generated rhythm of a transcription factor, NPAS2, serves as an output signal to generate the rhythms of cAMP, NAS, and melatonin synthesis. These studies will be conducted using an integrated research approach involving biochemical, pharmacological, genetic, and cellular/molecular biological methodologies. The research is significant because it characterizes cellular and biochemical systems that play an important role in the regulation of retinal physiology and photoreceptor cell function. It is anticipated that characterization of these systems will contribute to the understanding of visual cell physiology and some of the pathological processes that underlie photoreceptor degeneration. Circadian function and the synthesis of NAS and melatonin synthesis decline with age, and disruption of circadian clock genes can cause premature aging and age-related pathologies. Melatonin and NAS decrease oxidative damage. Damage due to oxidative stress may contribute to the development of age- related macular degeneration (AMD), the major cause of blindness in people over 50. This research investigates the circadian control of NAS and melatonin synthesis in photoreceptors, as well as the control of circadian clock networks throughout the retina, which may lead to novel, rationale strategies to prevent AMD and other age-related ocular pathologies.

描述（由申请人提供）：昼夜节律时钟会产生每日生物节奏，通过允许它们预测并为环境中的常规日常变化，例如白天和黑夜之间的光强度变化，从而为有机体提供适应性优势。褪黑激素和N-乙酰基旋蛋白（NAS）是在视网膜中合成的昼夜节律调节剂，主要是在感光细胞中。 NAS和褪黑激素合成的昼夜节律（夜间峰值水平）直接由位于视网膜细胞中的时钟控制。褪黑激素会影响感光细胞，色素上皮细胞和多巴胺神经元的细胞功能，并调节视网膜中的昼夜节律生理学。与多巴胺一起，褪黑激素在光周期和昼夜节律时钟的视觉敏感性和适应性调节中起关键作用。褪黑激素还保护视网膜细胞免受氧化损伤。我们的长期目标是了解视网膜昼夜节律及其输出信号的控制-NAS，Metatonin和Dopamine。 In this application, we propose to test the hypotheses that a light-evoked surge in dopamine release at dawn resets and synchronizes the circadian clocks throughout the retina, serving as a master regulator of circadian physiology, and that a clock generated rhythm of a transcription factor, NPAS2, serves as an output signal to generate the rhythms of cAMP, NAS, and melatonin synthesis.这些研究将使用涉及生化，药理，遗传和细胞/分子生物学方法的综合研究方法进行。这项研究很重要，因为它表征了细胞和生化系统，这些系统在视网膜生理和感光细胞功能的调节中起重要作用。可以预料，这些系统的表征将有助于理解视觉细胞生理和一些受感染受体变性的病理过程。 昼夜节律功能以及NAS和褪黑激素合成的合成随着年龄的增长而下降，而昼夜节律基因的破坏会导致过早衰老和与年龄相关的病理。褪黑激素和NAS减少氧化损伤。氧化压力造成的损害可能有助于与年龄相关的黄斑变性（AMD）的发展，这是50岁以上的人失明的主要原因。这项研究调查了光感受器中NAS和褪黑激素合成的昼夜节律控制，以及整个视网膜的昼夜节律控制，可能导致新颖的策略，以预防新的策略和其他病态。