REGULATION OF PINEAL AND RETINA MELATONIN BIOSYNTHESIS

松果体和视网膜褪黑激素生物合成的调节

• 批准号: 6393883
• 负责人: DANIEL R STORM
• 金额: $ 21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393883
• 关键词: adenylate cyclase; animal genetic material tag; circadian rhythms; enzyme activity; gene induction /repression; genetic regulatory element; genetically modified animals; hormone biosynthesis; laboratory mouse; melatonin; pineal body; retina; suprachiasmatic nucleus; tissue /cell culture; transcription factor

DESCRIPTION (from the applicant's abstract) The circadian organization of behavior determines how complex organisms respond to light/dark cues on a daily and seasonal basis. Disruption of the circadian rhythm in humans can lead to sleep disorders, mental fatigue, and depression, particularly with aging patients. The daily cycle of melatonin synthesis in the pineal is controlled by the circadian clock in the suprachiasmatic nucleus (SCN). Melatonin may stabilize the sleep cycle by maintaining steady-state entrainment of circadian pacemakers. Melatonin biosynthesis in the pineal and retina is regulated by cAMP which stimulates transcription of genes encoding enzymes important for circadian expression of melatonin. Nocturnal release of norepinephrine at the pineal increases cAMP by activation of beta- and alpha-1-adrenergic receptors. Calcium stimulated adenylyl cyclases (AC1 and AC8) may play a major role in regulating melatonin biosynthesis because of their unique regulatory properties. The applicants hypothesize that costimulation of AC1 by Ca++ and beta-adrenergic receptors may generate cAMP signals of sufficient strength and duration to regulate the transcription of specific genes important for melatonin synthesis. They hypothesize that the diurnal variation in expression of AC1 and its stimulation by nocturnal NE regulates the synthesis of melatonin. Furthermore, they hypothesize that cAMP may also play an important role in circadian time keeping in the SCN by regulating gene transcription through the cAMP response element (CRE). The overall goals of this project are to define the role of the Ca++-stimulated adenylyl cyclases and CRE-mediated transcription in the regulation of melatonin synthesis and in circadian rhythm. This proposal uses two unique tools developed in this laboratory; mutant mice lacking Ca++-sensitive adenylyl cyclases and a CRE-lacZ transgenic mouse strain that is used to monitor CRE-mediated transcription in vivo.

描述（来自申请人的摘要） 行为决定了复杂的生物体如何对光/暗线索作出反应， 每日和季节性的基础上。 人体生理节奏的紊乱 导致睡眠障碍、精神疲劳和抑郁，特别是 老年患者 松果体中褪黑激素合成的日周期是 由视交叉上核（SCN）中的昼夜节律钟控制。 褪黑激素可以通过维持稳态来稳定睡眠周期 昼夜节律起搏器的夹带。 松果体中褪黑激素的生物合成 视网膜受cAMP调节，cAMP刺激基因转录 编码对褪黑激素的昼夜表达重要的酶。 夜间 在松果体释放去甲肾上腺素通过激活 β和α 1肾上腺素能受体。 钙刺激腺苷酸 环化酶（AC 1和AC 8）可能在调节褪黑激素中起主要作用 由于其独特的调节特性，生物合成。 申请人 假设Ca++和β-肾上腺素能受体对AC 1共刺激 可以产生足够强度和持续时间的cAMP信号来调节 对褪黑激素合成重要的特定基因的转录。 他们 假设AC 1表达的日变化及其 夜间NE的刺激调节褪黑激素的合成。 此外，他们假设cAMP也可能在以下方面发挥重要作用： 通过调节基因转录来维持SCN中的昼夜节律时间， cAMP反应元件（CRE）。 该项目的总体目标是 确定Ca++刺激的腺苷酸环化酶和CRE介导的 转录调节褪黑激素合成和昼夜节律 节奏 该提案使用了本实验室开发的两种独特工具; 缺乏Ca++敏感腺苷酸环化酶和CRE-lacZ的突变小鼠 用于监测CRE介导的转录的转基因小鼠品系 in vivo.