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: 6325267
• 负责人: DANIEL R STORM
• 金额: $ 3.5万
• 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 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325267
• 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（摘自申请人摘要）…的昼夜节律组织