Circadian Regulation of the PER2::LUC Bioluminescence Rhythm in the Mouse RPE

小鼠 RPE 中 PER2::LUC 生物发光节律的昼夜节律调节

• 批准号: 8103890
• 负责人: Gianluca Tosini
• 金额: $ 16.98万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103890
• 关键词: Affect; Applications Grants; Ascorbic Acid; Bioluminescence; Blood; Cessation of life; Circadian Rhythms; Data; Dopamine; Dopamine Receptor; Environment; Event; Eye; Gene Expression Profile; Genes; Glucose; Health; In Vitro; Knowledge; Laboratories; Lead; Lesion; Life Style; Light; Maintenance; Molecular; Monitor; Mus; National Eye Institute; Organ; Pathology; Pathway interactions; Pattern; Phagocytosis; Phase; Photoreceptors; Physiological; Physiology; Play; Preparation; Process; Regulation; Retina; Retinal; Role; Structure of retinal pigment epithelium; System; Time; Transcriptional Regulation; Vision research; circadian pacemaker; gene discovery; improved; novel; programs; public health relevance; receptor; small molecule; tool

DESCRIPTION (provided by applicant): The retinal pigment epithelium (RPE) plays an important role in the maintenance of photoreceptors health and functioning. Previous studies have shown that RPE is also involved in the regulation of the disc shedding, a process that is that is vital for the health of the photoreceptors. This process has been shown to be under circadian control, albeit the mechanisms controlling this circadian rhythm are still poorly understood. Our laboratory has developed a novel preparation in which circadian rhythms in RPE can be easily monitored using the PER2::LUC mouse. Our preliminary data indicate that a circadian rhythm in PER2::LUC bioluminescence can be recorded from cultured RPE and the phase of such a rhythm is different from the phase observed in the retina. Light does phase-shift the circadian rhythm in the RPE, and SCN lesion does not affect the phase of this rhythm. Interestingly, we discovered that Dopamine application can shift the circadian rhythm in the RPE. In this exploratory application, we propose to investigate the role of Dopamine and Dopamine receptors in the regulation of the circadian rhythms in the RPE and the circadian regulation of the RPE transcriptome. PUBLIC HEALTH RELEVANCE: The retinal pigment epithelium (RPE) plays an important role in the maintenance of photoreceptors health and functioning. Previous studies have shown that RPE is also involved in the regulation of the disc shedding, a process that is that is vital for the health of the photoreceptors. This process has been shown to be under circadian control, albeit the mechanisms controlling this circadian rhythm are still poorly understood. Modern life style has tremendously changed the time at which we expose ourselves to light; hence, it is important to understand how the circadian clock controls the rhythmic event in this organ. Indeed, the national plan for the eye and vision research of the National Eyes Institute states as one of its primary program objective the understanding of the mechanisms controlling the circadian shedding of photoreceptor outer segments and their phagocytosis by the RPE. In this grant application, we propose first to determine the role of DA in the entrainment of PER2::LUC circadian rhythm in the RPE and then to identify genes showing a circadian pattern of expression in RPE. This effort could prove a valuable tool to discovering genes and molecular pathways regulating rhythmic event in the RPE.

描述（由申请人提供）：视网膜色素上皮（RPE）在维持光感受器健康和功能方面起着重要作用。以前的研究表明，RPE也参与了椎间盘脱落的调节，这是一个对光感受器健康至关重要的过程。这一过程已被证明是在昼夜节律的控制下，尽管控制这种昼夜节律的机制仍然知之甚少。我们的实验室已经开发了一种新的制剂，其中可以使用PER 2：：LUC小鼠轻松监测RPE中的昼夜节律。我们的初步数据表明，PER 2：：LUC生物发光的昼夜节律可以从培养的RPE中记录，并且这种节律的相位与在视网膜中观察到的相位不同。光确实使RPE中的昼夜节律发生相移，而SCN损伤不影响该节律的相位。有趣的是，我们发现多巴胺的应用可以改变RPE中的昼夜节律。 在这个探索性的应用中，我们建议研究多巴胺和多巴胺受体在调节RPE中的昼夜节律和RPE转录组的昼夜调节中的作用。 公共卫生相关性：视网膜色素上皮（RPE）在维持光感受器健康和功能方面起着重要作用。以前的研究表明，RPE也参与了椎间盘脱落的调节，这是一个对光感受器健康至关重要的过程。这一过程已被证明是在昼夜节律的控制下，尽管控制这种昼夜节律的机制仍然知之甚少。现代生活方式极大地改变了我们暴露在光下的时间;因此，了解生物钟如何控制这个器官的节奏事件是很重要的。事实上，国家眼科研究所的国家眼睛和视力研究计划将了解控制感光细胞外节昼夜脱落及其被RPE吞噬的机制作为其主要计划目标之一。在该资助申请中，我们建议首先确定DA在RPE中夹带PER 2：：LUC昼夜节律中的作用，然后鉴定在RPE中显示昼夜节律表达模式的基因。这项工作可能被证明是一个有价值的工具，发现基因和分子通路调节的节奏事件的RPE。