Functions of OPN5 and OPN3 in the eye

OPN5 和 OPN3 在眼睛中的功能

• 批准号: 9380871
• 负责人: Russell N. Van Gelder
• 金额: $ 48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380871
• 关键词: Affect; Anatomy; Animals; Cells; Circadian Rhythms; Cornea; Darkness; Data; Diffuse; Electrophysiology (science); Electroretinography; Eye; Functional disorder; Genes; Hour; Image; Impairment; Laboratories; Life; Light; Malignant Neoplasms; Mental disorders; Morphology; Nature; Neurotransmitters; Opsin; Orphan; Periodicity; Pharmacology; Photophobia; Photoreceptors; Photosensitivity; Phototransduction; Physiology; Process; Pupil light reflex; Retina; Retinal; Retinal Ganglion Cells; Signal Transduction; Sleep Disorders; System; Techniques; Tissues; Transgenic Animals; Vertebrate Photoreceptors; Visual; Work; circadian pacemaker; experimental study; genetic analysis; insight; knockout animal; melanopsin; novel; patch clamp; response; suprachiasmatic nucleus; tool

PROJECT SUMMARY/ABSTRACT Circadian rhythms are the near-24-hour rhythms of physiology ubiquitous to almost all eukaryotic life. Dysfunction of circadian rhythms underlies a variety of common sleep disorders and is thought to contribute to other conditions ranging from psychiatric disease to cancer. The mammalian retina serves a critical function in synchronizing the master circadian pacemaker (the suprachiasmatic nucleus) to the daily light-dark cycle. Work over many years has also demonstrated that the retina itself is a strong circadian oscillator. Indeed, many critical retinal functions, including visual sensitivity, the pupillary light reflex, the electroretinogram, and the expression of hundreds of retinal genes, are under strong circadian control; and that loss of retinal circadian rhythms results in impaired retinal function. Our preliminary data have demonstrated that: 1) the retinal circadian clock can be entrained to light- dark cycles in culture ex vivo, 2) this entrainment is not dependent on the classical rods and cones or the melanopsin-expressing, intrinsically-photosensitive retinal ganglion cells, 3) the orphan opsin neuropsin (OPN5) is necessary for this photoentrainment, and the orphan opsin encephalopsin (OPN3) affects this process, 4) the retina utilizes a light-dependent, diffusible substance to synchronize its rhythms, and 5) the cornea also contains a circadian clock which, remarkably, can be entrained to light- dark cycles as well via an OPN5-dependent mechanism. We propose experiments to elucidate the signaling mechanisms of OPN5 and OPN3; experiments to characterize the diffusible signal(s) emanating from the retina, and experiments to elucidate the mechanism by which non-retinal tissues in the eye maintain circadian rhythmicity and entrain to light-dark cycles. These data will provide a critical basis for understanding how the circadian clock modulates retinal function as well as mechanistic insights into two novel ocular photoreceptors.

项目概要/摘要 昼夜节律是几乎所有人都普遍存在的近 24 小时的生理节律 真核生命。昼夜节律失调是多种常见睡眠障碍的根源， 人们认为它会导致从精神疾病到癌症等其他疾病。哺乳动物 视网膜在同步主昼夜节律起搏器（视交叉上 核）到每日的明暗周期。多年的工作还表明，视网膜本身 是一个强大的昼夜节律振荡器。事实上，许多关键的视网膜功能，包括视觉敏感性、 瞳孔对光反射、视网膜电图以及数百个视网膜基因的表达都在研究中 强大的昼夜节律控制；视网膜昼夜节律的丧失会导致视网膜功能受损。 我们的初步数据表明：1）视网膜生物钟可以被光所控制—— 离体培养中的暗循环，2) 这种夹带不依赖于经典的视杆细胞和视锥细胞或 表达黑视蛋白、本质上感光的视网膜神经节细胞，3) 孤儿视蛋白 神经蛋白酶 (OPN5) 对于这种光夹带是必需的，而孤儿视蛋白脑视蛋白 (OPN3) 影响这一过程，4) 视网膜利用光依赖性、可扩散物质来同步其 节律，5）角膜还包含一个生物钟，值得注意的是，它可以被光所控制—— 暗循环也通过 OPN5 依赖机制实现。我们提出实验来阐明 OPN5和OPN3的信号传导机制；表征扩散信号的实验 源自视网膜，并通过实验阐明非视网膜组织在 眼睛保持昼夜节律并伴随明暗循环。这些数据将提供关键的 理解生物钟如何调节视网膜功能以及机制的基础 对两种新型眼部感光器的见解。