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Functions of OPN5 and OPN3 in the eye

OPN5 和 OPN3 在眼睛中的功能

基本信息

批准号：
10176501
负责人：
Russell N. Van Gelder
金额：
$ 53.62万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要/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。真核生物昼夜节律的功能障碍是各种常见睡眠障碍的基础，被认为会导致从精神疾病到癌症的其他疾病。哺乳动物视网膜在同步主昼夜节律起搏点（视交叉上的核心）到每日的光暗周期。多年来的研究也证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，包括视觉灵敏度，瞳孔对光反射、视网膜电图以及数百种视网膜基因的表达，强昼夜节律控制;以及视网膜昼夜节律的丧失导致视网膜功能受损。我们的初步数据表明：1）视网膜昼夜节律钟可以被光线携带- 离体培养物中的暗循环，2）这种夹带不依赖于经典的视杆细胞和视锥细胞，或者表达黑视蛋白的本质光敏视网膜神经节细胞，3）孤儿视蛋白神经视蛋白（OPN 5）是这种光夹带所必需的，孤儿视蛋白脑视蛋白（OPN 3）影响这一过程，4）视网膜利用光依赖性，可扩散的物质，以同步其节奏，5）角膜还包含一个昼夜节律钟，值得注意的是，它可以被光线带走- 黑暗周期以及通过OPN 5依赖机制。我们提出实验来阐明 OPN 5和OPN 3的信号传导机制;表征可扩散信号的实验以及阐明非视网膜组织在视网膜中的作用机制的实验。眼睛维持昼夜节律并参与明暗循环。这些数据将提供一个关键的了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光感受器的见解。