Functions of OPN5 and OPN3 in the eye

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（OPN5）是这种光夹带所必需的，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OPN5依赖机制。我们提出实验来阐明 OPN5和OPN3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。

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.