Functions of OPN5 and OPN3 in the eye

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。 真核生物的生命。昼夜节律紊乱是多种常见睡眠障碍的基础， 被认为是其他疾病的诱因，从精神疾病到癌症。哺乳动物 视网膜在同步主昼夜节律起搏器(视交叉上起搏器)中起着关键作用 到每日的明暗循环。多年来的研究也证明了视网膜本身 是一种强大的昼夜节律振荡器。事实上，许多关键的视网膜功能，包括视觉敏感度， 瞳孔的光反射、视网膜电信号和数百个视网膜基因的表达 较强的昼夜节律控制；而视网膜昼夜节律的丧失会导致视网膜功能受损。 我们的初步数据已经证明：1)视网膜生物钟可以被携带到光- 体外培养中的暗循环，2)这种夹带不依赖于经典的视杆和视锥或 表达黑素的固有光敏性视网膜神经节细胞，3)孤儿视蛋白 神经蛋白(OPN5)是这种光包裹所必需的，而孤儿视蛋白脑视蛋白(OPN3) 影响这一过程，4)视网膜利用一种依赖光的、可扩散的物质来同步其 5)角膜还含有一个生物钟，值得注意的是，它可以被带入光中-- 暗周期也是通过OPN5依赖机制实现的。我们建议通过实验来阐明 OPN5和OPN3的信号机制；可扩散信号的实验表征(S) 从视网膜发出的，并通过实验阐明非视网膜组织在 眼睛保持昼夜节律性，并陷入明暗循环。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 对两个新的眼部感光器的洞察。

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.