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。