PHOTIC REGULATION OF CIRCADIAN RHYTHMS

昼夜节律的光调节

• 批准号: 6226862
• 负责人: IGNACIO PROVENCIO
• 金额: $ 29.64万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6226862
• 关键词: circadian rhythms; gene targeting; genetically modified animals; laboratory mouse; neuronal transport; nonvisual photoreceptor; photostimulus; retinal ganglion; rhodopsin; suprachiasmatic nucleus; transfection /expression vector

DESCRIPTION (Applicant's Description): Society's reluctance to accept the importance of our body's circadian clock has resulted in maladies ranging from jet lag to tragic, fatigue-induced commercial accidents. Administration of drugs with no regard to the time of day can result in widely variable drug efficacy and capricious tolerance of side effects. Several psychiatric and sleep disorders have been attributed to a dysfunctional circadian system. A better understanding of how the circadian clock is regulated and synchronized to the environment will lead to phototherapeutic and pharmacologic strategies to address these "chronopathologies." Light detected through the eyes is the primary agent responsible for synchronizing the mammalian circadian clock to the environment. Paradoxically, the only known photoreceptors in retina (the rods and cones) are not required for this synchronizing effect of light. Animals lacking rods and cones continue to regulate their circadian systems normally. These data suggest that a non-rod, non-cone class of photoreceptor must exist within the mammalian eye. We have identified a novel human and mouse opsin, melanopsin, that is similar to the rod and cone opsin photopigments. Melanopsin is not localized to rods or cones, but rather to very few cells within the ganglion cell layer of the mouse inner retina. Interestingly, this unique distribution is identical to the distribution of ganglion cells known to project to the hypothalamic suprachiasmatic nuclei (SCN), the central circadian oscillator of mammals. These melanopsin-containing cells are the best candidate circadian photoreceptors known to date. The central hypothesis of this application is that melanopsin is required for normal photic regulation of circadian rhythms in mammals. To test this hypothesis, we will determine the spectral absorption profile of heterologously expressed mouse melanopsin to see if it matches the known spectral sensitivity of the murine circadian system. We will determine if melanopsin is localized in ganglion cells labeled by retrograde neuronal tract tracers originating in the SCN. Finally, we will assay the circadian photosensitivity of mice lacking functional melanopsin. Successful completion of these aims will give us a better understanding of melanopsin's role in the photoregulation of circadian rhythms. Confirmation of melanopsin's involvement in circadian rhythm regulation will provide a therapeutic "entry point" for the treatment of circadian disorders.

描述（申请人的描述）：社会不愿意接受 我们身体生物钟的重要性导致了各种疾病， 从时差到疲劳导致的悲惨商业事故。总局 不考虑一天中的时间的药物可能导致广泛的药物变化， 疗效和对副作用的耐受性。一些精神病和 睡眠障碍归因于生理节律系统功能失调。一 更好地了解生物钟是如何调节和同步的 将导致光疗和药理学策略 来解决这些"时间病理学" "通过眼睛检测到的光是 负责同步哺乳动物生物钟的主要代理人， 环境保护奇怪的是，视网膜中唯一已知的光感受器（ 视杆细胞和视锥细胞）对于这种光的同步效应是不需要的。 缺少视杆细胞和视锥细胞的动物继续调节它们的昼夜节律系统 正常情况下这些数据表明，非杆，非锥类感光细胞 必须存在于哺乳动物的眼睛里我们发现了一种新的人类和老鼠 视蛋白，黑视蛋白，即类似视杆和视锥的视蛋白色素。 黑视蛋白不局限于视杆细胞或视锥细胞，而是局限于极少数细胞 在小鼠视网膜内层的神经节细胞层内。有趣的是， 独特的分布与已知的神经节细胞的分布相同， 投射到下丘脑视交叉上核（SCN），中枢昼夜节律 哺乳动物的振荡器这些含有黑视蛋白的细胞是最好的候选者 迄今已知的昼夜光感受器。 本申请的中心假设是黑视素是用于 哺乳动物昼夜节律的正常光调节。为了验证这一 假设，我们将确定异相的光谱吸收曲线， 表达的小鼠黑视蛋白，看看它是否符合已知的光谱灵敏度 的生理节律系统。我们将确定黑视素是否位于 神经节细胞标记的逆行神经束示踪剂起源于 SCN。最后，我们将分析缺乏光敏感性的小鼠的昼夜光敏感性。 功能性黑视蛋白成功地完成这些目标将使我们 更好地理解黑视素在昼夜节律光调节中的作用 节奏证实黑视素参与昼夜节律 监管将提供一个治疗"切入点"， 昼夜节律紊乱