PHOTIC REGULATION OF CIRCADIAN RHYTHMS

描述(申请人的描述)：社会不愿接受 我们身体生物钟的重要性导致了各种疾病，包括 时差导致了悲惨的、由疲劳引起的商业事故。管理 不考虑一天中的时间的药物会导致药物的广泛变化 副作用的疗效和反复无常的耐受性。几个精神病学家和 睡眠障碍被归因于昼夜节律系统失调。一个 更好地理解生物钟是如何调节和同步的 将导致光治疗和药物治疗的策略 来解决这些“时间病理学”问题。通过眼睛检测到的光是 负责使哺乳动物生物钟同步的主要因素 环境。矛盾的是，视网膜中唯一已知的光感受器( 杆和锥体)不是光的这种同步效果所必需的。 缺少视杆和视锥的动物继续调节其昼夜节律系统 通常是这样的。这些数据表明，一种非杆状、非视锥类型的光感受器 必须存在于哺乳动物的眼睛里。我们发现了一种新的人和老鼠 视黄素、黑视素，即类似于感光颜料中的视杆和视锥. 黑素不定位于视杆或视锥细胞，而是定位于极少数细胞。 在小鼠视网膜内的神经节细胞层内。有趣的是，这 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)，即中央昼夜节律 哺乳动物的振荡器。这些含有黑素的细胞是最好的候选者 迄今已知的昼夜节律光感受器。 这一应用的中心假设是黑色素是必需的 哺乳动物昼夜节律的正常光调节。为了测试这一点 假设，我们将确定异源分子的光谱吸收分布 表达小鼠黑素蛋白，看看它是否与已知的光谱敏感性相匹配 小鼠的昼夜节律系统。我们将确定黑色素是否定位于 神经束逆行示踪剂标记的神经节细胞 SCN.最后，我们将测试缺乏的小鼠的昼夜节律光敏性。 功能性黑素。这些目标的成功实现将给我们带来 更好地理解黑素在昼夜节律光调节中的作用 节奏。证实黑素参与昼夜节律 监管将为治疗黑色素瘤提供一个治疗“切入点” 生理节律紊乱。

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.