Circadian Clock Regulation of the Mammalian Retina

描述（由申请人提供）：我们现在知道哺乳动物有多个生物钟。第一个被确认的生物钟是视交叉上核的生物钟，它被证明是调节行为活动的。其次是视网膜，最近在外周器官和中枢神经系统的各个部位发现了生物钟。与SCN时钟相反，SCN外的昼夜节律时钟的重要性尚未确定用于体内生理学的任何方面。这个问题对于理解哺乳动物的生理学是非常重要的。本提案的总体目标是确定非SCN生物钟在体内的重要性，并在分子方面表征其功能。哺乳动物视网膜中的生物钟为此提供了巨大的优势：1）许多视网膜现象显示出昼夜节律调节，2）关于视网膜及其组成细胞类型的精确生理作用已知很多，3）可以获得允许视网膜的选择性遗传操作的工具，4）可以方便地收集视网膜用于分子研究，和5）视网膜电描记术提供活体动物中视网膜功能的快速和信息性测试。具体目的是1）确定生物钟功能对于体内视网膜对光的反应是否重要; 2）以综合尺度表征视网膜中由生物钟、光或两者调节的基因; 3）确定视网膜内的生物钟对视网膜对光的反应和视网膜基因表达的节律的贡献;以及4）确定视网膜内的生物钟功能是否影响恒定黑暗中SCN生物钟的功能。对哺乳动物昼夜节律系统更深入的了解可能对人类健康和疾病具有重要意义，特别是关于复杂生理系统的控制，例如睡眠/觉醒调节、生育力、葡萄糖稳态/糖尿病以及细胞周期和癌症的调节。详细了解视网膜的昼夜节律生物学将可能为视网膜生理学和代谢以及视网膜变性疾病（如视网膜色素变性和年龄相关性黄斑变性）的病理生理学提供新的见解。

DESCRIPTION (provided by applicant): We now know that mammals have multiple circadian clocks. The first clock identified was that of the suprachiasmatic nucleus, shown to regulate behavioral activity. The next was that of the retina, and more recently circadian clocks have been found in peripheral organs and at various sites in the central nervous system. In contrast to the SCN clock, the importance of circadian clocks outside the SCN is not yet established for any aspect of physiology in vivo. This issue is of major importance for understanding mammalian physiology. The general objective of this proposal is to determine the importance in vivo of a non-SCN circadian clock and characterize its functions in molecular terms. The circadian clock in the mammalian retina provides great advantages for this purpose: 1) many retinal phenomena show circadian regulation, 2) much is known about the retina and the precise physiological roles of its constituent cell types, 3) tools are available that permit selective genetic manipulation of the retina, 4) retinas can be conveniently collected for molecular studies, and 5) electroretinography provides a rapid and informative test of retinal function in living animals. The specific aims are 1) to determine if circadian clock function is important for retinal responses to light in vivo; 2) to characterize on a comprehensive scale genes regulated in the retina by a circadian clock, light, or both; 3) to determine the contribution of circadian clocks within the retina to retinal responses to light and to rhythms of retinal gene expression; and 4) to determine if circadian clock function within the retina influences the function of the SCN circadian clock in constant darkness. Deeper general understanding of the mammalian circadian system will likely have important implications for human health and disease, particularly with regard to the control of complex physiological systems, such as sleep/wake regulation, fertility, glucose homeostasis/diabetes, and regulation of the cell cycle and cancer. Detailed knowledge of the circadian biology of the retina will likely provide new insights into retinal physiology and metabolism and pathophysiology of retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration.