Circadian Clock Regulation of the Mammalian Retina

描述(申请人提供)：我们现在知道哺乳动物有多个生物钟。第一个被发现的时钟是交叉上核的时钟，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不同部位发现了生物钟。与SCN时钟不同的是，SCN外的生物钟在体内生理学的任何方面的重要性尚未得到证实。这一问题对于理解哺乳动物生理学具有重要意义。这项建议的总体目标是确定非SCN生物钟在体内的重要性，并从分子角度表征其功能。哺乳动物视网膜的生物钟为这一目的提供了巨大的优势：1)许多视网膜现象显示了昼夜节律，2)人们对视网膜及其组成细胞类型的精确生理作用有了更多的了解，3)可以使用工具对视网膜进行选择性的基因操作，4)可以方便地收集视网膜用于分子研究，5)视网膜电描记术提供了对活体动物视网膜功能的快速和信息测试。其具体目标是：1)确定生物钟功能对活体视网膜对光的反应是否重要；2)在全面的尺度上表征视网膜中由生物钟、光或两者共同调节的基因；3)确定视网膜内生物钟对光的反应和对视网膜基因表达节律的贡献；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的深入了解可能会对人类的健康和疾病产生重要的影响，特别是在控制复杂的生理系统方面，如睡眠/觉醒调节、生育、葡萄糖稳态/糖尿病以及细胞周期和癌症的调节。对视网膜昼夜节律生物学的详细了解可能会为视网膜生理学和新陈代谢以及视网膜退行性疾病的病理生理学提供新的见解，如视网膜色素变性和老年性黄斑变性。

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.