Human circadian, sleep, cardiovascular and neurobehavioral responses to light

描述（由申请人提供）：本提案的目的有两个：(1)为kleerman博士提供保护时间和支持，同时她指导研究生，博士后研究员和初级教师从事以患者为导向的研究；(2)开展面向患者的光对多种生理功能影响的相关研究。他积极参与以患者为导向的实验工作和数学分析和建模，这将使研究结果转化为现实世界的应用。哺乳动物的眼睛具有视觉和非图像形成功能。一些非视觉反应是由于光对昼夜节律的影响，昼夜节律是由下丘脑视交叉上核（SCN）中的起搏器产生的内源性~24小时节律。昼夜节律起搏器或其与当地时间的正常相位关系（如夜班或轮班或时差）的中断与疾病、错误和事故有关。眼光照射的其他非视觉影响包括褪黑激素抑制（作为季节性生殖变化的信号）、瞳孔反射、心率、表现和警觉性的变化。SCN接受眼部光刺激主要是由内在光敏的视网膜神经节细胞介导的，而不是由杆状和锥状光感受器介导的。SCN的输出影响几乎所有的生理功能，包括睡眠的时间和内容、激素释放、心血管和胃肠功能、客观表现、主观警觉性和情绪。我们将使用实验、建模和数据库方法量化光对昼夜节律和其他生理功能的影响。实验上，我们将记录短时间光刺激和黑暗暴露的持续时间对重置昼夜节律敏感性的影响。来自这些实验的数据将与已经在类似协议中研究过的2000多个受试者的数据合并到一个数据库中。然后，所有这些数据将用于完善我们验证过的光对人类昼夜节律起搏器影响的数学模型。这个模型和一个昼夜节律和睡眠-觉醒时间表对表现和警觉性影响的关联模型以及对策应用程序将在互联网上提供。本建议概述的活动对科学、公共卫生和业务（工作）情况都有影响。这项指导工作将解决睡眠和昼夜节律研究人员严重短缺的问题，这一问题在美国卫生与公众服务部资助的国家睡眠障碍研究中心的一份报告中得到了记录。这项实验工作对了解人类昼夜节律、激素、心率、表现和警觉性功能的基本生理学以及以患者为导向的研究（包括视网膜/眼睛护理和老年人睡眠）具有重要意义。研究结果可用于预测光的影响，提出有关接触或避免光线的建议，以及设计环境照明，从而改善健康和警觉性，减少错误和事故。

DESCRIPTION (provided by applicant): The purpose of this proposal is two-fold: (1) to provide protected time and support to Dr. Klerman while she mentors graduate students, post-doctoral fellows and junior faculty towards careers in patient-oriented research; and (2) to conduct patient-oriented research related to the effects of light on multiple physiologic functions. Dr. Klerman is actively involved in both patient-oriented experimental work and mathematical analyses and modeling that will enable translation of research results into real-world applications. The mammalian eye serves both visual and non-image-forming functions. Some of the non-visual responses are due to the effect of light on circadian rhythms, the endogenous ~24-hour rhythms generated by a pacemaker in the hypothalamic suprachiasmatic nucleus (SCN). Disruption of the circadian pacemaker or of its normal phase relationship with local time, such as with night or rotating work shifts or jet lag, is associated with illness, errors and accidents. Other non-visual effects of ocular light exposure include melatonin suppression (as a signal for seasonal reproductive changes), pupillary reflexes, and changes in heart rate, performance, and alertness. The SCN receives ocular light stimuli primarily mediated by intrinsically photosensitive retinal ganglion cells, rather than rod and cone photoreceptors. The outputs of the SCN influence almost every physiologic function, including the timing and content of sleep, hormone release, cardiovascular and gastrointestinal function, objective performance, subjective alertness, and mood. We will quantify the effects of light on circadian rhythms and other physiologic functions using experimental, modeling, and database approaches. Experimentally, we will document the effects of short duration light stimuli and the duration of darkness exposure required to reset circadian sensitivity. The data from these experiments will be combined into a database with data from over 2000 subjects already studied in similar protocols. All these data then will be used to refine our validated mathematical model of the effects of light on the human circadian pacemaker. This model and a linked model of circadian and sleep-wake schedule effects on performance and alertness with countermeasure applications will be made available on the internet. The activities outlined in this proposal have implications for science, for public health, and operational (work) situations. The mentoring work will address a critical shortage of researchers in sleep and circadian rhythms, documented in a US Department of Health and Human Services-sponsored National Center on Sleep Disorders Research report. The experimental work is relevant both for understanding the basic physiology of human circadian, hormone, heart rate, performance and alertness functions and for patient-oriented research including retinal/eye care and sleep of older persons. The results can be used to make predictions about the effects of light, to make recommendations involving exposure to or avoidance of light, and to design environmental lighting, resulting in improved health and alertness and decreased errors and accidents.