Human circadian, sleep, cardiovascular and neurobehavioral responses to light

描述(由申请人提供)：这项建议的目的有两个：(1)在Klerman博士指导研究生、博士后研究员和初级教员从事以患者为导向的研究事业的同时，为她提供有保障的时间和支持；(2)进行与光对多种生理功能的影响相关的患者导向研究。Klerman博士积极参与以患者为中心的实验工作以及数学分析和建模，这些工作将使研究结果能够转化为现实世界的应用。哺乳动物的眼睛既有视觉功能，也有非成像功能。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)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的中断，如夜间或轮换工作班次或时差，与疾病、错误和事故有关。眼光暴露的其他非视觉影响包括褪黑素抑制(作为季节性生殖变化的信号)、瞳孔反射以及心率、表现和警觉性的变化。SCN主要由固有的感光性视网膜神经节细胞而不是视杆细胞和视锥感受器来接受眼部光刺激。SCN的输出几乎影响每一个生理功能，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、建模和数据库方法来量化光对昼夜节律和其他生理功能的影响。在实验上，我们将记录短持续时间光刺激的效果和重置昼夜敏感度所需的黑暗暴露时间。来自这些实验的数据将被合并到一个数据库中，数据库中有来自2000多个已经用类似方案进行研究的受试者的数据。所有这些数据将被用来改进我们验证过的光对人体昼夜节律起搏器影响的数学模型。这个模型以及昼夜节律和睡眠-觉醒时间表对性能和警觉性的影响与对策应用程序的链接模型将在互联网上提供。本提案中概述的活动对科学、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，美国卫生与公众服务部赞助的国家睡眠障碍研究中心的一份报告记录了这一问题。这项实验工作对于了解人类昼夜节律、激素、心率、表现和警觉功能的基本生理学以及面向患者的研究(包括视网膜/眼睛护理和老年人的睡眠)都是相关的。这些结果可以用来预测光线的影响，提出暴露于光线或避免光线的建议，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。 与公共卫生相关：这项建议的目的有两个：(1)在Klerman博士继续指导研究生、博士后研究员和初级教员从事以患者为导向的研究工作时，为她提供受保护的时间和支持；(2)量化短光刺激对人类昼夜节律、表现、警觉性和其他生理功能的影响。

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. PUBLIC HEALTH RELEVANCE: The purpose of this proposal is two-fold: (1) to provide protected time and support to Dr. Klerman as she continues mentoring graduate students, post-doctoral fellows and junior faculty towards careers in patient- oriented research; and (2) to quantify the effects of short light stimuli on human circadian rhythms, performance, alertness, and other physiologic functions.