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Light as a Controlling Stimulas for Behavior Cancer Research: Bridging Human Expo

光作为行为癌症研究的控制刺激：架起人类博览会的桥梁

基本信息

批准号：
7894871
负责人：
Mariana Gross Figueiro
金额：
$ 6.55万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894871
关键词：
Affect Animal Model Behavior Biological Clocks Biological Process Body Temperature Brain Cancer Etiology Cell division Circadian Rhythms Color Visions Controlled Study DNA Repair Environment Epidemiologic Studies Exhibits Exposure to Health High-Risk Cancer Hormones Hour Human Incidence Indium Investigation Knowledge Laboratories Light Measures Modeling Morbidity - disease rate Mus Nurses Nurses&apos Health Study Pattern Phototransduction Pigments Play Production Rat Strains Rattus Research Research Project Grants Retina Role Scientist Sleep Stimulus System Techniques Time Translating Vulnerable Populations World Health Organization albino rat alertness anticancer research base biological systems cancer risk experience exposed human population malignant breast neoplasm meter mortality novel strategies public health relevance response shift work suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Light as a Controlling Stimulus for Behavior Cancer Research: Bridging Human Exposures to Animal Models for Parametric Investigations Proposed is a research project that is a key element in a broad strategic research plan to develop a completely new framework for parametrically studying cancer risk as it is affected by circadian disruption of biological systems. The suprachiasmatic nuclei (SCN) serve as the mammalian brain's internal clock, regulating the circadian rhythms of a wide variety of biological functions. Light and dark control the timing of the SCN. The modern built environment has, however, changed human light-dark exposures by episodically blunting our daytime light exposures and extending our light exposures into the night. Several lines of research indicate that disruption of the natural and regular 24-hour light-dark cycle increases morbidity and mortality. Recently, the World Health Organization characterized shift work, exemplified by a significant disruption of a regular, 24-hour pattern of light and dark, as a potential carcinogenic. Since circadian disruption probably plays an important role in the etiology of cancer, it is important to quantify patterns of light and dark actually experienced by vulnerable populations like shift workers and then to be able to parametrically translate those patterns into controlled studies of circadian disruption in animal models. Our laboratory has in fact developed a personal circadian light meter that has been used in the Nurses Health Study to gather patterns of light and dark actually experienced by dayshift and rotating-shift nurses. We have developed a biophysical model of circadian phototransduction for humans and one for a nocturnal species (murine). We have also developed a mathematical technique, known as phasor analysis, to quantify circadian disruption in humans and in mouse. Thus, we have created a bridge between ecological studies of circadian disruption actually experienced by diurnal humans to parametrically controlled studies of circadian disruption in a nocturnal animal model. Mouse, however, is not as commonly used as an animal model for cancer research as rats, so it is important that a biophysical model of circadian phototransduction be developed for species more commonly used in cancer research. Humans exhibit a subadditive response to polychromatic light because spectral opponent mechanisms in the retina that form the basis for human color vision participate in circadian phototransduction. The circadian system of mouse is nearly three orders of magnitude more sensitive to light than humans and they respond to light in an additive manner because they only have rudimentary color vision. It is yet unknown whether rats have a circadian system with the same absolute sensitivity to light as mouse and whether their rudimentary form of color vision plays a role in circadian phototransduction as it does in diurnal humans. For this R03, we propose to develop the absolute and spectral sensitivity functions for two rat species. This basic information will provide an essential next step in the radically new research plan to investigate the role of circadian disruption on cancer risk. PUBLIC HEALTH RELEVANCE: Light as a Controlling Stimulus for Behavior Cancer Research: Bridging Human Exposures to Animal Models for Parametric Investigations Circadian disruption has been implicated as a significant contributor to the increasing incidence of many modern maladies such as breast cancer. Proposed here is a small, sophisticated study of the absolute and spectral sensitivities of two strains of rats commonly used as models for cancer research. With this knowledge, combined with the progress already made in overcoming other identified barriers, it will be possible to develop a radically new approach to the study of modern environmental light exposures on human health and well being. Specifically, with the knowledge gain in this study, scientists can quickly and economically investigate the impact of circadian disruption actually experienced by shift workers on animal models using biologically meaningful levels and spectra.

描述（由申请人提供）：项目摘要：光作为行为癌症研究的控制刺激：将人类暴露于动物模型进行参数研究是一个研究项目，是广泛战略研究计划的关键要素，该计划旨在开发一个全新的框架，用于参数化研究癌症风险，因为癌症风险受到生物系统昼夜节律破坏的影响。视交叉上核（SCN）充当哺乳动物大脑的内部时钟，调节多种生物功能的昼夜节律。光和暗控制 SCN 的时序。然而，现代建筑环境通过间歇性减弱我们的白天光照并将我们的光照延长到夜间，改变了人类的明暗暴露。多项研究表明，破坏自然规律的 24 小时光暗循环会增加发病率和死亡率。最近，世界卫生组织将轮班工作定性为潜在的致癌物质，其典型例子就是严重扰乱 24 小时的昼夜规律。由于昼夜节律紊乱可能在癌症病因学中发挥着重要作用，因此量化轮班工人等弱势群体实际经历的光和暗模式非常重要，然后能够将这些模式参数化地转化为动物模型中昼夜节律紊乱的对照研究。事实上，我们的实验室开发了一种个人昼夜节律光度计，已用于护士健康研究，以收集白班和轮班护士实际经历的光和暗模式。我们开发了一种针对人类和夜间活动物种（鼠类）的昼夜节律光转导生物物理模型。我们还开发了一种称为相量分析的数学技术，用于量化人类和小鼠的昼夜节律破坏。因此，我们在白天人类实际经历的昼夜节律破坏的生态研究与夜间动物模型中昼夜节律破坏的参数控制研究之间建立了一座桥梁。然而，小鼠并不像大鼠那样常用作为癌症研究的动物模型，因此为癌症研究中更常用的物种开发昼夜节律光转导的生物物理模型非常重要。人类对多色光表现出亚加性反应，因为视网膜中构成人类色觉基础的光谱对抗机制参与昼夜节律光转导。小鼠的昼夜节律系统对光的敏感度比人类高出近三个数量级，并且它们以累加的方式对光做出反应，因为它们只具有基本的色觉。目前尚不清楚大鼠的昼夜节律系统是否与小鼠具有相同的对光的绝对敏感性，以及它们的基本形式的色觉是否像昼间人类一样在昼夜节律光转导中发挥作用。对于此 R03，我们建议开发两种大鼠物种的绝对灵敏度函数和光谱灵敏度函数。这些基本信息将为全新研究计划提供重要的下一步，以调查昼夜节律紊乱对癌症风险的影响。公共健康相关性：光作为行为癌症研究的控制刺激：将人类暴露于动物模型以进行参数研究昼夜节律紊乱被认为是乳腺癌等许多现代疾病发病率不断增加的重要原因。这里提出了一项小型、复杂的研究，研究通常用作癌症研究模型的两种大鼠品系的绝对敏感性和光谱敏感性。有了这些知识，再加上在克服其他已知障碍方面已经取得的进展，就有可能开发出一种全新的方法来研究现代环境光照射对人类健康和福祉的影响。具体来说，通过这项研究中获得的知识，科学家可以使用具有生物学意义的水平和光谱，快速、经济地研究轮班工人实际经历的昼夜节律紊乱对动物模型的影响。