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.
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