Shift work and longevity in disease-prone inbred mice

描述（由申请人提供）：人类和其他动物在进化上适应于生活在24小时太阳日的背景下，该太阳日被组织成相对稳定的光明和黑暗时期。然而，从电气化开始，在信息互联网时代的支持下，偏离“典型”的夜间睡眠和白天活动的日常模式在我们的社会中变得越来越普遍，每天“规律”的休息和活动时间变得越来越不稳定。许多人通常会经历与工作要求，护理，生活方式选择或健康状况有关的昼夜混乱。这种情况对于必须执行轮班工作（SW）的个人来说尤其成问题。 SW在西方社会与吸烟一样常见-约占人口的20-25%，对许多人来说不是可选的或短期的，并且越来越被视为许多疾病的风险因素。如果这种关联得到证实，并反映了因果关系，那么即使是轻微减少SW的有害影响也可能具有显着的公共卫生效益。识别 行为和生理的自然昼夜整合的长期干扰对健康的长期影响对于制定合理的建议和预防战略至关重要，这些建议和战略将在我们日益“24/7”的社会中保护公共健康并减轻疾病风险。 这项R 03资助将检验这样一种假设，即长期暴露于重复的昼夜相移（DPS），模仿SW，将加速具有慢性疾病遗传易感性的个体的疾病发作和死亡。我们将通过完成一个特定的目标来测试这个想法：确定暴露于终身重复的DPS/SW是否会缩短处于癌症（AKR/J小鼠）或自身免疫性疾病（MRL/MpJ小鼠）遗传风险的小鼠品系的寿命。我们预测AKR/J和MRL/MpJ小鼠从5周龄开始暴露于DPS/SW将分别加速癌症和自身免疫性疾病引起的疾病发作和死亡率。然而，其他结果也将提供信息。 对昼夜节律协调在维持健康中的重要性的日益认识正在促进在各种疾病状况的发病机制和治疗中考虑昼夜定时。然而，由于生活方式和临床治疗的昼夜定制在社会和后勤方面具有挑战性，因此明确和明确的影响证明将在1）促进对昼夜节律风险的认识和接受以及2）制定和实施减轻风险的策略方面非常重要。慢性昼夜紊乱在我们社会中的流行及其相关的健康风险强调了定义昼夜紊乱对慢性疾病发展和进展的影响的必要性。我们提出的实验应该为进一步研究这些重要问题提供一个强有力的平台。

DESCRIPTION (provided by applicant): People and other animals are evolutionarily adapted to live in the context of a 24 hr solar day that is organized into relatively stable periods of ligt and darkness. However, beginning with electrification and bolstered by the information-internet age, deviations from the "typical" daily pattern of nocturnal sleep and daytime activity have become increasingly common in our society, and daily "regular" periods of rest and activity have become increasingly unstable. Many people commonly experience day-night disorganization in association with work requirements, care-giving, life style choice, or health conditions. This situation is particularly problematic for individuals who must perform shift work (SW). SW is as common as smoking in Western societies - around 20-25% of the population, is not optional or short-term for many individuals, and is increasingly viewed as a risk factor for many disease conditions. If such associations are confirmed and reflect causality, then even a modest reduction in the detrimental impact of SW could have significant public health benefit. Identifying the long-term health impact of chronic perturbation of the natural diurnal integration of behavior and physiology is crucial to developing sound recommendations and preventive strategies that will protect public health and mitigate disease risk in our increasingly "24/7" society. This R03 grant will test the hypothesis that chronic exposure to repeated diurnal phase shifts (DPS), mimicking SW, will accelerate the disease onset and death in individuals with genetic predisposition to chronic disease. We will test this idea by completing one specific aim: determine whether exposure to life-long repeated DPS/SW will shorten lifespan in strains of mice that are at genetic risk for the development of cancer (AKR/J mice) or autoimmune disease (MRL/MpJ mice). We predict that exposure of AKR/J and MRL/MpJ mice to DPS/SW beginning at 5 weeks of age will accelerate the onset of disease and mortality due to cancer and autoimmune disease, respectively. However, alternative outcomes will also be informative. Growing awareness of the importance of circadian coordination in maintaining health is fostering consideration of diurnal timing in the pathogenesis and treatment of various disease conditions. However, because diurnal tailoring of both life styles and clinical therapies is socially and logistically challenging, clear and unambiguous demonstration of impact will be important in 1) fostering awareness and acceptance of the risks of diurnal asynchrony and 2) developing and implementing strategies to mitigate risk. The prevalence of chronic diurnal disturbance in our society and its associated health risks underscore the need to define the impact of circadian disorganization on the development and progression of chronic diseases. The experiment we propose should provide a powerful platform for further investigation of these important issues.