Alcohol Alters the Circadian Response to Light in Humans

过度饮酒是一个重大的公共卫生负担，影响30%的人口在他们生命中的某个时刻，导致多种疾病，包括肝病，心血管疾病，肥胖，糖尿病和癌症，估计每年花费246亿美元的医疗保健和1613亿美元的生产力损失。即使是50-70%的美国成年人参与的社交饮酒也与健康风险有关。大量饮酒和疾病之间的一个致病途径可能是昼夜节律失调，因为过量饮酒会延迟昼夜节律，导致睡眠障碍，以及更糟糕的身体（炎症，代谢，心血管）和心理健康（抑郁症，表现）。过量饮酒究竟如何导致昼夜节律失调仍有待确定。对啮齿动物的研究表明，酒精直接影响中枢昼夜节律起搏器对光的反应。然而，酒精对人类对光的昼夜节律反应的影响尚不清楚。我们提出了两个新的受试者内设计研究，以确定酒精是否会改变人类对光的相移。具体目标1是确定酒精是否改变健康人（n=15）对深夜光线的昼夜节律相位延迟。具体目标2是确定酒精是否会改变健康人（n=15）对晨光的昼夜节律相位提前。一个探索性的目的是确定酒精对光的相移的影响在mn和女性中是否不同。我们的初步数据表明，单剂量的酒精可以改变人类对光的相移。这些研究将提供一个迫切需要的机制，了解酒精如何可能产生昼夜节律失调的人类。这些结果也将为未来的临床试验提供重要的基础，这些临床试验可以（1）确定戒酒酗酒者向光线的相移是否异常，（2）测试非成瘾性，负担得起的和可获得的时间生物学治疗（晚上外源性褪黑激素和/或增强早晨光照），以减少昼夜节律失调并改善健康。该R21申请回答了PA-11-179昼夜节律和酒精诱导的组织损伤，该申请要求“探索性/发展性资助申请，建议对昼夜节律进行机械研究......适当的课题包括酒精对昼夜节律的影响。这项研究还提出了2011年NIH睡眠障碍研究计划中提出的目标，即“促进对昼夜节律功能和基本昼夜节律机制的理解......确定导致昼夜节律紊乱风险的生活方式因素[如酒精]”。最后，这项研究直接解决了NIAAA的目标，如2013财年NIAAA预算理由中所概述的国会：“减少酒精相关的问题，重点是识别酒精导致病理的机制”。

DESCRIPTION (provided by applicant): Excessive alcohol consumption is a significant public health burden that affects 30% of the population at some point in their lives, contributes to multiple diseases including liver disease, cardiovascular disease, obesity, diabetes and cancer, and is estimated to cost $24.6 billion in health care and $161.3 billion in lost productivity annually. Even the social drinking that 50-70% of the adult US population engages in is associated with health risks. One causative pathway between heavier alcohol consumption and disease may be circadian misalignment because excessive alcohol consumption delays circadian rhythms, leading to sleep disturbance, and worse physical (inflammation, metabolic, cardiovascular) and mental health (depression, performance). Precisely how excessive alcohol consumption leads to circadian misalignment remains to be determined. Studies in rodents have demonstrated that alcohol directly impacts the central circadian pacemaker's response to light. However, the effect of alcohol on the circadian response to light in humans is not known. We propose two novel within-subjects design studies to determine if alcohol alters phase shifts to light in humans. Specific Aim 1 is to determine if alcohol alters circadian phase delays in response to late night light in healthy humans (n=15). Specific Aim 2 is to determine if alcohol alters circadian phase advances in response to morning light in healthy humans (n=15). An exploratory aim is to determine if the effect of alcohol on phase shifts to light is different in mn versus women. Our preliminary data suggests that a single dose of alcohol can alter phase shifts to light in humans. These studies will provide a critically needed mechanistic understanding of how alcohol may produce circadian misalignment in humans. The results will also provide an important foundation for future clinical trials which can (1) determine if phase shifts to light in abstinent alcoholics are abnormal and (2) test nonaddictive, affordable and accessible chronobiological treatments (evening exogenous melatonin and/or enhanced morning light exposure) to reduce circadian misalignment and improve health. This R21 application answers PA-11-179 Circadian Rhythms and Alcohol Induced Tissue Injury which calls for "exploratory/developmental grant applications that propose to conduct mechanistic studies of circadian rhythms...appropriate topics include alcohol's effects on circadian rhythms". This research also addresses goals set forth in the recent 2011 NIH Sleep Disorders Research Plan to "advance the understanding of circadian functions and basic circadian mechanisms...identify lifestyle factors [e.g. alcohol] contributing to the risk of circadian disturbances". Finally, this research directly addresses a goal of the NIAAA as outlined in the FY 2013 NIAAA Budget Justification to Congress to: "reduce alcohol-related problems focus on identification of mechanisms by which alcohol causes pathologies".