Molecular circadian clocks and alcohol-induced liver injury

在美国，过度饮酒仍然是可预防的死亡的主要原因。酗酒者 肝病(ALD)是大量饮酒导致发病率和死亡率的主要原因，是最常见的 肝病相关死亡的主要原因。尽管对许多细胞和 在ALD中发生的分子事件，其原因机制仍然难以捉摸，特别是关于 导致疾病进展和严重程度的因素。推进对这一点的机械性理解 严重的肝病，目前的提案将调查生物钟扰乱和 “一天中的时间”是ALD的关键危险因素。这些观点源于人们越来越多地认识到生物钟 破坏与许多病理和疾病有关。分子昼夜节律的一个基本功能 时钟是为了提供一种选择性的预期优势，允许快速和暂时合适 适应新陈代谢压力、免疫挑战和环境侮辱。当这些过程失败时， 疾病接踵而至。我们认为，生物钟的扰动是许多新陈代谢和 导致酒精性肝损伤的炎症事件。因此，我们将确定 酒精性肝损伤中的肝细胞钟和单核细胞钟。为了支持这一概念，我们有 研究发现，慢性饮酒小鼠肝脏的生物钟显著改变，基因中断 肝钟增加肝脏炎症介质的水平，以及酒精诱导的肝损伤和 在肝钟紊乱的小鼠中，脂肪变性会加剧。此外，研究表明，正常情况下的干扰 饮酒的时间模式会增加ALD的风险，现在人们已经认识到，酗酒 对健康有害。总的来说，这些观察结果让我们假设生物钟的扰乱 加重酒精引起的肝脏损伤和炎症。同样，我们认为酒精的大小 毒性取决于一天中摄入酒精的时间。我们将通过两个具体的例子来检验这些假设 目标。在目标1中，我们将机械地展示细胞自主时钟在慢性酒精中的关键作用- 利用两种遗传小鼠模型诱导肝损伤，肝细胞特异性BMAL1基因敲除小鼠和 单核细胞(髓系细胞)特异性BMAL1基因敲除小鼠。在目标2中，我们将使用‘慢性狂欢’ 建立酒精模型，确定肝脏对酗酒最敏感的“窗口”或时间 毒性。该项目的成功完成将揭示特定于细胞的生物钟在 酒精介导的组织损伤和炎症，并表明每天的时间是肝脏的一个重要危险因素 酗酒造成的伤害。我们的长期目标是，从这些前期研究中获得的科学知识 临床动物研究将导致未来使用各种基于时间生物学的翻译研究 ALD和其他相关肝病的治疗方法。

Excessive alcohol consumption remains a leading cause of preventable death in the United States. Alcoholic liver disease (ALD) is a major cause of morbidity and mortality from heavy alcohol drinking and is the most prevalent cause of liver disease-related death. Despite increased understanding of the many cellular and molecular events occurring in ALD, the causal mechanisms remain elusive, especially with regards to the factors responsible for disease progression and severity. To advance mechanistic understanding of this serious liver disease, the current proposal will investigate the importance of circadian clock disruption and `time-of-day' as critical risk factors for ALD. These views stem from the growing recognition that circadian clock disruption is linked to numerous pathologies and diseases. One essential function of the molecular circadian clock is to provide a selective advantage of anticipation, allowing for rapid and temporally appropriate adaptation to metabolic stress, immune challenges, and environmental insults. When these processes fail, disease ensues. We propose that perturbation of circadian clocks underlie many of the metabolic and inflammatory events contributing to alcohol-induced liver injury. As such, we will determine the role of the hepatocyte clock and the monocyte clock in alcohol-induced liver injury. In support of this concept, we have found that the circadian clock is significantly altered in livers of chronic alcohol-fed mice, genetic disruption of the liver clock increases levels of hepatic inflammatory mediators, and alcohol-induced liver injury and steatosis are elevated in mice with a disrupted liver clock. Furthermore, studies show that disruptions in normal time-of-day patterns in alcohol drinking increases risk for ALD and binge alcohol drinking is now recognized to be harmful to health. Collectively, these observations have led us to hypothesize that circadian clock disruption exacerbates alcohol-induced liver injury and inflammation. Similarly, we propose that the magnitude of alcohol toxicity is dependent on the time of day of alcohol ingestion. We will test these hypotheses through two specific aims. In Aim 1, we will mechanistically show the critical role of cell autonomous clocks in chronic alcohol- induced liver injury by using two genetic mouse models, the hepatocyte-specific BMAL1 knockout mouse and the monocyte (myeloid cell)-specific BMAL1 knockout mouse. In Aim 2, we will use the `chronic + binge' alcohol model and determine the `window' or time of day that the liver is most sensitive to alcohol binge toxicity. Successful completion of this project will reveal the importance of cell-specific circadian clocks in alcohol-mediated tissue injury and inflammation and show that `time-of-day' is a significant risk factor for liver injury from binge alcohol drinking. Our long-term goal is that the scientific knowledge gained from these pre- clinical animal studies will lead to future translational investigations using various chronobiology-based therapeutic approaches for treatment of ALD and other related liver diseases.