Molecular circadian clocks and alcohol-induced liver injury

过量饮酒仍然是美国可预防死亡的主要原因。酗酒者 肝病（ALD）是酗酒导致发病和死亡的主要原因，也是最常见的疾病 肝病相关死亡的常见原因。尽管人们对许多细胞和 ALD 中发生的分子事件，其因果机制仍然难以捉摸，特别是在 影响疾病进展和严重程度的因素。为了促进对此的机械理解 严重的肝脏疾病，目前的提案将调查生物钟破坏的重要性和 “一天中的时间”是 ALD 的关键风险因素。这些观点源于人们日益认识到生物钟 破坏与许多病理和疾病有关。分子昼夜节律的一项基本功能 时钟的目的是提供预期的选择性优势，允许快速且暂时适当的 适应代谢压力、免疫挑战和环境侵害。当这些过程失败时， 疾病随之而来。我们认为，生物钟的扰动是许多新陈代谢和生物钟的基础。 炎症事件导致酒精性肝损伤。因此，我们将确定 酒精性肝损伤中的肝细胞时钟和单核细胞时钟。为了支持这个概念，我们有 发现长期饮酒小鼠的肝脏生物钟发生显着改变， 肝脏时钟增加肝脏炎症介质的水平，以及酒精引起的肝损伤和 肝脏生物钟紊乱的小鼠脂肪变性升高。此外，研究表明，正常的 一天中不同时段的饮酒模式会增加患 ALD 的风险，而现在人们认识到，酗酒会导致酒精性肝病 (ALD) 对健康有害。总的来说，这些观察结果使我们推测生物钟被破坏 加剧酒精引起的肝损伤和炎症。同样，我们建议酒精含量 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测试来检验这些假设 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 通过使用两种基因小鼠模型诱导肝损伤，即肝细胞特异性 BMAL1 敲除小鼠和 单核细胞（骨髓细胞）特异性 BMAL1 敲除小鼠。在目标 2 中，我们将使用“慢性狂欢” 酒精模型并确定肝脏对酗酒最敏感的“窗口”或一天中的时间 毒性。该项目的成功完成将揭示细胞特异性生物钟的重要性 酒精介导的组织损伤和炎症，并表明“一天中的时间”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预先获得的科学知识 临床动物研究将导致未来使用各种基于时间生物学的转化研究 治疗 ALD 和其他相关肝脏疾病的治疗方法。

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.