Alcohol-mediated Clock genes interfere with lung injury and repair

在美国，急性呼吸窘迫综合征(ARDS)仍然是一个重要的公共卫生问题 有问题。尽管付出了很大努力来改善结果，但约80%的ARDS幸存者经历了减少 与健康相关的生活质量，并在确诊后长达5年的胸部影像上有纤维化改变。 长期酗酒显著增加ARDS的发病率和死亡率，而不是直接 造成肺部损伤。新出现的数据显示，酒精干扰昼夜节律信号通路。 肝脏和肠道，进而使组织对损伤和纤维化易感。昼夜节律途径 由多种转录因子组成，这些转录因子通过其转录因子调节各种器官的生理功能 监管网络。已知一些昼夜节律途径分子可以调节非编码RNA和 反之亦然，非编码RNA可以调节昼夜节律途径的分子。在这份提案中，我们提出 初步数据显示，酒精通过改变 昼夜节律途径分子BMAL1和核因子维甲酸相关孤儿受体-α(RoRα)。我们 认为这些变化导致酒精诱导的转化生长因子β1通过抑制RORα-miR-139的活性。此外，我们 鉴定了CIRC-RoRα-miR-155轴是BMAL1的一个新的调控机制。这些结果使我们得出了 假设慢性酒精摄入扰乱了昼夜节律通路信号和CIRC-RoRα-miR-155 轴，从而扰动RoRα-MIR-139轴，进而使肺易感性朝向 急性损伤后纤维增生性破坏。实验方法就是为了测试这一点而设计的 假设。这些研究将为酒精的潜在机制提供坚实的科学基础 干扰肺损伤后的组织修复。

In the United States, the acute respiratory distress syndrome (ARDS) remains a significant public health problem. Despite substantial efforts to improve the outcome, ~ 80% of ARDS survivors experience reduced health-related quality of life and have fibrotic changes on chest imaging for up to 5 years after diagnosis. Chronic alcohol abuse significantly increases the incidence of, and mortality from, ARDS, without directly causing lung damage. Emerging data show that alcohol interferes with the circadian signaling pathway in the liver and intestine which, in turn, render tissue susceptibility to injury and fibrosis. The circadian pathway consists of multiple transcription factors which mediate various organ physiological functions through its regulatory networks. It is known that some of circadian pathway molecules can regulate non-coding RNAs and vice versa, non-coding RNAs can regulate circadian pathway molecules. In this proposal, we present preliminary data showing that alcohol promotes circadian pathway dysfunction in the lung through alterations of circadian pathway molecules BMAL1 and nuclear factor Retinoid-Related Orphan Receptor-alpha (RORα). We believe these changes lead to alcohol-induced TGFβ1 by suppressing RORα-miR-139 activity. Further, we identified the circ-RORα-miR-155 axis as a novel regulatory mechanism of BMAL1. These results led us to hypothesize that chronic alcohol ingestion disrupts circadian pathway signaling and the circ-RORα-miR-155 axis which, thereby perturbing the RORα-miR-139 axis which, in turn, render lung susceptibility toward fibroproliferative disrepair following acute injury. The experimental approaches are designed to test this hypothesis. These studies will provide a firm scientific basis for the underlying mechanisms by which alcohol interferes with tissue repair following lung injury.