Impact of Peripheral Circadian Misalignment on Resiliency of Intestinal Barrier Function to Alcohol

项目摘要 只有20-30%的重度酗酒者会出现酒精诱导的肠道通透性增高和酒精肝 疾病（ALD）。因此，强调发挥关键作用的其他辅因子是必要的，以更好地 了解发病机制背后的机制。近年来，昼夜节律的流行率增加， 导致人类疾病发病机制如结肠通透性过高的节律破坏。 然而，外周昼夜节律失调在胃肠道（GIT）屏障稳态中的作用 是不完全理解的。我们的重点是与饮酒有关的外周生物钟。 在接近身体生物休息期的时候进食，可能会破坏周围的昼夜节律。现在不是时候 “进食”（WTE）可引起肠道微生物群及其代谢物的变化，这可能介导 肠道对酒精的泄漏。因此，我们将检验外周昼夜节律紊乱的总体假设， 将降低肠道屏障功能对酒精的弹性，通过微生物代谢物介导。 目的1：确定通过WTE的外周昼夜节律破坏降低结肠的弹性， 酒精我们将扰乱PERIOD 2荧光素酶（PER 2：：Luc）报告基因BL/6小鼠的外周昼夜节律 模型，并评估饮酒对肠通透性和肠屏障功能的影响 目的2：证明细菌代谢物影响外周昼夜节律并介导 结肠屏障功能的弹性降低。我们将证明细菌代谢物可以影响 昼夜节律以及通过结肠PER 2：：LUC介导肠屏障功能的变化 类器官在这项拟议的研究中，我将扩大有关周边昼夜节律的影响的知识， 对肠道弹性的影响此外，我将研究细菌代谢产物的影响， 来自外周昼夜节律被破坏的PER 2：：LUC小鼠。拟议的工作将阐明如何错误的时间 进食通过与微生物生态失调有关的机制使肠道更容易受到酒精的损伤， 细菌产物。这项研究的成功完成将大大增加我们对一个关键问题的理解。 酒精诱导的屏障功能障碍的辅助因子。最终，结肠外周昼夜节律的建立 ALD中的失调和鉴定与这种表型相关的微生物代谢物将导致 开发微生物和昼夜节律相关的干预措施，并确定治疗靶点， 酒精引起的损伤该建议将提高受训者的概念化、发展、执行， 并评估有意义的研究问题，增加独立性，并将帮助她发展成为一个 多产领先的独立研究科学家研究项目和事业发展将是 由一个优秀的赞助商和论文委员会谁是非常适合指导， 提供这种指导，如掌握最先进的方法/技术，指导， 发展合作网络，以确保受训者在短期和长期内取得成功。

Project Abstract Only 20-30% of heavy alcoholics develop alcohol-induced intestinal hyperpermeability and alcoholic liver disease (ALD). Thus, emphasizing other cofactors that play a critical role is necessary to better understand mechanisms behind pathogenesis. Recent years have seen an increased prevalence of circadian rhythm disruption that contributes to human disease pathogenesis such as colonic hyperpermeability. However, the role of peripheral circadian misalignment in barrier homeostasis of t he gastrointestinal tract (GIT) is incompletely understood. Our focus is on the peripheral circadian clock in relation to alcohol consumption. Peripheral circadian disruption can occur by eating close to the body’s biological rest period. This ‘wrong-time eating’ (WTE) can cause changes in the intestinal microbiota and their metabolites, which may mediate intestinal gut leakiness to alcohol. Thus, we will test the overall hypothesis that peripheral circadian disruption will decrease resiliency of the intestinal barrier function to alcohol, mediated through microbial metabolites . Aim 1: Establish that peripheral circadian disruption through WTE decreases resiliency of the colon to alcohol. We will disrupt peripheral circadian rhythms in PERIOD2 luciferase (PER2::Luc) reporter BL/6 mouse model and assess the effect of alcohol consumption on intestinal permeability and intestinal barrier function Aim 2: Demonstrate that bacterial metabolites impact peripheral circadian rhythms and mediate decreased resiliency of colonic barrier function. We will demonstrate that bacterial metabolites can affect circadian rhythms as well as mediate changes in intestinal barrier function through colonic PER2::LUC organoids. In this proposed research, I will expand knowledge regarding the impact of peripheral circadian misalignment on intestinal resiliency to alcohol. Additionally, I will investigate the effect of bacterial metabolites from peripherally circadian disrupted PER2::LUC mice. The proposed work will elucidate how wrong -time eating makes the gut more susceptible to injury by alcohol by mechanisms related to microbial dysbiosis and bacterial products. Successful completion of this research would greatly increase our understanding of a key co-factor in alcohol induced barrier disfunction. Ultimately, the establishment of colonic peripheral circadian misalignment in ALD and identifying the microbial metabolites associated with this phenotype will lead to the development of microbial and circadian related interventions and identify therapeutic targets to mitigate alcohol-induced damage. This proposal will enhance the trainee’s ability to conceptualize, develop, execute, and evaluate meaningful research questions with increasing independence and will help her develop into a productive, leading independent research scientist. The research project and ca reer development will be guided by an outstanding team of sponsors and the dissertation committee who are exceptionally well -suited to provide this guidance such as mastering state-of-the-art methods/techniques, mentorship, and the development of collaborative networks to ensure success of the trainee in the short-term and long-term.