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

外周昼夜节律失调对肠道屏障功能对酒精的弹性的影响

• 批准号: 10315546
• 负责人: Laura Tran
• 金额: $ 4.6万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315546
• 关键词: 3-nitrotyrosine; Affect; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Bacteria; Biological; Biological Clocks; Blood Circulation; Body Weight; Cause of Death; Cecum; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Colon; Complication; Development; Disease; E-Cadherin; Eating; Electrical Resistance; Ensure; Environment; Epithelial; Ethanol; Gastrointestinal tract structure; Genetic; Goals; Heavy Drinking; Homeostasis; Hour; Inflammation; Inflammatory Response; Injury; Interleukin-12; Interleukin-6; Intervention; Intestinal permeability; Intestines; Knowledge; Lead; Leaky Gut; Length; Leukocyte L1 Antigen Complex; Light; Lipopolysaccharides; Luciferases; Measures; Mediating; Mentorship; Methods; Modeling; Modernization; Mus; Onset of illness; Organ; Organoids; Outcome; Outcome Measure; Pathogenesis; Pattern; Peripheral; Permeability; Phenotype; Play; Prevalence; Proteins; Reporter; Research; Research Project Grants; Rest; Risk; Role; Scientist; Serum; Societies; Stains; System; Techniques; Testing; Time; Tissue Stains; United States; Volatile Fatty Acids; Work; alcohol content; alcohol effect; chronic alcohol ingestion; circadian; circadian pacemaker; claudin-1 protein; cofactor; dysbiosis; fecal microbiome; feeding; gut bacteria; gut microbiota; human disease; in vivo; interleukin-23; intestinal barrier; intestinal homeostasis; microbial; microbiome analysis; microbiota; mortality; mouse model; occludin; problem drinker; resilience; shift work; stressor; success; therapeutic target

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.

项目摘要 只有 20-30% 的酗酒者会出现酒精引起的肠道通透性过高和酒精肝 因此，有必要强调其他发挥关键作用的辅助因子。 近年来，昼夜节律的患病率有所增加。 节律紊乱会导致人类疾病的发病机制，例如结肠通透性过高。 然而，外周昼夜节律失调在胃肠道（GIT）屏障稳态中的作用 我们的重点是与饮酒相关的外周生物钟。 在接近身体生物休息时间的时间进食可能会导致外周昼夜节律紊乱。 “吃”（WTE）会引起肠道微生物群及其代谢物的变化，这可能会介导 因此，我们将检验外周昼夜节律紊乱的总体假设。 会降低通过微生物代谢物介导的肠道屏障功能对酒精的弹性。 目标 1：确定 WTE 导致的外周昼夜节律紊乱会降低结肠的弹性 我们将扰乱 PERIOD2 荧光素酶 (PER2::Luc) 报告基因 BL/6 小鼠的外周昼夜节律。 建立模型并评估饮酒对肠道通透性和肠道屏障功能的影响 目标 2：证明细菌代谢物影响外周昼夜节律并调节 结肠屏障功能弹性下降我们将证明细菌代谢物会影响。 昼夜节律以及通过结肠 PER2::LUC 介导肠道屏障功能的变化 在这项拟议的研究中，我将扩展有关外周昼夜节律影响的知识。 此外，我将研究细菌代谢产物的影响。 来自外周昼夜节律紊乱的 PER2::LUC 小鼠。拟议的工作将阐明错误的时间。 通过与微生物失调相关的机制，饮食使肠道更容易受到酒精的伤害 成功完成这项研究将大大增加我们对关键细菌产品的理解。 最终，结肠外周昼夜节律的建立是酒精引起的屏障功能障碍的辅助因素。 ALD 中的错位并识别与该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目标以减轻 该建议将增强受训者的概念化、发展、执行、 并以越来越独立的方式评估有意义的研究问题，这将帮助她发展成为一名 研究项目和职业发展将是富有成效的、领先的独立研究科学家。 由优秀的赞助商团队和论文委员会指导，他们非常适合 提供这种指导，例如掌握最先进的方法/技术、指导和 发展协作网络，以确保学员短期和长期的成功。