Circadian Desynchrony in Alcohol Induced Gut Leakiness

酒精引起的肠漏的昼夜节律不同步

• 批准号: 8239410
• 负责人: Garth R Swanson
• 金额: $ 17.69万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239410
• 关键词: Aftercare; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animals; Biology; Brain; Cells; Chronic; Chronic Phase; Circadian Rhythms; Clinical; Colitis; Collaborations; Collection; Development; Disease; Eating; Endotoxemia; Endotoxins; Environment; Epidemiology; Epithelial Cells; Ethanol; Functional disorder; Future; Gastrointestinal tract structure; Gene Expression; Gene Proteins; Genes; Glass; Health; Human; Inflammatory; Injury; Intestinal Mucosa; Intestines; Knowledge; Lead; Light; Measurement; Measures; Mediating; Melatonin; Mentors; Messenger RNA; Modeling; Mus; Organ; Pathogenesis; Patients; Peripheral; Permeability; Phase; Plasma; Predisposition; Prevention; Proteins; Publishing; Rattus; Research; Research Proposals; Risk; Role; Saliva; Sampling; Schedule; Scientist; Serum; Sleep; Small Interfering RNA; Societies; Sodium Dextran Sulfate; Solutions; Source; Testing; Therapeutic; Time; Tissues; Up-Regulation; Urine; Work; Wrist; actigraphy; alcohol abuse therapy; alcohol effect; alcohol research; career; chronic alcohol ingestion; circadian pacemaker; cofactor; effective intervention; feeding; human RORA protein; human subject; improved; knock-down; monolayer; non-alcoholic; patient oriented research; prevent; problem drinker; proctolin; programs; red wine; research study; shift work; sugar; suprachiasmatic nucleus; therapeutic target

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) occurs only in a subset of alcoholics ( 30%) that develop tissue injury and organ dysfunction. This well established epidemiological and clinical observation indicates that alcohol abuse is required but not sufficient to cause tissue injury and additional cofactors are required. We and other have shown that increased intestinal permeability (gut leakiness) and endotoxemia are two required cofactors. The key question is what additional cofactors are needed to develop gut leakiness and endotoxemia. We hypothesize that altered circadian rhythms are an important determinant in alcohol induced gut leakiness and endotoxemia. All subjects will undergo testing for (1) central circadian rhythm from the timing and phase angle of the dim light melatonin onset (DLMO) and (2) peripheral circadian clock gene expression in the gastrointestinal tract measured from buccal mucosal cells. Aim 1: To test the hypothesis that circadian disruption is present in chronic alcoholics with gut leakiness. We will compare chronic alcoholics with gut leakiness/endotoxemia and compare them to matched alcoholic controls without gut leakiness/endotoxemia. We hypothesize that alcoholics with gut leakiness will have greater central and/or peripheral circadian disruption than matched alcoholic controls without leakiness. Aim 2: To test the hypothesis that circadian disruption in shift workers increases susceptibility to alcohol induced gut leakiness. Non alcoholic shift workers and daytime workers will be prospectively studied before and after moderate alcohol consumption for one week (0.4 g ETOH/kg per day). We hypothesize that shift workers will be more susceptible to alcohol induced gut leakiness than the matched controls on a daytime work schedule. This study will reveal significant new information regarding the interaction of alcohol and circadian biology in ALD pathogenesis that could be used to improve prevention and treatment of ALD. PUBLIC HEALTH RELEVANCE: This study is a collaboration between scientists that study how alcohol damages the gut and scientists who study our body's natural rhythms (waking/sleeping, eating, etc.) called circadian rhythms. The proposed study uses human subjects to look for the first time at the relationships between circadian rhythms and alcohol consumption in the intestine. In this study we will answer two questions: 1) Does chronically drinking alcohol upset circadian rhythms (especially in the intestine) and thus result in intestinal injury that promotes disease? 2) Are patients who work nights at increased risk for damage in the intestine by acutely drinking alcohol (red wine). Answering these questions will result in a significant new understanding of the relationship between alcohol and circadian rhythms and could result in new preventative and therapeutic treatments for alcohol induced disease.

描述（由申请人提供）：酒精性肝病（ALD）仅发生在发生组织损伤和器官功能障碍的一部分酗酒者（30%）中。这一公认的流行病学和临床观察结果表明，需要酒精滥用，但不足以导致组织损伤，还需要其他辅助因子。我们和其他人已经表明，增加肠道通透性（肠漏）和内毒素血症是两个必要的辅因子。关键的问题是需要什么额外的辅因子来发展肠漏和内毒素血症。我们假设昼夜节律的改变是酒精引起的肠漏和内毒素血症的重要决定因素。所有受试者都将接受以下测试：（1）来自微光褪黑激素起始（DLMO）的定时和相位角的中枢昼夜节律，以及（2）从颊粘膜细胞测量的胃肠道中的外周昼夜节律钟基因表达。目的1：检验昼夜节律紊乱存在于慢性酒精中毒伴肠漏的假设。我们将比较有肠漏/内毒素血症的慢性酗酒者，并将其与无肠漏/内毒素血症的酒精对照组进行比较。我们假设，酗酒者与肠道泄漏将有更大的中央和/或外周昼夜节律的破坏比匹配的酒精控制无泄漏。目的2：检验轮班工人昼夜节律紊乱增加酒精诱导的肠漏易感性的假设。将在适度饮酒（0.4 g ETOH/kg/天）之前和之后前瞻性研究非酒精轮班工人和日间工作者，持续一周。我们假设轮班工人将更容易受到酒精诱导的肠道泄漏比匹配的控制在白天的工作时间表。这项研究将揭示关于酒精和昼夜节律生物学在ALD发病机制中的相互作用的重要新信息，可用于改善ALD的预防和治疗。 公共卫生关系：这项研究是研究酒精如何损害肠道的科学家和研究我们身体自然节律（清醒/睡眠，进食等）的科学家之间的合作。叫做昼夜节律。这项拟议中的研究首次使用人类受试者来研究昼夜节律与肠道饮酒之间的关系。在这项研究中，我们将回答两个问题：1）长期饮酒是否会扰乱昼夜节律（特别是在肠道），从而导致肠道损伤，促进疾病？2)夜间工作的患者急性饮酒（红葡萄酒）会增加肠道损伤的风险。回答这些问题将导致对酒精和昼夜节律之间关系的新的理解，并可能导致酒精引起的疾病的新的预防和治疗方法。