Circadian Desynchrony in Alcohol Induced Gut Leakiness

酒精引起的肠漏的昼夜节律不同步

基本信息

批准号：
8426149
负责人：
Garth R Swanson
金额：
$ 16.45万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8426149
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

项目摘要

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.

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酗酒者（30％）中。这个良好的流行病学和临床观察表明，需要酗酒，但不足以造成组织损伤，需要其他辅助因子。我们和其他人已经表明，肠道通透性增加（肠泄漏）和内毒素血症是两个所需的辅助因子。关键问题是需要哪些其他辅助因子来发展肠道泄漏和内毒素血症。我们假设改变的昼夜节律是酒精诱导的肠道泄漏和内毒素血症的重要决定因素。所有受试者将从昏暗的光褪黑激素发作（DLMO）的时间和相位角度进行（1）中央昼夜节律进行测试。目的1：检验以下假设：慢性酗酒者肠道渗漏存在昼夜节律的破坏。我们将将慢性酒精中毒与肠道泄漏/内毒素血症进行比较，并将它们与无肠泄漏/内毒素血症的酒精对照进行比较。我们假设肠道泄漏的酗酒者比没有泄漏的酒精对照将具有更大的中央和/或外围昼夜节律破坏。目的2：测试以下假设：示威者在转移工人中的破坏会增加对酒精引起的肠道渗漏的敏感性。非酒精班次工人和白天工人将在中度饮酒前和之后进行一周（每天0.4 g etoh/kg）的前瞻性研究。我们假设轮班工人比白天的工作时间表中的匹配控制措施更容易受到酒精引起的肠道泄漏的影响。这项研究将揭示有关酒精和昼夜节律生物学在ALD发病机理中相互作用的重要新信息，这些信息可用于改善ALD的预防和治疗。