The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

昼夜节律失调对溃疡性结肠炎结肠屏障稳态的影响

• 批准号: 10330596
• 负责人: Garth R Swanson
• 金额: $ 58.8万
• 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: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330596
• 关键词: Affect; Alcohols; American; Animal Model; Apical; Behavioral; Biological Process; Brain; Cell Line; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Coculture Techniques; Colitis; Colon Carcinoma; Colonic inflammation; Communities; Complex; Crohn' s disease; Data; Diabetes Mellitus; Digestive System Disorders; Disease; Eating; Endoscopy; Environment; Epithelial Cells; Exhibits; Exposure to; Fasting; Feces; Flare; Flexible fiberoptic sigmoidoscopy; Future; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Goals; Homeostasis; Hour; Human; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-6; Intervention; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Jet Lag Syndrome; Laboratories; Left; Leukocyte L1 Antigen Complex; Light; Measures; Melatonin; Messenger RNA; Metabolic; Metabolism; Modeling; Modernization; Molecular; Molecular Profiling; Molecular Target; Mucositis; Mucous Membrane; Occupations; Organ; Organoids; Pathogenesis; Pathway interactions; Patients; Peptic Ulcer; Peripheral; Peripheral Blood Mononuclear Cell; Permeability; Phase; Phototherapy; Predisposition; Prevalence; Process; Production; Proteins; Protocols documentation; Research; Rest; Rodent; Role; Sampling; Serum; Severities; Shotguns; Side; Sleep; Sleep Wake Cycle; Sleep disturbances; Societies; Structure; TNF gene; Testing; Tight Junctions; Time; Tissues; Toll-like receptors; Travel; Ulcerative Colitis; Volatile Fatty Acids; base; circadian; circadian pacemaker; cytokine; design; disorder risk; dysbiosis; feeding; gut microbiota; human subject; immune function; in vitro Model; innovation; intestinal barrier; intestinal epithelium; melatonin supplementation; metabolomics; microbial; microbial community; microbial composition; microbiota; monolayer; mortality; mouse model; prevent; prospective; protein biomarkers; protein complex; repaired; shift work; sleep onset; transcriptome sequencing

ABSTRACT Recently there has been compelling evidence that inflammatory bowel disease (IBD) subjects, both Crohn's disease (CD) and Ulcerative Colitis (UC), commonly have disrupted sleep, and disrupted sleep correlates with the risk of disease flare. Sleep/wake cycle, immune function, metabolism and multiple biological processes are all orchestrated by circadian rhythms. Circadian misalignment between the central circadian clock in the brain and environment has been found to contribute to a variety of metabolic and gastrointestinal tract (GIT) diseases. Yet, the prevalence and impact of circadian misalignment on IBD disease activity and GIT mucosal inflammation have not been established. The long-term objective of our research is to investigate the hypothesis that circadian malalignment worsens GIT mucosal inflammation and disease course in IBD. To test this hypothesis, we will conduct a prospective in lab study with human subjects on the impact of circadian misalignment in left sided mild to moderate Ulcerative Colitis. We will perform two circadian measures phase assessments under strictly controlled laboratory conditions at: 1) baseline, and after 2) circadian misalignment after three days of simulated night shifts in both inactive UC patients and healthy control subjects. To test the hypothesis that UC patients (compared to healthy subject controls) are less resilient to circadian misalignment we will assess: time impact of our protocol on circadian rhythms (Aim 1) by the following: phase angle of entrainment [time from dim light melatonin onset to sleep onset] (Aim1a); peripheral circadian rhythms by clock gene expression in colonic tissue from a flexible sigmoidoscopy and in subjects peripheral blood mononuclear cells (Aim1b); and colonic clock gene expression and Per2::Luc activity over 24 hours utilizing an in-vitro model of colonic organoids (Aim1c). Next, we will test the hypothesis that circadian misalignment will increase colonic permeability and mucosal inflammation in UC patients (vs. Controls) (Aim2) through the following: endoscopy score, stool calprotectin, colonic barrier (permeability, AJC proteins), and markers of systemic barrier function and inflammation (Aim 2a); adversely impacting microbial community structure/function (Aim 2b); and use 2D colonic organoid monolayers to explore ex-vivo barrier function by co- culturing with TNF-α/INF-γ (Aim 2c). The results of this innovative proposal will greatly increase our understanding of the important role circadian misalignment may have in UC disease activity and colonic inflammation, and identify new circadian regulated targets for treatment in UC.

抽象的 最近有令人信服的证据表明炎症性肠病（IBD）受试者，都是克罗恩 疾病（CD）和溃疡性结肠炎（UC）通常会破坏睡眠，睡眠中断与 疾病爆发的风险。睡眠/唤醒周期，免疫功能，代谢和多种生物学过程是 全部由昼夜节律精心策划。大脑中央昼夜节律之间的昼夜节律错位 已经发现环境有助于各种代谢和胃肠道（GIT） 疾病。然而，昼夜节律对IBD疾病活动和GIT粘膜的流行和影响 尚未确定炎症。我们研究的长期目标是调查 假设昼夜节律疾病使IBD中的GIT粘膜注射和疾病病程都恶化。测试 这个假设，我们将与人类受试者对昼夜节律的影响进行实验室研究的前瞻性研究 左侧轻度至中度溃疡性结肠炎的不对对准。我们将执行两个昼夜节律阶段 严格控制的实验室条件下的评估：1）基线，以及2）昼夜节律未对准 经过三天的模拟夜班和健康对照受试者的模拟夜班。测试 假设UC患者（与健康受试者对照组相比）对昼夜节律的弹性较小 我们将评估：协议对昼夜节律的时间影响（目标1）以下： （从昏暗的淡化褪黑激素发作到睡眠发作的时间）（aim1a）；外围昼夜节律 柔性乙状结肠镜和受试者外周血中的结肠组织中的时钟基因表达 单核细胞（AIM1B）；和结肠时钟基因表达和PER2 :: LUC活性在24小时内使用 结肠机身的体外模型（AIM1C）。接下来，我们将测试昼夜节律未对准的假设 通过UC患者（与对照组）（AIM2）增加结肠通透性和粘膜感染 以下：内窥镜分数，粪便钙透明蛋白，结肠屏障（渗透率，AJC蛋白质）和标记 全身性屏障功能和注射（AIM 2A）；不利影响微生物社区 结构/功能（AIM 2B）;并使用2D结肠类器官单层来探索通过共同的体内屏障功能 用TNF-α/INF-γ培养（AIM 2C）。这项创新提议的结果将大大增加我们的 了解昼夜节律未对准的重要作用在UC疾病活动和结肠中可能具有 炎症，并确定UC中新的昼夜节律治疗靶标。