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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，包括克罗恩病疾病（CD）和溃疡性结肠炎（UC）通常会扰乱睡眠，而睡眠扰乱与睡眠/觉醒周期、免疫功能、新陈代谢和多种生物过程的风险。所有这些都是由大脑中央生物钟之间的昼夜节律失调所精心安排的。已发现环境有助于多种代谢和胃肠道 (GIT) 然而，昼夜节律失调对 IBD 疾病活动和胃肠道粘膜的影响。我们研究的长期目标是调查炎症。昼夜节律失调会加重 IBD 中胃肠道粘膜炎症和病程的假设。根据这个假设，我们将对人类受试者进行一项关于昼夜节律影响的前瞻性实验室研究左侧轻度至中度溃疡性结肠炎的错位我们将执行两个昼夜节律测量阶段。在严格控制的实验室条件下进行评估：1) 基线，以及 2) 昼夜节律失调后在不活动的 UC 患者和健康对照受试者中进行三天模拟夜班后进行测试。假设 UC 患者（与健康受试者对照相比）对昼夜节律失调的抵抗力较差我们将通过以下方式评估：我们的方案对昼夜节律（目标 1）的时间影响：夹带[从弱光褪黑激素开始到入睡的时间]（Aim1a）；通过灵活的乙状结肠镜检查结肠组织和受试者外周血中的时钟基因表达单核细胞 (Aim1b)；以及利用 24 小时内的结肠时钟基因表达和 Per2::Luc 活性接下来，我们将测试昼夜节律失调的假设。通过以下方式增加 UC 患者（与对照组）的结肠通透性和粘膜炎症（目标 2）：以下内容：内窥镜评分、粪便钙卫蛋白、结肠屏障（渗透性、AJC 蛋白）以及结肠屏障标记物系统屏障功能和炎症（目标 2a）；结构/功能（目标 2b）；并使用 2D 结肠类器官单层通过共同探索离体屏障功能用 TNF-α/INF-γ 进行培养（目标 2c）这一创新提案的结果将大大提高我们的能力。了解昼夜节律失调在 UC 疾病活动和结肠癌中可能发挥的重要作用炎症，并确定治疗 UC 的新的昼夜节律调节目标。