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: 10555227
• 负责人: Garth R Swanson
• 金额: $ 60.1万
• 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 2023-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555227
• 关键词: Affect; Alcohols; American; Animal Model; Apical; Behavioral; Biological Process; Brain; Cell Line; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Colitis; Colon; Colon Carcinoma; Colonic inflammation; Communities; Complex; Crohn' s disease; Darkness; 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; 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 community; microbial composition; microbial products; microbiota; monolayer; mortality; mouse model; prevent; prospective; protein complex; repaired; resilience; shift work; sleep onset; systemic barrier; 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.

摘要