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Roles of circadian rhythms in gastrointestinal systems

昼夜节律在胃肠系统中的作用

基本信息

批准号：
9495490
负责人：
CHRISTIAN I HONG
金额：
$ 38万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9495490
关键词：
Ablation Address American Biological Models Biological Process Cell Count Cell Cycle Cell Cycle Regulation Cell Proliferation Cell division Cells Circadian Rhythms Colorectal Cancer Coupling DNA Damage Data Defensins Development Diffuse Digestion Disease Dysplasia Epithelial Foundations Gastrointestinal Diseases Gastrointestinal Process Gastrointestinal tract structure Genes Health Homeostasis Housing Immunity In Vitro Innate Immune Response Intestines Jet Lag Syndrome Knock-out Knockout Mice Lead Light Link Malignant Neoplasms Mediating Messenger RNA Metaplasia Microfluidics Molecular Mus Natural regeneration Nature Normal Cell Paneth Cells Peptic Ulcer Perfusion Periodicity Play Predisposition Process Proteins Regimen Reporter Research Risk Role Salmonella infections Signal Transduction Small Intestines Stem cells System Testing Tight Junctions Time Venus WNT Signaling Pathway Work adult stem cell antimicrobial peptide base beta catenin cell type circadian pacemaker design feeding gastrointestinal gastrointestinal epithelium gastrointestinal system in vivo innate immune function insight intestinal crypt novel response shift work stem cell niche

项目摘要

PROJECT SUMMARY Over 1 in 4 American workers are shift workers with frequent disruptions in their circadian rhythms and increased risks of gastrointestinal (GI) diseases. Circadian rhythms influence fundamental GI processes, including digestion, immunity, and regeneration of the GI epithelium. Thus, disruption of circadian rhythms is associated with GI diseases ranging from peptic ulcers to cancer. Recent studies demonstrated that the circadian clock influences the cell cycle and vice versa, but the nature and consequences of this connection remain largely unknown. One major limitation is the lack of a tractable model system to investigate the molecular basis of these interactions. To address this, we developed 3D mouse enteroids, or an in vitro “mini-gut”, as a system to identify the molecular mechanisms and consequences of this coupling. This system allows manipulation and tracking of both cell cycle and circadian clock components as gut stem cells undergo differentiation into specialized cells. Importantly, we have demonstrated that mouse enteroids possess robust circadian rhythms, and mimic the response of gene ablation that is observed in mouse intestine. Specifically, we demonstrated that the circadian clock in Paneth cells regulate coordinated cell division cycles via intercellular WNT signaling in enteroids, and elimination of circadian rhythms results in disrupted development of intestinal crypts. In the proposed project, we will determine: (1) cell type-specific roles of circadian rhythms in the small intestine, (2) WNT signaling-mediated intercellular coupling between the GI circadian clock and cell cycle, (3) circadian clock-regulated epithelial barrier function, and (4) circadian clock and Paneth cell- mediated innate immune response to Salmonella infection. Our results will lay a foundation for identifying potential targets and temporal regimens to restore circadian clock-dependent adult stem cell regeneration, epithelial barrier function, and innate immune response for GI-related diseases.

项目总结