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：
10407508
负责人：
CHRISTIAN I HONG
金额：
$ 36.14万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407508
关键词：
3-Dimensional Ablation Address American Biological Models Biological Process Cell Count Cell Cycle Cell Cycle Regulation Cell Proliferation Cell division Cells Circadian Dysregulation 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 System Testing Tight Junctions Time Venus WNT Signaling Pathway Work adult stem cell antimicrobial peptide base beta catenin cell type circadian circadian pacemaker design epithelium regeneration feeding gastrointestinal gastrointestinal epithelium gastrointestinal system in vivo innate immune function insight intestinal crypt novel response shift work stem cell niche stem cell proliferation stem cell self renewal stem cells

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.

项目概要超过四分之一的美国工人是轮班工人，他们的昼夜节律经常受到干扰，胃肠道 (GI) 疾病的风险增加会影响基本的胃肠道节律。过程，包括胃肠道上皮的消化、免疫和再生。昼夜节律与消化性溃疡和癌症等胃肠道疾病有关。证明生物钟影响细胞周期，反之亦然，但本质和这种联系的后果在很大程度上仍然未知。一个主要限制是缺乏易于处理的方法。为了解决这个问题，我们开发了模型系统来研究这些相互作用的分子基础。 3D 小鼠肠类，或体外“迷你肠道”，作为识别分子机制和这种耦合的结果允许操纵和跟踪细胞周期和肠道干细胞分化为特化细胞时的生物钟成分。我们已经证明，小鼠肠类具有强大的昼夜节律，并模仿具体而言，我们证明了在小鼠肠道中观察到的基因消融反应。潘氏细胞的生物钟通过细胞间 WNT 信号传导调节协调的细胞分裂周期在肠类中，昼夜节律的消除会导致肠隐窝发育中断。在拟议的项目中，我们将确定：（1）昼夜节律在小细胞中的细胞类型特异性作用 (2) WNT信号介导的胃肠道生物钟与细胞之间的细胞间耦合周期，（3）昼夜节律时钟调节的上皮屏障功能，以及（4）昼夜节律时钟和潘氏细胞- 我们的结果将为沙门氏菌感染介导的先天免疫反应奠定基础。确定恢复昼夜节律时钟依赖性成体干细胞的潜在目标和时间方案再生、上皮屏障功能和胃肠道相关疾病的先天免疫反应。