The role of FMO5 to maintain mucosal barrier integrity in the mouse colon

FMO5 在维持小鼠结肠粘膜屏障完整性中的作用

基本信息

批准号：
10667319
负责人：
Megan Lynn Schaller
金额：
$ 4.05万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667319
关键词：
Activities of Daily Living Acute Adult Anti-Inflammatory Agents Antigens Bacteria Bacterial Antigens Caenorhabditis elegans Cell Differentiation process Cell Maturation Cell physiology Cells Cellular Stress Characteristics Chronic Colon Complex Data Defect Defense Mechanisms Development Disease Environment Enzymes Epithelial Cells Epithelium Exhibits Exposure to FMO2 Failure Family Fluorescent in Situ Hybridization Functional disorder Future Gastrointestinal Diseases Gastrointestinal tract structure Goals Goblet Cells Health Histology Homeostasis Homologous Gene Human Hypoxia Immunofluorescence Immunologic Immunologics In Vitro Inflammatory Inflammatory Bowel Diseases Interleukin-10 Intestinal Diseases Intestinal permeability Intestines Invaded Knockout Mice Label Lead Life Longevity LoxP-flanked allele Maintenance Maps Measures Mediating Mediator Metabolic Metabolism Mining Modeling Molecular Mucins Mucosal Immune Responses Mucous Membrane Mucous body substance Mus Nematoda Nutrient Onset of illness Organ Organism Pathogenesis Pathogenicity Pathway interactions Patients Personal Satisfaction Physiological Play Process Production Resistance Role Secretory Cell Sodium Dextran Sulfate Stains Stimulus Stress Stress Tests Structure System Tamoxifen Techniques Testing Therapeutic Time Tissues Water Work Xenobiotics absorption antimicrobial biological adaptation to stress cell injury cell motility cellular microvillus coping crypt cell dietary dietary restriction experimental study flavin-containing monooxygenase fluorescein isothiocyanate dextran genetic manipulation healthspan immune cell infiltrate improved in vivo insight intestinal barrier intestinal epithelium intestinal homeostasis intestinal injury knockout animal metabolomics microbial morphogens mouse model novel physical property pre-clinical preservation prevent stem cells transcriptome sequencing

项目摘要

Project Summary/Abstract The ability of an organism to cope with environmental and physiological stress is essential to sustain life. Failure to appropriately respond to stress can lead to cellular damage, loss of organ function, development of disease, and shortened lifespan. The gastrointestinal (GI) tract exhibits complex and extensive defense mechanisms that are critical for maintaining intestinal integrity and function. The intestine plays a key role in metabolism, nutrient and water absorption, and provides both physical and immunological defense against dietary and luminal antigens. Dysfunctional intestinal barriers are a defining characteristic of inflammatory bowel disease (IBD). While many studies have characterized how intestinal barriers fail during IBD, identification of the stimuli and cellular mechanisms responsible for IBD remain elusive. This project focuses on the interplay between the flavin-containing monooxygenase (FMO) enzyme family and intestinal barrier integrity and function. FMOs are a family of enzymes involved in xenobiotic and endogenous metabolism. Our previous work defined nematode FMO-2 as both necessary and sufficient to preserve health and longevity during hypoxic, nutrient, and pathogenic stress. We now expand these studies to focus on mammalian models of intestinal stress resistance, and our initial results suggest that the mammalian homolog of Cefmo-2, FMO5, plays an essential role in maintaining intestinal homeostasis. Having generated an intestine-specific, tamoxifen-inducible Fmo5 KO mouse line, our primary goal is to understand the interplay between FMO5 and the mammalian intestine. We will achieve this goal by 1. mapping the complex interactions between the development and maintenance of the mucosal barrier in FMO5 KO animals, 2. assessing the structural durability of the intestinal epithelial lining when Fmo5 is acutely removed from the system, and 3. defining how alterations in Fmo5 levels contribute to the chronic development of IBD. We will use cutting edge techniques in combination with common physiological measures to understand the role of Fmo5 in the mammalian gut. The results will identify how Fmo5 modifies physiological aspects including 1) goblet cell development, 2) crypt metabolism and its contribution to goblet cell dysfunction, 3) mucosal barrier function and 4) the pathogenesis of IBD. The resulting data will be lead toward understanding the molecular cause of mucosal barrier dysfunction and will investigate, for the first time, Fmo5 action in the context of IBD. Together, this work will define the role and necessity of Fmo5, a previously unknown player in intestinal health maintenance, in regulating intestinal barrier formation and resistance to inflammatory disease. The completion of this project will identify key mechanisms regulating the onset of GI disease and reveal potential mechanistic targets for future therapeutic efforts to improve human health.

项目概要/摘要生物体应对环境和生理压力的能力对于维持生命至关重要。未能对压力做出适当反应可能会导致细胞损伤、器官功能丧失、疾病，并缩短寿命。胃肠道 (GI) 具有复杂而广泛的防御能力对于维持肠道完整性和功能至关重要的机制。肠道起着关键作用代谢、营养和水分吸收，并提供物理和免疫防御饮食和管腔抗原。肠道屏障功能失调是炎症的一个决定性特征肠道疾病（IBD）。虽然许多研究已经描述了 IBD 期间肠道屏障如何失效的特征，导致 IBD 的刺激和细胞机制的鉴定仍然难以捉摸。该项目重点关注含黄素单加氧酶 (FMO) 酶家族与肠道屏障之间的相互作用完整性和功能。 FMO 是参与外源代谢和内源代谢的酶家族。我们的先前的工作将线虫 FMO-2 定义为保持健康和长寿的必要且充分的条件在缺氧、营养和致病应激期间。我们现在将这些研究扩展到哺乳动物模型肠道应激抵抗力，我们的初步结果表明，Cefmo-2、FMO5 的哺乳动物同源物，在维持肠道稳态方面发挥着重要作用。产生了肠道特异性，他莫昔芬诱导的 Fmo5 KO 小鼠系，我们的主要目标是了解 FMO5 和哺乳动物的肠道。我们将通过以下方式实现这一目标： 1. 绘制 FMO5 KO 动物粘膜屏障的发育和维持，2. 评估结构当 Fmo5 从系统中急剧去除时，肠上皮内壁的耐久性，以及 3. 定义如何 Fmo5 水平的改变导致 IBD 的慢性发展。我们将使用尖端技术结合常见的生理测量来了解 Fmo5 在哺乳动物肠道中的作用。这结果将确定 Fmo5 如何改变生理方面，包括 1) 杯状细胞发育，2) 隐窝代谢及其对杯状细胞功能障碍的贡献，3) 粘膜屏障功能和 4) 发病机制炎症性肠病。由此产生的数据将有助于理解粘膜屏障的分子原因功能障碍并将首次研究 Fmo5 在 IBD 背景下的作用。共同努力，这项工作将定义 Fmo5 的作用和必要性，Fmo5 是肠道健康维护中以前未知的参与者调节肠道屏障的形成和抵抗炎症性疾病。本项目完成情况将确定调节胃肠道疾病发病的关键机制，并揭示潜在的机制目标未来改善人类健康的治疗努力。