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

• 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
• 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

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.

项目摘要/摘要 有机体应对环境和生理压力的能力对于维持生命至关重要。 不适当应对压力会导致细胞损伤，器官功能丧失，发展 疾病和寿命缩短。胃肠道（GI）表现出复杂而广泛的防御 对于维持肠道完整性和功能至关重要的机制。肠在 代谢，营养和吸水 饮食和腔抗原。功能失调的肠壁是炎症的定义特征 肠病（IBD）。尽管许多研究表征了IBD期间肠道屏障的失败程度，但 识别负责IBD的刺激和细胞机制仍然难以捉摸。这个项目重点 含黄素单加氧酶（FMO）酶家族与肠屏障之间的相互作用 完整性和功能。 FMO是参与异种生物和内源代谢的酶家族。我们的 以前的工作将线虫FMO-2定义为保持健康和寿命的必要和足够 在缺氧，营养和致病应力期间。现在，我们将这些研究扩展到专注于哺乳动物模型 肠应力抗性，我们的最初结果表明CEFMO-2，FMO5，FMO5的哺乳动物同源物 在维持肠道稳态中起着至关重要的作用。产生了特定肠道的 他莫昔芬可诱导的FMO5 KO小鼠系列，我们的主要目标是了解FMO5和FMO5之间的相互作用 哺乳动物肠。我们将通过1来实现这一目标。映射 FMO5 KO动物中粘膜屏障的开发和维护，2。评估结构 当FMO5从系统中急剧清除时，肠上皮衬里的耐用性和3。 FMO5水平的改变有助于IBD的长期发展。我们将在 结合常见的生理方法，以了解FMO5在哺乳动物肠道中的作用。这 结果将确定FMO5如何修饰生理方面，包括1）杯状细胞开发，2） 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）发病机理 IBD。最终的数据将导致理解粘膜屏障的分子原因 功能障碍，并将在IBD的背景下首次调查FMO5动作。在一起，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对炎症性疾病的抵抗力。该项目的完成 将确定调节胃肠道疾病发作的关键机制，并揭示潜在的机理目标 未来改善人类健康的治疗努力。