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

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。 未能对压力做出适当的反应可导致细胞损伤、器官功能丧失、 疾病和缩短的寿命。胃肠道(GI)表现出复杂而广泛的防御 对维持肠道完整性和功能至关重要的机制。肠道起着关键的作用。 新陈代谢、营养和水分吸收，并提供身体和免疫防御 饮食和管腔抗原。肠道屏障功能障碍是炎症性疾病的一个明显特征 肠道疾病(IBD)。虽然许多研究都描述了IBD期间肠道屏障是如何失效的， 对IBD的刺激因素和细胞机制的识别仍然难以捉摸。这个项目的重点是 含黄素单加氧酶家族与肠道屏障的相互作用 完整性和功能性。FMOS是一个参与异源代谢和内源代谢的酶家族。我们的 以前的工作将线虫FMO-2定义为保持健康和长寿的必要条件和充分条件 在低氧、营养和致病应激期间。我们现在将这些研究扩展到专注于哺乳动物模型 我们的初步结果表明，Cefmo-2，Fmo5， 在维持肠道内环境稳定方面起着至关重要的作用。在产生了一种肠道特异的， 我们的主要目标是了解Fmo5和Tamoxifen之间的相互作用 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动物黏膜屏障的建立和维持，2.评估粘膜屏障的结构 当Fmo5从系统中迅速去除时肠上皮衬里的耐久性，以及3.定义如何 Fmo5水平的改变有助于IBD的慢性发展。我们将使用尖端技术在 结合常见的生理指标，了解Fmo5在哺乳动物肠道中的作用。这个 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 代谢及其在杯状细胞功能障碍中的作用；3)粘膜屏障功能；4)发病机制 IBD的症状。所得数据将有助于理解粘膜屏障的分子原因。 并将首次在IBD的背景下研究Fmo5的作用。共同努力，这项工作将 定义Fmo5的作用和必要性，Fmo5是以前不为人所知的肠道健康维护参与者 调节肠道屏障形成和抗炎症性疾病。这项工程的完成 将确定调节胃肠道疾病发病的关键机制，并揭示潜在的机制靶点 未来的治疗努力，以改善人类健康。

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.