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

项目总结/摘要 生物体科普环境和生理压力的能力对维持生命至关重要。 不能适当地应对压力会导致细胞损伤，器官功能丧失， 疾病和缩短寿命。胃肠道（GI）表现出复杂和广泛的防御 这些机制对于维持肠道完整性和功能至关重要。肠道在 代谢，营养和水分吸收，并提供物理和免疫防御， 食物和管腔抗原。肠道屏障功能障碍是炎症性疾病的一个定义性特征。 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， 导致IBD的刺激和细胞机制的鉴定仍然是难以捉摸的。该项目的重点是 含黄素单加氧酶（FMO）家族与肠屏障之间的相互作用 完整性和功能。FMO是参与外源性和内源性代谢的酶家族。我们 以前的工作将线虫FMO-2定义为保持健康和长寿的必要和充分条件 在缺氧、营养和病原体压力下。我们现在将这些研究扩展到关注哺乳动物模型 我们的初步结果表明，哺乳动物的Cefmo-2同系物，FMO 5， 在维持肠道内环境稳定方面起着重要作用。在产生了一个特定的尼古丁， 我们的主要目标是了解FMO 5和三苯氧胺之间的相互作用， 哺乳动物的肠道我们将在1.绘制出 在FMO 5 KO动物中粘膜屏障的发育和维持，2.评估结构 当从系统中急性去除Fmo 5时肠上皮衬里的耐久性，以及3.定义如何 Fmo 5水平的改变有助于IBD的慢性发展。我们将使用尖端技术， 结合常见的生理学措施，以了解Fmo 5在哺乳动物肠道中的作用。的 结果将确定Fmo 5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 IBD。所得数据将有助于了解粘膜屏障的分子原因 功能障碍，并将调查，第一次，在炎症性肠病的背景下，Fmo 5的行动。这项工作将 确定Fmo 5的作用和必要性，这是一种以前未知的肠道健康维护参与者， 调节肠屏障形成和对炎性疾病的抵抗。该项目的建成 将确定调节胃肠道疾病发病的关键机制，并揭示潜在的机制目标， 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.