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

点击翻译按钮获取中文摘要

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.