Molecular and functional analysis of the GUT circadian clock

胃肠道的功能对免疫稳态至关重要。肠上皮细胞是肠道免疫防御的主要调节因子。它们形成生化和物理屏障，保持外来病原体或肠道微生物群落与胃肠道免疫系统之间的隔离，并预防胃肠道疾病。肠上皮的核心功能是维持肠屏障和免疫系统的保护。免疫稳态紊乱与gi疾病的发生和发展有关。有趣的是，肠粘膜增殖、肠通透性和免疫反应等过程是昼夜节律调节的基础。先前对不同周围器官（如胰腺、肝脏和视网膜）的研究表明，局部生物钟对于这些器官的功能是不可或缺的。在肠道中也发现了一个功能性的昼夜节律系统，但局部肠道时钟的作用尚未得到描述。由于其他外周器官的功能受其内在时钟的调节，因此很可能节律性肠功能受其局部肠道生物钟的控制。因此，肠道昼夜节律系统的紊乱可能对肠道保护性免疫防御产生负面影响。轮班工作或时差引起的昼夜节律紊乱与胃肠道疾病有关，如炎症性肠病（IBD）、肠易激综合征、消化性溃疡甚至胃肠道癌症。分析昼夜节律在gi功能中的作用可以为未来gi疾病的治疗提供重要线索。本提案的总体目标是研究哪些肠道免疫功能受当地生物钟调节，以及肠道生物钟紊乱对gi疾病的发展和严重程度的贡献。所描述的项目应解决以下目标：目标1。研究人员将使用Cre-lox技术，对肠道中存在遗传时钟紊乱的小鼠进行体外和体内肠道昼夜节律功能的表征。目标2。为了分析局部肠道功能的昼夜节律控制是否对IBD的进展至关重要，将使用IBD相关的小鼠模型。Cre-lox技术将被用于专门清除易患IBD的小鼠肠道中的生物钟。目标3。在倒班工作期间，紊乱的昼夜节律系统是否会对肠道免疫功能产生负面影响，从而在IBD相关小鼠模型中促进IBD的进展，应该在倒班工作的动物模型中进行研究。

The functions of the gastrointestinal (GI) tract are essential for immune homeostasis. Intestinal epithelial cells are major regulators of the intestinal immune defense. They form a biochemical and physical barrier that maintains segregation between foreign pathogens or luminal microbial communities from the GI-immune system and prevents GI-diseases. Core function of the intestine epithelium is maintenance of the protective intestinal barrier and the immune system. A disturbed immune homeostasis is linked to the development and progression of GI-diseases. Interestingly, processes such as intestine mucosal proliferation, intestine permeability and immune responses underlie circadian regulation. Previous examples for different peripheral organs, such as the pancreas, the liver and the retina showed that local circadian clocks are indispensable for functionality of these organs. A functional circadian system was also found in the intestine, however the role of the local intestine clock has not been described. Since functions of other peripheral organs are regulated by their intrinsic clocks, it is very likely that rhythmic intestine functions are under the control of its local intestine circadian clock. Thus, disturbance of the intestinal circadian system could have a negative impact on the protective intestinal immune defense. Disturbance of circadian rhythm due to shift work or Jetlag have been associated with GI- disorders, such as Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome, Peptic Ulcers and even GI-cancer. Analysis of the role of circadian rhythms in GI-functions could provide important clues for future therapies of GI-diseases. The general objective of this proposal is to study which intestine immune functions are regulated by the local circadian clock, and the contribution of a disturbed intestine clock to the development and severity of GI-diseases. The described project should address the following aims:AIM 1. TO DETERMINE LOCAL REGULATED INTESTINAL CIRCADIAN FUNCTIONS The characterization of circadian intestine function in vitro and in vivo will be performed with mice with a genetically disrupted clock specifically in the intestine using the Cre-lox technology.AIM 2. TO DEFINE THE ROLE OF INTESTINAL CIRCADIAN FUNCTIONS IN IBDTo analyse whether the circadian control of local intestine functions is critical for the progression of IBD, an IBD-relevant mouse model will be used. The Cre-lox technology will be used to specifically abolish the clock in the intestine of mice which are prone to evolve IBD.AIM 3. TO ANALYZE DISTURBANCE OF RHYTHMIC INTESTINE FUNCTIONS PROMOTING IBD DURING SHIFT WORKIt should be investigated in an animal model for shift work whether a disrupted circadian system negatively influences intestine immune functions and thereby promotes IBD progression in an IBD-relevant mouse model.