Molecular and functional analysis of the GUT circadian clock

点击翻译按钮获取中文摘要

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.