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GRK 1482 Jahrbuch 2011-2014

PROFILE AND RESEARCH PROGRAM OF THE GRK 1482 GRK Annual Report 2011-2014 | Page 5 Profile of the GRK 1482 Nutrition and gut luminal factors such as microbes are most likely prime environmental factors that not only determine a healthy gut phenotype but also shape a disease-conditioning situation in the susceptible host. Although substantial progress has been made in identifying genetic variations associated with IBD, obesity and type-2 diabetes, striking evidence has been generated in both immune-mediated and metabolic disorders demonstrating that environmental triggers are the driving force for chronic disease development. Mechanisms that determine the transition from normal func- tions in healthy subjects towards disease-relevant situations are critical to understand in the life-long exposure to nutritio- nal factors and commensal microbes. Specifically the intestinal microbiome, with an enormous microbial density outnumbering the cellularity of the human body by 10 times and the complexity of the human genome by 150 times, provides a striking degree of genetic variation and comes more and more into focus of metabolic functions and metabolic disorders. There can be no doubt that the intestinal interface as a barrier and communica- tion organ plays a pivotal role in this interaction. Bacteria are crucial determinants in chronic inflammatory disorders and IBD serves as a paradigm to study the principles of microbe-host interactions in the gut. The potential for future development and innovation lies within the interaction of disease categories with the gut interface as a potential target. Research Program of the GRK 1482 A key hypothesis of the GRK 1482 is that nutritional compo- nents (high fat diet, dietary lipid composition, iron) and luminal bacteria (derived from fermented food and inherent gut micro- biota) modulate a highly interactive network of cells (epithelial, immune and nerve cells) and mediators (hormones and meta- bolic intermediates) in the gut. A careful evaluation of the first generation of PhD projects based on the publication output and the research potential for future development was used to guide the selection process for the future research program. Research projects of the 1st PhD generation successfully esta- blished molecular mechanisms of microbe-host interactions in infectious and IBD-related animal models. Specifically lactoba- cilli and enterococci served as model organisms to identify bac- terial structures that mediate beneficial or deleterious effects in the disease-susceptible host. As a consequence, we further focus on commensal bacteria to characterize the molecular mechanisms of microbe-host interaction (blue labelled pro- jects). A first step to implement metagenomic tools in studying the complex gut microbial ecosystem was integrated as a new angle towards the GRK theme of microbe-host interactions. In addition to microbes, we decided to emphasize on iron as an additional luminal factor with great relevance in human nutriti- on and IBD. Parallel to research axis of microbe-inflammation- immune function, the second major line of research within the GRK highlights the role of the gut interface as a sensing and signaling organ for metabolic dysfunctions. Thus, projects la- belled green (epithelial) and orange (subepithelial) will address the role of epithelial-derived inflammatory signals on metabolic pathologies, bile acids on brown adipocyte differentiation and energy expenditure, as well as effects of enteric endocrine sig- nals on melanocortinergic circuits in the enteric nervous system and the brain. Finally, human studies on the genetic and mole- cular basis of fructose-intolerance as well as angiotensin and RANTES effects on gut hormone secretion relate to the effort to move basic science into human translation. A unique technology and research model platform: The research consortium compiles a unique list of methodologies at the level of molecular and cellular technologies as well as a vari- ety of animal models in the research areas of IBD as well as diet-induced obesity and metabolic dysregulations. A variety of new cutting-edge technologies are availabe within the next generation of GRK including a new germfree mouse facility for gnotobiotic experiments, a mouse metabolic phenotyping unit and sequencing facilities. Together with capturing and imaging techniques including laser dissection and confocal microscopy, luminescent reporter gene imaging in mice (Xenogen-LUX-Ca- mera system) and fast neuro-imaging the GRK is fully equipped to study cellular mechanisms in model systems with different levels of complexity (cultured cell, nematode, mouse), as well as in humans. Profile and Research Program of the GRK 1482 Schematic overview of the research program