SYSMEDIBD · Systems medicine of chronic inflammatory bowel disease

Inflammatory bowel disease (IBD) is a major health problem with severe co-morbidities, requiring life-long treatment. Oscillating processes, like biological clocks are well studied and modeled in a number of systems. Circadian rhythms are extremely important for optimal treatments of patients. Recently, the NfkB pathway has been shown to be oscillating. In this project, we will model NfkB oscillation in chronic inflammatory bowel diseases in animal models and patient cohorts with immunosuppressive treatments and controls. The aim is to build an experimentally validated model the NfkB oscillation in 4D within the gut tissue. Dynamic, experimental validation will be done for various types of cells in the gut by a combination of methods, including single-cell based transcriptomics, multi-photon microscopy and time-dependent, multi-component profiling. The validated model framework will enable searching for critical components of the NfB oscillation and to assess their relevance for the disease in patients. Interfering with the oscillation of biological pathways may provide new possibilities to influence biological processes like inflammation. Hence, we will search (assisted by the models and databases developed) for small molecules interfering with the NfkB oscillation in chemical databases and validate selected candidates in experimental systems. To this end, we will use cell lines with the correct indicator constructs using high content microscopy. To better translate the findings in animal models to patients, we will use a mouse model with transplanted human tissue so that we can verify the mathematical model in human tissue and verify functionality of small molecules in vivo.Owing to its systems, highly focused approach, the project will generate substantial insights into key mechanisms underlying IBD and will provide ways to modulate the oscillatory behavior of the NfB in IBD and IBD-dependent co-morbidities.