Molecular investigations into the role of IL-36 receptor signaling for colorectal tumorigenesis

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Colorectal cancer (CRC) is a frequent malignant disease with limited therapeutic options. IL-36a, IL-36b und IL-36g are ligands of the IL-36 receptor (IL-36R) and belong to the family of IL-1 related cytokines. Several lines of evidence including own work suggest a contribution of the IL-36R signalling pathway to intestinal tumorigenesis. The main goal of this project is to elucidate the role of IL-36R signalling for the development of CRCs.The designated project will comprise in vivo studies with established model systems and molecular analyses of intestinal tumorigenesis which will include work with IL36R-deficient mice. The consequences of systemic overexpression of IL-36R-ligands on intestinal tumorigenesis will be studied with help of a minicircle-vector based expression system. Mini-endoscopy will allow for serial analyses of tumor development in vivo. The designated project aims to address the following questions: 1. What are the consequences of the inhibition or the activation of the IL-36R on the intestinal homeostasis in vivo? 2. What is the role of the IL-36R signalling pathway and its modulation during tumour initiation, tumour growth and tumour progression in various models of CRC? 3. What molecular mechanisms related to intestinal tumour development are induced by the activation or the inhibition of the IL-36R in tumour fibroblasts? 4. What triggers the induction of the different IL-36R ligands in CRC? 5. What are the expression patterns of the IL-36R and its ligands at different stages of human CRCs? In conclusion, this project aims to clarify the role of the IL-36R signalling for the initiation and the growth of CRCs, and it will be studied how the blockade of the IL-36R pathway could serve as a therapeutic approach. Thus, this project may provide a basis for the development of novel therapeutic options for a frequent tumour disease.