A02: Tissue regeneration as a critical component of gut‐liver homeostasis
The intestinal epithelium is characterized by a high cell turnover involving proliferation of progenitor cells and apoptosis of differentiated enterocytes. Any disturbance of this homeostasis e.g. through impaired proliferation or by toxic agents may result in increased intestinal permeability, translocation of bacterial products from the gut to the liver and secondarily to chronic liver disease. E-type cyclins and the associated Cyclin-dependent kinase 2 (Cdk2) drive the transition of quiescent cells or stem-like cells into the active phase of the cell cycle.
In this project we will
- analyse the impact of E-type Cyclins and Cdk2 for basal intestinal cell turnover and maintenance of gut-liver homeostasis.
- define Cyclin E1 protein complexes involved in gut-liver communication upon alcoholic exposition.
- investigate the role of E-type cyclins for development of colorectal cancer and liver metastasis.
Working hypothesis and research concept: External stimuli such as alcohol, fat and toxins trigger injury and disease progression in the liver, as well as in the intestine. This process involves bivalent functions of Cyclin E (CcnE) alone or in complex with Cdk2. Our data indicate essential functions of Cyclin E for maintenance of the gut barrier thereby preventing translocation of bacterial products (LPS) to the liver and secondary hepatic inflammation. Furthermore, we hypothesize that Cyclin E/Cdk2 is required for initiation of colon cancer and derived liver metastasis.