Helicobacter pylori infection and gastric barrier function
Prof. Dr. Michael Naumann
The development of a chronic inflammation in the stomach can be triggered by H. pylori, thus the human pathogen is a risk factor for gastric cancer. H. pylori induces a proinflammatory response by activating NF-κB in gastric epithelial cells. In particular, there exist alterations in the NF-κB termination under the control of the deubiquitinylase A20. Therefore, understanding the crosstalk between NF-κB and apoptosis should bring a new view on the apoptosis resistance in gastric cancer, including also aspects of autophagy and cellular senescence. These processes are not restricted to the epithelial cell populations, but due to cellular interactions within a specific disease-promoting micromilieu involve subepithelial myofibroblasts and vascular endothelial cells. Dysfunction of these cellular barriers will create a disease promoting micromilieu including the interaction with immune cells. In order to identify suitable therapeutic targets and diagnostic markers for the prevention and treatment of chronic gastric diseases, we plan to identify intra- and intercellular signaling mechanisms promoting a maladaptive response at epithelial gastric barriers. These studies will scrutinize the role of NF-κB (cooperation with Project 2), modulation of protein-expression via the ubiquitin-proteasomal system (cooperation with Project 8), and the role of proteostasis (cooperation with Project 5) and cellular senescence (cooperation with Project 9). In systematic approaches we intend to study whole gastric tissue arrays from H. pylori infected patients (gastritis → adenoma → adenocarcinoma), aiming to identify specific molecular pathologic signatures involving mass spectrometry. The identified factors involved in H. pylori-associated chronic gastric diseases will be selected for detailed mechanistic studies using in vitro co-culture system combining epithelial cells with myofibroblasts and endothelial cells (cooperation with Project 5). The in vitro approach will be cross-validated with detailed morphological ex vivo studies including imaging of the maladaptive spatial epithelial-endothelial interaction (cooperation with Project 4). Drug design using biomolecular modeling/computational chemistry and preclinical efficacy tests will be conducted to evaluate the potential therapeutic value of potential novel targets.
H. pylori crosstalk with mucosal EpiC and LEndoC
The molecular gastric pathology studies address the role of DUBs, e.g. A20, USP47 in H. pylori-induced NF-κB-dependent chemokine release and cell survival. The chronic inflammatory micromilieu and maladaptive processes will be studied in biopsies from patients. Explanted cells from patient material will be differentiated in pit- and gland-type organoids to perform knockdown of DUBs prior to infection. To investigate the crosstalk of epithelial gland-type cells with LEndoC, co-cultures will be analyzed in Boyden.