Chronic pancreatitis can be described as the recurrence of repetetive phases of acute pancreatitis. The source of the disease is suggested to be premature intracellular protease activation of digestive enzymes within acinar cells, which will finally lead to self-digestion of the pancreas by its own proteases. Mutations in the genes of these proteases like trypsinogen or chymotrypsin C or mutations within the trypsin inhibitor Spink-1 are associated with an increased risk to develop chronic pancreatitis. However, a multitude of mutations does not lead to an increased activity of the protease, but to a misfolded protein structure. This suggests that ER-stress is a disease relevant pathomechanism of pancreatitis. To prove this hypothesis, the research group wants to establish an ER-stress induced mouse model of chronic pancreatitis. For this purpose a misfolded mutation of murine trypsinogen 7 is to be overexpressed in the pancreas to examine the role of ER-stress during pancreatitis. This subproject should clarify to what extent ER-stress is responsible for pancreatitis and influences the severity of disease.
In addition to the mouse model the research group will evaluate to what extent ER-stress is a targetable option for patients' treatment. ER-stress reducing agents will be extracted from plants and will be tested in a cell culture model on their effectiveness. Therefor a green fluorescent protein will be used as a signal for the induction of ER-stress. Different extracts from local plants like sea buckthorn will be investigated to isolate naturally occurring ER-stress reducing substances. The most effective substances will be tested in further experiments in isolated acinar cells or in mouse models of pancreatitis.
Supervisors
Prof. Dr. med. Markus M. Lerch
Dr. rer. nat. Matthias Sendler
Dr. rer. nat. Frank Ulrich Weiß
Team