Doctoral Thesis
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Institute
Pancreatitis is an inflammatory disorder of the pancreas with a mortality rate of 5% and severe negative effects on the quality of life. Of all non-malignant gastrointestinal diseases, it is the most common reason for hospitalization. Pancreatitis is a disease of multiple etiologies with different underlying pathomechanisms. Due to the diversity of mechanisms by which homeostasis within the exocrine pancreas can be disrupted, finding appropriate therapeutic approaches is challenging. Current treatment options are inadequate and are mostly limited to supportive treatment like fluid administration, bowel rest, antibiotics and pain control. Although significant advancements have been achieved in recent decades, the mortality rate for pancreatitis has not decreased. Furthermore, progress is slow due to limited patient sample availability and lack of an appropriate cell model. Taking samples from a human pancreas is typically avoided, because damaging the pancreatic tissue can itself induce pancreatitis. Additionally, while it is possible to keep individual acini in culture, it is not possible to grow pancreatic acinar cells. Thus, less appropriate cell models, often derived from pancreatic cancer samples, have to be used. The most common animal model for pancreatitis is mice, with caerulein administration being the most common method of inducing pancreatitis. However, the use of animal models has significant drawbacks, as they are time-consuming, costly, and pose ethical questions. Furthermore, exposing the pancreas to appropriate stimuli in animal models is difficult. For example, alcohol is the leading cause of pancreatitis in humans, but is typically avoided by animals. Thus, alcohol feeding methods had to be developed to overcome the natural aversion of rodents to alcohol. Results obtained from animal models are also often not transferable into clinical trials and outcomes in humans remain largely unpredictable. Due to the lack of experimental models, our understanding of this highly complex disease is still limited and significant progress is required for the development of effective therapy options.
In this dissertation recombinantly expressed trypsin isoforms and variants of the serine protease inhibitor Kazal-type 1 (SPINK1) inhibitor are used to investigate mechanisms, by which tryptic activity is regulated in pancreatic acinar cells. With premature tryptic activity in the exocrine pancreas being the common focal point of most etiologies connected to pancreatitis, trypsin represents by far the most promising target for treating pancreatitis. Understanding the mechanisms by which the pancreas protects itself and rationalizing mutations that can undermine these protective mechanisms, are important steps towards developing effective therapies.