The role of lysosomal protease cathepsin D in acute experimental pancreatitis

• Applicant: Professor Dr. Ali Alexander Aghdassi
• Subject Area: Gastroenterology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281235944

The early phase of acute pancreatitis is characterized by a premature intracellular activation of digestive proteases within the acinar cells. One of the best-characterized proteases is trypsin, which is synthesized as an inactive pro-form (zymogen) and normally activated in the duodenum by enterokinase. Animal experiments have shown that a co-localization of trypsinogen with the lysosomal enzyme cathepsin B (CTSB) leads to premature trypsinogen activation. Genetic deletion of cathepsin B dramatically reduces severity of pancreatitis in a mouse model of experimental pancreatitis. Recently it could be shown that the lysosomal cysteine protease cathepsin L (CTSL) is able to degrade both trypsinogen and trypsin, which stands in contrast to the function of CTSB. Furthermore CTSL is involved in the regulation of severity of pancreatitis and modulates apoptosis and necrosis within the pancreas. Cathepsin D (CTSD) is an almost ubiquitously expressed aspartic protease. However, its role in acute pancreatitis is not elucidated so far. In preliminary experiments we could show that CTSD is found in the secretory compartment and co-localizes with trypsinogen as well, similar to CTSB and CTSL. In this project we want to investigate the role of CTSD in the pathogenesis and the course of acute experimental pancreatitis. This will be done by using two different mouse models.

• DFG Programme: Research Grants