A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation

Area of Science:

• Gastroenterology
• Molecular Biology
• Pathology

Background:

• Specific therapies for inflammatory pancreatic diseases are lacking.
• The genetic basis of chronic pancreatitis implicates trypsin as a therapeutic target.
• Preclinical studies are limited by the absence of suitable animal models.

Purpose of the Study:

• To develop a novel animal model for studying chronic pancreatitis.
• To investigate the role of trypsinogen autoactivation in pancreatitis pathogenesis.
• To provide in vivo proof of concept for targeting intra-pancreatic trypsin.

Main Methods:

• Generation of a T7D23A knock-in mouse model with a mutation in mouse cationic trypsinogen (isoform T7).
• Characterization of the accelerated autoactivation of the mutant trypsinogen.
• Assessment of spontaneous pancreatitis development, including histological and biochemical markers.

Main Results:

• The T7D23A mouse exhibits 50-fold faster trypsinogen autoactivation compared to wild type.
• T7D23A mice develop spontaneous acute and progressive chronic pancreatitis.
• Elevated trypsin activity correlates with pancreatitis onset and progression in this model.

Conclusions:

• Trypsinogen autoactivation is a key driver of acute and chronic pancreatitis.
• The T7D23A mouse is a valuable model for preclinical testing of pancreatitis therapies.
• Therapeutic strategies should focus on inhibiting intra-pancreatic trypsin activity.