# Mechanisms of Trypsin Activation in Pancreatitis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $348,480

## Abstract

ABSTRACT
The principal objective of this grant proposal entitled “Mechanisms of trypsin activation in
pancreatitis“ is to identify the process by which the digestive protease trypsin becomes activated inside
the pancreas and initiates pancreatitis. The premature, ectopic activation of trypsinogen to trypsin is
one of the earliest events in the development of pancreatitis. However, the mechanism of
intrapancreatic trypsin activation has remained contentious as animal experiments and human genetic
studies pointed to different activation pathways. Thus, trypsinogen may be activated by cathepsin B but
it can also undergo autoactivation, when trypsin activates trypsinogen. The respective contribution of
these two mechanisms to trypsin activation associated with pancreatitis onset is unknown. To address
this knowledge gap, we propose three distinct scenarios of trypsinogen activation. 1) In the absence of
increased trypsinogen autoactivation caused by genetic mutations, cathepsin B can induce significant
intrapancreatic trypsin activation, without affecting pancreatitis severity. (2) If genetic mutations in
trypsinogen moderately increase autoactivation, severity of experimentally-induced pancreatitis will
depend on the degree of cathepsin B-mediated trypsinogen activation. (3) Finally, if a genetic change
that causes robust trypsinogen autoactivation, age of onset and severity of spontaneous pancreatitis is
determined by cathepsin B-mediated trypsinogen activation. In this grant proposal, we will test each of
these three pathological circumstances using unique mouse models with trypsinogen mutations.
Successful completion of the proposed project will offer fresh mechanistic insight into the pathogenesis
of pancreatitis and will facilitate the development of novel therapeutic and preventive approaches.

## Key facts

- **NIH application ID:** 10783030
- **Project number:** 5R01DK132471-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Andrea Geisz-Fremy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $348,480
- **Award type:** 5
- **Project period:** 2023-02-09 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783030

## Citation

> US National Institutes of Health, RePORTER application 10783030, Mechanisms of Trypsin Activation in Pancreatitis (5R01DK132471-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10783030. Licensed CC0.

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