# Trypsin-dependent mechanisms in pancreatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $487,848

## Abstract

ABSTRACT
The main objective of this grant is to use genetically engineered mouse models to determine the
mechanisms by which trypsinogen (PRSS1) mutations in humans cause hereditary pancreatitis. The
majority of non-alcoholic cases of chronic pancreatitis develop on the basis of genetic susceptibility,
driven by mutations in risk genes that encode digestive enzymes or their inhibitor, such as cationic
trypsinogen (protease serine 1, PRSS1), chymotrypsin C (CTRC) or the pancreatic secretory trypsin
inhibitor (serine protease inhibitor Kazal type 1, SPINK1). Our previous studies defined a trypsin-
dependent pathological pathway associated with mutations in these risk genes that promote intra-
pancreatic trypsinogen autoactivation and result in increased ectopic trypsin activity. In the present
proposal, we will validate this model in vivo. To this end, we developed novel mouse lines T7 D23A and
T7 K24R that carry mutations in the activation peptide of the native mouse cationic trypsinogen (isoform
T7). In vitro the D23A mutation causes a dramatic 50-fold increase in trypsinogen autoactivation, while
mutation K24R increases autoactivation by 4-fold. Thus, the models can provide information on how
different trypsin levels determine pancreatitis responses and pathology. We hypothesize that mice with
trypsinogen mutations that stimulate autoactivation will develop spontaneous pancreatitis or exhibit
heightened pancreatitis responses when challenged with hyperstimulation insults. In our specific aims
we will study the spontaneous pancreatitis in the T7 D23A mouse; evaluate the increased sensitivity to
secretagogue induced pancreatitis in the T7 K24R mouse and investigate the protective role of trypsin
inhibition against pancreatitis by altering Spink3 (ortholog of human SPINK1) expression levels in these
models. Successful completion of these aims will firmly establish that increased trypsinogen
autoactivation leading to elevated intra-pancreatic trypsin activity is a relevant disease-mechanism in
pancreatitis and should be the focus of future therapeutic strategies.

## Key facts

- **NIH application ID:** 10355498
- **Project number:** 5R01DK117809-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Miklos Sahin-Toth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,848
- **Award type:** 5
- **Project period:** 2019-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355498

## Citation

> US National Institutes of Health, RePORTER application 10355498, Trypsin-dependent mechanisms in pancreatitis (5R01DK117809-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355498. Licensed CC0.

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