# Chymotrypsin in pancreatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $497,503

## Abstract

ABSTRACT
The main objective of this grant is to use genetically engineered mouse models to determine how
genetic changes in human chymotrypsin increase risk for chronic pancreatitis. Previous studies
demonstrated the protective role of chymotrypsin against pancreatitis in humans and in mouse models.
In this proposal, the overarching hypothesis is that loss of protective chymotrypsin function leads to
pancreatitis in the context of additional genetic or environmental risk factors that facilitate
intrapancreatic trypsin activation. To prove this notion, a CTRB1-deleted mouse strain (Ctrb1-del) will
be crossed with mice carrying various pancreatitis risk alleles or will be exposed to an alcohol diet.
Although CTRB1-deleted mice show heightened pancreatitis responses when disease is induced
experimentally by cerulein stimulation; they do not develop pancreatitis naturally. Introduction of
additional risk factors in the setting of chymotrypsin deficiency is predicted to result in the spontaneous
onset and progression of pancreatitis. Alternatively, mice will exhibit additive susceptibility to cerulein-
induced pancreatitis. The following specific aims will be studied. (1) Chymotrypsin deficiency synergizes
with trypsinogen mutations to cause pancreatitis. In this aim, the hypothesis is that mice deficient in
chymotrypsin and carrying mutations in mouse cationic trypsinogen (isoform T7) will develop
spontaneous acute pancreatitis that will progress to chronic pancreatitis. Alternatively, mice will exhibit
increased susceptibility to cerulein-induced pancreatitis. Adjusting gene dosage through combinations
of heterozygous and homozygous alleles should result in variations in age of onset and/or severity. (2)
Combined insufficiency of chymotrypsin and trypsin inhibitor in pancreatitis. In this aim, Ctrb1-del mice
will be crossed either with a SPINK1-deleted strain (Spink1-KO) or with mice carrying a T7 trypsinogen
allele with the p.G199R mutation, which conveys inhibitor-degrading properties (functional ortholog of
human mesotrypsin). The hypothesis is that mice with combined deficiency in chymotrypsin and trypsin
inhibitor will develop either spontaneous pancreatitis or will exhibit increased severity of cerulein-
induced pancreatitis. (3) Alcoholic pancreatitis in the setting of chymotrypsin deficiency. In this aim,
chymotrypsin-deficient mice will be fed the Lieber-DeCarli alcohol liquid diet. The hypothesis is that in
the background of chymotrypsin-deficiency alcohol will cause spontaneous pancreatitis through
selective upregulation of trypsinogen. Successful completion of these aims will offer conclusive
evidence that alterations in chymotrypsin genes in humans promote the development of pancreatitis by
interacting with other genetic and environmental factors that increase intrapancreatic trypsin activity.

## Key facts

- **NIH application ID:** 10360688
- **Project number:** 5R01DK082412-11
- **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:** $497,503
- **Award type:** 5
- **Project period:** 2009-09-05 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360688

## Citation

> US National Institutes of Health, RePORTER application 10360688, Chymotrypsin in pancreatitis (5R01DK082412-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10360688. Licensed CC0.

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