# Pathophysiology of Chronic Pancreatitis Associated with Misfolded PNLIP Risk Variants

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $462,868

## Abstract

PROJECT SUMMARY
The primary goal of this application is to determine the mechanisms by which pancreatic triglyceride lipase
(PNLIP) variants increase the risk for chronic pancreatitis (CP) in humans. Proteotoxicity caused by misfolded
mutant digestive enzymes has been recognized as a novel trypsin-independent mechanism for CP, referred to
as misfolding CP. Recent studies indicate that the development of CP is often a process of discrete recurrent
acute pancreatitis (RAP) driven by genetic risk factors. Restoring proteostasis in the presence of misfolded
proteins is an attractive therapeutic strategy to stop RAP and prevent progression to end-stage disease in
misfolding CP patients. Critical knowledge gaps remain in understanding how misfolded proteins contribute to
pancreatitis onset and progression primarily stemming from the paucity of animal models that recapitulate
misfolding CP in humans. We have developed a pre-clinical model of human PNLIP T221M disease. PNLIP
has no known role in trypsinogen activation or trypsin inactivation. In vitro, PNLIP T221M misfolds and causes
proteotoxicty by triggering unmitigated ER stress. Our preliminary data show that Pnlip T221M mice exhibit
progressive pancreatic acinar atrophy, inflammatory cell infiltration, fibrosis, and apoptotic and necrotic cell
death; the pathological changes occur as early as at 1 month and become severe at 3-4 month. Our working
hypothesis is that proteins encoded by risk variants of PNLIP cause CP by gain-of-function proteotoxicity
through protein misfolding. To test this hypothesis, first we will systematically characterize Pnlip T221 mice
including CP-like phenotypes, secondary complications, and the susceptibility to pancreatic injury when being
challenged with ethanol feeding. Second, we will methodically investigate early biological responses triggered
by pancreatic expression of pathogenic PNLIP T221M in mice to uncover potential novel targets to halt or
prevent disease onset and progression. Third, we will assess the prevalence of protein misfolding and
proteotoxicity underlies the disease mechanism of PNLIP variants of uncertain significance (VUS) found in CP
patients using cell cultures and another mouse model of Pnlip F300L. Completion of these studies will
establish mutation-induced misfolding of digestive enzymes as a relevant disease mechanism in the
pathogenesis of CP and will identify potential therapeutic targets to stop RAP and prevent CP.

## Key facts

- **NIH application ID:** 10444623
- **Project number:** 1R01DK128188-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Xunjun Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,868
- **Award type:** 1
- **Project period:** 2022-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444623

## Citation

> US National Institutes of Health, RePORTER application 10444623, Pathophysiology of Chronic Pancreatitis Associated with Misfolded PNLIP Risk Variants (1R01DK128188-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10444623. Licensed CC0.

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