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Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H
Fu Gui, … , Yan Bi, Baoan Ji
Fu Gui, … , Yan Bi, Baoan Ji
Published September 24, 2019
Citation Information: J Clin Invest. 2020;130(1):189-202. https://doi.org/10.1172/JCI130172.
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Research Article Gastroenterology

Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H

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Abstract

Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

Authors

Fu Gui, Yuebo Zhang, Jianhua Wan, Xianbao Zhan, Yao Yao, Yinghua Li, Ashley N. Haddock, Ji Shi, Jia Guo, Jiaxiang Chen, Xiaohui Zhu, Brandy H. Edenfield, Lu Zhuang, Cheng Hu, Ying Wang, Debabrata Mukhopadhyay, Evette S. Radisky, Lizhi Zhang, Aurelia Lugea, Stephen J. Pandol, Yan Bi, Baoan Ji

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Figure 1

Transgenic expression of human PRSS1R122H in mice.

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Transgenic expression of human PRSS1R122H in mice.
(A) Schema of generat...
(A) Schema of generation of the transgenic human PRSS1R122H mouse model. An R122H mutation was introduced into a BAC harboring the full-length human PRSS1 gene by GalK-mediated recombineering technology. (B) Sanger DNA sequencing confirmed a CGC>CAC mutation, which confers R122H mutation. (C) Western blot showed a high level of PRSS1R122H expression in the pancreas of transgenic mice and no expression in WT C57BL/6J mice. Human pancreas lysate was used as a control. Representative blots from 3 independent assays are shown. (D) Higher and prolonged trypsin activity was observed in the pancreatic acinar cells isolated from transgenic PRSS1R122H mice than was seen in those from C57BL/6J mice. Mean ± SEM (n = 3). **P < 0.01; ***P < 0.001; 2-way ANOVA with Tukey’s multiple comparisons test.
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