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 PRSS1^R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1^R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1^R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1^R122H mice with PRSS1^WT mice, as well as enzymatically inactivated Dead-PRSS1^R122H 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 PRSS1^R122H 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.

中文翻译：

---

胰蛋白酶活性控制表达人PRSS1 ^R122H的小鼠对胰腺炎的敏感性增加

当前，缺乏针对胰腺炎的有效靶向治疗。遗传性胰腺炎（HP）是一种遗传性，常染色体显性疾病，复发性急性胰腺炎（AP）发展为慢性胰腺炎（CP），胰腺癌的风险显着增加。1996年，PRSS1的突变与HP的发展有关。在这里，我们通过将全长人类PRSS1 ^R122H基因（人类HP中最常见的突变基因）插入小鼠体内，建立了小鼠模型。胰腺中PRSS1 ^R122H蛋白的表达显着增加了应激信号通路并加重了AP。AP攻击后，所有PRSS1 ^R122H小鼠的疾病进展为CP，其组织学特征与人类HP相似。通过将PRSS1 ^R122H小鼠与PRSS1 ^WT小鼠以及酶促灭活的Dead-PRSS1 ^R122H小鼠进行比较，我们了解到胰蛋白酶活性的提高是R122H突变使小鼠对胰腺炎发展敏感的机制。我们进一步发现，胰蛋白酶抑制与抗凝治疗相结合，可以协同阻止PRSS1 ^R122H小鼠发展为CP 。这些动物模型有助于我们更好地了解这种疾病的复杂性质，并为开发和测试人类胰腺炎的新疗法提供有力工具。