A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen
A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen
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DOI：
10.1053/j.gastro.2006.09.049
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发表时间：
2006-12-01
期刊：
影响因子：
29.4
通讯作者：
Bar-Sagi, Dafna
中科院分区：
文献类型：
--
作者：
Archer, Herbert;Jura, Natalia;Bar-Sagi, Dafna
背景与目的：遗传性胰腺炎是一种罕见的胰腺遗传性疾病，以自身消化坏死、慢性炎症和纤维化为特征，在遗传性胰腺炎患者中经常检测到人阳离子胰蛋白酶原PRSS1错义突变。为了研究PRSS1突变与遗传性胰腺炎发生和进展之间的联系，我们试图培养一种携带PRSS1错义突变的转基因小鼠，这种突变在患者中最常见。方法：通过将小鼠PRSS1突变体R122H （Rl22H_mPRSS1）与弹性酶启动子融合，靶向胰腺腺泡细胞，构建转基因小鼠。通过免疫组织化学染色和实时逆转录聚合酶链反应分析评估突变型胰蛋白酶原的表达。通过h&e染色组织切片的形态学评估、对冠状蛋白诱导的胰腺炎的反应性以及炎症反应的细胞和生化成分的免疫组织化学鉴定来分析转基因表达与炎症的关系。结果：转基因小鼠胰腺表现出早发性腺泡细胞损伤和炎症细胞浸润。随着年龄的增长，转基因小鼠出现胰腺纤维化和腺泡细胞去分化。此外，R122H_mPRSS1转基因的表达与对冠状蛋白诱导的胰腺炎的反应增强有关。最后，在R122H_mPRSS1的表达下，观察到炎症相关信号通路c-jun- n末端激酶和细胞外信号调节激酶的细胞特异性激活。结论：这些结果强调了PRSSI突变作为遗传性胰腺炎致病介质的重要性，并表明持续胰腺损伤可能与慢性胰腺炎有因果关系。
Background & Aims: Missense mutations in human cationic trypsinogen PRSS1 are frequently detected in patients with hereditary pancreatitis, a rare genetic disease of the pancreas characterized by autodigestive necrosis, chronic inflammation, and fibrosis. To examine the link between PRSS1 mutations and the initiation and progression of hereditary pancreatitis, we have sought to generate a transgenic mouse that carries a missense mutation in the PRSS1 that is most frequently observed in patients. Methods: A transgenic mouse was generated in which the expression of the mouse PRSS1 mutant R122H (Rl22H_mPRSS1) is targeted to pancreatic acinar cells by fusion to the elastase promoter. The expression of the mutant trypsinogen was assessed by immunohistochemical staining and real-time reverse transcription polymerase chain reaction analysis. The relationship between transgene expression and inflammation was analyzed by morphologic assessment of H&E-stained tissue sections, responsiveness to cerulein-induced pancreatitis, and immunohistochemical identification of cellular and biochemical components of the inflammatory response. Results: Pancreata from transgenic mice display earlyonset acinar cell injury and inflammatory cell infiltration. With progressing age, the transgenic mice develop pancreatic fibrosis and display acinar cell dedifferentiation. Moreover, the expression of R122H_mPRSS1 transgene is associated with enhanced response to cerulein-induced pancreatitis. Finally, cell-specific activation of the inflammation-associated signaling pathways, c-jun-N-terminal kinase and extracellular signal-regulated kinase, was observed in response to expression of R122H_mPRSS1. Conclusions: These results underscore the importance of PRSSI mutations as pathogenic mediators of hereditary pancreatitis and indicate that persistent pancreatic injury might be causally linked to chronic pancreatitis.