Selig Lena, Sack Ulrich, Gaiser Sebastian, Klöppel Günter, Savkovic Vuk, Mössner Joachim, Keim Volker, Bödeker Hans
Medizinische Klinik und Poliklinik II, Universitätsklinikum Leipzig, Leipzig, Germany.
BMC Gastroenterol. 2006 Oct 27;6:30. doi: 10.1186/1471-230X-6-30.
The R122H mutation of the cationic trypsinogen was found in patients with hereditary pancreatitis. A transgenic animal carrying this mutation could be useful as a genetic model system of pancreatitis.
Mice transgenic for the human R122H cationic trypsinogen were generated using the -205 fragment of the rat elastase promoter. The presence of the transgene was assayed in the DNA, in pancreatic mRNA and in zymogen granule lysates. Serum levels of amylase, lipase and cytokines (MCP-1, IL-6) were monitored and the histological appearance of the tissue was investigated. Pancreatitis was induced by 7 hourly injections of 50 mug/kg cerulein. The procedure was repeated twice weekly for 10 consecutive weeks. The animals were sacrificed 24 (n = 8) and 48 hours (n = 8) after the first injection and at the end of the whole treatment (n = 7).
The transgene was detected at the genomic level and in pancreatic mRNA. The corresponding protein was found in low amounts in zymogen granule lysates. R122H mice showed elevated pancreatic lipase, but there was no spontaneous development of pancreatitis within 18 months. After induction of pancreatitis, levels of lipase (after 24 hours) and amylase (after 48 hours) were higher in R122H mice compared to controls. Repeated treatment with cerulein resulted in a slightly more severe pancreatitis in R122H animals. Amylase, lipase, and the cytokine levels were similar to controls.
The R122H transgenic mouse failed to develop a spontaneous pancreatitis but a repeatedly provoked cerulein-induced pancreatitis led to a slightly more severe pancreatitis. The rather small difference in comparison to controls could be due to the low expression of the transgene in the mouse pancreas.
遗传性胰腺炎患者中发现了阳离子胰蛋白酶原的R122H突变。携带此突变的转基因动物可用作胰腺炎的遗传模型系统。
使用大鼠弹性蛋白酶启动子的-205片段生成了携带人R122H阳离子胰蛋白酶原的转基因小鼠。在DNA、胰腺mRNA和酶原颗粒裂解物中检测转基因的存在。监测血清淀粉酶、脂肪酶和细胞因子（MCP-1、IL-6）水平，并研究组织的组织学外观。通过每7小时注射50μg/kg雨蛙素诱导胰腺炎。该过程每周重复两次，连续10周。在第一次注射后24小时（n = 8）和48小时（n = 8）以及整个治疗结束时（n = 7）处死动物。
在基因组水平和胰腺mRNA中检测到转基因。在酶原颗粒裂解物中发现了少量相应的蛋白质。R122H小鼠的胰腺脂肪酶升高，但在18个月内没有自发发生胰腺炎。诱导胰腺炎后，与对照组相比，R122H小鼠的脂肪酶水平（24小时后）和淀粉酶水平（48小时后）更高。用雨蛙素反复治疗导致R122H动物的胰腺炎略严重。淀粉酶、脂肪酶和细胞因子水平与对照组相似。
R122H转基因小鼠未能自发发生胰腺炎，但反复诱发的雨蛙素诱导的胰腺炎导致略严重的胰腺炎。与对照组相比差异较小可能是由于转基因在小鼠胰腺中的低表达。
