A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation.
A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation.
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DOI：
10.1038/s41467-018-07347-y
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发表时间：
2018-11-28
影响因子：
16.6
通讯作者：
Sahin-Tóth M
中科院分区：
文献类型：
--
作者：
Geisz A;Sahin-Tóth M
胰腺炎性疾病没有特异性治疗。慢性胰腺炎的遗传基础的发现确定了消化酶胰蛋白酶作为治疗靶点。由于缺乏动物模型，胰蛋白酶抑制作用的临床前测试受到阻碍。在这里，我们报告T7D23A基因敲入小鼠，它携带一个杂合的p.D23A突变的小鼠阳离子胰蛋白酶原（亚型T7）。这种胰蛋白酶原突变体自动激活成胰蛋白酶的速度比野生型快50倍。T7D23A小鼠在早期发生自发性急性胰腺炎，伴有水肿、坏死和血清淀粉酶升高，随后发生进行性萎缩性慢性胰腺炎，伴有腺泡细胞丢失、纤维化、导管扩张和脂肪替代。胰蛋白酶活性显著升高在胰腺炎的最初症状时是明显的，并持续到疾病的后期。这一显著的模型提供了胰蛋白酶原自激活可以驱动慢性胰腺炎的发作和进展的体内概念证明，并且治疗应该针对胰腺内胰蛋白酶。胰腺炎性疾病目前无法治疗，并且缺乏概括人类病理学特征的临床前模型。在这里，作者产生了一个敲入小鼠品系与增加胰蛋白酶原自动激活，并表明它发展自发胰腺病理与人类胰腺炎的一些关键特征。
Inflammatory diseases of the pancreas have no specific therapy. Discovery of the genetic basis of chronic pancreatitis identified the digestive enzyme trypsin as a therapeutic target. Preclinical testing of trypsin inhibition has been hampered by the lack of animal models. Here we report the T7D23A knock-in mouse, which carries a heterozygous p.D23A mutation in mouse cationic trypsinogen (isoform T7). This trypsinogen mutant autoactivates to trypsin 50-fold faster than wild type. T7D23A mice develop spontaneous acute pancreatitis with edema, necrosis and serum amylase elevation at an early age followed by progressive atrophic chronic pancreatitis with acinar cell loss, fibrosis, dilated ducts and adipose replacement. Markedly elevated trypsin activity is apparent at first signs of pancreatitis and persists into later stages of the disease. This remarkable model provides in vivo proof of concept that trypsinogen autoactivation can drive onset and progression of chronic pancreatitis and therapy should be directed against intra-pancreatic trypsin. Inflammatory diseases of the pancreas are currently untreatable and lack a pre-clinical model that recapitulates the hallmarks of the human pathology. Here, the authors generate a knock-in mouse strain with increased tripsinogen autoactivation and show that it develops spontaneous pancreatic pathology with some key features of human pancreatitis.
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影响因子：
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作者：
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