Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, USA.
Nat Commun. 2018 Nov 28;9(1):5033. doi: 10.1038/s41467-018-07347-y.
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.
胰腺的炎症性疾病尚无特定疗法。慢性胰腺炎的遗传基础的发现确定了消化酶胰蛋白酶是一个治疗靶点。由于缺乏动物模型，胰蛋白酶抑制的临床前测试受到了阻碍。在这里，我们报告了 T7D23A 敲入小鼠，其携带阳离子胰蛋白酶原（同工型 T7）中的杂合 p.D23A 突变。这种胰蛋白酶原突变体比野生型自动激活为胰蛋白酶的速度快 50 倍。T7D23A 小鼠在早期就会自发发生急性胰腺炎，伴有水肿、坏死和血清淀粉酶升高，随后会进展为进行性萎缩性慢性胰腺炎，伴有腺泡细胞丢失、纤维化、扩张的导管和脂肪替代。在胰腺炎的最初迹象时就明显出现显著升高的胰蛋白酶活性，并持续存在于疾病的后期阶段。这个显著的模型提供了体内概念验证，即胰蛋白酶原自动激活可以驱动慢性胰腺炎的发生和进展，并且治疗应该针对胰腺内的胰蛋白酶。
