Chymotrypsin C in pancreatitis

摘要 这项资助的主要目的是确定凝乳酶C(CTRC)的机制。 突变是人类慢性胰腺炎的危险因素。该项目构成了我们广泛的， 了解遗传风险因素分子机制的长期研究计划 与人类胰腺炎有关。到目前为止，这些研究结合了生化和细胞生物学。 利用从人类遗传关联研究中获得的数据来制定分子 复发性急性和慢性胰腺炎的疾病模型。我们目前的工作假设是 胰腺炎的遗传风险通过两条独立的病理途径介导，这可能导致 腺泡细胞损伤。在胰酶依赖的病理途径中胰腺内自激活 胰酶原到活性胰酶负责细胞损伤；而在错误折叠依赖 错误折叠突变蛋白的病理途径保留可通过以下途径损伤腺泡细胞 内质网应激的诱导。在上一个供资期间，我们设立了反恐委员会 突变是慢性胰腺炎的非常重要的危险因素，这些突变发挥了 主要通过依赖胰酶的途径发挥作用，而CTRC突变体的子集也 参与错误折叠依赖的途径。在下一个资助期，我们的目标是验证我们的 结论在体内，并建立和表征小鼠模型，将测试基因缺失 小鼠CTRC可增加胰腺内胰酶原激活和胰腺炎反应； 人错折叠CTRC突变体在小鼠胰腺中的转基因表达是否导致 内质网应激、腺泡细胞损伤和胰腺炎易感性增加。

ABSTRACT The main objective of this grant is to determine the mechanisms by which chymotrypsin C (CTRC) mutations act as risk factors for chronic pancreatitis in humans. The project forms a part of our broad, long-term research program to understand the molecular mechanisms of genetic risk factors associated with human pancreatitis. These studies so far combined biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a molecular disease model for recurrent acute and chronic pancreatitis. Our current working hypothesis is that genetic risk in pancreatitis is mediated via two independent pathological pathways, which can result in acinar cell damage. In the trypsin-dependent pathological pathway intra-pancreatic autoactivation of trypsinogen to active trypsin is responsible for cell injury; whereas in the misfolding-dependent pathological pathway retention of misfolded mutant proteins can damage acinar cells through induction of endoplasmic reticulum stress. In the previous funding period we established that CTRC mutations are highly significant risk factors for chronic pancreatitis and these mutations exert their effect primarily through the trypsin-dependent pathway, while a subset of CTRC mutants also engages the misfolding-dependent pathway. In the next funding period our aim is to validate our conclusions in vivo and create and characterize mouse models that will test whether genetic deletion of mouse Ctrc increases intra-pancreatic trypsinogen activation and pancreatitis responses; and whether transgenic expression of a misfolding human CTRC mutant in the mouse pancreas causes endoplasmic reticulum stress, acinar cell damage and increased susceptibility to pancreatitis.