Chymotrypsin C in pancreatitis

描述（由申请人提供）：本拨款提案的具体目标是确定凝乳胰蛋白酶C （CTRC）在消化酶激活和降解调节中的作用，并研究CTRC突变体作为人类慢性胰腺炎危险因素的机制。该项目是人类慢性胰腺炎相关遗传危险因素分子病理机制的广泛、长期研究计划的一部分。这些研究将生化和细胞生物学方法与从人类遗传关联研究中获得的数据结合起来，形成了慢性胰腺炎的分子疾病模型。根据我们的工作假设，胰凝乳蛋白酶C是消化酶激活和降解的重要调节剂，这种调节功能的突变诱导缺陷易导致慢性胰腺炎。我们还将探讨另一种假设，即CTRC突变体的细胞内错误折叠会引起内质网应激；诱导未折叠蛋白反应，通过活化核因子B触发炎症过程。因此，CTRC基因突变与胰腺炎症之间可能存在直接联系。

DESCRIPTION (provided by applicant): The specific objectives of the present grant proposal are to determine the role of chymotrypsin C (CTRC) in the regulation of digestive enzyme activation and degradation and to investigate the mechanism(s) by which CTRC mutants act as risk factors for chronic pancreatitis in humans. This project forms a part of a broad, long-term research program on the molecular pathomechanism of genetic risk factors associated with human chronic pancreatitis. The studies combine biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a molecular disease model that underlies chronic pancreatitis. According to our working hypothesis chymotrypsin C is an essential regulator of digestive enzyme activation and degradation and mutation-induced defects in this regulatory function predisposes to chronic pancreatitis. An alternative hypothesis will be also explored, which suggests that intracellular misfolding of CTRC mutants would elicit endoplasmic reticulum stress; induce the unfolded protein response and trigger the inflammatory process through activation of nuclear factor ?B. Thus, a direct link might be established between mutations in the CTRC gene and pancreatic inflammation.