Chymotrypsin C in pancreatitis

描述(由申请者提供)：本资助方案的具体目标是确定凝乳酶C(CTRC)在调节消化酶激活和降解中的作用，并研究CTRC突变作为人类慢性胰腺炎危险因素的机制(S)。该项目是关于与人类慢性胰腺炎相关的遗传风险因素的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，形成了一个慢性胰腺炎的分子疾病模型。根据我们的工作假设，糜蛋白酶C是消化酶激活和降解的重要调节因子，突变导致的这一调节功能缺陷易导致慢性胰腺炎。还将探索另一种假说，即CTRC突变体的细胞内错误折叠会引发内质网应激，诱导未折叠的蛋白质反应，并通过激活核因子kB来触发炎症过程。因此，可能在CTRC基因突变和胰腺炎症之间建立了直接联系。公共卫生相关性：目前的拨款提案旨在描述慢性胰腺炎的一种新的遗传风险因素，慢性胰腺炎是一种经常使人虚弱并具有潜在致命性的人类疾病。我们希望找出为什么消化酶糜蛋白酶C的突变会增加人类患慢性胰腺炎的风险。这一结果可以促进人类胰腺炎新的诊断和治疗干预措施的发展。

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 kB. Thus, a direc link might be established between mutations in the CTRC gene and pancreatic inflammation. PUBLIC HEALTH RELEVANCE: The present grant proposal intends to characterize a novel genetic risk factor for chronic pancreatitis, an often debilitating and potentially fatal human disease. We wish to find out why mutations in the digestive enzyme chymotrypsin C can increase the risk of chronic pancreatitis in humans. The results can advance the development of novel diagnostic and therapeutic interventions for human pancreatitis.