Chymotrypsin C in pancreatitis

胰凝乳蛋白酶 C 在胰腺炎中的作用

• 批准号: 8627388
• 负责人: Miklos Sahin-Toth
• 金额: $ 35.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627388
• 关键词: Acinar Cell; Advanced Development; Applications Grants; Back; Biochemical; Biochemical Pathway; Biological; Cells; Comparative Study; Data; Defect; Disease; Disease model; Enzymes; Funding; Genes; Genetic; Genetic Risk; Grant; Hereditary Disease; Human; Human Genetics; In Vitro; Inbred Strains Mice; Inbreeding; Inflammatory; Injury; Knock-out; Mediating; Molecular; Mus; Mutation; Pancreas; Pancreatitis; Pathway interactions; Predisposition; Protein Isoforms; Proteins; Recurrence; Research; Risk; Risk Factors; Specificity; Testing; Transgenic Mice; Transgenic Organisms; Trypsin; Trypsinogen; Work; acute pancreatitis; cell injury; chronic pancreatitis; chymotrypsin; chymotrypsin C; clinically relevant; congenic; endoplasmic reticulum stress; genetic association; genetic risk factor; in vivo; insight; mouse model; mutant; novel diagnostics; novel therapeutic intervention; premature; programs; public health relevance; response

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.

摘要 该基金的主要目的是确定糜蛋白酶C（CTRC） 突变是人类慢性胰腺炎的危险因素。该项目是我们广泛的， 长期研究计划，以了解遗传风险因素的分子机制 与人类胰腺炎有关迄今为止，这些研究结合了生物化学和细胞生物学 从人类遗传关联研究中获得的数据， 复发性急性和慢性胰腺炎的疾病模型。我们目前的假设是 胰腺炎的遗传风险是通过两个独立的病理途径介导的， 腺泡细胞损伤。在胰蛋白酶依赖的病理途径中， 胰蛋白酶原到活性胰蛋白酶负责细胞损伤;而在错误折叠依赖性 错误折叠的突变蛋白的病理途径滞留可通过以下途径损伤腺泡细胞： 诱导内质网应激。在上一个资助期内，我们设立了CTRC， 突变是慢性胰腺炎的高度重要的危险因素，这些突变发挥其 主要通过胰蛋白酶依赖性途径发挥作用，而CTRC突变体的一个子集也 参与了错误折叠依赖性途径。在下一个融资期，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，将测试是否遗传缺失 增加胰腺内胰蛋白酶原活化和胰腺炎反应;和 在小鼠胰腺中错误折叠的人CTRC突变体的转基因表达是否引起 内质网应激、腺泡细胞损伤和胰腺炎易感性增加。