Chymotrypsin C in pancreatitis

胰凝乳蛋白酶 C 在胰腺炎中的作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的此项资助的主要目的是确定胰凝乳蛋白酶 C (CTRC) 的作用机制突变是人类慢性胰腺炎的危险因素。该项目是我们广泛的、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。迄今为止，这些研究结合了生物化学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是通过两个独立的病理途径介导的，这可能导致腺泡细胞损伤。在胰蛋白酶依赖性病理途径中，胰内自动激活胰蛋白酶原转化为活性胰蛋白酶是造成细胞损伤的原因；而在错误折叠依赖的错误折叠突变蛋白的病理途径保留可通过以下方式损害腺泡细胞诱导内质网应激。在上一个资助期间，我们建立了 CTRC 突变是慢性胰腺炎非常重要的危险因素，这些突变发挥其作用主要通过胰蛋白酶依赖性途径发挥作用，而 CTRC 突变体的子集也参与错误折叠依赖性途径。在下一个资助期内，我们的目标是验证我们的体内结论，并创建和表征小鼠模型，以测试基因删除是否小鼠 Ctrc 增加胰腺内胰蛋白酶原激活和胰腺炎反应；和错误折叠的人类 CTRC 突变体在小鼠胰腺中的转基因表达是否会导致内质网应激、腺泡细胞损伤和胰腺炎易感性增加。