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：
7647711
负责人：
Miklos Sahin-Toth
金额：
$ 39万
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647711
关键词：
Acinar Cell Acinus organ component Adenoviruses Advanced Development Apoptosis Applications Grants Biochemical Biological Carboxypeptidase Cell Line Cells Classification Data Defect Disease model Elastases Embryo Endoplasmic Reticulum Enzyme Activation Enzymes Genes Hereditary Disease Human Human Genetics Induced Mutation Inflammation Inflammatory Investigation Kidney Lectin Link Measures Mediating Methods Molecular Mus Mutation N-Glycosylation Site Nuclear Nuclear Translocation Pancreas Pancreatitis Peptide Hydrolases Post-Translational Protein Processing Process Proteins Quality Control Rattus Recombinants Regulation Research Risk Risk Factors Role System Therapeutic Intervention Transfection Trypsin Variant Work chronic pancreatitis chymotrypsin chymotrypsin C chymotrypsin-like enzyme chymotrypsinogen C design endoplasmic reticulum stress genetic association genetic risk factor glycosylation human disease insight mutant novel novel diagnostics programs public health relevance research study response transcription factor

项目摘要

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.

描述（由申请人提供）：本赠款提案的具体目的是确定甲状腺癌C（CTRC）在调节消化酶激活和降解中的作用，并研究CTRC突变体作为风险的机制人类慢性胰腺炎的因素。该项目构成了有关与人类慢性胰腺炎相关的遗传危险因素分子病理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获得的数据结合在一起，以制定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以及突变诱导的缺陷的必不可少的调节剂，在这种调节功能中易于慢性胰腺炎。还将探讨另一种假设，这表明CTRC突变体的细胞内错误折叠会引起内质网应激。诱导展开的蛋白质反应，并通过激活核因子Kb触发炎症过程。因此，可以在CTRC基因和胰腺炎症中的突变之间建立DIREC链接。公共卫生相关性：目前的赠款提案旨在表征慢性胰腺炎的新型遗传危险因素，这是一种经常令人衰弱的且潜在的致命人类疾病。我们希望找出为什么消化酶Chymotrypsin C中的突变会增加人类慢性胰腺炎的风险。结果可以推动人类胰腺炎的新型诊断和治疗干预措施的发展。