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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082412-02
Application #
7781389
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Serrano, Jose
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$386,100
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Hegyi, Eszter; Sahin-Tóth, Miklós (2017) Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway. Dig Dis Sci 62:1692-1701
Wu, Hao; Zhou, Dai-Zhan; Berki, Dorottya et al. (2017) No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort. Hum Mutat 38:959-963
Boros, Eszter; Szabó, András; Zboray, Katalin et al. (2017) Overlapping Specificity of Duplicated Human Pancreatic Elastase 3 Isoforms and Archetypal Porcine Elastase 1 Provides Clues to Evolution of Digestive Enzymes. J Biol Chem 292:2690-2702
Jancsó, Zsanett; Sahin-Tóth, Miklós (2016) Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis. J Biol Chem 291:12897-905
Balázs, Anita; Németh, Balázs Csaba; Ördög, Balázs et al. (2016) A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort. Pancreas 45:541-5
Párniczky, Andrea; Hegyi, Eszter; Tóth, Anna Zsófia et al. (2016) Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis. Int J Mol Sci 17:2148
Balázs, Anita; Hegyi, Péter; Sahin-Tóth, Miklós (2016) Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 310:G477-86
Szabó, András; Pilsak, Claudia; Bence, Melinda et al. (2016) Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2. J Biol Chem 291:17706-16
Derikx, Monique H M; Geisz, Andrea; Kereszturi, Éva et al. (2015) Functional significance of SPINK1 promoter variants in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 308:G779-84
Szabó, András; Ludwig, Maren; Hegyi, Eszter et al. (2015) Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis. J Biol Chem 290:17282-92

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