The objectives of the present grant proposal are to characterize the physiological functions of pancreatic elastases and to investigate the mechanism by which elastase mutants act as risk factors for chronic pancreatitis in humans. This grant application is intended to meet a growing need in the pancreas community for the understanding of elastase function both in pancreatic physiology and disease. In humans, there are five pancreatic elastase genes (ELA1, ELA2A, ELA2B, ELA3A, and ELA3B) which give rise to three functional elastases (ELA2A, ELA3A and ELA3B). In the mouse ELA1, ELA2A and ELA3B seem to be expressed.
The specific aims studied are designed to address (i) the substrate specificity of human and mouse elastases;(ii) complex formation between proelastases and other pancreatic proteases;and (iii) the functional consequences of proelastase mutations identified in subjects with chronic pancreatitis.

Public Health Relevance

The present grant proposal investigates how various forms of the pancreatic digestive enzyme elastase function and how mutations in elastase genes increase the risk for chronic pancreatitis, a progressive inflammatory disease of the pancreas. Results from this study can advance the development of novel diagnostic and therapeutic interventions for all forms of human pancreatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095753-02
Application #
8588922
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
2013-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$320,443
Indirect Cost
$124,693
Name
Boston University
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Sahin-Tóth, Miklós (2017) Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol 33:390-395
Tóth, Anna Zsófia; Szabó, András; Hegyi, Eszter et al. (2017) Detection of human elastase isoforms by the ScheBo Pancreatic Elastase 1 Test. Am J Physiol Gastrointest Liver Physiol 312:G606-G614
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

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