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 #
1R01DK095753-01A1
Application #
8437036
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
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$356,048
Indirect Cost
$138,548
Name
Boston University
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
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
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
Szabó, András; Xiao, Xunjun; Haughney, Margaret et al. (2015) A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding. Biochim Biophys Acta 1852:1372-9
Rygiel, Agnieszka Magdalena; Beer, Sebastian; Simon, Peter et al. (2015) Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis. Hum Mutat 36:350-6
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
Nakano, Eriko; Geisz, Andrea; Masamune, Atsushi et al. (2015) Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 309:G688-94
Szabó, András; Radisky, Evette S; Sahin-Tóth, Miklós (2014) Zymogen activation confers thermodynamic stability on a key peptide bond and protects human cationic trypsin from degradation. J Biol Chem 289:4753-61
Beer, Sebastian; Sahin-Toth, Miklos (2014) Exonic variants affecting pre-mRNA splicing add to genetic burden in chronic pancreatitis. Gut 63:860-1

Showing the most recent 10 out of 17 publications