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
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
Szabó, András; Salameh, Moh'd A; Ludwig, Maren et al. (2014) Tyrosine sulfation of human trypsin steers S2' subsite selectivity towards basic amino acids. PLoS One 9:e102063
Németh, Balázs Csaba; Sahin-Tóth, Miklós (2014) Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 306:G466-73
Beer, Sebastian; Sahin-Toth, Miklos (2014) Exonic variants affecting pre-mRNA splicing add to genetic burden in chronic pancreatitis. Gut 63:860-1
Schnur, Andrea; Beer, Sebastian; Witt, Heiko et al. (2014) Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut 63:337-43
Witt, Heiko; Beer, Sebastian; Rosendahl, Jonas et al. (2013) Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet 45:1216-20
Nemeth, Balazs Csaba; Wartmann, Thomas; Halangk, Walter et al. (2013) Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop. J Biol Chem 288:24049-62
Batra, Jyotica; Szabo, Andras; Caulfield, Thomas R et al. (2013) Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activation. J Biol Chem 288:9848-59
Geisz, Andrea; Hegyi, Peter; Sahin-Toth, Miklos (2013) Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants. FEBS J 280:2888-99