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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Serrano, Jose
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Boston University
Schools of Dentistry
United States
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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
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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
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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

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