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.
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.
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|SzabÃ³, AndrÃ¡s; Radisky, Evette S; Sahin-TÃ³th, MiklÃ³s (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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