The main objective of this grant is to determine the mechanisms by which chymotrypsin C (CTRC) mutations act as risk factors for chronic pancreatitis in humans. The project forms a part of our broad, long-term research program to understand the molecular mechanisms of genetic risk factors associated with human pancreatitis. These studies so far combined biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a molecular disease model for recurrent acute and chronic pancreatitis. Our current working hypothesis is that genetic risk in pancreatitis is mediated via two independent pathological pathways, which can result in acinar cell damage. In the trypsin-dependent pathological pathway intra-pancreatic autoactivation of trypsinogen to active trypsin is responsible for cell injury;whereas in the misfolding-dependent pathological pathway retention of misfolded mutant proteins can damage acinar cells through induction of endoplasmic reticulum stress. In the previous funding period we established that CTRC mutations are highly significant risk factors for chronic pancreatitis and these mutations exert their effect primarily through the trypsin-dependent pathway, while a subset of CTRC mutants also engages the misfolding-dependent pathway. In the next funding period our aim is to validate our conclusions in vivo and create and characterize mouse models that will test whether genetic deletion of mouse Ctrc increases intra-pancreatic trypsinogen activation and pancreatitis responses;and whether transgenic expression of a misfolding human CTRC mutant in the mouse pancreas causes endoplasmic reticulum stress, acinar cell damage and increased susceptibility to pancreatitis.

Public Health Relevance

The present grant proposal investigates how mutations in the gene for the pancreatic digestive enzyme chymotrypsin C (CTRC) 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)
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/Oral Hygn
United States
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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
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
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
Beer, Sebastian; Zhou, Jiayi; Szabo, Andras et al. (2013) Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut 62:1616-24
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

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