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.
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.
|JancsÃ³, Zsanett; Sahin-TÃ³th, MiklÃ³s (2016) Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis. J Biol Chem 291:12897-905|
|BalÃ¡zs, Anita; NÃ©meth, BalÃ¡zs Csaba; Ã–rdÃ¶g, BalÃ¡zs et al. (2016) A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort. Pancreas 45:541-5|
|SzabÃ³, AndrÃ¡s; Pilsak, Claudia; Bence, Melinda et al. (2016) Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2. J Biol Chem 291:17706-16|
|SzabÃ³, AndrÃ¡s; 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|
|SzabÃ³, AndrÃ¡s; 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, Ã‰va 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|
|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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