The broad, long-term objectives of this grant proposal are to understand the molecular mechanisms of genetic risk factors associated with chronic hereditary pancreatitis in humans. The studied genetic alterations include mutations of the cationic trypsinogen (PRSS1) and pro-carboxypeptidase A1 (CPA1). The research design combines biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a disease model that can explain the higher susceptibility of mutation carriers to chronic pancreatitis. We hypothesize that genetic risk in chronic pancreatitis is mediated via two independent pathological pathways, both of which can result in acinar cell damage and death. In the trypsin-dependent pathological pathway intracellular autoactivation of trypsinogen to active trypsin causes acinar cell apoptosis;whereas in the misfolding-dependent pathological pathway retention of misfolded mutant proenzymes induces endoplasmic reticulum stress, which can trigger apoptotic cell death. In the next funding period, the following specific aims will be studied. (1) Acinar cell damage caused by intracellular autoactivation of cationic trypsinogen (PRSS1) mutants;(2) Misfolding of cationic trypsinogen (PRSS1) mutants and endoplasmic reticulum stress (3) Analysis of the enzymatic and cellular effects of novel CPA1 mutations associated with chronic pancreatitis.

Public Health Relevance

The present grant proposal investigates how gene mutations in digestive enzymes cause hereditary pancreatitis, an inherited, 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 #
5R01DK058088-12
Application #
8286409
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Serrano, Jose
Project Start
2000-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$336,281
Indirect Cost
$130,856
Name
Boston University
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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
Balázs, Anita; Németh, Balázs Csaba; Ördög, Balázs et al. (2016) A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort. Pancreas 45:541-5
Hegyi, Péter; Wilschanski, Michael; Muallem, Shmuel et al. (2016) CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis. Rev Physiol Biochem Pharmacol 170:37-66
Szabó, András; Pilsak, Claudia; Bence, Melinda et al. (2016) Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2. J Biol Chem 291:17706-16
Maléth, József; Balázs, Anita; Pallagi, Petra et al. (2015) Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. Gastroenterology 148:427-39.e16
Szabó, András; 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
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
Derikx, Monique H M; Geisz, Andrea; Kereszturi, Éva 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

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