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.

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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Hegyi, Eszter; Sahin-Tóth, Miklós (2018) Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. Gut :
Hegyi, Eszter; Sahin-Tóth, Miklós (2018) Trypsinogen isoforms in the ferret pancreas. Sci Rep 8:15094
Jancsó, Zsanett; Hegyi, Eszter; Sahin-Tóth, Miklós (2018) Chymotrypsin Reduces the Severity of Secretagogue-Induced Pancreatitis in Mice. Gastroenterology 155:1017-1021
Németh, Balázs Csaba; Patai, Árpád V; Sahin-Tóth, Miklós et al. (2017) Misfolding cationic trypsinogen variant p.L104P causes hereditary pancreatitis. Gut 66:1727-1728
Tóth, Anna Zsófia; Szabó, András; Hegyi, Eszter et al. (2017) Detection of human elastase isoforms by the ScheBo Pancreatic Elastase 1 Test. Am J Physiol Gastrointest Liver Physiol 312:G606-G614
Sahin-Tóth, Miklós (2017) Genetic risk in chronic pancreatitis: the misfolding-dependent pathway. Curr Opin Gastroenterol 33:390-395
Hegyi, Eszter; Sahin-Tóth, Miklós (2017) Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway. Dig Dis Sci 62:1692-1701
Kujko, Aleksandra A; Berki, Dorottya M; Oracz, Grzegorz et al. (2017) A novel p.Ser282Pro CPA1 variant is associated with autosomal dominant hereditary pancreatitis. Gut 66:1728-1730
Wu, Hao; Zhou, Dai-Zhan; Berki, Dorottya et al. (2017) No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort. Hum Mutat 38:959-963
Boros, Eszter; Szabó, András; Zboray, Katalin et al. (2017) Overlapping Specificity of Duplicated Human Pancreatic Elastase 3 Isoforms and Archetypal Porcine Elastase 1 Provides Clues to Evolution of Digestive Enzymes. J Biol Chem 292:2690-2702

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