The broad, long-term objectives of this grant-proposal are to understand the molecular mechanisms of human pancreatitis using hereditary pancreatitis and other forms of genetically determined pancreatitis as biochemical models. The most frequently found mutations in genetic pancreatitis affect the PRSS1 gene that codes for human cationic trypsinogen and the SPINK1 gene encoding pancreatic secretory trypsin inhibitor. In the previous funding period our laboratory has developed methodology for the in vitro study of human trypsinogen mutations and through characterization of several pancreatitis-associated mutants we have formulated a working hypothesis. This model states that elevated intraacinar trypsin activity is the fundamental initiating step of genetic pancreatitis and trypsinogen mutations generally exert this effect through increased autocatalytic activation. In the present proposal we seek to extend our mechanistic model, and prove that increased trypsin activity plays the central role in all forms of genetic pancreatitis. The following specific aims will be studied. (1) The role of human mesotrypsin in pancreatitis. Mesotrypsin is a unique protease specialized for the degradation of trypsin inhibitors. Premature mesotrypsinogen activation might lower protective SPINK1 levels in the pancreas and contribute to the pathogenesis of pancreatitis. (2) Characterization of pancreatitis-associated cationic trypsinogen (PRSS1) mutants. Identification of novel mutation-dependent biochemical defects will allow us to refine our model of molecular pathogenesis. (3) Functional analysis of novel anionic trypsinogen (PRSS2) mutants that afford protection against pancreatitis. The concept that loss-of-function trypsinogen mutations can protect against pancreatitis provides independent evidence for the central role of trypsin in this disease. (4) Identification of the disease-causing biochemical defects in pancreatitis-associated SPINK1 mutants. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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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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