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.
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.
|Hegyi, Eszter; Sahin-Tóth, Miklós (2017) Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway. Dig Dis Sci 62:1692-1701|
|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|
|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|
|Kereszturi, Éva; Sahin-Tóth, Miklós (2017) Pancreatic Cancer Cell Lines Heterozygous for the SPINK1 p.N34S Haplotype Exhibit Diminished Expression of the Variant Allele. Pancreas 46:e54-e55|
|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|
|Párniczky, Andrea; Hegyi, Eszter; Tóth, Anna Zsófia et al. (2016) Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis. Int J Mol Sci 17:2148|
|Balázs, Anita; Hegyi, Péter; Sahin-Tóth, Miklós (2016) Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 310:G477-86|
|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|
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