Principal Investigator: Miklos Sahin-Toth
Abstract: DESCRIPTION (provided by applicant): The objectives of the present grant proposal are to characterize the physiological functions of pancreatic elastases and to investigate the mechanism by which elastase mutants act as risk factors for chronic pancreatitis in humans. This grant application is intended to meet a growing need in the pancreas community for the understanding of elastase function both in pancreatic physiology and disease. In humans, there are five pancreatic elastase genes (ELA1, ELA2A, ELA2B, ELA3A, and ELA3B) which give rise to three functional elastases (ELA2A, ELA3A and ELA3B). In the mouse ELA1, ELA2A and ELA3B seem to be expressed. The specific aims studied are designed to address (i) the substrate specificity of human and mouse elastases;(ii) complex formation between proelastases and other pancreatic proteases;and (iii) the functional consequences of proelastase mutations identified in subjects with chronic pancreatitis.
Funding Period: 2013-01-01 - 2016-12-31
more information: NIH RePORT
- Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activationJyotica Batra
Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida 32224, USA
J Biol Chem 288:9848-59. 2013..Our results indicate that long-range electrostatic attraction toward substrates of concentrated negative charge governs substrate discrimination, which explains CTRC selectivity in regulating active digestive enzyme levels...
- Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitisAndrea Schnúr
Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, USA
Gut 63:337-43. 2014..Functional comparison of PRSS1 variants found in sporadic and hereditary cases is needed to resolve this dilemma...
- Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutantsAndrea Geisz
Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, MA, USA
FEBS J 280:2888-99. 2013..The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype that is indistinguishable from typical hereditary pancreatitis...
- Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loopBalázs Csaba Németh
Department of Molecular and Cell Biology, Boston University Henry M Goldman School of Dental Medicine, Boston, Massachusetts 02118, USA
J Biol Chem 288:24049-62. 2013..Instead, inhibition of autoactivation via cleavage of the autolysis loop is the dominant mechanism that can mitigate intrapancreatic trypsinogen activation. ..
- Variants in CPA1 are strongly associated with early onset chronic pancreatitisHeiko Witt
1 Else Kröner Fresenius Zentrum für Ernährungsmedizin EKFZ, Technische Universität München TUM, Freising, Germany 2 Zentralinstitut für Ernährungs und Lebensmittelforschung ZIEL, TUM, Freising, Germany 3 Department of Pediatrics, Klinikum Rechts der Isar MRI, TUM, Munich, Germany
Nat Genet 45:1216-20. 2013..013). The mechanism by which CPA1 variants confer increased pancreatitis risk may involve misfolding-induced endoplasmic reticulum stress rather than elevated trypsin activity, as is seen with other genetic risk factors for this disease...
- Zymogen activation confers thermodynamic stability on a key peptide bond and protects human cationic trypsin from degradationAndras Szabo
From the Department of Molecular and Cell Biology, Boston University Henry M Goldman School of Dental Medicine, Boston, Massachusetts 02118 and
J Biol Chem 289:4753-61. 2014....
- Human cationic trypsinogen (PRSS1) variants and chronic pancreatitisBalázs Csaba Németh
Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, Boston, Massachusetts
Am J Physiol Gastrointest Liver Physiol 306:G466-73. 2014..Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in chronic pancreatitis. ..
- Alcohol Induced Chronic PancreatitisCraig D Logsdon; Fiscal Year: 2013..We will also investigate the mechanisms of alcohol reduction of MT expression. Together these novel models and approaches will provide important new information about the relationship between alcohol and pancreatic disease. ..
- Trafficking mechanisms for secretory vesicles in pancreatic duct epithelial cellsDuk Su Koh; Fiscal Year: 2013..The experiments are broadly relevant to treatment of disorders of the digestive system. ..
- Interactions Between Inflammation, Oxidant Stress and Cardiovascular DiseaseDavid G Harrison; Fiscal Year: 2013..Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease. ..
- The role of cigarette smoke toxin and alcohol in pancreatitisEdwin C Thrower; Fiscal Year: 2013..Findings from this proposal could be broadly relevant to pancreatitis and other diseases in which smoking and alcohol might act together to cause pathology and could also lead to therapeutic targets. ..