Pancreatic elastases

Summary

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

Top Publications

  1. pmc Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activation
    Jyotica Batra
    Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida 32224, USA
    J Biol Chem 288:9848-59. 2013
  2. pmc Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis
    Andrea Schnúr
    Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, USA
    Gut 63:337-43. 2014
  3. pmc Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants
    Andrea Geisz
    Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, MA, USA
    FEBS J 280:2888-99. 2013
  4. pmc Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop
    Balázs 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
  5. pmc Variants in CPA1 are strongly associated with early onset chronic pancreatitis
    Heiko 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
  6. pmc Zymogen activation confers thermodynamic stability on a key peptide bond and protects human cationic trypsin from degradation
    Andras 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
  7. pmc Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis
    Balázs 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

Detail Information

Publications8

  1. pmc Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activation
    Jyotica 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...
  2. pmc Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis
    Andrea 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...
  3. pmc Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants
    Andrea 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...
  4. pmc Autoactivation of mouse trypsinogens is regulated by chymotrypsin C via cleavage of the autolysis loop
    Balázs 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. ..
  5. pmc Variants in CPA1 are strongly associated with early onset chronic pancreatitis
    Heiko 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...
  6. pmc Zymogen activation confers thermodynamic stability on a key peptide bond and protects human cationic trypsin from degradation
    Andras 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
    ....
  7. pmc Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis
    Balázs 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. ..

Research Grants30

  1. Alcohol Induced Chronic Pancreatitis
    Craig 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. ..
  2. Trafficking mechanisms for secretory vesicles in pancreatic duct epithelial cells
    Duk Su Koh; Fiscal Year: 2013
    ..The experiments are broadly relevant to treatment of disorders of the digestive system. ..
  3. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
    ..Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease. ..
  4. The role of cigarette smoke toxin and alcohol in pancreatitis
    Edwin 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. ..