Role of trypsinogen sulfation in alcoholic pancreatitis

Boston University Medical Campus, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The main objective of this exploratory grant is to investigate the hypothesis that alcoholic pancreatitis is caused by premature intrapancreatic trypsinogen activation, as a result of altered post-translational modification of trypsinogen. We propose that alcohol might alter the functional properties of trypsin(ogen) by affecting the extent of post-translational sulfation of a tyrosyl sidechain on the surface of the trypsinogen molecule. This aberrant trypsinogen would result in [unreadable] enhanced trypsinogen activation or increased trypsin stability in the pancreas. This hypothesis draws support from our recent knowledge that hereditary pancreatitis-associated mutations in the cationic trypsinogen result in atypical trypsinogen molecules, which exhibit faster activation or higher stability. We propose that ethanol-induced changes in the post-translational sulfation of human trypsinogens might mimic the effects of certain hereditary pancreatitis-associated mutations, and cause alcoholic pancreatitis. Our major specific aims are to (1) characterize the posttranslational modifying group on human trypsinogens; (2) examine the functional consequences of post-translational sulfation of human trypsinogens; (3) develop a facile method to monitor the extent of post-translational sulfation of trypsinogens, and (4) investigate how trypsinogen sulfation is altered in alcoholic and idiopathic chronic pancreatitis. [unreadable] [unreadable] [unreadable]