Associate Provost for Research Boston University Medical Campus
NIA - National Institute on Aging	Research Resources

Abstract

Abstract: 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 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.

Thesaurus Terms:
enzyme activity, pancreatitis, sulfation, trypsinogen
alcoholism /alcohol abuse, molecular pathology, pancreatic juice, posttranslational modification, trypsin
clinical research, enzyme induction /repression, human subject, patient oriented research

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2006
Department:	MOLECULAR AND CELL BIOLOGY
Project Start:	20-SEP-2005
Project End:	31-AUG-2007
ICD:	NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
IRG:	AA