Associate Provost for Research Boston University Medical Campus
NIDDK - National Institute of Diabetes & Digestive & Kidney Diseases	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): The broad, long-term objectives of this grant-proposal are to understand the molecular mechanisms of human pancreatitis using hereditary pancreatitis and other forms of genetically determined pancreatitis as biochemical models. The most frequently found mutations in genetic pancreatitis affect the PRSS1 gene that codes for human cationic trypsinogen and the SPINK1 gene encoding pancreatic secretory trypsin inhibitor. In the previous funding period our laboratory has developed methodology for the in vitro study of human trypsinogen mutations and through characterization of several pancreatitis-associated mutants we have formulated a working hypothesis. This model states that elevated intraacinar trypsin activity is the fundamental initiating step of genetic pancreatitis and trypsinogen mutations generally exert this effect through increased autocatalytic activation. In the present proposal we seek to extend our mechanistic model, and prove that increased trypsin activity plays the central role in all forms of genetic pancreatitis. The following specific aims will be studied. (1) The role of human mesotrypsin in pancreatitis. Mesotrypsin is a unique protease specialized for the degradation of trypsin inhibitors. Premature mesotrypsinogen activation might lower protective SPINK1 levels in the pancreas and contribute to the pathogenesis of pancreatitis. (2) Characterization of pancreatitis-associated cationic trypsinogen (PRSS1) mutants. Identification of novel mutation-dependent biochemical defects will allow us to refine our model of molecular pathogenesis. (3) Functional analysis of novel anionic trypsinogen (PRSS2) mutants that afford protection against pancreatitis. The concept that loss-of-function trypsinogen mutations can protect against pancreatitis provides independent evidence for the central role of trypsin in this disease. (4) Identification of the disease-causing biochemical defects in pancreatitis-associated SPINK1 mutants.

Thesaurus Terms:
genetic disorder, pancreatitis, protein structure function, trypsin
anion, cathepsin B, disease /disorder model, genetic polymorphism, model design /development, mutant, protein degradation, zymogen
SDS polyacrylamide gel electrophoresis

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2006
Department:	MOLECULAR AND CELL BIOLOGY
Project Start:	01-MAY-2001
Project End:	31-JAN-2010
ICD:	NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
IRG:	CIGP