The proposed studies will explore the cell biology of several different experimental forms of acute pancreatitis, identify factors which favor the worsening of mild forms of pancreatitis, and test several potential therapies for acute pancreatitis. These studies will build upon and are the natural extension of many investigations already completed by our group which have suggested that intracellular activation of digestive enzyme zymogens by lysosomal hydrolases may be an important triggering event in pancreatitis. To accomplish the goals of these studies, a number of experimental model systems will be selectively employed. These include the diet-induced, secretagogue-induced, and opossum duct ligation models of acute pancreatitis. The effect of ligating the rat pancreatic duct and of obstructing flow in the rabbit pancreatic duct and of supramaximal in-vitro stimulation of rat pancreatic lobules will be studied. This will be a highly collaborative effort in which biochemical-cell physiological studies will be undertaken in Boston by the P.I. while morphological and fluorescence microscopy studies will be performed by a co-investigator in Milan. It can be expected that these studies will greatly expand our understanding of the cell biology of acute pancreatitis and suggest strategies by which this disease can be treated and/or prevented.
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