THE ABSENCE OF AN EXOCRINE SPECIFIC TRANSCRIPTION FACTOR, MIST1, LEADS TO INCREASED SEVERITY IN SECRETAGOGUE INDUCED PANCREATITIS.

Abstract

Gallstone migration into the common duct and alcohol abuse are the most common causes of pancreatitis. There is also evidence for genetic basis for the susceptibility to the disease. Unfortunately, with the exception of the cationic trypsinogen gene and SPINK, there is a lack of knowledge of the factors leading to increased disease susceptibility and severity. In an effort to link factors that regulate pancreatic development and function to disease susceptibility, we have examined of the role of Mist1 in pancreatitis. Mist1 is a basic helix-loop-helix (bHLH) transcription factor, highly expressed in acinar cells and the absence of Mist1 in mice (Mist1KO) results in incomplete maturation of acinar cells. In addition, Mist1KO mice exhibit premature enzyme activation and an increased presence of stellate cells, which are hallmarks of pancreatitis yet these mice do not develop the disease. We hypothesize that Mist1KO mice will develop more severe pancreatitis than wild type litter mates. To address this hypothesis, we have injected supramaximal amounts of caerulein, a cholecystokinin analogue. Analysis of serum following initiation of pancreatitis reveal higher levels of amylase in Mist1KO mice suggesting a more severe form of pancreatitis. Histological analysis confirms this suggestion as Mist1KO pancreatic tissue exhibits a progressive degeneration characterized by distended duct formation, vacuolization, pronounced fibrosis and a decrease in cells undergoing apoptosis. To identify additional factors that may play a role in disease susceptibility, widespread analysis by gene microarray was used to compare the molecular profile of wild type and Mist1KO mice. We have identified a number of genes that are differentially expressed in wild type and Mist1KO mice that may be linked to either protection or severity to pancreatitis. Current studies are underway to determine the importance of these factors in the disease process and their potential regulation by Mist1. Our results indicate that the transcription factor, Mist1 plays a role in dictating the severity of pancreatitis making the Mist1KO mouse a good model for studying the factors involved in the modulation of the disease process.