Altered Morphology And Composition Of Zymogen Granules In Acute Pancreatitis

ALTERED MORPHOLOGY AND COMPOSITION OF ZYMOGEN GRANULES INACUTE PANCREATITISby AMANDA FLACKAugust 2014Advisor: Dr. Bhanu JenaMajor: PhysiologyDegree: Doctor of PhilosophyIn healthy physiology, pancreatic digestive enzymes secreted following a meal are storedas inactive zymogens within membrane-bound secretory vesicles called Zymogen Granules(ZG), and activated extracellularly. In acute pancreatitis however, the digestive enzymes areprematurely activated within the cell, resulting in autodigestion of the tissue. Pancreatitis isgastrointestinal disorder in which there are over 200,000 hospitalizations per year with a 5%mortality rate. It has been demonstrated that in acute pancreatitis the digestive enzymes areblocked from being secreted and are activated within the cell leading to acinar cell andsurrounding pancreatic tissue death. Little is known about the specific mechanism and the proteins and lipids that might participate in this process. Here it is reported that in acute pancreatitis, there are specific changes to both the proteome and lipidome of the ZG, contributing to altered ZG morphology and function. Using EM and AFM it is demonstrated that there is an increase in ZG size as early as 2h following induction of acute pancreatitis. LC-MS-based lipid and protein profiling and immunochemistry, collectively demonstrate altered ZG volume and activity regulating proteins and lipids, in acute pancreatitis.