Alcohol-related acute and chronic pancreatitis is a major health care problem in the U.S. Much effort has been directed at determining the effects of alcohol on the acinar cell, but other factors may be even more important. Earliest changes in patients who ingest alcohol and eventually develop pancreatitis is a functional hyperstimulation of the pancreas which involves over-expression and over-secretion of pancreatic proteins and digestive enzymes that is seen with chronic alcohol use. The mechanism responsible for this phenomena has never been explained. The hypothesis of this proposed project is that it represents a disruption in the neurohormonal control mechanisms regulating the pancreas. This hypothesis is based on a number of recent findings indicating that, under physiologic conditions, the pancreas is primarily under neural control, and that functional hyperstimulation is neurally mediated. The investigators' aims are to clarify the mechanism of alcohol-induced disruption of neurohormonal regulation of pancreatic secretion and to understand the adaptive changes that accompany chronic alcohol ingestion which may predispose patents to acute and chronic pancreatitis.
The specific aims are: (1) to test the hypothesis that alcohol causes pathophysiological differences in functional response of the pancreas to physiologic stimuli and regulatory peptides by disrupting key points that regulate pancreatic secretion; (2) to test the hypothesis that alcohol causes differences in mRNA expression patterns through inhibiting specific genes and/or causing adaptive overexpression of other genes in the key regulatory control tissues of the duodenum, brain, and pancreas; and (3) to test the hypothesis that alcohol- induced changes are mediated through a subset of cells in key control sites. Within this application, specific experiments are outlined to clarify the mechanism through which alcohol disrupts neurally mediated pancreatic exocrine secretion. Different rat models will be used for studies of alcohol ingestion (Lieber-DeCarli diet model) and for measurement of pancreatic secretion (Green conscious rat model). Alcohol-induced changes in the mechanism controlling pancreatic secretion will be determined at a functional level using four different routes of pancreatic stimulation, at a molecular level using quantitative polymerase chain reaction (PCR) and differential display (DD), and at a cellular level using quantitative receptor autoradiography, immunohistochemistry, and in situ hybridization. The investigators expect that this approach will allow identification of significant regulatory mechanism that impact on pancreatic secretion. It is hoped that this new information will be useful in developing new procedures for the management of patients developing alcohol related pancreatitis.
