The overall, long-term objective of this application is to better understand the lineage relationships of pancreatic duct and acinar cells and the potential for these cells to alter their phenotypes in the adult animal. The normal adult pancreas is a tissue of low mitotic activity composed of an arrangement of acinar, duct, and islet cells whose phenotypes are stable. The two major diseases of the pancreas, pancreatitis and cancer, involve cell division and alterations in exocrine cell phenotype. After acute pancreatitis cell division is activated for recovery of normal function. While the tissue is recovering acinar cells can exhibit an altered morphology and may appear dedifferentiated or duct cell-like. Eventually, the differentiated morphology returns. In pancreatic cancer loss of regulation of cell division and aberrant cell growth occurs. Because most cancers of the pancreas have an undifferentiated (duct cell-like) morphology, they have been considered to be of ductal origin, but the possibility that they arise from acinar cells of altered phenotype should be considered. A better understanding of regulation of the induction and maintenance of differentiation, and the potential for phenotypic changes in pancreatic exocrine cells will add knowledge that will be useful understanding the etiology and possible treatments of these pancreatic diseases.
The specific aims are: (1) to document and determine the extent of the phenotypic switching of acinar cells to duct-like cells and back to acinar-like cells in primary culture; (2) to determine the phenotypic stability of duct cells in culture and their suitability as immunogen for generating mAbs to duct cells and duct cell precursors; (3) to develop monoclonal antibodies that differentiate between mature duct and acinar cells and their precursor cell(s); (4) using the monoclonal antibodies, to follow the appearance and loss of these cell-type specific markers as the pancreas develops in the embryo; (5) to follow the expression of duct cell markers on growing acinar cells in vivo using fetal development and recovery from experimentally-induced acute pancreatitis as models.
