HORMONAL REGULATION OF CULTURED PANCREATIC ACINAR CELLS

点击翻译按钮获取中文摘要

The objective of this research is to elucidate the physiologic regulation of pancreatic acinar cell growth. We propose to utilize in vitro models to characterize intracellular mechanisms involved in pancreatic acinar cell growth regulation. In vitro models are required due to the complexity of the regulatory systems modulating growth. Furthermore, in vitro models make available biochemical and molecular biological techniques that are difficult or impossible to use in vivo. Previously, we developed a primary culture of mouse acinar cells which responds trophically to cholecystokinin (CCK). We also developed as a physiologic model the rat acinar AR42J cell line, which retains differentiated responses to CCK. In the present proposal, we will pursue three major aims: 1) Characterize the intracellular mechanisms involved in cholecystokinin (CCK) stimulation of acinar cell growth. We will investigate the roles of PI hydrolysis, Ca2+, protein kinase C, eicosinoids, cAMP, and oncogenes. 2) Study the inhibition of acinar cell growth by transforming growth factor-B (TGF-B). TGF-B inhibits pancreatic acinar cell growth in vitro and may have an important role in the regulation of acinar cell growth in vivo. We will characterize this inhibitory action and investigate the intracellular mechanisms involved. 3) Investigate the regulation of expression of the nuclear oncogenes c-fos, c-jun, and c-myc and their relevance to pancreatic acinar cell growth. We will elucidate the mechanisms underlying the effects of CCK and TGF-B on the expression of these oncogenes and the relevance of their expression on acinar cell growth. Information on acinar cell growth is relevant to the understanding of pancreatic diseases including pancreatitis, cystic fibrosis, and cancer.