application) Acute pancreatitis is an inflammatory disease with significant mortality, affecting about 80,000 Americans a year. The pathophysiologic mechanisms are not thoroughly elucidated, and to date there are few if any effective treatments. Calcium and lipid mediators are integral components of the signaling cascade involved in pancreatic inflammation. Changes in blood calcium levels have been associated with acute pancreatitis, both in humans and in laboratory animals. The recently cloned calcium-sensing receptor (CaSR), a G protein-coupled receptor (GPCR), by virtue of its ability to stimulate inflammatory lipid mediator synthesis, provides a possible mechanism for how calcium, lipid mediators and acute pancreatitis are linked. In fact, recent findings suggest that the CaSR in the pancreas is upregulated during acute pancreatitis in the rat. The hypothesis for the proposed studies is that the pancreatic CaSR is involved in initiating and/or propagating acute pancreatitis by activating PLA2, which stimulates lipid mediators involved in the inflammatory cascade. In this proposal, molecular biologic, biochemical and physiologic approaches will be combined to investigate the role of the pancreatic CaSR in experimental acute pancreatitis. The secretagogue (eg. cerulein) hyperstimulation model in rats is a well established model in which hourly administration of high doses of cerulein for 6 hours induces an edematous acute pancreatitis. Multiple techniques will be used to test the hypothesis by addressing the following specific aims: (1) to identify the pancreatic cells which express the functional CaSR; (2) to determine whether the CaSR is directly involved in acute pancreatitis in the rat; (3) to examine whether cytoskeletal depolymerization during acute pancreatitis provides a mechanism for how the CaSR is upregulated in cerulein-induced pancreatitis; (4) to examine whether there is """"""""cross-talk"""""""" between the cholecystokinin A (CCK-A) receptor and the CaSR which might lead to activation of the CaSR in cerulein-treated rats. While the role of the CaSR in inherited diseases is emerging, its function in inflammatory conditions remains unknown. Since the CaSR activates lipid mediator synthesis, its potential role in inflammation seems logical and represents an exciting and novel possibility. Also, this study might serve as a paradigm for inflammatory conditions other than pancreatitis, the treatments for which have remained elusive.
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