The broad, long-term aim of the work proposed in the present application is to determine the role of prior stress and heat shock proteins in regulating the severity of pancreatitis-a disease with considerable morbidity and mortality. The pathophysiological alterations underlying the development and ultimate severity of pancreatitis are not fully understood, but it is generally believed that premature activation of digestive enzyme zymogens within the pancreatic acinar cells themselves leads to acinar cell injury and pancreatitis. The mechanisms involved in this activation process are still controversial. Recent observations suggest that prior stress by either water immersion or hyperthermia ameliorates subsequent development of pancreatitis in rats. This proposal is based on our hypothesis that prior stress prevents pancreatitis by specifically increasing the expression of heat shock proteins (HSPs). Once upregulated, HSPs prevent premature activation of trypsinogen by blocking its colocalization with lysosomal enzymes. Furthermore, we believe that HSPs affect these phenomena by attenuating the sustained rise in intracellular Ca2+ which is normally observed during pancreatitis. The proposed studies will pursue the following specific aims: (a) to determine whether HSPs are actually responsible for post-stress protection against pancreatitis and whether that protection is generalizable to models of pancreatitis other than the caerulein-induced model; (b) to elucidate the mechanism of stress-induced protection against pancreatitis, and (c) to determine the mechanism by which HSPs alter intracellular Ca2+ homeostasis. These studies will use two different models of pancreatitis: (a) caerulein model in mice and rats and (b) bile salt-induced pancreatitis in rats. Stress and HSP expression will be induced by both physical and chemical approaches. Successful completion of these studies will eventually help us in planning strategies to pharmacologically manipulate the levels of HSPs, so that their induction can be used as a tool to decrease the severity of clinical pancreatitis.
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