Acute and chronic pancreatitis occurs in some people who abuse alcohol. In these disorders, the pancreatic acinar cell represents a key participant in the pathogenesis of the disease. Past work from our laboratory has shown that the acinar cell generates pro-inflammatory cytokines and chemokines and undergoes cell death through apoptosis and necrosis. The levels of protein synthesis in the acinar cell required for digestive processes are among the highest in the body and increase further after physiologic stimulation. Many of these nascent proteins must undergo folding before exiting the endoplasmic reticulum (ER). ? ? When the proteins do not fold appropriately because of genetic or epigenetic changes in their structures, they are not able to exit the ER and cause """"""""ER stress"""""""" or unfolded protein response (UPR). The UPR represents a set of signaling networks that can attenuate the ER stress by upregulation of the expression of ER chaperones and folding enzymes as well as decrease the protein synthetic load. Based on the observations related to the UPR presented in our preliminary studies we present novel hypotheses for testing. These include the suggestion that alcohol abuse can initiate an ER stress response in the pancreatic acinar cell by causing epigenetic alterations in nascent proteins. In most cases of alcohol abuse the protective components of the UPR (i.e. expression of ER chaperones and folding enzymes; and repression of translation of mRNA) prevail and prevent cellular pathology. ? ? However, in other cases the protective components of the UPR are exceeded leading to pathologic responses (i.e. inflammation, cell cycle arrest and cell death). The present project is designed to further characterize the effects of both alcohol treatments and neurohumoral stimulation on the signaling networks of the UPR and correlate these effects with the pathologic signaling responses of pancreatitis such as inflammation and cell death. In addition, we will directly test the protective role one of the UPR signals, X-box binding protein 1 (XBP1) using animals with gene deletion for this signal. The results deriving from this project will allow us to pursue further projects on integrating the effects of ethanol on the UPR to the pathological responses of pancreatitis due to ethanol as well as provide. ? ?
