Project 4: Abstract Spliced X box-binding protein-1 (sXBP1) is prominent endoplasmic reticulum (ER) stress response factor of the Unfolded Protein Response (UPR) of the ER. The highly developed ER and protein processing and trafficking organelles of the pancreatic acinar cell are consistent with its specialized role as the site of synthesis and trafficking of large quantities of digestive enzymes. XBP1 is specifically necessary for development of exocrine pancreatic tissue and we have published and present further preliminary data here that inhibition of its expression promotes organellar disorders and cellular failure of the pancreatic acinar cell;and that increases in its expression are associated with protection from organellar disorders and cellular failure with stressors that cause pancreatitis. We find that XBP1s inhibition correlates with activation of additional ER- originating signals associated with inflammation and cell death, i.e., the PKR-like endoplasmic reticulum kinase (PERK) and C/EBP homologous protein (CHOP), i.e., pathways that promote the latter responses. Little is known about the regulation of XBP1s in exocrine pancreas. Our preliminary data suggest roles for calcium metabolism, ATP and a functionally pleiotropic ER transmembrane protein, Bax inhibitor-1 (BI-1) in regulating sXBP1. On the basis of these observations, we propose a series of hypotheses: that pancreatic acinar cell sXBP1 expression is subject to regulation by multiple factors including cellular Ca2+ responses;BI-1 expression;and mitochondrial ATP production. In response to stress, sufficient sXBP1 responses are required to feed back to restore control over many of these same factors to maintain cellular homeostasis. In contrast, sXBP1 deficiency exacerbates ER stress and leads to over-activation of the pathologic arm of the UPR (PERK/eIF2 /CHOP), disturbances of protein trafficking, and pancreatitis. We will pursue 3 aims in this project.
Aim 1 will investigate the regulation of sXBP1 expression;
Aim 2 is to determine the effects of sXBP1 expression insufficiency on UPR (PERK/eIF2 /CHOP), disturbances of protein trafficking, and pancreatitis;and the final aim is devoted to demonstrating that increasing sXBP1 expression enhances protective responses in the exocrine pancreas. Because of our initial findings that sXBP1 has significant effects on the endo-lysosomal/trafficking systems investigated in other projects in this program, it is highly integrated into the Program Project. Because we will show that sXBP1 can attenuate trafficking disorders and protect against pancreatitis, the project is highly translational.
Project 4: Narrative Pancreatitis is initiated in the acinar cell of the pancreas, which is a protein factory making significant amounts of digestive enzyme proteins to digest meals. These digestive enzymes are made in the endoplasmic reticulum that uses a signal called X-box protein-1 (XBP1) to help operate the function of machinery in the acinar cell to make sure that the digestive enzymes made are moved safely through the acinar cell and secreted out into the intestine. The project is designed to determine how problems with regulation of XBP1 lead to disorders of movement of the digestive enzymes which, in turn, results in pancreatitis.
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