The IKKNF-?B system is a master regulator of inflammation in pancreatitis. However, we have recently reported that mice with pancreas-specific deletion of I?B kinase ? (IKK?) spontaneously develop pancreatitis, revealing a new role for IKK? in maintaining normal pancreatic function. These mice, termed Ikk??pan, present with acinar cell vacuolation at 3 weeks of age and subsequently progress to pronounced pancreatic damage associated with endoplasmic reticulum (ER) stress, release of digestive enzymes into the circulation, and inflammation. By 3-5 months of age, Ikk??pan mice develop fibrosis and severe chronic pancreatitis. IKK? role in maintaining pancreatic homeostasis is independent of its kinase activity and is unrelated to effects on NF- ?B. Rather, IKK? is required for the completion of autophagy. As a result, IKK?-deficient acinar cells exhibit accumulation of autolysosomes containing partially digested organelles, leading to accumulation of the ubiquitin binding chaperone p62/SQSTM1. Pancreas-specific ablation of p62 attenuates pancreatitis in Ikk??pan mice and reduces expression of ER- and oxidative-stress markers. To further investigate the relationship between autophagy and pancreatitis, and gain better insight into IKK? function in the pancreas, we blocked the initiation of pancreatic autophagy by specific deletion of ATG7 in pancreatic epithelial cells. Atg7?pan mice also developed spontaneous pancreatitis with massive accumulation of p62 aggregates. Importantly, we found prominent accumulation of p62 aggregates in approximately 60% of human chronic pancreatitis specimens that were analyzed. We propose that detailed analysis of p62 function and downstream effectors of IKK? in exocrine pancreas will provide novel insights into the pathogenesis of human pancreatitis leading to new therapeutic and early intervention opportunities. Accordingly, we will pursue the following Specific Aims: 1). Determine the impact of p62 ablation on pancreatic homeostasis in experimental models of pancreatitis. 2). Investigate pancreatic pathology in Atg7?pan mice and determine whether it is attenuated by p62 ablation. 3). Determine the impact of ATG16L2 ablation on pancreatic homeostasis and whether its effects on pancreatic pathology are p62 dependent. 4). Investigate the pathogenic function of p62 and its underlying mechanisms. Project

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