Abstract: The 5-year relative survival of pancreatic ductal adenocarcinoma (PDA) patients is only 8%. PDA is predicted to be the second-leading cause of cancer related death in the U.S. by 2030. Understanding the key signaling mechanisms of tumorigenesis is critical for developing life-saving interventions. Hereditary pancreatitis (HP), an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) which eventually develops into chronic pancreatitis (CP), has a cumulative risk of pancreatic cancer of 44% by age 70 years. Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from human pancreas at early stages of the disease and the lack of animal models that recapitulate the human form of this disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice (J Clin Invest. 2020 Jan 2;130(1):189-202). Transgenic expression of mutant PRSS1 caused severe AP which progresses to CP, precancerous PanIN lesions, and pancreatic cancer. This model of HP will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies to prevent its progression to pancreatic cancer. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors and PRSS1 gene mutation cooperatively cause pancreatic tumorigenesis by intra-acinar cell stress signaling pathways and a trypsin receptor-mediated constant inflammatory milieu. We will characterize these signaling pathways in this newly developed HP model and investigate their roles in pancreatic cancer tumorigenesis by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the pathogenesis of HP, its progression to pancreatic cancer, and provide new insights for developing/testing novel preventive and therapeutic interventions.