PROJECT SUMMARY/Abstract Acute pancreatitis (AP) accounts for over 300,000 admissions in the U.S. with annual costs exceeding $3 billion. Most cases of AP are mild (MAP) with a hospital stay of 3-4 days, but approximately 15% of AP subjects develop severe disease (SAP), defined by presence of persistent organ failure. Up to a third of SAP patients expire from multi-system organ failure after weeks in the intensive care unit. To date, no therapeutic agents have been successful at ameliorating the protracted hospital course of SAP. The National Institute of Diabetes and Digestive and Kidney Diseases workshops identified two critical knowledge gaps as barriers to developing pharmacologic interventions: 1) the establishment of a highly accurate, early prediction tool to identify which subjects will develop SAP during hospitalization; 2) a more in-depth knowledge of SAP mechanistic pathways and immuno-pathogenesis to identify novel therapeutic targets. We propose the MoSAIC Study (iMmune SIgnAtures and ClIniCal outcomes in AP), a prospective multi- center, observational cohort that will address both of these knowledge gaps in SAP. We recently discovered a novel multi-cytokine panel (angiopoetin-2, hepatocyte growth factor, interleukin-8, resistin, and tumor necrosis factor-α receptor-1) that accurately predicts SAP early in the disease process with an accuracy of 0.89 and significantly outperforms existing prediction tools. Aim 1 of this project is to validate the multi-cytokine panel in a large, ethnically diverse AP population across multiple U.S. clinical sites. In preliminary studies, immunologists at the Benaroya Research Institute (BRI) have identified unique immune cell changes such as an increase in monocytes and a decrease of T follicular helper and memory B cells in blood samples of AP patients compared to healthy controls. In Aim 2, the MoSAIC study will extend this work by defining the circulating immune cells that correspond with cytokine signatures in early AP and identifying the immune pathways driving the development of SAP. This will generate the first high-dimensional phenotypic analysis of immune cell types in human AP and provide new insights into its immune mechanisms. MoSAIC investigators have NIH-funded complementary expertise in pancreatitis and immunology. The team is led by well-published pancreatologists at the Ohio State University and immunologists at BRI, supported by a dedicated bioinformatics core at BRI. It also includes three additional academic medical centers with proven track-records of enrolling ethnically diverse populations into prospective AP research trials. Successful completion of the MoSAIC study will have the following impact by: 1) establishing an accurate, early prediction tool for SAP, 2) providing groundbreaking insight into the early immune events of SAP based on robust human data, 3) identifying therapeutic immune targets for further testing, and 4) establishing a U.S. multicenter research platform f...