M1871 Use of Mathematical and Statistical Model Predictions to Identify a Novel Pancreas-Specific Class of CFTR Variants Linked to SPINK1 Mutations and Idiopathic Chronic Pancreatitis

Introduction: The genetic events and molecular mechanisms underlying pancreatic regeneration after acute pancreatitis are poorly understood. Cerulein, a cholecystokinin analog, induces acute pancreatitis in mice with pronounced acinar cell injury and acinar-ductal metaplasia within three days. Thereafter, regeneration with normal pancreatic cellular morphology and function occurs. Methods: To address what molecular factors promote injury and regeneration, we isolated RNA and performed gene expression analysis of the challenged cell population at different time points (day 0, 1, 3, and 5) by using the cerulein-induced acute pancreatitis in C57BL/6 mice and saline in age-matched wild-type littermates. Results: Unsupervised gene clustering analysis underscored that changes in gene expression are mostly limited to the early time points, specifically days 1-3, consistent with the observed morphologically changes. The experimental design of this study allowed us to identify temporally regulated genes during defined phases of injury and regeneration. On day 1 of pancreatitis 224 genes were highly significant upor down-regulated, respectively (more than 2.5-fold, false discovery rate 0.1), compared to day 0 and matched controls. Analysis of the gene expression data by computational pathway analysis tools revealed several specific regulatory networks that are deregulated. Interestingly, besides pathways that regulate DNA replication, and repair, cell cycle, cellular assembly and organization, as well as embryonic development, the top networks are related to growth, proliferation, tumor morphology, and cancer. Conclusion: This study not only provides new insights into gene expression during regeneration but might provide evidence for overlapping and distinct gene expression signatures of development, regeneration, and cancer in the pancreas.