Acute pancreatitis, an inflammatory disease of the pancreas, causes death in over 30% of those with severe disease. Specific therapies to prevent pancreatitis or reduce injury are lacking. The disease usually originates in the pancreatic acinar cell after exposure to specific insults that cause pathologic acinar cell signaling. These changes in acinar cell signaling change the function of specific target proteins and cause organelle dysfunction. Among the most characteristic acinar cell early pancreatitis responses are intracellular activation of digestive enzymes (especially proteases) and inhibited secretion. Recent studies from Program investigators have also shown that there is decreased lysosomal function in acute pancreatitis. This Project will examine two recently characterized proteins (AP3 and D52) that can modulate zymogen activation, secretion, and may also affect autophagy and lysosomal function. We hypothesize that these two proteins regulate the biogenesis and trafficking of the minor secretory compartment (MSC), a pathway needed to form zymogen granules (ZG) from immature secretory granules (ISG). We posit that this compartment also regulates apical secretion and contributes to the normal function of the endo-lysosomal pathway. Finally, we propose a new model for zymogen activation at the onset of pancreatitis that begins with zymogen activation in the MSC then proceeds to decreased degradation of active enzymes by lysosomes.
Three Specific Aims relating to AP3 and D52 and its binding partner, Rab5, are planned: 1) Investigate their role in regulating physiologic secretion and membrane trafficking 2) Examine their expression and localization in pancreatitis models 3) Determine whether changing their expression levels affects pancreatitis responses. Finally, we will collaborate with other Projects to determine whether these molecules affect other pathways under study. Studies are planned using isolated mouse and human pancreatic acinar cells and in vivo mouse pancreatitis models. Our preliminary studies indicate that during pancreatitis, the levels of expression of these proteins change. Further, over-expression or deletion of these proteins by genetic or molecular means has dramatic effects on lysosomal protein trafficking, zymogen activation, and cell injury. Preliminary findings also suggest that the functions of AP3 and D52 may interact with pathways under study by other projects, such as Rab GTPases in Project 1, autophagic pathways in Project 3, and ER stress in Project 4. Extensive use of the Program's Animal and Pathology, Vector and Human Acinar, and Resource Management and Biostatistics Cores is planned.

Public Health Relevance

Project 2: Narrative Acute pancreatitis is an inflammatory disease of the pancreas that can cause death in 30% of those with severe disease. We have identified a new mechanism involving specific proteins that regulate trafficking in the pancreatic acinar cell and find that these can be manipulated to protect against pancreatitis. We will study these proteins to understand their role in health and disease with the goal of designing a therapy.

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University of California Los Angeles
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Donahue, Timothy R; Dawson, David W (2016) Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality. Trends Endocrinol Metab 27:770-781
Birtolo, Chiara; Pham, Hung; Morvaridi, Susan et al. (2016) Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration. Am J Pathol :
Yuan, Jingzhen; Pandol, Stephen J (2016) PKD signaling and pancreatitis. J Gastroenterol 51:651-9
Principe, Daniel R; DeCant, Brian; Mascariñas, Emman et al. (2016) TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76:2525-39
Birtolo, Chiara; Go, Vay Liang W; Ptasznik, Andrzej et al. (2016) Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer. Pancreas 45:21-31
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Moris, Maria; Dawson, David W; Jiang, Jennifer et al. (2016) Plectin-1 as a Biomarker of Malignant Progression in Intraductal Papillary Mucinous Neoplasms: A Multicenter Study. Pancreas 45:1353-8
Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910
Toste, Paul A; Nguyen, Andrew H; Kadera, Brian E et al. (2016) Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK. Mol Cancer Res 14:437-47
Setiawan, Veronica Wendy; Pandol, Stephen J; Porcel, Jacqueline et al. (2016) Dietary Factors Reduce Risk of Acute Pancreatitis in a Large Multiethnic Cohort. Clin Gastroenterol Hepatol :

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