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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Setiawan, Veronica Wendy; Monroe, Kristine R; Pandol, Stephen J (2017) Reply. Clin Gastroenterol Hepatol 15:1139
Messenger, Scott W; Jones, Elaina K; Holthaus, Conner L et al. (2017) Acute acinar pancreatitis blocks vesicle-associated membrane protein 8 (VAMP8)-dependent secretion, resulting in intracellular trypsin accumulation. J Biol Chem 292:7828-7839
Bustos, Victor; Pulina, Maria V; Kelahmetoglu, Yildiz et al. (2017) Bidirectional regulation of A? levels by Presenilin 1. Proc Natl Acad Sci U S A 114:7142-7147
Bustos, Victor; Pulina, Maria V; Bispo, Ashley et al. (2017) Phosphorylated Presenilin 1 decreases ?-amyloid by facilitating autophagosome-lysosome fusion. Proc Natl Acad Sci U S A 114:7148-7153
Eibl, Guido; Cruz-Monserrate, Zobeida; Korc, Murray et al. (2017) Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet :
Birtolo, Chiara; Pham, Hung; Morvaridi, Susan et al. (2017) 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 187:146-155
Gorelick, Fred S; Lerch, Markus M (2017) Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cell Mol Gastroenterol Hepatol 4:251-262
Lew, Daniel; Afghani, Elham; Pandol, Stephen (2017) Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment. Dig Dis Sci 62:1702-1712
Lugea, Aurelia; Gerloff, Andreas; Su, Hsin-Yuan et al. (2017) The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells. Gastroenterology 153:1674-1686

Showing the most recent 10 out of 63 publications