Pancreatitis is a potentially fatal disease with significant morbidity and mortality the pathogenesis of which remains obscure. Specific therapies to prevent pancreatitis or reduce injury are lacking. The proposed Program focuses on disorders of key orgenells in the pancreatic acinar cell as a central pathogenic mechanism initiating and driving pancreatitis. The physiologic function of the acinar cell is to synthesize, transport, store, and secrete digestive enzymes. These functions rely on the actions of endoplasmic reticulum (ER), the endo- lysosomal system and autophagy to coordinate protein synthesis, processing, trafficking and degradation. Based on our published and preliminary studies, we propose the following novel hypothesis: dysfunction of acinar cell organellar machinery that mediates protein processing, trafficking, and degradation initiates and promotes the cellular pathology of pancreatitis. We propose four Projects that use multidisciplinary approaches to study the following in the context of acute pancreatitis: The role of key regulators of protein trafficking, Rab GTPases, in endosomal and lysosomal/autophagic dysfunction in pancreatitis (Project 1);The role of regulatory proteins D52, Rab5 and AP3 in inhibition of secretion and intracellular zymogen activation (Project 2);The roles of the multifunctional scaffold protein p62/SQSTM1 and impaired autophagy in the pathogenesis of pancreatitis (Project 3);The role of ER stress responses, and particularly the ER stress regulator sXBP1, in defective endosomal function, autophagy, and secretion inhibition (Project 4). The Projects use three supporting Cores which will perform standardized animal models of pancreatitis on wild-type and genetically modified mice, generate new mouse lines, provide histopathologic evaluation of human pancreatic tissue, isolation of human acinar cells, viral transduction of both mouse and human acinar cells, and Web-based resource repository and data sharing system. Thus, the Program will elucidate novel pathogenic mechanisms of pancreatitis resulting from disorders of key acinar cell organelles; identify new molecular targets and promote the development of new therapeutic approaches for disease treatment;integrate and catalyze the work of investigators with various areas of expertise to define the mechanism of pancreatitis.

Public Health Relevance

Overall Research Strategy: Narrative Pancreatitis is a potentially fatal disease with significant morbidity and mortality the pathogenesis of which remains obscure. Specific therapies to prevent pancreatitis or reduce injury are lacking. The proposed Program focuses on disorders of key orgenells in the pancreatic acinar cell as a central pathogenic mechanism initiating and driving pancreatitis. It is comprised of four research Projects and three supporting Cores. The results of proposed studies will elucidate novel pathogenic mechanisms of pancreatitis, identify new molecular targets and promote the development of new therapeutic approaches for disease treatment, and integrate and catalyze the work of investigators with various areas of expertise to define the mechanism of pancreatitis.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
1P01DK098108-01A1
Application #
8743013
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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 :

Showing the most recent 10 out of 40 publications