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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK098108-05
Application #
9527127
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Serrano, Jose
Project Start
2014-09-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Buxbaum, James; Quezada, Michael; Chong, Bradford et al. (2018) The Pancreatitis Activity Scoring System predicts clinical outcomes in acute pancreatitis: findings from a prospective cohort study. Am J Gastroenterol 113:755-764
Zhao, Qinglan; Wei, Yi; Pandol, Stephen J et al. (2018) STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology 154:1822-1835.e2
Yuan, Jingzhen; Tan, Tanya; Geng, Meng et al. (2017) Novel Small Molecule Inhibitors of Protein Kinase D Suppress NF-kappaB Activation and Attenuate the Severity of Rat Cerulein Pancreatitis. Front Physiol 8:1014
Setiawan, Veronica Wendy; Monroe, Kristine R; Pandol, Stephen J (2017) Reply. Clin Gastroenterol Hepatol 15:1139

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