Pancreatic fibrosis is a key feature of alcoholic chronic pancreatitis, a pathology for which effective treatments are currently lacking. To develop rational strategies for the prevention and treatment of pancreatic fibrosis, the regulation of extracellular matrix (ECM) synthesis and degradation needs to be fully understood. Activated pancreatic stellate cells (PSC) are the major source of ECM proteins in fibrotic pancreatic tissues. Pro-inflammatory cytokines and ethanol have been identified as major factors involved in PSC activation. However, the precise mechanisms underlying ethanol-induced PSC activation remain unclear. Extracellular proteolysis associated with the urokinase-type plasminogen activator system (uPA) is increasingly recognized as central to processes including ECM degradation, cell migration, cell adhesion and cell proliferation. Although compelling evidence associates the uPA system with fibrogenesis and inflammation, its participation in pancreas pathology remains largely unknown. In particular, the role of the uPA system in PSC, the main player in pancreatic fibrosis, has not been investigated. Our preliminary studies demonstrate that components of the system (uPA, its receptor uPAR and its specific inhibitor PAI-1) are produced in culture-activated but not in freshly isolated quiescent PSC, suggesting a role for the uPA system in the activated phenotype. Furthermore, addition of known PSC activators such as ethanol or growth factors in the culture medium promotes the activity of uPA. Active uPA in turn activates ECM- degrading proteases such as plasmin and metalloproteases. Therefore, we hypothesize that the uPA system is an important regulator of the activated phenotype in PSCs The system can participate in ECM remodeling through its capacity to break down ECM proteins and activate other ECM-degrading proteases. In addition, the system can modulate cell proliferation, cell migration and cell adhesion through activation of latent growth factors and cytokines and through non-proteolytic functions related with complex interactions with other systems such as integrins and signal transduction via protein kinase cascades. In addition, we hypothesize that ethanol or other factors modify PSC behavior by inducing changes in the uPA system.
The specific aims of this proposal are to examine whether known activators such as ethanol and growth factors modulate the expression and activity of the uPA system in rat PSC in culture and to explore the role of the uPA system on PSC responses (activation, proliferation and migration) to growth factors and ethanol. The completion of these objectives will provide insights into the participation of the uPA system in the maintenance of pancreas architecture and in the pathogenesis associated with alcohol abuse. Therapeutic strategies focusing on the regulation of uPA activation may be central in preventing or reverting alcohol-induced pancreas fibrosis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
1R03AA016008-01A1
Application #
7144743
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Purohit, Vishnu
Project Start
2006-09-05
Project End
2008-08-31
Budget Start
2006-09-05
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$61,800
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Shi, Jian-Yu; Huang, Hua; Li, Jia-Xin et al. (2018) TMFUF: a triple matrix factorization-based unified framework for predicting comprehensive drug-drug interactions of new drugs. BMC Bioinformatics 19:411
Shi, Jian-Yu; Li, Jia-Xin; Gao, Ke et al. (2017) Predicting combinative drug pairs towards realistic screening via integrating heterogeneous features. BMC Bioinformatics 18:409
Shi, Jian-Yu; Huang, Hua; Zhang, Yan-Ning et al. (2017) Predicting binary, discrete and continued lncRNA-disease associations via a unified framework based on graph regression. BMC Med Genomics 10:65
Pandol, Stephen; Gukovskaya, Anna; Edderkaoui, Mouad et al. (2012) Epidemiology, risk factors, and the promotion of pancreatic cancer: role of the stellate cell. J Gastroenterol Hepatol 27 Suppl 2:127-34
Schmitz, John C; Protiva, Petr; Gattu, Arijeet K et al. (2011) Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1. Am J Pathol 179:2990-9
Pandol, Stephen; Edderkaoui, Mouad; Gukovsky, Ilya et al. (2009) Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 7:S44-7