Hepatocyte apoptosis results in repair responses including hepatic stellate cell (HSC) chemotaxis, contraction and matrix remodeling. The signals from apoptotic hepatocytes which modulate these responses are poorly identified. The uric acid pathway (UAP) mediates the breakdown of purines to uric acid. Flux through this pathway is greatly increased in tissues .undergoing cellular death by necrosis or apoptosis, and UAP metabolites regulate cellular responses to injury in many organs. We show that in primary mouse HSC adenosine i) results in inhibition of PDGF induced Ca++ mobilization and chemotaxis in HSC ii) induces actin reorganization and contraction of HSC via the A2a receptor iii) upregulates TGF beta and collagen 1 mRNA. A number of other UAP metabolites including uric acid also induce HSC contraction, and in addition upregulate TGF beta and collagen 1 mRNA. Distal inhibition of the UAP results in greater fibrosis in two models of liver injury. The hypothesis for this proposal is that metabolites of the UAP regulate HSC differentiation in response to tissue injury in the liver.
Specific Aim 1 : a) Determine the intracellular signaling pathways responsible for adenosine mediated actin reorganization and HSC contraction b) Determine the role of the cAMP, PKA pathway in adenosine mediated inhibition of PDGF induced cytosolic Ca++ increase.
Specific Aim 2 : a) Determine if UAP metabolites downstream of adenosine inhibit ATP and PDGF mediated Ca++ mobilization and chemotaxis of primary HSC b) Establish the requirement for adenosine receptors in the effect of UAP metabolites downstream of adenosine with the exception of uric acid c) Determine the intracellular signaling pathways responsible for uric acid induced HSC differentiation.
Specific Aim 3 : a) Determine the role of the immune system in adenosine mediated regulation of liver fibrosis in-vivo. b) Determine the ability of adenosine to regulate intrahepatic vascular resistance in cirrhotic livers. We have identified a new role for the UAP in HSC differentiation and regulation. This identifies a new set of molecules with a role in hepatic repair, and has implications for new therapies in liver fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK076674-05
Application #
8103840
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2007-08-10
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$325,873
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hoque, Rafaz; Mehal, Wajahat Z (2015) Inflammasomes in pancreatic physiology and disease. Am J Physiol Gastrointest Liver Physiol 308:G643-51
Farooq, Ahmad; Hoque, Rafaz; Ouyang, Xinshou et al. (2014) Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a ?-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307:G732-40
Hoque, Rafaz; Farooq, Ahmad; Ghani, Ayaz et al. (2014) Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 146:1763-74
Hoque, Rafaz; Farooq, Ahmad; Malik, Ahsan et al. (2013) A novel small-molecule enantiomeric analogue of traditional (-)-morphinans has specific TLR9 antagonist properties and reduces sterile inflammation-induced organ damage. J Immunol 190:4297-304
Shaker, Mohamed E; Ghani, Ayaz; Shiha, Gamal E et al. (2013) Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases. Biochim Biophys Acta 1833:1992-2003
Hoque, Rafaz; Vodovotz, Yoram; Mehal, Wajahat (2013) Therapeutic strategies in inflammasome mediated diseases of the liver. J Hepatol 58:1047-52
Ouyang, Xinshou; Ghani, Ayaz; Malik, Ahsan et al. (2013) Adenosine is required for sustained inflammasome activation via the A?A receptor and the HIF-1? pathway. Nat Commun 4:2909
Watanabe, Azuma; Sohail, Muhammad Adnan; Gautam, Samir et al. (2012) Adenine induces differentiation of rat hepatic stellate cells. Dig Dis Sci 57:2371-8
Hoque, Rafaz; Sohail, Muhammed Adnan; Salhanick, Steven et al. (2012) P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol 302:G1171-9
Henao-Mejia, Jorge; Elinav, Eran; Jin, Chengcheng et al. (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179-85

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