The overall objective of the proposed research is to elucidate the role of the DDR2 receptor (discoidin domain receptor 2) in stellate cell activation and hepatic fibrosis. In progressive fibrosis stellate cells undergo an activation in which they proliferate and synthesize a """"""""scar"""""""" matrix rich in type I collagen. Although tyrosine kinase (RTK), 'DDR2', has been cloned from activated stellate cells by degenerate PCR. DDR2 has the unique feature of signaling in response to type I collagen rather than a peptide growth factor, unlike other RTKs. The Hypotheses are: 1) Stellate cell activation is perpetuated by DDR2 signaling in response to type I collagen. 2) Loss of DDR2 responses in stellate cells will diminish their activation and attenuate hepatic fibrosis.
The Specific Aims to test these hypotheses are: 1. To characterize DDR2 expression in vivo in experimental and human liver injury. 2. To explore how extracellular matrix modulates DDR2 expression in cultured rat stellate cells. 3. To characterize cellular events following DDR2 signaling in stellate cells. 4. To assess the importance of DDR2 in hepatic fibrosis using DDR2 knockout mice. The experiments are a direct extension of earlier work in the laboratory elucidating the role of RTKs in stellate cell activation, and are immediately relevant to the pathogenesis of cirrhosis in patients with chronic liver injury and fibrosis. The findings could lead to new treatments for this debilitating and incurable condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056621-03
Application #
6517663
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Doo, Edward
Project Start
2000-05-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$279,192
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Zeng, Zhiping; Wu, Yujing; Cao, Yirong et al. (2018) Slit2-Robo2 signaling modulates the fibrogenic activity and migration of hepatic stellate cells. Life Sci 203:39-47
Tsuchida, Takuma; Lee, Youngmin A; Fujiwara, Naoto et al. (2018) A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol 69:385-395
Lee, Youngmin A; Noon, Luke A; Akat, Kemal M et al. (2018) Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nat Commun 9:4962
de Oliveira da Silva, Brenda; Alberici, Luciane Carla; Ramos, Letícia Ferreira et al. (2018) Altered global microRNA expression in hepatic stellate cells LX-2 by angiotensin-(1-7) and miRNA-1914-5p identification as regulator of pro-fibrogenic elements and lipid metabolism. Int J Biochem Cell Biol 98:137-155
Shalom-Barak, Tali; Liersemann, Jaclyn; Memari, Babak et al. (2018) Ligand-Dependent Corepressor (LCoR) Is a Rexinoid-Inhibited Peroxisome Proliferator-Activated Receptor ?-Retinoid X Receptor ? Coactivator. Mol Cell Biol 38:
Bansal, Ruchi; Nakagawa, Shigeki; Yazdani, Saleh et al. (2017) Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med 49:e396
Wooden, Benjamin; Goossens, Nicolas; Hoshida, Yujin et al. (2017) Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases. Gastroenterology 152:53-67.e3
Hicks, Daniel F; Goossens, Nicolas; Blas-García, Ana et al. (2017) Transcriptome-based repurposing of apigenin as a potential anti-fibrotic agent targeting hepatic stellate cells. Sci Rep 7:42563
Zhang, David Y; Goossens, Nicolas; Guo, Jinsheng et al. (2016) A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut 65:1754-64
Dyvorne, Hadrien A; Jajamovich, Guido H; Bane, Octavia et al. (2016) Prospective comparison of magnetic resonance imaging to transient elastography and serum markers for liver fibrosis detection. Liver Int 36:659-66

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