The broad, long-term objectives are to determine the mechanisms of action of connective tissue growth factor (CTGF), which stimulates vital biological processes such as chondrogenesis, angiogenesis and matrigenesis. CTGF, a 38kDa protein comprising 4 structural modules (modules 1-4), drives cell differentiation during embryogenesis, and tissue remodeling during development, wound healing and placentation. CTGF-null mice exhibit lethal angiogenic and skeletal defects. Excessive CTGF production is a hallmark of hepatic fibrosis and cirrhosis, which are the 9th leading cause of death in the West. CTGF contributes to liver pathogenesis because it promotes adhesion, chemotaxis, proliferation and collagen production in hepatic stellate cells (HSC), a major fibrogenic cell type. This is achieved via binding between CTGF and cell surface receptors such as integrins and low density lipoprotein receptor related protein (LRP). Chronic liver fibrosis, such as that caused by excessive alcohol consumption, may require a sustained interaction between CTGF and transforming growth factor beta (TGF-b), the latter of which is also strongly implicated in liver fibrosis and is a stimulus for CTGF production. Our hypothesis is that CTGF-mediated HSC fibrogenesis is driven through the ability of CTGF to interact with specific integrin subtypes or LRP, downstream of TGF-b- or ethanol-induced CTGF production.
The Specific Aims to test this hypothesis are: 1. Establish the integrin avb3-dependency of CTGF-mediated fibrogenesis and survival in HSC in vitro; 2. Establish the regulation of HSC function by interactions between LRP or integrin a6b1 and module 3 of CTGF 3. Establish the mechanisms of ethanol-mediated CTGF regulation in HSC. Through the proposed studies, we will establish the underlying mechanisms of CTGF-induced fibrogenic pathways in HSC. In the USA, 5.5 million people suffer from chronic liver disease or cirrhosis yet fibrotic disease represents one of the largest groups of disorders for which there is no effective therapy, and thus represents a major unsolved medical challenge. Our studies will give a new lead to the development of novel anti-fibrotic treatments by identifying critical points of intervention in pathways of CTGF action. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA016003-01A2
Application #
7263604
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2007-04-15
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$324,000
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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Sun, Li; Zhou, Qiang; Brigstock, David R et al. (2014) Focal autoimmune pancreatitis and chronic sclerosing sialadenitis mimicking pancreatic cancer and neck metastasis. World J Gastroenterol 20:17674-9
Qu, Li-Mei; Liu, Ya-Hui; Brigstock, David R et al. (2013) IgG4-related autoimmune pancreatitis overlapping with Mikulicz's disease and lymphadenitis: a case report. World J Gastroenterol 19:9490-4
Nagaraja, Tirumuru; Chen, Li; Balasubramanian, Anuradha et al. (2012) Activation of the connective tissue growth factor (CTGF)-transforming growth factor ? 1 (TGF-? 1) axis in hepatitis C virus-expressing hepatocytes. PLoS One 7:e46526
Huang, Guangcun; Besner, Gail E; Brigstock, David R (2012) Heparin-binding epidermal growth factor-like growth factor suppresses experimental liver fibrosis in mice. Lab Invest 92:703-12
Piao, Rong-Li; Brigstock, David R; Zhu, Jie et al. (2012) Clinical significance of connective tissue growth factor in hepatitis B virus-induced hepatic fibrosis. World J Gastroenterol 18:2280-6
Huang, Guangcun; Brigstock, David R (2012) Regulation of hepatic stellate cells by connective tissue growth factor. Front Biosci (Landmark Ed) 17:2495-507
Chen, Li; Charrier, Alyssa L; Leask, Andrew et al. (2011) Ethanol-stimulated differentiated functions of human or mouse hepatic stellate cells are mediated by connective tissue growth factor. J Hepatol 55:399-406
Huang, Guangcun; Brigstock, David R (2011) Integrin expression and function in the response of primary culture hepatic stellate cells to connective tissue growth factor (CCN2). J Cell Mol Med 15:1087-95
Gao, Run-Ping; Brigstock, David R (2009) Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function. World J Gastroenterol 15:3807-13

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