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. ? ? ?
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