Hepatic fibrosis, regardless of etiology, is characterized by an increased deposition of type I collagen that disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ. Chronic ethanol consumption often leads to liver fibrosis and is associated with an increase in the synthesis of tumor growth factor beta (TGFb), a potent fibrogenic cytokine that enhances type I collagen gene expression. The hepatic stellate cell (HSC) (formally called the Ito cell, fat storing cell, perisinusoidal cell, and lipocyte) is the primary cell-type in the liver responsible for excess collagen synthesis during hepatic fibrosis. Following a fibrotic stimulus, such as excess ethanol consumption, the HSC undergoes a transformation or activation process changing from a quiescent vitamin A storing cell to that of an activated myofibroblast-like cell. HSC activation results in changes in cellular morphology, an increase in proliferation rate, and changes in the pattern of gene expression that includes a dramatic increase in the synthesis of type I collagen. In addition, the activated HSC secretes TGFb, a potent fibrogenic cytokine for the HSC, and expresses TGFb receptors on the cell surface. Many of the molecular changes that are observed when HSCs are activated in vivo are also found when HSCs are cultured on plastic. Therefore, culturing HSCs provides a convenient model system to study HSC activation. The molecular mechanisms that controls type 1 collagen synthesis in the HSC following cellular activation are not well understood. Furthermore, little is known about the pathway for TGFb signaling in the HSC following cellular activation or during ethanol-induced liver disease. This proposal is aimed at investigating the molecular mechanisms of collagen gene expression following HSC activation and the signaling pathway for TGFb in the HSC. It is anticipated that these studies will provide a foundation for the development of novel therapeutics aimed at preventing the progression of hepatic fibrosis. 1. To analyze the role of distant 5' DNase I hypersensitive sites in regulating al (I) collagen gene expression following HSC activation. 2. To assess the role of SMAD3 in mediating TGFb-stimulated expression of czl(I) collagen in culture-activated HSCs. 3. To directly assess the role of SMAD3 in regulating a 1(I) collagen expression in the HSC during alcohol-induced liver fibrosis in vivo. 4. To investigate the molecular mechanism responsible for TGFf3 stimulation in the al (I) collagen gene.
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| Mathurin, Philippe; Xiong, Shigang; Kharbanda, Kusum K et al. (2002) IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 282:G981-90 |
