Exploiting the Functional Role of TGF BETA 1 in Bile Duct Ligation Induced Liver Cirrhosis---From Gene Expression to Epigenetic Control

Transforming growth factor β1 (TGF-β1), a peptide widely distributed in tissues, is reported to have diverse biological activities. TGF-β1 may regulate the proliferation of epithelial and mesenchymal cells as well as immunocompetent cells, TGF also exerts stimulatory effects on the deposition of extracellular matrix and the proliferation of fibroblasts; these effects are typically shown in wounded tissue repair. Inhibition of liver cell regeneration has been claimed to be one of the important biological activities of TGF-β1. Liver cirrhosis results from chronic damage to the liver in conjunction with the accumulation of extracellular matrix (ECM) proteins, which is characteristic of most types of chronic liver disease. High levels of TGF-β1 are often found in many fibrotic tissues. Delivery of exogenous TGF-β1 by various means to tissues could result in severe fibrosis in experimental animals, and hepatic fibrosis will be seen, which facilitates the understanding of TGF-β1 action and liver fibrogenic mechanisms. These studies establish TGF-β1 as a primary mediator in pathological fibrosis. On the other hand, alterations of DNA methylation status and histone modification have been observed in many liver disorders. Current interest in the role that methylation plays has been focused on abnormal methylation events that activate, by demethylation or silence by hypermethylation, the genes that are important for regeneration, inflammation, and cirrhosis.Mapping of methylated regions in DNA has relied primarily on Southern hybridization approachesand secondarily on polymerase chain reaction (PCR) based on chemical modification of cytosine to uracil by bisulfite treatment. In our project, we will first establish the time course of TGF-β1expression following bile duct ligation (BDL). We will then examine the relationship between the methylation status of the TGF-β1 gene promoter and its steady-state expression in liver from BDL rats by Northern blot and in situ hybridization (ISH) and analyzed the expression of TGF-beta gene together with its related genes, TGF-β R1, TGF-β R2, Smad molecules and THBS1in sham and BDL lesions by ISH and high-sensitive methylation mapping of methylated cytosine.

Project ID:PC9902-1657
External Project ID:NSC98-2314-B182-027-MY3