COLLAGEN GENE REGULATION DURING ETHANOL INDUCED FIBROSIS

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Hepatic fibrosis is characterized by an increase in the deposition of Type I collagen. It is believed that the activated Ito cell is responsible for the increase in production of Type I collagen during fibrogenesis. Following a fibrogenic stimulus, such as ethanol consumption, the Ito cell undergoes a transformation process changing from a quiescent vitamin A storing cell to an activated myofibroblast- like cell. Activated Ito cells are larger than the quiescent Ito cell, express the cytoskeletal protein alpha smooth muscle actin, and lose the vitamin A stores characteristic for quiescent Ito cells. Additionally, a large increase in Type I collagen mRNA levels and in Type I collagen protein synthesis are observed in the normal liver architecture and results in abnormal liver function. The long-term goals of this research are to understand the molecular mechanisms which contribute to Ito cell activation following a fibrogenic stimulus. The molecular mechanisms responsible for increased Type I collagen synthesis by the activated Ito cell will be investigated. Specifically, transcriptional regulation of the alpha 1(I) collagen gene will be examined in both freshly isolated quiescent Ito cells and activated Ito cells in order to determine the molecular mechanisms responsible for the increased Type I collagen expression in activated Ito cells. The location of important cis-acting elements in the alpha 1(I) gene required for efficient transcription in Ito cells and the identification of the corresponding trans-acting factors which interact with the cis-acting elements will be determined. To investigate the molecular mechanisms responsible for Ito cell activation we will clone differentially expressed genes from quiescent Ito cells and activated Ito cells. The roles of these genes in the activation process will be determined. Finally, since Ito cells are activated by different fibrogenic stimuli and yet display similar morphological and metabolic changes, the molecular mechanisms responsible for Ito cell activation as a result of different fibrogenic stimuli will be investigated. Differentially expressed genes will be compared from different animal models of hepatic fibrosis in order to ascertain if a common pattern of gene expression exists. It is anticipated that the results from this work will provide a foundation to develop novel therapeutic strategies to prevent the progression of hepatic fibrosis.