CELLULAR PATHOPHYSIOLOGY OF HEPATIC FIBROSIS

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The proposed research is directed at defining the cellular and molecular events underlying pathologic fibrosis in the liver. It builds on recent studies that have characterized the specific cell types within the liver that produce extracellular matrix. The data point to hepatic lipocytes (also known as Ito or fat-storing cells) as the major source of extracellular matrix proteins, particularly in liver injury, such as inflammation, where these cells undergo activation with proliferation and increased synthesis of matrix components. Because of their location in the Space of Disse, their impact on the biological function of extracellular matrix in the space of Disse is likely to be important. Of the array of changes exhibited by these cells in fibrosing injury, it is unclear which are central to the altered biologic effects of the pathologic matrix. Proteins that have been assigned cell-binding roles include laminin and fibronectin; thus, changes in their synthesis or conformation within the extracellular matrix could directly affect cell-matrix interaction and the expression of liver-specific functions by hepatocytes. In liver injury, lipocytes may produce variant forms of these proteins. The proposed work will characterize laminin synthesis by lipocytes with specific attention to the presence of putative cell-binding regions in the protein; it will similarly evaluate fibronectin expression, with quantitation of individual isoforms (at the mRNA level) that have been implicated in the injury response of tissues other than liver. A third aim is the isolation of laminin receptors from normal rat hepatocytes using a novel affinity matrix in which the biological activity of laminin is preserved. The project will provide the first detailed data on synthesis of laminin and fibronectin by hepatic lipocytes, in both the normal and activated state, in culture and in vivo. By characterizing at a molecular level key events associated with fibrosis, it will contribute importantly to efforts at prophylaxis or therapy for this prevalent and debilitating manifestation of liver disease.