This proposal has the long term goal to elucidate the role that integrins have in hepatic stellate cell activation and hepatic fibrosis. Hepatic stellate cells are responsible for producing most of the extracellular matrix components (""""""""scar"""""""" tissue) found in a wide variety of hepatic diseases. Stellate cells in normal liver are """"""""quiescent"""""""" (non-scar forming) but undergo a process called """"""""activation"""""""" in which they begin to proliferate and synthesize fibrous tissue leading to cirrhosis. Integrins are receptors located on the cell surface of stellate cells that allow the stellate cells to interact with the hepatic extracellular matrix. Specific extracellular matrix proteins are known to bind to the integrins and cause multiple signals to be sent to the stellate cell, inducing them to activate. The hypothesis to be tested in this series of experiments is that integrins (especially the fibronectin receptor alpha-5 beta-1) modulate and perpetuate the activation of hepatic stellate cells through their interaction with the extracellular matrix. To test this hypothesis, the following specific aims will be completed:1). Determine the mechanisms by which stellate cells control the expression of active integrin receptors on their cell surface. 2). Determine the mechanisms of integrin signaling during activation of stellate cells. 3). Determine if interrupting integrin signaling can block the perpetuation step of stellate cell-mediated fibrogenesis. These studies are designed to unravel the molecular mechanisms involved in integrin-mediated activation of stellate cells. Understanding the complex array of integrin interactions, modulations, and signaling events may elucidate potential mechanisms that can be therapeutically targeted to stop the fibrogenesis that occurs in chronic liver disease.
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