Regulation of Hepatic Stellate Cell Responses to Injury

University Of California, San Francisco, San Francisco CA

Investigators

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Hepatic stellate cells mediate the liver's response to injury. Consequently, these perisinusoidally-located non-parenchymal cells control normal wound healing and the development of fibrosis. The broad, long-term objective of this project is to elucidate the signal transduction pathways that direct stellate cell responses in order to facilitate development of novel strategies for the prevention and treatment of cirrhosis from diverse causes, including alcoholism and viral hepatitis. We have developed new assays and reagents for quantitatively measuring myosin-dependent contractility in stellate cells. Employing these new methods, and other more standard procedures, we have started to demonstrate the role of myosin and focal adhesion kinase (FAK) in the regulation of essential cell functions. These results have led to this proposal's main hypothesis that the coordinated regulation of myosin and FAK, by injury induced factors, play a central role in the signal transduction pathways that mediate the stellate cell behaviors responsible for fibrosis. This hypothesis will be tested by the following specific aims: 1) Characterize the mechanisms by which injury-induced factors regulate myosin-dependent contractility. To address this aim we will determine the relative roles of myosin light chain kinase and rho-associated kinase signal transduction pathways in myosin-dependent contractility. 2) Elucidate the mechanisms by which injury-induced factors regulate activation of FAK. This will be achieved by testing our proposal that ET-1, LPA, and PDGF-BB stimulate FAK activation through distinct signaling pathways involving myosin-dependent contractility and membrane ruffling. 3) Test the hypothesis that myosin-dependent contractility and FAK activation control stellate cell behaviors responsible for fibrosis. We will demonstrate the roles of myosin and FAK in the regulation of stellate cell morphology, contraction, migration, proliferation, and collagen synthesis. In summary, the signal transduction mechanisms through which the injury-induced mediators, ET-1, LPA, and PDGF-BB, regulate critical stellate cell responses will be systematically defined using established pharmacological and genetic interventions in primary cultures of hepatic stellate cells isolated from normal rats and rats that have undergone chronic hepatic injury.