Hepatic lipocytes (perisinusoidal fat-storing cells) play a central role in generation of hepatic fibrosis. With liver injury, they undergo activation with resultant proliferation and enhanced extracellular matrix deposition. Preliminary studies by the applicant have shown that a component of the activation response is new expression of a smooth muscle-specific cytoskeletal protein, smooth muscle alpha actin. Furthermore, expression of this protein is inhibited by gamma interferon.
The specific aims of the outlined experiments are (1) to further characterize the smooth muscle phenotype of lipocytes as well as to determine whether activated lipocytes function as contractile cells (a feature suggested by their smooth muscle-like phenotype) and (2) to elucidate mechanisms of lipocyte activation with particular emphasis on the inhibitory cytokine gamma interferon. Smooth muscle alpha actin protein and gene expression will be characterized in experimental liver injury and transcriptional run-on assays will be performed to determine the level of regulation of the smooth muscle a actin gene. Contractility of activated lipocytes in experimental liver injury and in culture will be investigated. Lipocyte activation will be studied in vivo and in culture by measuring expression of smooth muscle alpha actin in response to cytokines. Further studies will define the DNA elements that could account for the inhibitory effect of gamma interferon. These studies will provide the first data on the contractility of hepatic lipocytes, and will delineate mechanisms of their activation. Work with gamma interferon-besides having direct therapeutic implications-will clarify molecular mechanisms important in regulation of hepatic lipocytes. The work will be performed in the Liver Center Laboratory at UCSF, under the supervision of Dr. D.M. Bissell. This laboratory is dedicated to the study of liver cell biology, with particular emphasis on hepatic fibrosis. The candidate has completed 2 years of postdoctoral training in this laboratory. The research proposal will enable the applicant to advance his foundation in basic science while leading to an academic career with an independent research program.
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