Investigation of factors that inhibit Interferon-alpha signaling
 Elizabeth Powell
There is increasing evidence from clinical studies that hepatitis C virus (HCV)-infected patients with higher body weight have reduced response rates following antiviral therapy, although the mechanisms responsible are not well understood. The underlying hypothesis of this proposal is that cytokines associated with obesity lead to increased insulin resistance, steatosis and increased expression of factors that inhibit interferon-alpha (IFN) signaling. In addition, we hypothesize that peripheral blood mononuclear cells (PBMC) can be used as a surrogate cell population to reflect the effect of metabolic and inflammatory factors on IFN and insulin signaling pathways in the liver. Lastly, we hypothesize that insulin sensitizing agents or modulation of inflammatory pathways can improve response to IFN treatment.
The overall goal of this proposal is to delineate the obesity associated factors that inhibit IFN signaling. The effect of obesity on the severity of insulin resistance, oxidative stress and the expression of biomarkers of chronic inflammation in patients with HCV will be determined and whether these factors are associated with the expression of proteins that interfere with IFN signaling eg the suppressor of cytokine signaling (SOCS) family of proteins. The role of selected insulin sensitizing and anti-inflammatory agents on SOCS expression and IFN signaling will be evaluated in human hepatoma cell lines and the Huh7 replicon system with or without insulin resistance and in the presence or absence of steatosis. In addition, the role of PBMC as a surrogate cell population to reflect hepatic IFN and insulin signaling pathways will be determined.
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