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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
2012 Hans Popper Memorial Postdoctoral Research Fellowship
University of Kansas Medical Center
Project Title: HCV/alcohol induced posttranslational modifications of FOXO3 transcription factor
Chronic alcohol consumption increases the rate of liver fibrosis, risk for cirrhosis and HCC in HCV infected patients. FOXO3 is a key longevity factor and one of several transcriptional regulators of the oxidative stress resistance program. It was shown that three FOXO3 dependent genes (SOD2, BIM, and FOXO3 itself) were downregulated in liver biopsy specimens by at least a factor of 2 in the HCV patients. In cells HCV or alcohol alone lead to an increase in FOXO3 dependent transcription, while combined they cause the loss of nuclear FOXO3 and decrease of FOXO transcriptional activity.
FOXO3 activity is regulated by a combination of phosphorylation, acetylation, methylation and ubiquitination. HCV and alcohol effects on FOXO3 localization and transcriptional activity are thus almost certainly due to changes in its pattern of post-translational modifications (PTMs).
Recent developments in nanoscale capillary isoelectric focusing (cIEF) make it possible to
quantitatively measure FOXO3 modifications with high resolution and reproducibility. Mass-spec analysis approach in combination with cIEF will allow Dr. Tikhanovich to identify HCV/alcohol-induced FOXO3 posttranslational modifications. Preliminary data show that there is a major change in the FOXO3 PTMs following infection. cIEF reveal the presence of c-Jun N-terminal kinase (JNK)-dependent HCV-induced modifications. These data correlate with the finding that FOXO transcriptional activity increase after infection was entirely blocked by JNK inhibitor. Dr. Tikhanovich also found presence of JNK-independent FOXO modifications. After the FOXO3 PTMs will be identified by mass-spec analysis, PTM patterns will be studied in human liver biopsy specimens to correlate these findings with the disease severity.
By developing a novel method for the analysis of molecular mechanisms of HCV pathogenesis this research may yield novel targets for treatment of chronically infected HCV patients.