Hepatitis C virus infects approximately 3 million Americans and is the most common cause of cirrhosis, liver failure and hepatocellular carcinoma in the United States. Current therapies benefit less than half of those infected and new approaches to eradicate the virus and slow progression of the disease are needed. Patients who consume alcohol have a particularly rapid state of disease progression and markedly reduced response to antiviral therapy. Measures to slow disease progression in this cohort would have enormous potential benefit. The mechanism of liver pathogenesis of Hepatitis C is poorly understood and involves an immune process, direct viral effects, and the hepatic response. Multiple studies have demonstrated that hepatic oxidative stress is more prominent in Hepatitis C than other chronic liver diseases. Recent studies have shown that HCV viral proteins stimulate reactive oxygen species production and exacerbate the hepatic effects of alcohol. The HCV core protein itself directly associates with mitochondria, inhibits electron transport, and increases mitochondrial ROS production. Synergistic effects of HCV and alcohol on mitochondrial function may therefore contribute importantly to disease progression. This proposal will evaluate the hypothesis that HCV core protein binds specifically to mitochondrial targets causing alterations in mitochondrial protein function either directly via protein-protein interactions, or indirectly via changes in mitochondrial calcium homeostasis. Mitochondrial injury is a primary mechanism responsible for HCV-alcohol synergy and increasing mitochondrial antioxidant capacity can prevent some of these effects. This hypothesis will be tested by the following specific aims: 1. To determine if direct core-protein mitochondria interactions are responsible for mitochondrial functional changes. 2. To determine the proteomic mechanisms of HCV-induced complex I inhibition. 3. To determine whether mitochondrial calcium accumulation contributes to for core-induced changes in mitochondrial function. 4. To determine the role of mitochondrial oxidant-antioxidant balance in HCV protein and alcohol induced liver injury.
These aims will be achieved by specifically altering core protein targeting, measuring mitochondrial electron transport, determining the state oxidative derivitization of mitochondrial proteins, measuring mitochondrial calcium homeostasis, and examining the effects of novel antioxidants and overexpressed mitochondrial superoxide dismutase on mitochondrial function in alcohol fed HCV transgenic mice. ? ?
|Zhao, Jie; Adams, Abby; Roberts, Ben et al. (2018) Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice. Hepatology 67:1109-1126|
|Li, Zhuan; Zhao, Jie; Zhang, Shujun et al. (2018) FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. Cell Death Discov 4:16|
|Woolbright, Benjamin L; Bridges, Brian W; Dunn, Winston et al. (2017) Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18. Gene Expr 17:301-312|
|Li, Z; Bridges, B; Olson, J et al. (2017) The interaction between acetylation and serine-574 phosphorylation regulates the apoptotic function of FOXO3. Oncogene 36:1887-1898|
|Tikhanovich, Irina; Zhao, Jie; Olson, Jody et al. (2017) Protein arginine methyltransferase 1 modulates innate immune responses through regulation of peroxisome proliferator-activated receptor ?-dependent macrophage differentiation. J Biol Chem 292:6882-6894|
|Tikhanovich, Irina; Zhao, Jie; Bridges, Brian et al. (2017) Arginine methylation regulates c-Myc-dependent transcription by altering promoter recruitment of the acetyltransferase p300. J Biol Chem 292:13333-13344|
|Li, Z; Zhao, J; Tikhanovich, I et al. (2016) Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression. Cell Death Differ 23:583-95|
|Weinman, Steven A; Tikhanovich, Irina (2016) Retinoids: The Link Between Alcohol and Interferon? Hepatology 63:1759-61|
|Cox, Josiah; Weinman, Steven (2016) Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hepat Oncol 3:57-59|
|Bi, Qian; Ranjan, Atul; Fan, Rui et al. (2015) MTBP inhibits migration and metastasis of hepatocellular carcinoma. Clin Exp Metastasis 32:301-11|
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