Specific AimsHepatocellular carcinoma (HOC) is common following hepatitis C virus (HCV) infection and in diabeticsor alcoholics with inflammation-related liver pathology. Alcoholism and obesity increases the gut-derivedendotoxin whose co-receptor is TLR4. We have previously shown that HCV infection increases expression ofTLR4. Commonality of TLR4 suggests synergism between HCV and alcoholism/obesity. Our studies in amouse model of HCC suggest that the combination of inflammation-induced hepatocyte regeneration plusimpairment of DNA damage repair caused by the viral core protein leads to chromosomal instability andhepatic oncogenesis. According to the model diagrammed below, activation of the IKKp/c-Jun/Stat3 plusinflammation cytokines (TNF-a, IL-6) by viral infection and alcoholism/obesity leads to hepatocyte DNAdamage plus upregulation of mitogens and hepatocyte proliferation. Together, these changes lead toincreased incidence of HCC.HYPOTHESES1. HCV-induced Toll-like receptor 4 (TLR4) enhances TNF-a, leading to synergism between HCV andalcoholism/diabetes for oncogenic potential.2. HCV inhibits DNA damage defense barrier, including DNA damage-induced signal transduction (ATMsand ATR) and complex formation of nonhomologous end-joining (NHEJ).3. HCV infection-associated inflammation facilitates carcinogenesis through IKKp/c-jun/STAT3 activation.
SPECIFIC AIMS1. Determine the effect of TLR4 gene disruption on HCC in an alcohol/diabetes mouse model andcore/NS5A transgenic mice.2. Determine the mechanism of inhibition of DNA damage-repair by viral proteins, and the possibleassociation of the core with the NHEJ complex by proteomics analysis with Dr. Deshaies (CaliforniaInstitute of Technology).3. Determine the role of c-jun/IKKp/STAT3 in HCV-associated HCC in a conditional knockout animalmodel.
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