Ubiquitous pollutant acrolein inhibits IFN?? antiviral signaling: relevance to HC

描述(申请人提供)：慢性丙型肝炎病毒(丙型肝炎病毒)感染仍然是一个全球关注的健康问题，全世界有近2亿携带者。它可能是肝硬变、肝细胞癌和终末期肝病的前兆。在缺乏疫苗的情况下，目前FDA批准的慢性丙型肝炎的治疗标准是聚乙二醇化干扰素-α(IFN1)和利巴韦林的组合。不幸的是，这种方案只对大约50%的患者有效，强调需要研究确定对IFN1耐药的分子机制。临床研究已经确定了几个可能导致抗丙型肝炎病毒治疗失败的潜在辅助因素，包括肥胖、糖尿病、酗酒、氧化应激、吸烟和环境污染。丙烯醛是一种普遍存在的、高活性的环境和工业污染物，被美国环境保护局(EPA)指定为高度优先的空气和水污染物。值得注意的是，丙烯醛也是作为脂质过氧化(LPO)的副产物在体内形成的，本身就已知会导致氧化应激。此外，丙烯醛是香烟烟雾的主要成分，最近的研究表明，与不吸烟的人相比，患有慢性丙型肝炎的吸烟者对IFN1的应答率较低。我们有令人信服的初步数据表明，无毒浓度的丙烯醛在体外(培养的人肝细胞)和体内(小鼠)显著下调IFN1信号和抗病毒基因的表达。已发表的文献和我们自己令人信服的数据有力地支持了我们的假设，即丙烯醛通过抑制或干扰IFN1介导的信号和抗病毒基因在肝细胞中的表达而对IFN1治疗结果产生不利影响，并且高水平的丙烯醛暴露(环境和/或内源性)将与丙型肝炎病毒感染者较差的IFN1反应相关。我们的假设将通过使用成熟的体外和体内实验系统以及直接报告丙型肝炎病毒复制的丙型肝炎病毒复制子来检验丙烯醛对早期IFN1介导的信号传递(包括JAK/STAT途径的组件)和抗病毒基因表达的影响。此外，研究人员将通过使用来自健康、未感染的个人和感染丙型肝炎病毒的患者(应答者和无应答者)的库存血清、尿液和/或肝活检样本进行回顾分析，建立我们假设的临床/翻译方面。这项分析将探索丙烯醛暴露与IFN1反应差(缺乏持续病毒学反应，SVR)之间的可能相关性。研究人员预计，他们的研究将阐明对IFN1治疗产生耐药性的关键机制，并将确定新的治疗干预的潜在靶点。

DESCRIPTION (provided by applicant): Chronic Hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. It can be a precursor to cirrhosis, hepatocellular carcinoma and end-stage liver disease. In the absence of a vaccine, the current FDA approved standard of care for chronic hepatitis C is a combination of pegylated interferon-alpha (IFN1) and ribavirin. Unfortunately, this regimen is only effective in about 50% of patients, emphasizing the need for studies defining the molecular mechanisms underlying resistance to IFN1. Clinical studies have identified several potential cofactors that may contribute to the failure of anti-HCV therapy, including obesity, diabetes, alcohol abuse, oxidative stress, cigarette smoking and environmental pollutants. Acrolein is a ubiquitous, highly reactive environmental and industrial pollutant, and is designated by the U.S. Environmental Protection Agency (EPA) as a high priority air and water pollutant. Notably, acrolein is also formed endogenously as a byproduct of lipid peroxidation (LPO) and is, itself, known to cause oxidative stress. Moreover, acrolein is a major component of cigarette smoke and recent studies suggest that smokers with chronic hepatitis C have a lower response rate to IFN1 compared to non-smokers. We have convincing preliminary data showing that non-toxic concentrations of acrolein significantly down-regulate IFN1 signaling and antiviral gene expression in vitro (cultured human hepatic cells) and in vivo (mice). Published literature and our own compelling data strongly support our hypothesis that acrolein adversely influences IFN1 therapy outcomes by inhibiting or disrupting IFN1 mediated signaling and antiviral gene expression in hepatocytes, and that high acrolein exposure (environmental and/or endogenous) will correlate with poor IFN1 response in HCV infected individuals. Our hypotheses will be tested by examining the effects of acrolein on early IFN1-mediated signaling (including components of the Jak/STAT pathway) and antiviral gene expression using well established in vitro and in vivo experimental systems, as well as an HCV replicon that directly reports on HCV viral replication. Additionally, the investigators will establish a clinical/translational aspect of our hypothesis by conducting a retrospective analysis using banked serum, urine and/or liver biopsy samples from healthy, uninfected individuals and HCV-infected patients (responders and non-responders). This analysis will explore a possible correlation between acrolein exposure and poor IFN1 response (lack of sustained virologic response, SVR). The investigators expect their studies will elucidate critical mechanisms underlying resistance to IFN1 treatment and will identify potential targets for novel therapeutic intervention.