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

无处不在的污染物丙烯醛抑制干扰素??

• 批准号: 8411149
• 负责人: Swati Joshi-Barve
• 金额: $ 13.11万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411149
• 关键词: Acrolein; Acrylates; Air Pollutants; Alcohol abuse; Aldehydes; Alzheimer' s Disease; Amino Acids; Antiviral Agents; Atherosclerosis; Automobile Exhaust; Binding; Biocide; Biological Markers; Biological Models; Biology; Biopsy Specimen; Cell Line; Cessation of life; Chemical Weapons; Chronic Disease; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Research; Cysteine; Data; Development; Diabetes Mellitus; Disease; Dose; Double-Stranded RNA; Environment; Environmental Exposure; Environmental Pollutants; Exposure to; FDA approved; Failure; Family; Fatty acid glycerol esters; Food; Free Radicals; Functional disorder; Future; Gene Expression; Genes; Genotype; Hepatitis C; Hepatitis C virus; Hepatocyte; Histidine; Human; Hydroxyl Radical; Imidazole; In Vitro; Individual; Industrial Waste; Inflammation; Interferons; Kidney Failure; Ligand Binding; Ligase; Lipid Peroxidation; Literature; Liver; Liver diseases; Lysine; Mediating; Medicine; Messenger RNA; Metabolism; Methionine; Modeling; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obesity; Organic Chemicals; Outcome; Oxidative Stress; PTPN11 gene; Pathway interactions; Patients; Pegylated Interferon Alfa; Phospholipids; Phosphorylation; Plastics; Play; Polyamines; Polymers; Primary carcinoma of the liver cells; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Tyrosine Kinase; Protein phosphatase; Proteins; Publications; Publishing; Rattus; Regimen; Replicon; Reporting; Research; Research Personnel; Resistance; Response Elements; Ribavirin; Role; STAT protein; STAT1 gene; STAT2 gene; Serum; Side; Signal Transduction; Smoke; Smoker; Smoking; Source; Specimen; Staging; System; TYK2; Testing; Therapeutic; Tissues; Transcriptional Activation; Treatment outcome; United States; United States Environmental Protection Agency; Urine; Vaccines; Viral; Water; Water Pollutants; Wood material; adduct; amino group; anti-hepatitis C; base; chronic liver disease; cigarette smoking; cigarette smoking; cofactor; cooking; eIF-2 Kinase; efficacy testing; global health; improved; in vivo; insight; liver biopsy; mouse model; non-smoker; novel therapeutic intervention; oligoadenylate; pollutant; protein activation; public health relevance; receptor; receptor internalization; response; standard of care; therapy outcome

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.

描述（由申请人提供）：慢性丙型肝炎病毒（HCV）感染仍然是全球健康问题，全球有近2亿携带者。它可能是肝硬化、肝细胞癌和终末期肝病的前兆。在没有疫苗的情况下，目前FDA批准的慢性丙型肝炎的护理标准是聚乙二醇化干扰素-α（IFN 1）和利巴韦林的组合。不幸的是，这种治疗方案仅对约50%的患者有效，因此需要进行研究以确定IFN 1耐药的分子机制。临床研究已经确定了几个可能导致抗HCV治疗失败的潜在辅助因子，包括肥胖、糖尿病、酗酒、氧化应激、吸烟和环境污染物。丙烯醛是一种普遍存在的、高反应性的环境和工业污染物，并且被美国环境保护署（EPA）指定为高度优先的空气和水污染物。值得注意的是，丙烯醛也作为脂质过氧化（LPO）的副产物内源性形成，并且已知其本身会引起氧化应激。此外，丙烯醛是香烟烟雾的主要成分，最近的研究表明，与非吸烟者相比，患有慢性丙型肝炎的吸烟者对IFN 1的反应率较低。我们有令人信服的初步数据表明，无毒浓度的丙烯醛显着下调IFN 1信号和抗病毒基因表达在体外（培养的人肝细胞）和体内（小鼠）。 已发表的文献和我们自己的令人信服的数据强烈支持我们的假设，丙烯醛通过抑制或破坏肝细胞中IFN 1介导的信号传导和抗病毒基因表达对IFN 1治疗结果产生不利影响，并且高丙烯醛暴露（环境和/或内源性）将与HCV感染个体中IFN 1应答不良相关。我们的假设将通过检查丙烯醛对早期IFN 1介导的信号传导（包括Jak/STAT途径的组分）和抗病毒基因表达的影响进行测试，使用完善的体外和体内实验系统，以及直接报告HCV病毒复制的HCV复制子。此外，研究者将通过使用来自健康、未感染个体和HCV感染患者（应答者和非应答者）的库存血清、尿液和/或肝活检样本进行回顾性分析，建立我们假设的临床/转化方面。该分析将探索丙烯醛暴露与IFN 1应答差（缺乏持续病毒学应答，SVR）之间可能的相关性。 研究人员预计他们的研究将阐明对IFN 1治疗产生耐药性的关键机制，并将确定新型治疗干预的潜在靶点。