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: 8212455
• 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/8212455
• 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. Public Health Relevance: Acrolein is one of the major reactive aldehydes ubiquitously present in foods, water and in the environment. It is a major constituent of cigarette smoke. Recent data suggest that HCV- infected smokers have worse IFN1 therapeutic outcomes compared with non-smokers. Acrolein is also generated endogenously due to cellular metabolism, and this may constitute a significant source of intracellular acrolein in situations of oxidative stress and inflammation. Elevated acrolein adducts have been detected in several disease conditions that are also known to be associated with failure of IFN therapy. Hence, based on available literature and the investigators' own compelling preliminary results, they have opted to use acrolein as the model compound for this study. The aim of the study is to determine the contribution of acrolein to the mechanisms of IFN1 resistance. The investigators have preliminary evidence to demonstrate that acrolein, at nontoxic concentrations, significantly down-regulates IFN1 signaling and antiviral/anti-HCV gene expression.

描述（由申请人提供）：慢性丙型肝炎病毒 (HCV) 感染仍然是一个全球性的健康问题，全世界有近 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护理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，这种疗法仅对约 50% 的患者有效，这强调需要进行研究来确定 IFN1 耐药性的分子机制。临床研究已经确定了一些可能导致抗 HCV 治疗失败的潜在辅助因素，包括肥胖、糖尿病、酗酒、氧化应激、吸烟和环境污染物。丙烯醛是一种普遍存在的高反应性环境和工业污染物，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，丙烯醛也是作为脂质过氧化 (LPO) 的副产物内源性形成的，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，与不吸烟者相比，患有慢性丙型肝炎的吸烟者对 IFN1 的反应率较低。我们有令人信服的初步数据表明，无毒浓度的丙烯醛在体外（培养的人肝细胞）和体内（小鼠）显着下调 IFN1 信号传导和抗病毒基因表达。 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，即丙烯醛通过抑制或破坏肝细胞中 IFN1 介导的信号传导和抗病毒基因表达对 IFN1 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 IFN1 反应不佳相关HCV 感染者。我们的假设将通过检查丙烯醛对早期 IFN1 介导的信号传导（包括 Jak/STAT 途径的组成部分）和抗病毒基因表达的影响进行检验，使用完善的体外和体内实验系统以及直接复制的 HCV 复制子关于 HCV 病毒复制的报道。此外，研究人员将通过使用来自健康、未感染者和 HCV 感染者（有反应者和无反应者）的血清、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。该分析将探讨丙烯醛暴露与 IFN1 反应不良（缺乏持续病毒学反应，SVR）之间可能存在的相关性。 研究人员预计他们的研究将阐明 IFN1 治疗耐药的关键机制，并确定新型治疗干预的潜在目标。 公共健康相关性：丙烯醛是食品、水和环境中普遍存在的主要活性醛之一。它是香烟烟雾的主要成分。最近的数据表明，与非吸烟者相比，感染 HCV 的吸烟者的 IFN1 治疗结果较差。丙烯醛也因细胞代谢而内源性产生，这可能构成氧化应激和炎症情况下细胞内丙烯醛的重要来源。在几种疾病中已检测到丙烯醛加合物升高，这些疾病也已知与干扰素治疗失败有关。因此，根据现有文献和研究人员自己令人信服的初步结果，他们选择使用丙烯醛作为本研究的模型化合物。该研究的目的是确定丙烯醛对 IFN1 耐药机制的贡献。研究人员有初步证据表明，无毒浓度的丙烯醛可显着下调 IFN1 信号传导和抗病毒/抗 HCV 基因表达。