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??

基本信息

批准号：
7788500
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
项目类别：
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/7788500
关键词：
Acrolein Acrylates Air Air Pollutants Alcohol abuse Aldehydes Alzheimer&apos 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 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 Interferon-alpha 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 Phosphotransferases 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 cigarette smoking cigarette smoking cofactor cooking eIF-2 Kinase efficacy testing global health improved in vivo insight interferon alpha receptor 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

项目摘要

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）感染仍然是全球健康问题，全球近2亿载体。它可能是肝硬化，肝细胞癌和终末期肝病的先驱。在没有疫苗的情况下，慢性丙型肝炎的当前FDA批准的护理标准是pe乙酸酯干扰素 - α（IFN1）和利巴韦林的组合。不幸的是，该方案仅在约50％的患者中有效，这强调了定义IFN1耐药性分子机制的研究的必要性。临床研究已经确定了几种潜在的辅助因子，这些辅助因子可能导致抗HCV疗法的失败，包括肥胖，糖尿病，酗酒，氧化应激，吸烟和环境污染物。 Acrolein是一种无处不在的，高反应性的环境和工业污染物，由美国环境保护局（EPA）指定为高优先空气和水污染物。值得注意的是，丙烯醛还作为脂质过氧化（LPO）的副产品内源形成，并且自身已知会引起氧化应激。此外，丙烯醛是香烟烟雾的主要组成部分，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IFN1的反应率较低。我们有令人信服的初步数据表明，丙烯醛的无毒浓度显着下调IFN1信号传导和抗病毒基因表达体外（培养的人肝细胞）和体内（小鼠）。发表的文献和我们自己的引人注目的数据强烈支持我们的假设，即丙烯醛通过抑制或破坏肝素中IFN1介导的信号传导和抗病毒基因表达来不利地影响IFN1治疗结果，并且高丙烯蛋白暴露（环境和/或内源性）将与较差的IFN1相互抗体（环境和/或内源性）与IFN1反应相关。我们的假设将通过检查丙烯醛对早期IFN1介导的信号传导的影响（包括JAK/STAT途径的组件）和使用良好的体外和体内实验系统的抗病毒基因表达，以及直接在HCV病毒复制上报告的HCV重复子。此外，研究人员将使用来自健康的，未感染的个体和HCV感染的患者（响应者和非反应者）进行回顾性分析来建立我们假设的临床/翻译方面。该分析将探讨丙烯醛暴露与IFN1反应差（缺乏持续的病毒学反应，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治疗的耐药性的关键机制，并将确定新型治疗干预措施的潜在靶标。公共卫生相关性：丙烯醛是食品，水和环境中普遍存在的主要反应性醛之一。它是香烟烟的主要组成部分。最近的数据表明，与非吸烟者相比，HCV感染的吸烟者的IFN1治疗结果更差。由于细胞代谢，丙烯醛也是内源性的，这可能构成了氧化应激和炎症情况下细胞内丙烯醛的重要来源。在几种疾病疾病中发现了丙烯醛加合物的升高，这些疾病也已知与IFN治疗失败有关。因此，基于可用文献和研究者自己引人注目的初步结果，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抗性机制的贡献。研究人员有初步证据表明，丙烯醛以无毒的浓度显着下调IFN1信号传导和抗病毒/抗HCV基因表达。