Exposure and biological response biomarkers of cigarette smoke

香烟烟雾的暴露和生物反应生物标志物

基本信息

批准号：
7822322
负责人：
Ian Alexander Blair
金额：
$ 2.58万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822322
关键词：
11p 2&apos -deoxyadenosine 8-Oxo-2&apos -Deoxyguanosine Acids Anabolism Antibodies Antioxidants Arachidonic Acids Aromatic Polycyclic Hydrocarbons Arts Atmospheric Pressure Basic Science Benzo(a)pyrene Binding Biological Biological Assay Biological Markers Bronchoconstriction Bronchoconstrictor Agents Carcinogens Cardiovascular Diseases Cardiovascular system Cause of Death Cell Line Cells Chemicals Chronic Obstructive Airway Disease Cigarette Cigarette Smoker Comet Assay Complex Mixtures Cotinine Coupled Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Damage Deoxyguanosine Digestion Dinoprost Disease Electrons Environment Environmental Exposure Environmental Tobacco Smoke Enzymes Epithelial Epithelial Cells Epoxide hydrolase Excretory function Exhalation Exposure to Family Feedback Future Generations Genes Genomics Glutathione Glycols Guanine Human Hydrolysis Hydroxyeicosatetraenoic Acids Inflammatory Inflammatory Response Isomerism Isoprostanes Isotopes Label Lead Lesion Link Linoleic Acids Lipid Peroxidation Lipid Peroxides Lipids Lipoxygenase Liquid Chromatography Liquid substance Lung Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mass Spectrum Analysis Measurement Measures Mediating Messenger RNA Metabolic Activation Metabolism Methodology Methods Modeling Monitor Mutagens Nicotine Oxidation-Reduction Oxidative Stress Oxides Oxidoreductase PGF receptor PTGS2 gene Pathway interactions Peptide Hydrolases Phenotype Polyunsaturated Fatty Acids Population Principal Investigator Production Prostaglandin D2 Prostaglandin H2 Prostaglandins Protein Isoforms Protein Secretion Proteins Proteome Proteomics Protocols documentation Pyrenes Quinones Reaction Reactive Oxygen Species Regulation Relative (related person)Reporting Research Research Design Research Personnel Resolution Response Elements Role Sampling Sensitivity and Specificity Serum Serum Proteins Skin Smoke Smoker Smoking Smooth Muscle Smooth Muscle Myocytes Specificity Stable Isotope Labeling Sulforaphane Techniques Testing Time Tobacco Tobacco smoke Transcript Transferase Urine adduct base cell type cigarette smoking cigarette smoking cohort cytokine detoxication enantiomer feeding gene environment interaction human subject in vivo interest ionization killings multiple reaction monitoring non-smoker novel therapeutics oxidation oxidative DNA damage oxidized lipid perhydroxyl radical peroxidation promoter prostaglandin-F synthase respiratory smooth muscle response small molecule stable isotope stem tandem mass spectrometry urinary

项目摘要

DESCRIPTION (provided by applicant): Exposure and biological response biomarkers of cigarette smoke. Exposure to tobacco smoke (mainstream and environmental) is a leading cause of death in the US. Cigarette smoke is an extremely complex mixture, which some 3800 constituents including numerous polycyclic aromatic hydrocarbons (PAHs), in both the mainstream and sidestream (environmental) smoke fractions. Cigarette smokers provide an extreme model of PAH exposure that will permit both exposure and biological response biomarkers to be developed. There is substantial evidence that PAHs are causative agents in lung, skin, and bladder cancer. Furthermore, tobacco smoke is associated with oxidative stress, pancreatic cancer, cardiovascular disease, and chronic obstructive pulmonary disease (COPD), although the specific role of PAHs is not clear. Interestingly, the cardiovascular effects of sidestream smoke are almost as great as mainstream smoke. The present proposal stems from significant advances we have made over the last six years in the quantification of protein, lipid, and DNA biomarkers using stable isotope methodology and our basic research into enzyme regulation during oxidative stress. Previous methods for analyzing oxidative DNA damage have been fraught with numerous methodological problems so that the current state-of-the-art involves the use of a COMET assay to measure 8-oxo-2'-deoxyguanosine (dGuo) lesions. We have recently devised a more quantitative method based on immunoaffinity stable isotope dilution liquid chromatography- tandem mass spectrometry (LC-MS/MS) that can be readily elaborated to studies of tobacco smokers. We also showed that oxidative stress could induce the formation of aldo-keto reductases (AKRs) of the 1C family. AKR1C3 is the enzyme, which we recently showed is responsible for the conversion of prostaglandin (PG) D2 to the potent bronchoconstrictor 11p-PGF2. This provides an additional potential link between oxidative stress and COPD as well as the potential for a new therapeutic strategy, which involves AKR1C3 inhibition. Finally, preliminary studies have revealed that a DNA-adduct than can only arise from lipid peroxidation is present in the urine of cigarette smokers but is completely absent in urine from non-smokers. We propose to build on these exciting new findings by developing panels of in vivo biomarkers of exposure and biological response, which we hypothesize will make it possible to distinguish a cohort of non-smokers from a cohort of disease-free tobacco smokers. The hypothesis will be tested by conducting research under the following three specific aims: Aim 1. To discover whether B[a]P and B[a]P-7,8-dione induce AKR1C/2 in NHBE cells and increase oxidative stress to form 8-oxo-dGuo and HedGuo in DNA, induce AKR1C3 in HASM cells and increase the biosynthesis of the potent bronchoconstrictor 11p-PGF2, as potential urine and EEC biological response biomarkers of PAH exposure. Aim 2: To discover secreted proteins following treatment of NHBE and HASM cells with B[a]P and its oxidative metabolites as potential serum biological response biomarkers of PAH exposure. Aim 3: To conduct predictive and refinement analyses of in vivo exposure and response biomarkers in urine together with biological response biomarkers in EBC and serum in order to distinguish non-smokers from disease-free tobacco smokers. Successful completion of the proposed research will provide a panel of biomarkers of exposure and biological response to tobacco smoke will have significant utility in future studies designed to elucidate the relationship between gene environment interactions and diseases such as cancer, cardiovascular disease, and COPD.

描述（由申请人提供）：烟雾的暴露和生物反应生物标志物。在美国，暴露于烟草烟雾（主流和环境）是死亡的主要原因。香烟烟雾是一种极其复杂的混合物，在主流和侧面（环境）烟雾分数中，大约3800个成分，包括许多多环芳烃（PAHS）。吸烟者提供了极端的PAH暴露模型，该模型将允许开发暴露和生物反应生物标志物。有大量证据表明，PAH是肺，皮肤和膀胱癌中的病因。此外，烟草烟雾与氧化应激，胰腺癌，心血管疾病和慢性阻塞性肺疾病（COPD）有关，尽管PAHS的具体作用尚不清楚。有趣的是，横向烟雾的心血管效应几乎与主流烟一样大。目前的提议源于我们在过去六年中在蛋白质，脂质和DNA生物标志物定量中取得的重大进步，并使用稳定的同位素方法和我们对氧化应激期间酶调节的基础研究。先前用于分析氧化DNA损伤的方法已经充满了许多方法论问题，因此当前的最新方法涉及使用彗星测定法测量8-oxo-2'-脱氧藻氨酸（DGUO）病变。我们最近设计了一种基于免疫亲和力稳定的同位素稀释液色谱 - 串联质谱法（LC-MS/MS）的更定量方法，该方法可以很容易地详细阐述用于烟草吸烟者的研究。我们还表明，氧化应激可以诱导1C家族的Aldo-Keto还原酶（AKR）的形成。 AKR1C3是酶，我们最近显示的是促进脂蛋白（PG）D2转化为有效的支气管收缩11P-PGF2的原因。这提供了氧化应激与COPD之间的附加潜在联系，以及涉及AKR1C3抑制的新治疗策略的潜力。最后，初步研究表明，DNA添加剂仅来自脂质过氧化而产生的DNA - 吸烟者的尿液中存在，但在非吸烟者中尿液中完全不存在。我们建议通过开发暴露和生物反应的体内生物标志物的小组来建立这些令人兴奋的新发现，我们假设这将使他们有可能区分一群非吸烟者与无疾病的烟草吸烟者的同类。该假设将通过以下三个具体目的进行研究来检验：目的1。发现B [a] p和b [a] p-7,8-dione在NHBE细胞中诱导AKR1C/2是否在NHBE细胞中诱导AKR1C/2，并增加氧化应激以形成8-oxo-dguo和Hedguo，在DNA中诱导AKR1C3，并增加了AKR1C3，并增加了akr1c3 brictor的作用。 11P-PGF2，作为PAH暴露的潜在尿液和EEC生物反应生物标志物。目的2：在用B [A] P [A] P [A]及其氧化代谢物治疗NHBE和HASM细胞后发现分泌的蛋白质作为PAH暴露的潜在血清生物学反应生物标志物。目的3：进行尿液中体内暴露和反应生物标志物的预测性和完善分析，以及EBC和血清中的生物反应生物标志物，以将非吸烟者与无疾病吸烟者区分开。拟议研究的成功完成将为烟草烟雾的生物标志物提供一组生物标志物，对烟草烟雾的生物反应将在未来的研究中具有重要的效用，旨在阐明基因环境相互作用与癌症，心血管疾病和COPD等疾病之间的关系。