A non-invasive gene-expression biomarker of airway response to tobacco exposure

烟草暴露气道反应的非侵入性基因表达生物标志物

• 批准号: 7849586
• 负责人: Avrum E Spira
• 金额: $ 60.01万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849586
• 关键词: Accounting; Biological; Biological Markers; Blood; Bronchoscopy; Cause of Death; Cessation of life; Chronic Obstructive Airway Disease; Cigarette Smoker; Clinical; Cohort Studies; Data; Development; Disease; Dose; Environment; Environmental Exposure; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Exons; Exposure to; Functional disorder; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Genes; Genetic; Genomics; Glutathione; Goals; Human; IL8 gene; Immune response; In Vitro; Individual; Inflammation; Injury; Interdisciplinary Study; Interleukin-6; Knowledge; Lung; Lung diseases; Malignant neoplasm of lung; Measures; Methods; Molecular; Molecular Profiling; Nasal Epithelium; Nitric Oxide; Nose; Oral; Oral mucous membrane structure; Outcome; Oxidative Stress; Passive Smoking; Pathogenesis; Pathway interactions; Patients; Persons; Physiological; Physiological Processes; Pilot Projects; Population Study; Production; Public Health; Recovery; Regulator Genes; Reproducibility; Research Personnel; Respiratory System; Respiratory physiology; Respiratory tract structure; Risk; Role; Sampling; Series; Serum; Site; Smoke; Smoker; Smoking; Spirometry; Staging; Statistical Models; Structure of mucous membrane of nose; Testing; Time; Tobacco; Tobacco smoke; Tobacco smoking; Toxin; Tumor Necrosis Factor-alpha; United States; Work; airway epithelium; base; bronchial epithelium; cell injury; cigarette smoking; cigarette smoking; computerized tools; disorder risk; experience; genome-wide; high risk; human TNF protein; immune activation; in vivo; injured airway; innovation; non-smoker; novel; oxidant stress; programs; response; small airways disease; smoking cessation; tobacco exposure; tool

DESCRIPTION (provided by applicant): There are approximately 45 million current smokers and 46 million former smokers who are at increased risk for tobacco-related disease in the United States. The public health implications of this widespread environmental exposure are profound; tobacco smoke is the leading preventable cause of death in the United States and is projected to cause nearly 450 million deaths worldwide during the next 50 years. Despite the causal role of cigarette smoking in lung cancer and COPD, only 10-20% of smokers develop these diseases. There are few indicators of which smokers are at highest risk for disease, and it is unclear why individuals remain at high risk decades after they have stopped smoking. Current standard methods for quantifying exposure to tobacco smoke are limited in their ability to accurately assess cumulative dose and past exposure, and they do not capture the physiologic host response to tobacco exposure. We have previously shown that cigarette smoke causes an airway-wide epithelial cell "field of injury" and that gene expression, in airway epithelial cells obtained at bronchoscopy, reflects host response to smoking. We propose here to extend the "field of injury" concept to easily-accessible airway epithelial cells that can be obtained from nasal or buccal mucosa in a non-invasive fashion. By measuring global gene expression at these sites using a new "all-exon" expression platform, we will develop a series of biomarkers that assess host response to current tobacco exposure (active vs. passive vs. never smokers), intensity of current exposure, cumulative exposure among current smokers, time since last exposure among smokers who recently quit, and lifetime exposure. Furthermore, we will develop molecular pathway-based gene expression biomarkers that may be more accurate markers of individual responses to tobacco smoking. We also propose to correlate airway gene expression biomarkers with lung function and systemic markers of oxidative stress and inflammation, setting the stage for a more detailed understanding of how variability in epithelial response contributes to variability in disease-related pulmonary and systemic sequelae of tobacco smoke exposure. These studies will establish a new non-invasive tool that can be used to measure the host responses to tobacco smoke that can be used in subsequent large scale population studies as part of the Genes and Environment Initiative.

描述（由申请人提供）： 在美国，目前大约有4500万吸烟者和4600万以前的吸烟者患烟草相关疾病的风险增加。这种广泛的环境暴露对公共卫生的影响是深远的。烟草烟雾是美国的主要可预防原因，预计在未来50年内将在全球造成近4.5亿次死亡。尽管吸烟在肺癌和COPD中的因​​果作用，但只有10-20％的吸烟者患上了这些疾病。几乎没有什么指标表明吸烟者患疾病的风险最高，目前尚不清楚个人停止吸烟后几十年保持高风险。量化暴露于烟草烟雾的当前标准方法的准确评估累积剂量和过去暴露的能力受到限制，并且不会捕获生理宿主对烟草暴露的反应。我们先前已经表明，香烟烟雾会引起范围内的上皮细胞“损伤场”，在支气管镜检查时获得的气道上皮细胞中，该基因表达反映了宿主对吸烟的反应。我们在这里建议将“损伤场”概念扩展到易于接近的气道上皮细胞，这些细胞可以以非侵入性方式从鼻或颊粘膜获得。通过使用新的“ All-EXON”表达平台在这些位点测量全球基因表达，我们将开发一系列生物标志物，以评估宿主对当前烟草暴露的反应（主动与无源与永不吸烟者），当前暴露的强度，自最近戒烟和生命暴露的吸烟者中的时间以来，当前吸烟者的累积暴露者累积暴露。此外，我们将开发基于分子途径的基因表达生物标志物，这些基因表达生物标志物可能是对烟草吸烟的单个反应的更准确的标志。我们还建议将气道基因表达生物标志物与肺功能和氧化应激和炎症的全身标志相关联，为更详细地理解上皮反应的可变性如何有助于疾病相关的肺和全身红口的可变性。这些研究将建立一种新的非侵入性工具，该工具可用于衡量宿主对烟草烟雾的反应，可作为基因和环境倡议的一部分，可在随后的大规模人群研究中使用。