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

描述（由申请人提供）： 在美国，大约有4500万吸烟者和4600万前吸烟者，他们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;烟草烟雾是美国主要的可预防的死亡原因，预计在今后50年内将在全世界造成近4.5亿人死亡。尽管吸烟在肺癌和COPD中起着因果作用，但只有10-20%的吸烟者会患上这些疾病。几乎没有什么指标表明吸烟者的疾病风险最高，也不清楚为什么个人在戒烟几十年后仍然处于高风险状态。目前用于量化烟草烟雾暴露的标准方法在准确评估累积剂量和过去暴露的能力方面受到限制，并且它们不能捕获宿主对烟草暴露的生理反应。我们以前已经表明，香烟烟雾会导致气道上皮细胞的“领域的伤害”和基因表达，在气道上皮细胞在支气管镜检查，反映了主机响应吸烟。我们建议将“损伤领域”的概念扩展到容易获得的气道上皮细胞，这些细胞可以以非侵入性的方式从鼻或颊粘膜获得。通过使用新的“全外显子”表达平台测量这些位点的全局基因表达，我们将开发一系列生物标志物，评估宿主对当前烟草暴露的反应（主动与被动与从不吸烟者），当前暴露的强度，当前吸烟者的累积暴露，最近戒烟的吸烟者自上次暴露以来的时间，以及终生暴露。此外，我们将开发基于分子途径的基因表达生物标志物，这些生物标志物可能是对吸烟的个体反应的更准确的标志物。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物相关联，为更详细地了解上皮反应的变异性如何导致烟草烟雾暴露的疾病相关肺部和全身后遗症的变异性奠定基础。这些研究将建立一种新的非侵入性工具，可用于测量宿主对烟草烟雾的反应，可用于随后的大规模人口研究，作为基因与环境倡议的一部分。

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.