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4500万现任吸烟者和4600万曾经吸烟者面临与烟草相关的疾病风险增加。这种广泛的环境暴露对公共健康的影响是深远的；烟草烟雾是美国可预防的主要死亡原因，预计在未来50年内将导致全球近4.5亿人死亡。尽管吸烟会导致肺癌和慢性阻塞性肺病，但只有10%-20%的吸烟者会患上这些疾病。几乎没有指标表明吸烟者患疾病的风险最高，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存在局限性，而且它们没有捕捉到宿主对烟草暴露的生理反应。我们以前已经证明，香烟烟雾会导致整个呼吸道上皮细胞的“损伤区域”，而在支气管镜检查中获得的呼吸道上皮细胞中的基因表达，反映了宿主对吸烟的反应。我们建议将“损伤野”的概念扩展到容易获得的呼吸道上皮细胞，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”表达平台测量这些部位的全球基因表达，我们将开发一系列生物标记物，评估宿主对当前烟草暴露(主动与被动与从不吸烟者)的反应、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记物，这些生物标记物可能会更准确地反映个体对吸烟的反应。我们还建议将呼吸道基因表达生物标记物与肺功能和氧化应激和炎症的系统标记物相关联，为更详细地理解上皮反应的可变性如何导致烟草烟雾暴露的疾病相关肺部和系统性后遗症的可变性奠定了基础。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.