Comparative Transcriptomic Signatures of Inhaled Tobacco Smoke

描述(由申请人提供)：烟草烟雾暴露导致许多炎症性肺部疾病的终身风险显著增加。胎儿和新生儿接触烟草是早产儿慢性肺部疾病的主要风险因素，该疾病影响极其脆弱的人群，估计每年造成超过25亿美元的负担。在美国。流行病学研究有力地支持了吸烟史和COPD之间的因果关系，COPD是美国第三大死因，肺癌是男性和女性癌症死亡的主要原因。动物模型和体外系统已被用于结合对人类疾病样本的研究来确定与疾病相关的途径。不幸的是，虽然人们普遍认识到烟草烟雾暴露的健康风险，但目前还没有体外测试来确定与暴露负担或不同类型烟草产品有关的风险。我们假设，特定的、可靠的基因表达变化可以作为烟草烟雾暴露的生物标记物，准确地预测人类疾病的风险。该项目的目标是开发基于细胞的检测方法，以检测香烟烟雾暴露的特定疾病相关基因表达特征。我们提出了三个具体的目标：第一个目标是在体外调查全基因组对烟草烟雾的反应，并最终产生一套准确和预测人类疾病的转录生物标志物集。第二个目标将利用一种经过验证的烟雾引起的肺部疾病的小鼠模型，确定肺部内不同类型和剂量的烟草对吸入烟雾的特定生理反应。这一目标还将确定成年人和更易受伤害的青少年和新生儿的不同反应。第三个目标将有助于完善一套生物标记物，以侧重于在吸烟暴露和/或由此导致的疾病状态下在人类肺部观察到哪些生物标记物失调，并评估这些特定生物标记物的预测潜力。该项目高度响应该计划的目标，并将支持FDA的使命，即通过开发多种与疾病相关、符合法规要求的分析方法来监管烟草产品，FDA可以使用这些方法来定量和定性地衡量烟草烟雾暴露的不利影响。

DESCRIPTION (provided by applicant): Tobacco smoke exposure results in a significantly increased life-long risk for numerous inflammatory lung diseases. Fetal and neonatal exposure to tobacco is a major risk factor for chronic lung disease of prematurity, which affects an extremely vulnerable population, with an estimated burden of more than $2.5 B/yr. in the US. Epidemiological studies strongly support a causal association between smoking history and COPD, the third leading cause of death in the US and lung cancer, the leading cause of cancer death for both men and women. Animal models and in vitro systems have been used, in combination with studies of human disease samples, to identify disease-associated pathways. Unfortunately, while the health risks of tobacco smoke exposure are widely-appreciated, there are no existing in vitro tests to ascertain risks associated with exposure burden or different type of tobacco products. We hypothesize that specific, reliable changes in gene expression can serve as biomarkers of tobacco smoke exposures that are accurate and predictive of human disease risk. The goal of this Project is to develop cell-based assays for specific disease-relevant gene expression signatures of cigarette smoke exposure. We propose three Specific Aims: The first Aim will survey genome-wide responses to tobacco smoke in vitro and ultimately result in a set of transcriptional biomarker sets which are accurate and predictive of human disease. The second Aim will define specific, physiological responses to inhaled smoke from a variety of tobacco types and doses within the lung, using a validated mouse model of smoke-induced lung disease. This Aim will also identify distinct responses in adults and more vulnerable juveniles and neonates. The third Aim will help to refine the set of biomarkers to focus upon whose dysregulation are observed in human lungs upon tobacco smoke exposure and/or in resulting disease states, and assess the predictive potential of those specific biomarkers. This project is highly responsive to the goals of the Program and will support the FDA mission to regulate tobacco products by developing multiple, disease-relevant, regulatory-appropriate assays that could be used by the FDA to quantitatively and qualitatively measure the adverse impact of tobacco smoke exposure.