Comparative Transcriptomic Signatures of Inhaled Tobacco Smoke

吸入烟草烟雾的比较转录组特征

• 批准号: 9112983
• 负责人: THOMAS J MARIANI
• 金额: $ 42.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112983
• 关键词: Address; Adolescent; Adult; Affect; Animal Model; Bioinformatics; Biological Assay; Biological Markers; Breathing; Cancer Etiology; Cause of Death; Cell model; Cells; Cessation of life; Childhood; Chronic Obstructive Airway Disease; Chronic lung disease; Cigarette; Custom; Databases; Detection; Development; Disease; Disease Outcome; Dose; Epidemiologic Studies; Epithelial Cells; Exposure to; Fibroblasts; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Health; Human; In Vitro; Knowledge; Lead; Life; Lung; Lung diseases; Malignant neoplasm of lung; Measures; Messenger RNA; MicroRNAs; Mining; Mission; Modeling; Mus; Neonatal; Newborn Infant; Outcome; Pathology; Pathway interactions; Perinatal Exposure; Physiological; Population; Pulmonary Inflammation; Regulation; Research; Risk; Risk Factors; Rodent; Sampling; Smoke; Smoking History; Stem cells; Surveys; System; Tobacco; Tobacco smoke; Vulnerable Populations; Woman; Work; base; cell type; comparative; disorder risk; environmental tobacco smoke exposure; genome-wide; human disease; in vitro testing; in vivo; inflammatory lung disease; malignant breast neoplasm; men; mouse model; neonatal exposure; neonate; premature; programs; research study; response; specific biomarkers; tobacco exposure; transcriptome; transcriptomics

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.

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生风险显着增加。胎儿和新生儿接触烟草是早产慢性肺部疾病的一个主要危险因素，影响到极其脆弱的人群，估计每年的负担超过25亿美元。在美国。流行病学研究强烈支持吸烟史与慢性阻塞性肺病之间的因果关系。慢性阻塞性肺病是美国第三大死亡原因，肺癌是男性和女性癌症死亡的主要原因。已使用动物模型和体外系统，结合对人类疾病样本的研究，以确定与疾病相关的途径。遗憾的是，虽然人们普遍认识到接触烟草烟雾的健康风险，但目前尚无体外试验来确定与接触负担或不同类型烟草制品相关的风险。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志物，准确预测人类疾病风险。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目标：第一个目标将在体外调查烟草烟雾对全基因组的反应，并最终产生一套准确和预测人类疾病的转录生物标记集。第二个目标将使用经过验证的烟雾引起的肺部疾病小鼠模型，确定肺部对吸入各种烟草类型和剂量的烟雾的具体生理反应。该目标还将确定成人和更脆弱的少年和新生儿的不同反应。第三个目标将有助于完善一组生物标志物，重点关注在烟草烟雾暴露和/或由此导致的疾病状态下在人体肺部观察到的失调，并评估这些特定生物标志物的预测潜力。该项目高度响应了该计划的目标，并将通过开发多种与疾病相关的、符合监管要求的检测方法来支持FDA监管烟草制品的使命，这些检测方法可被FDA用于定量和定性地测量烟草烟雾暴露的不利影响。