Biology of the Oral Epithelium of E-Cigarette Smokers

电子烟吸烟者口腔上皮的生物学

• 批准号: 9208723
• 负责人: RONALD G CRYSTAL
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-03 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208723
• 关键词: 21 year old; Acute; Adverse effects; Aerosols; Affect; Age; Attention; Biology; Biopsy; Breathing; Cells; Cellular biology; Chronic; Cigarette; Cigarette Smoker; Clinical; Code; Cohort Studies; Communities; Computational Biology; DNA Methylation; Data; Data Set; Devices; Disease; Electronic cigarette; Electronics; Elements; Epithelial; Epithelium; Ethnic Origin; Future; Gender; Gene Expression; Genes; Glycerol; Health; Host Defense; Human; In Vitro; Ions; Knowledge; Laboratories; Link; Liquid substance; Lithium; Marketing; Messenger RNA; MicroRNAs; Mouth Diseases; Nicotine; Oral; Oral health; Oral mucous membrane structure; Pathway interactions; Pilot Projects; Population; Process; Propylene Glycols; Proteins; Recording of previous events; Respiratory System; Respiratory tract structure; Risk; Smoke; Smoker; Smoking; Smoking History; Suction; TP53 gene; Tobacco; Tobacco smoking; Untranslated RNA; aerosolized; age group; base; carcinogenesis; cigarette smoking; cohort; disorder risk; epigenome; experience; genome-wide; in vivo; insight; never smoker; non-smoker; oral cavity epithelium; propellant; receptor; sensor; transcriptome; vapor; young adult

 DESCRIPTION (provided by applicant): Electronic cigarettes (EC) are battery powered nicotine delivery devices that aerosolize nicotine. Despite the increasing use of EC, little attention has been paid to their possible adverse effects on human health. Theoretically, the risk relates to nicotine per se and/or the propellants or contaminants in the EC aerosol. The hypothesis underlying our application is that chronic EC smoking disorders the biology of the oral epithelium, the first cell population exposed to inhaled EC vapors. There is compelling evidence to support this hypothesis: (1) EC vapors contain nicotine, the oral epithelium expresses nicotine receptors, and exposure of epithelia to nicotine activates the nicotine pathway; (2) EC vapors also contain contaminants that potentially can affect oral epithelial biology; and (3) in vitro studies suggest that EC vapors modify epithelial biology and data generated by our laboratory demonstrates that even a brief, acute exposure of healthy nonsmokers to EC vapors induces significant changes in the airway epithelial transcriptome, including the expression of genes in the nicotine and p53 pathways. Using a cross-sectional, cohort-comparison of EC smokers compared to age, gender and ethnicity-matched never smokers, we propose to assess the oral epithelium obtained by biopsy from 200 EC smokers and 50 nonsmokers. The EC study cohort will be restricted to young adults (age 21-35 yr) with no prior history of tobacco smoking, but who have smoked EC for >6 months. With the knowledge that disordering of cell biology occurs long before clinical disease, we will evaluate the oral epithelium at the epigenome (DNA methylation) and transcriptome (mRNA and miRNA) levels (Specific Aim 1). With the complementary expertise of the co-PIs (R. Crystal, biology of the epithelium, J. Mezey, computational biology), by integrating analysis at the epigenome and transcriptome levels, we will identify gene(s)/pathways/communities disordered by EC vapors (Specific Aim 2). Based on our preliminary data, we will initially focus on the nicotine, p53 and related pathways at the protein and post-translational levels. Because there is so little known about the effects of EC smoking on the oral epithelium, we cannot predict which other biologic processes will be affected, but it is likely that EC vapors influence biology linked to host defens and/or early carcinogenesis. Based on these considerations, we propose 2 Specific Aims. Specific Aim 1: To evaluate the hypothesis that EC smoking alters oral epithelial biology, biopsies will be collected from the buccal mucosa of chronic EC smokers and healthy nonsmoker controls, none of whom have a history of smoking any tobacco products. Genome-wide datasets will be generated to assess DNA methylation and both coding and non-coding RNA transcriptomes. Specific Aim 2: Using both computational and experimental approaches, the biopsies and genome-wide datasets generated in Specific Aim 1 will be assessed to identify genes, pathways and gene communities altered in the oral epithelium of EC smokers, including analyses of two pathways (nicotine, p53) identified in our pilot study.

 描述(申请人提供)：电子烟(EC)是一种电池供电的尼古丁输送装置，可以雾化尼古丁。尽管EC的使用越来越多，但人们很少注意到它们可能对人类健康造成的不利影响。从理论上讲，这种风险与尼古丁本身和/或欧盟气雾剂中的推进剂或污染物有关。我们应用的假设是，慢性EC吸烟扰乱了口腔上皮的生物学，口腔上皮是暴露在吸入EC蒸气中的第一个细胞群体。有令人信服的证据支持这一假设：(1)EC蒸气含有尼古丁，口腔上皮表达尼古丁受体，上皮细胞暴露于尼古丁可激活尼古丁途径；(2)EC蒸气也含有可能影响口腔上皮生物学的污染物；(3)体外研究表明，EC蒸气可改变上皮生物学，我们实验室产生的数据表明，即使是健康的不吸烟者短暂、急性暴露于EC蒸气中，也会诱导呼吸道上皮转录组发生显著变化，包括尼古丁和p53途径中的基因表达。通过对EC吸烟者与年龄、性别和种族匹配的从不吸烟者进行横断面队列比较，我们建议评估从200名EC吸烟者和50名不吸烟者的活检中获得的口腔上皮。EC研究队列将仅限于年轻人(21-35岁)，无烟草吸烟史，但吸食EC已有6个月。鉴于细胞生物学的紊乱在临床疾病之前很久就会发生，我们将在表观基因组(DNA甲基化)和转录组(mRNA和miRNA)水平(特定目标1)评估口腔上皮。借助联合PI(R.Crystal，上皮生物学，J.Mezey，计算生物学)的互补专业知识，通过在表观基因组和转录组水平上的整合分析，我们将识别因EC蒸气而紊乱的基因(S)/途径/群落(具体目标2)。基于我们的初步数据，我们将首先在蛋白质和翻译后水平上关注尼古丁、P53和相关通路。由于EC吸烟对口腔上皮的影响知之甚少，我们无法预测哪些其他生物过程会受到影响，但EC蒸气可能会影响与宿主防御和/或早期致癌有关的生物学。基于这些考虑，我们提出了两个具体目标。具体目的1：为了评估EC吸烟改变口腔上皮生物学的假说，将从慢性EC吸烟者和健康非吸烟者对照组的口腔粘膜收集活检组织，他们都没有吸食任何烟草产品的历史。将生成全基因组数据集，以评估DNA甲基化以及编码和非编码RNA转录本。具体目标2：使用计算和实验方法，将评估在特定目标1中产生的活检和全基因组数据集，以确定EC吸烟者口腔上皮中改变的基因、途径和基因群落，包括对我们初步研究中确定的两条途径(尼古丁、p53)的分析。