Differentiating the biological effects of vaping from smoking by analyzing the methylome and transcriptome

通过分析甲基化组和转录组区分电子烟和吸烟的生物学效应

• 批准号: 10588059
• 负责人: AHMAD BESARATINIA
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588059
• 关键词: Aberrant DNA Methylation; Accounting; Adult; Affect; Benefits and Risks; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Markers; Biological Specimen Banks; Blood Cells; Carcinogens; Cells; Characteristics; Chemicals; Cigarette; Cigarette Smoker; Computer Models; DNA Methylation; Data; Data Analyses; Data Set; Devices; Diet; Disease; Dose; Electronic cigarette; Epigenetic Process; Evaluation; Funding; General Population; Generations; Genes; Genetic Transcription; Health; Human; Laboratories; Leukocytes; Life Style; Link; Measurement; Measures; Methylation; Modeling; Molecular; National Institute of Dental and Craniofacial Research; Nicotine; Ontology; Oral; Pathway Analysis; Pathway interactions; Pattern; Population; Process; Public Health; RNA analysis; Research; Risk; Safety; Science; Smoker; Smoking; Smoking History; Smoking Status; Source; Specimen; Study Subject; Tars; Tissues; Tobacco; Tobacco use; Translating; Validation; biomarker identification; bisulfite sequencing; cell type; cigarette smoke; cigarette smoking; combustible cigarette; comparison control; demographics; differential expression; disorder risk; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; electronic liquid; gene network; genome-wide; health assessment; innovation; methylome; model building; novel marker; novel strategies; patient population; peripheral blood; preservation; public health relevance; segregation; tobacco products; tobacco regulation; toxicant; transcriptome; transcriptome sequencing; transcriptomics; vaper; vaping; whole genome

Responsiveness to NOT-OD-22-022: This proposal will segregate the biological effects of electronic cigarette (e-cig) use (‘vaping’) from smoking by measuring the epigenetic and transcriptomic changes linked to risk of disease in cells and tissues of healthy adult vapers and/or cigarette smokers as compared to controls (non-users of either product). Furthermore, it will determine whether these molecular alterations are modulated by the intensity and duration of vaping/smoking and the characteristics of tobacco product(s) used, including e-cig device features and e-liquid ingredients, and cigarette brand, type, and chemical constituents. By elucidating the molecular mechanisms underlying the biological effects of vaping vs. smoking, we will develop novel biomarkers of exposure and effects, which will have significant utility for assessing the health risks or potential benefits of vaping relative to smoking. Rationale: Adult e-cig users are likely to have a prior history of smoking or co-use e-cigs and combustible cigarettes (i.e., dual users). To investigate the biological effects of e-cig use in adults, it is imperative to tease out the consequences of vaping, while accounting for the confounding effects of ‘past’ or ‘present’ smoking. Premise: Many toxicants and carcinogens present in e-cig vapor and cigarette smoke exert their biological effects through epigenetic effects, such as aberrant DNA methylation, and/or transcriptomic alterations that can lead to dysregulation of disease-related genes. Project outline: Leveraging the banked specimens from our recently completed NIDCR- and TRDRP-funded studies, we will differentiate the biological consequences of e-cig use from those of smoking by analyzing the whole methylome and transcriptome in oral- and blood cells of healthy adult ‘exclusive’ vapers, dual users, ‘exclusive’ cigarette smokers, and controls. We will use a novel approach, combining primary analysis of the whole methylome (Aim 1) and transcriptome (Aim 2) and ordinal sensitivity analysis of various models built on vaping/smoking dose and tobacco product characteristics (Aim 3). Integrative analysis of data from Aims 1 and 2 will determine the methylome and transcriptome changes that regulate disease-specific genes, thus identifying novel biomarkers of exposure and effects for vaping, dual use, and smoking. We will validate the identified biomarkers in patient populations using highly curated and quality-controlled ‘omics’ datasets processed from public sources. This will verify the utility of the identified biomarkers for assessing disease risk in exclusive’ e-cig users, dual users, and ‘exclusive’ smokers. The detailed computational modeling and sensitivity analysis in Aim 3 will determine the impact of vaping/smoking dose and product characteristics on the alterations of the methylome & transcriptome in vapers, dual users, and smokers. These data will inform the FDA’s regulation of tobacco products to protect public health. Innovation: We will investigate the effects of e-cig aerosol and cigarette smoke on cells and tissues of vapers and/or smokers using genome-wide sequencing of the methylome & transcriptome and integrative bioinformatic analysis & computational modeling, accounting for vaping/smoking dose and product characteristics.

对NOT-OD-22-022的反应：该提案将隔离电子烟的生物学效应 （e-e-cig）通过测量与与风险有关 与对照组相比，健康成人蒸气和/或吸烟者的细胞和组织中的疾病（非用户） 任何产品）。此外，它将确定这些分子改变是否由 烟/吸烟的强度和持续时间以及所用烟草产物的特性，包括电子烟 设备功能和电子液体成分以及香烟品牌，类型和化学构成。通过阐明 烟与吸烟的生物学效应的基础分子机制，我们将开发新型的生物标志物 暴露和影响，这将具有评估健康风险或潜在利益的重要效用 相对于吸烟烟。理由：成人电子烟的用户可能有先前的吸烟或共同使用史 电子烟和混合香烟（即双用户）。为了研究成人电子烟的生物学作用， 必须在考虑“过去”或 “现在”吸烟。前提：电子烟蒸气和香烟烟雾中存在的许多有毒物质和致癌物 它们通过表观遗传效应（例如异常DNA甲基化和/或转录组）的生物学作用 可能导致疾病相关基因失调的改变。项目大纲：利用银行 来自我们最近完成的NIDCR和TRDRP资助的研究的标本，我们将区分生物学 通过分析口腔中的整个甲基甲基和转录组，电子烟的使用的后果 以及健康的成人“独家”蒸气，双重用户，“独家”吸烟者和控制的血细胞。我们 将使用一种新颖的方法，结合了整个甲基组（AIM 1）和转录组的一级分析（AIM 2）以及基于烟雾/吸烟剂量和烟草产物的各种模型的顺序灵敏度分析 特征（目标3）。目标1和2的数据的综合分析将确定甲基甲基和 转录组的变化调节疾病特异性基因，从而识别出新的暴露生物标志物和 蒸发，双重使用和吸烟的效果。我们将使用 从公共来源处理的高度精心策划和质量控制的“ OMIC”数据集。这将验证 确定的生物标志物用于评估独家电子烟的使用者，双重用户和“独家”吸烟者的疾病风险。 AIM 3中的详细计算建模和灵敏度分析将确定 烟/吸烟剂量和产品特征关于甲基甲基组和vapers中转录组改变的特征， 双用户和吸烟者。这些数据将为FDA对保护公共卫生的烟草产品的规定提供信息。 创新：我们将研究E-cig气溶胶和香烟烟雾对蒸气细胞和组织的影响 和/或吸烟者使用甲基甲基和转录组和综合生物信息的全基因组测序 分析与计算建模，审计烟雾/吸烟剂量和产品特征。