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的响应：该提案将隔离电子烟的生物效应 通过测量与吸烟风险相关的表观遗传和转录组学变化， 与对照组（非使用者）相比，健康成人电子烟使用者和/或吸烟者的细胞和组织中的疾病 或产品）。此外，它还将确定这些分子改变是否受到 吸电子烟/吸烟的强度和持续时间以及所使用的烟草产品（包括电子烟）的特性 设备特征和电子液体成分，以及香烟品牌、类型和化学成分。通过阐明 vaping与吸烟的生物学效应的分子机制，我们将开发新的生物标志物 这将对评估以下方面的健康风险或潜在益处具有重要的实用性： 相对于吸烟，理由：成人电子烟使用者可能有吸烟或共同使用史 电子烟和可燃香烟（即，双重用户）。为了调查成年人使用电子烟的生物学效应， 必须梳理出vaping的后果，同时考虑到“过去”或“未来”的混淆效应。 “现在”吸烟。警告：电子烟蒸汽和香烟烟雾中存在的许多有毒物质和致癌物质 通过表观遗传效应，如异常DNA甲基化和/或转录组学， 可能导致疾病相关基因失调的改变。项目概要：利用银行 从我们最近完成的NIDCR和TRDRP资助的研究标本，我们将区分生物学 通过分析口腔中的整个甲基化组和转录组， 和健康成年人的血细胞“独家”vapers，双重用户，“独家”吸烟者，和控制。我们 将使用一种新的方法，结合对整个甲基化组（Aim 1）和转录组（Aim 2)对建立在电子烟/吸烟剂量和烟草产品上的各种模型进行了有序敏感性分析 特性（目标3）。对来自目的1和2的数据的综合分析将确定甲基化组， 转录组的变化，调节疾病特异性基因，从而确定新的生物标志物的暴露， 影响vaping，两用，和吸烟.我们将使用以下方法验证患者人群中确定的生物标志物： 高度策划和质量控制的“组学”数据集从公共来源处理。这将验证 所鉴定的生物标志物用于评估“排他性”电子烟使用者、双重使用者和“排他性”吸烟者的疾病风险。 目标3中详细的计算模型和敏感性分析将确定 vaping/smoking剂量和产品特性对vapers中甲基化组和转录组的改变， 双重使用者和吸烟者。这些数据将为FDA对烟草产品的监管提供信息，以保护公众健康。 创新：我们将研究电子烟气雾剂和香烟烟雾对vapers细胞和组织的影响 和/或吸烟者使用甲基化组和转录组的全基因组测序和整合生物信息学 分析和计算建模，说明电子烟/吸烟剂量和产品特性。