Development of biomarkers of exposure and effects for electronic cigarette vs. combustible cigarette use

电子烟与可燃香烟使用的暴露和影响的生物标志物的开发

• 批准号: 10493359
• 负责人: AHMAD BESARATINIA
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493359
• 关键词: Address; Adolescent; Adult; Age; Biological; Biological Assay; Biological Markers; Biological Specimen Banks; Blood Cells; California; Carcinogens; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Chemicals; Cigarette; Collaborations; Collection; Communities; Computer Models; DNA Methylation; Data; Data Analyses; Devices; Disease; Dose; Electronic cigarette; Epigenetic Process; Exposure to; Frequencies; Funding; Genes; Genetic; Genetic Transcription; Genomic DNA; Goals; Health; Immune; Immunity; Inflammation; Inflammatory; Laboratories; Leukocytes; Link; Malignant Neoplasms; Measures; Methylation; Modeling; Modification; Molecular; Mutation; National Institute of Dental and Craniofacial Research; Nicotine; Oncogene Deregulation; Ontology; Oral; Pathway interactions; Pattern; Population; Public Health; Race; Respiratory Disease; Risk; Sensitivity and Specificity; Smoker; Smoking; Specimen; Study Subject; Tissues; Tobacco; Tobacco use; authority; base; biomarker development; cell type; cigarette smoke; cigarette smoking; combustible cigarette; disorder risk; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; electronic liquid; gene network; multiple omics; never smoker; next generation sequencing; non-cigarette tobacco product; non-smoker; novel marker; public health relevance; public repository; recruit; respiratory; sex; smoking cessation; tobacco products; tobacco regulation; toxicant; transcriptome; transcriptome sequencing; transcriptomics; vaper; vaping; variant detection

While the reduced levels of toxicants and carcinogens in electronic cigarette (e-cig) vapor may imply lower health risk, it cannot, however, equate to no risk. In fact, exposure to many of the same constituents of e-cig vapor, at various concentrations, has been associated with a variety of respiratory-, cardiovascular-, and immune-related (inflammatory) diseases, and cancer. To date, the long-term health consequences of vaping are largely unknown. Rationale: The biological effects of many harmful chemicals present in both e-cig vapor and cigarette smoke are ascribed to their ability to induce genetic/epigenetic changes that cause transcriptional deregulation of disease-related genes. Approach: We will perform a multi-omics analysis to detect genetic/epigenetic alterations associated with transcriptional deregulation of key functional genes in oral cells and blood leukocytes of healthy adult vapers and smokers in comparison to controls (nonsmokers non-vapers) (N=45/group, matched for age, sex, and race). Aim 1: Applying RNA-sequencing and gene ontology analysis, “we will first screen for deregulation of disease-related genes in oral- and blood cells of vapers and smokers as compared to controls”. Having identified the deregulated genes in each group, we will then employ targeted next-generation sequencing “to detect genetic changes in Aim 2, and epigenetic modifications in Aim 3 within the deregulated genes”. Integration analysis of data from Aims 2 and 3 will identify loci with detectable genetic/epigenetic changes that differentiate, with the highest sensitivity and specificity, vapers and smokers from controls and from one another. Detectable genetic/epigenetic changes associated with aberrant expression of disease-related genes in cells from vapers vs. smokers can serve as novel biomarkers of exposure and effects for vaping vs. smoking. These biomarkers will help inform the health risks or potential benefits of e-cig use vs. smoking. As a secondary goal, we will perform computational modeling “to find correlations between the identified biomarkers and subjects’ tobacco product use frequency and patterns and product characteristics”. This will inform the impact of vaping/smoking dose and product characteristics, including e-cig device features (e.g., model & power) and e- liquid content (nicotine and flavor), and cigarette brand, type, and chemical constituents (e.g., tar), on the biological effects of e-cig use vs. cigarette smoking. Responsiveness to RFA: This proposal will maximize the use of existing biospecimens from our recently completed NIDCR-funded project whose study subjects were recruited through collaboration with USC-TCORS, which is sponsored by the FDA-CTP. This is a unique collection of biospecimens from a representative population in California. No publicly available repository in the US offers similar specimens required for this project. The specimens are currently stored in the PI’s laboratory, and readily available for use. Impact: The findings of this project may generalize to the broader population of vapers and smokers in the US and across the world, thus being of immediate use for the scientific community and regulatory authorities, and of great relevance to the public’s health.

虽然电子烟 (e-cig) 蒸汽中有毒物质和致癌物水平的降低可能意味着健康状况较差 有风险，但并不等于没有风险。事实上，接触电子烟蒸汽的许多相同成分，在 各种浓度，与多种呼吸、心血管和免疫相关的 （炎症）疾病和癌症。迄今为止，电子烟对健康的长期影响主要是 未知。理由：电子烟蒸汽和香烟中存在的许多有害化学物质的生物效应 烟雾归因于它们诱导遗传/表观遗传变化的能力，从而导致转录失调 疾病相关基因。方法：我们将进行多组学分析来检测遗传/表观遗传 与口腔细胞和血液白细胞中关键功能基因转录失调相关的改变 与对照组（不吸烟者、非电子烟者）相比，健康成年电子烟者和吸烟者的比例（N=45/组，匹配 年龄、性别和种族）。目标 1：应用 RNA 测序和基因本体分析，“我们将首先筛选 与对照组相比，电子烟使用者和吸烟者的口腔和血细胞中与疾病相关的基因失调”。 确定了每组中失调的基因后，我们将采用有针对性的下一代测序 “检测 Aim 2 中的遗传变化，以及 Aim 3 中失调基因的表观遗传修饰”。 对目标 2 和 3 的数据进行整合分析将识别具有可检测遗传/表观遗传变化的基因座，这些变化 以最高的灵敏度和特异性将电子烟使用者和吸烟者与对照者以及彼此区分开来。 与细胞中疾病相关基因的异常表达相关的可检测的遗传/表观遗传变化 电子烟使用者与吸烟者之间的差异可以作为电子烟与吸烟的接触和影响的新型生物标志物。这些 生物标志物将有助于了解使用电子烟与吸烟相比的健康风险或潜在益处。作为次要目标， 我们将进行计算建模“以找到已识别的生物标志物与受试者之间的相关性” 烟草产品的使用频率、模式和产品特征”。这将告知烟草产品的影响 电子烟/吸烟剂量和产品特性，包括电子烟​​设备特性（例如型号和功率）和电子烟 液体含量（尼古丁和香料）以及卷烟品牌、类型和化学成分（例如焦油） 使用电子烟与吸烟的生物效应。对 RFA 的响应：该提案将最大限度地提高 使用我们最近完成的 NIDCR 资助项目中的现有生物样本，该项目的研究对象是 通过与 USC-TCORS 合作招募，该项目由 FDA-CTP 赞助。这是一个独特的 从加利福尼亚州代表性人群中收集生物样本。中没有公开可用的存储库 美国提供了该项目所需的类似标本。这些标本目前保存在PI的实验室中， 并且随时可用。影响：该项目的研究结果可能会推广到更广泛的人群 美国和世界各地的电子烟爱好者和吸烟者，因此可以立即为科学界所用 和监管机构，并且与公众健康密切相关。