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）蒸气中有毒物质和致癌物的水平降低可能意味着健康状况降低 风险，但是它不能等于没有风险。实际上，暴露于许多相同构成电子烟蒸气的相同构成，在 各种浓度与各种呼吸道，心血管和免疫相关 （炎症）疾病和癌症。迄今为止，烟的长期健康后果在很大程度上是 未知。理由：电子烟蒸气和香烟中存在许多有害化学物质的生物学效应 将烟雾分配给其诱导遗传/表观遗传变化的能力，从而导致转录失调 与疾病有关的基因。方法：我们将执行多态分析以检测遗传/表观遗传学 与口腔细胞和血清细胞中关键功能基因的转录失调相关的改变 与对照组相比，健康的成年蒸气和吸烟者（非吸烟者）（n = 45/组，匹配） 对于年龄，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，蒸气和吸烟者的口腔和血细胞中与疾病相关的基因的放松管制。” 在确定了每个组中不受管制的基因后，我们将采用针对性的下一代测序 “检测AIM 2中的遗传变化，以及在放松管制基因内的AIM 3中的表观遗传学修饰”。 来自AIM 2和3的数据的集成分析将识别具有可检测的遗传/表观遗传变化的基因座， 以最高的灵敏度和特异性为特征，从对照组和彼此之间的吸烟者和吸烟者。 与细胞中疾病相关基因异常表达相关的可检测遗传/表观遗传变化 从vapers vs.吸烟者中，可以用作曝光和吸烟的效果的新型生物标志物。这些 生物标志物将有助于告知E-CIG使用与吸烟的健康风险或潜在的好处。作为次要目标， 我们将执行计算建模，“找到已确定的生物标志物与受试者之间的相关性” 烟草产品使用频率，模式和产品特征”。这将为您的影响 蒸发/吸烟剂量和产品特征，包括电子烟​​设备功能（例如，模型和功率）和E- 液体含量（尼古丁和风味），以及香烟品牌，类型和化学宪法（例如焦油） 电子烟的生物学作用与吸烟。对RFA的响应：此提案将最大化 从我们最近完成的NIDCR资助的项目中使用现有的生物测量，其研究对象是 通过与FDA-CTP赞助的USC-TCORS合作招募。这是一个独特的 来自加利福尼亚州代表人群的生物测量。没有公开可用的存储库 美国提供此项目所需的类似标本。这些标本目前存储在PI的实验室中， 并随时可用。影响：该项目的发现可能会推广到更广泛的人群 美国和世界各地的蒸气和吸烟者，因此可以立即用于科学界 和监管机构，并且与公众的健康有很大相关。