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

而电子烟(e-cig)蒸气中有毒物质和致癌物质水平的降低可能意味着健康状况不佳。 然而，风险不能等同于没有风险。事实上，暴露在电子烟蒸气的许多相同成分中， 不同的浓度，已经与各种与呼吸、心血管和免疫相关的 (炎症性)疾病和癌症。到目前为止，蒸发对健康的长期影响主要是 未知。理论基础：电子烟蒸气和香烟中存在的许多有害化学物质的生物效应 吸烟归因于它们诱导基因/表观遗传变化的能力，从而导致转录调控的放松 与疾病相关的基因。方法：我们将进行多组学分析来检测遗传/表观遗传学 口腔细胞和血白细胞中关键功能基因转录失控相关的改变 健康成人尿布和吸烟者与对照组(不吸烟者和非尿布者)的比较(N=45/组，匹配 年龄、性别和种族)。目标1：应用RNA测序和基因本体论分析，我们将首先筛选 与对照组相比，放松尿布和吸烟者口腔和血细胞中与疾病相关的基因的管制“。 在确定了每组中未受管制的基因后，我们将采用有针对性的下一代测序 “检测目标2中的遗传变化，以及目标3中非调控基因的表观遗传修饰”。 对来自AIMS 2和AIMS 3的数据的综合分析将识别具有可检测到的遗传/表观遗传变化的基因座 以最高的敏感度和特异度将尿布和吸烟者与对照组和彼此区分开来。 与细胞中疾病相关基因异常表达相关的可检测到的遗传/表观遗传变化 尿布和吸烟者可以作为接触和影响吸烟者和吸烟者之间的新的生物标志物。这些 生物标志物将有助于告知使用电子烟与吸烟相比的健康风险或潜在好处。作为次要目标， 我们将进行计算建模，以发现已识别的生物标志物和受试者之间的关联。 烟草产品的使用频率和模式以及产品特性“。这将使您了解 蒸发/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(尼古丁和香味)以及香烟品牌、类型和化学成分(例如焦油) 电子烟使用与吸烟的生物学效应。对RFA的响应：这项提议将最大限度地 使用我们最近完成的NIDCR资助项目中的现有生物检疫试剂，该项目的研究对象是 通过与FDA-CTP赞助的USC-TCORS合作招募。这是一个独一无二的 来自加利福尼亚州具有代表性的种群的生物标本收集。中没有公开可用的存储库 美国提供该项目所需的类似标本。这些标本目前储存在PI的实验室里， 并且随时可以使用。影响：本项目的发现可能会推广到更广泛的 美国和世界各地的尿布和吸烟者，因此立即为科学界所用 和监管当局，并与公众的健康密切相关。

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.