Prospective Health Outcomes and Inflammatory Biomarkers Associated with e-Cigarette Use

与电子烟使用相关的预期健康结果和炎症生物标志物

• 批准号: 10018099
• 负责人: Peter Castaldi
• 金额: $ 50.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018099
• 关键词: Acute; Adaptive Immune System; Address; Antibodies; Antibody Response; Autoantibodies; B-Lymphocytes; Biological; Biological Markers; Blood; Cells; Chronic Obstructive Airway Disease; Cigarette; Cigarette Smoker; Clinical; Control Groups; Controlled Study; Data; Disease; Electronic Nicotine Delivery Systems; Electronic cigarette; Elements; Evaluation; Genomics; Goals; Grant; Health; Human; Immunologic Receptors; Individual; Inflammation; Inflammatory; Inflammatory Response; Link; Longitudinal Studies; Lung; Machine Learning; Measures; Methods; Molecular; Mouse Strains; Oropharyngeal; Outcome; Pattern; Performance; Phenotype; Population; Positioning Attribute; Process; Proteomics; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Questionnaires; Recording of previous events; Respiratory Signs and Symptoms; Smoker; Spirometry; Surrogate Endpoint; T cell response; T-Lymphocyte; T-cell receptor repertoire; Testing; United States Food and Drug Administration; Visit; X-Ray Computed Tomography; adaptive immune response; authority; biomarker discovery; biomarker panel; candidate marker; chest computed tomography; cohort; design; electronic cigarette use; genome-wide; health assessment; lung injury; novel; novel strategies; patient population; phenotypic data; predictive modeling; prospective; public health relevance; random forest; response biomarker; study population; targeted sequencing; tool; transcriptome sequencing; transcriptomics; young adult

Project Summary. This project is designed to identify validated biomarkers for use in the assessment of electronic nicotine delivery systems (ENDS) by the FDA. Since the introduction of ENDS, commonly referred to as e-cigarettes, there has been a large increase in ENDS use among young adults and older traditional cigarette smokers who also use ENDS (dual users). Since 2016, the Food and Drug Administration (FDA) has had regulatory authority over ENDS, and there is an acute need for ENDS-related biomarkers that can be used as validated surrogate endpoints for evaluation of new ENDS products. With the goal of validated biomarker discovery in two independent cohorts, the COPDGene and UCSD ENDS studies, we propose to identify ENDS-related inflammatory biomarkers in ENDS only and dual users and relate these biomarkers to five-year lung health outcomes. COPDGene is an ongoing, longitudinal study of >6,000 current and former traditional cigarette (t-cig) smokers enriched for chronic obstructive pulmonary disease (COPD) with detailed longitudinal lung phenotyping data (including chest CT), genome-wide blood RNA-seq, and proteomic data. The UCSD ENDS Study is a controlled study of young ENDS only users and controls with detailed assessment of inflammatory biomarkers in the oropharynx, airways and blood. Biomarkers used as validated surrogate measures must be 1) associated with ENDS use, 2) predictive of health outcomes, and 3) have a strong biological rationale. We hypothesize that inflammatory biomarkers of ENDS use will be predictive of five-year lung health effects. In Aim 1 of this proposal, discovery of inflammatory transcriptomic and proteomic biomarkers of ENDS exposure will be performed in subjects from the COPDGene five-year study visit, and biomarkers will be validated in two independent sets of subjects from the COPDGene ten-year visit and the UCSD ENDS Study. In Aim 2 we will identify antibody-specific adaptive immune response biomarkers of ENDS exposure using adaptive immune receptor repertoire sequencing (AIRR-seq). Auto-antibodies are biomarkers that are associated with the degree of lung damage in COPD. AIRR-seq is a powerful tool for inflammatory biomarker discovery that characterizes an individual’s decades-long history of antibody responses. In Aim 3 we will use machine learning predictive models to relate ENDS-associated biomarker panels to five-year lung health outcomes from COPDGene. The investigative team for this grant is well-positioned to identify novel inflammatory biomarkers of ENDS use. The COPDGene and UCSD cohorts have the detailed lung phenotyping and molecular characterization necessary to discover and clinically validate biomarkers in two important populations of ENDS users, i.e. ENDS only and dual users.

项目摘要。该项目旨在识别经过验证的生物标志物以用于评估 FDA 批准电子尼古丁输送系统 (ENDS)。自 ENDS 引入以来，普遍 被称为电子烟的 ENDS 在年轻人和老年人中的使用大幅增加 也使用 ENDS 的传统吸烟者（双重使用者）。 2016年以来，食品药品监管总局 (FDA) 对 ENDS 拥有监管权，迫切需要 ENDS 相关生物标志物 可用作评估新 ENDS 产品的经过验证的替代终点。有了目标 在两个独立队列 COPDGene 和 UCSD ENDS 研究中发现经过验证的生物标志物，我们 建议在仅 ENDS 和双重用户中识别 ENDS 相关炎症生物标志物，并将其关联起来 这些生物标志物可反映五年肺部健康结果。 COPDGene 是一项正在进行的纵向研究 > 6,000 名当前和以前的传统香烟 (t-cig) 吸烟者患有慢性阻塞性肺病 疾病（慢性阻塞性肺病），具有详细的纵向肺表型数据（包括胸部 CT）、全基因组血液 RNA-seq 和蛋白质组数据。 UCSD ENDS 研究是一项针对仅使用 ENDS 的年轻用户的对照研究， 通过详细评估口咽、气道和血液中的炎症生物标志物进行控制。 用作经过验证的替代指标的生物标志物必须 1) 与 ENDS 的使用相关，2) 能够预测 健康结果，3) 具有强有力的生物学原理。我们假设炎症生物标志物 ENDS 使用率可预测五年肺部健康影响。在本提案的目标 1 中，发现 将在以下受试者中进行 ENDS 暴露的炎症转录组和蛋白质组生物标志物检测： COPDGene 为期五年的研究访问，生物标志物将在两组独立的受试者中得到验证 来自 COPDGene 十年访问和 UCSD ENDS 研究。在目标 2 中，我们将鉴定抗体特异性 使用适应性免疫受体库确定 ENDS 暴露的适应性免疫反应生物标志物 测序（AIRR-seq）。自身抗体是与肺损伤程度相关的生物标志物 慢性阻塞性肺病。 AIRR-seq 是发现炎症生物标志物的强大工具，可表征个体的炎症生物标志物 抗体反应已有数十年的历史。在目标 3 中，我们将使用机器学习预测模型来关联 来自 COPDGene 的五年肺部健康结果的 ENDS 相关生物标志物组。调查的 获得这笔资助的团队完全有能力识别 ENDS 使用的新型炎症生物标志物。慢性阻塞性肺病基因 和加州大学圣地亚哥分校队列拥有发现所需的详细肺表型和分子特征 并在两个重要的 ENDS 用户群体（即仅 ENDS 用户和双重用户）中临床验证生物标志物。