Circulating microRNAs in Extracellular Vesicles, Air Particulate Pollution, and Lung Function in an Aging Cohort

细胞外囊泡中的循环 microRNA、空气颗粒污染和衰老人群的肺功能

• 批准号: 9250770
• 负责人: Andrea Baccarelli
• 金额: $ 55.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250770
• 关键词: Acute; Address; Adverse effects; Affect; Age; Aging; Air; Air Pollution; Animals; Area; Biochemical; Biological; Biological Markers; Blood; Blood Circulation; Blood specimen; Breathing; Carbon Black; Cells; Cellular biology; Cessation of life; Chemicals; Clinical; Collection; Data; Data Set; Disease; Disease Pathway; Elderly; Encapsulated; Ensure; Exposure to; Fuel Oils; Funding; Gene Expression; Genetic Transcription; Germany; Goals; Health; Health Hazards; Home environment; Human; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Investments; Link; Longitudinal cohort; Lung; Measurement; Measures; Mediation; Membrane; Messenger RNA; Methods; MicroRNAs; Modeling; Modification; Molecular; Nickel; Participant; Particulate; Particulate Matter; Phenotype; Play; Pollution; Population; Power Plants; Prevention; Public Health; Public Health Applications Research; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Research; Resources; Respiratory physiology; Risk; Risk Factors; Role; Sampling; Signal Transduction; Source; Surface; System; Time; Tissues; Translations; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Vanadium; Vesicle; Visit; Vital capacity; age related; causal model; cell type; circulating microRNA; clinical effect; cohort; cost; design; digital; direct application; extracellular vesicles; fine particles; follow-up; human tissue; inflammatory marker; mRNA Expression; nano-string; novel; novel marker; particle; pre-clinical; prevent; public health relevance; remote sensing; respiratory; response; screening

 DESCRIPTION (provided by applicant): Biomarkers are cellular, biochemical, or molecular alterations that can be easily and non-invasively measured in human tissues and are directly or indirectly in the pathway of disease. Air particulate pollution, also known as particulate matter (PM), induces lung and systemic inflammation and acute reductions in lung function and accelerated lung aging. The limited availability of biomarkers that reflect at-risk exposures and preclinical effects on lung function dramatically limits opportunities for effective targeted prevention. To address this gap, our long-term goal is to identify novel biomarkers that reflect environmental influences and predict the risk of impaired lung function. We will leverage experimental and clinical evidence on the roles of Extracellular Vesicles (EVs)-i.e., tiny membrane-bound vesicles actively released by human cells into the bloodstream- and of their bioactive cargo of microRNAs (miRNAs) as conveyors of inflammatory responses. Animal and human studies have shown that PM induces release of EVs into the bloodstream from the lung and other relevant tissues. In particular, PM causes release of EV-encapsulated miRNAs, which are key bioactive molecules that can control the expression of genes in recipient cells. Yet to date, no data are available on EV biomarkers as part of the mechanistic paths linking PM exposure to its adverse effects on lung function. In this proposal, we will leverage the resources of two well-phenotyped longitudinal cohorts, the Normative Aging Study (NAS, n=750) and the Cooperative Health Research in the Region Augsburg (KORA), our replication partner cohort (n=750 in the proposed replication set). In both NAS and KORA, we have access to repeated collections of blood samples, exposure data, and lung function measurements from serial visits over ~10 years of follow up. We hypothesize that the number, size, and miRNA cargo of blood EVs are modified in response to short- and/or long-term exposures to ambient PM (Aim 1); and that the EV number, size, and miRNA cargo are altered in individuals with lower lung function in blood samples concurrent to lung function testing (Aim 2.a) and/or in serial samples collected up to 10 years before the most recent lung function testing (Aim 2.b). We will establish and make publicly available a reference dataset on the tissue/cell type of origin of blood EVs and of their miRNAs; we will use this dataset to estimate the sources of EV-encapsulated miRNAs linking PM to impaired lung function (Exploratory Aim 3.a); we will use causal modeling to determine whether EV biomarkers affect blood messenger RNA expression, are linked to inflammation markers, and predict- through mediation or modification-PM effects on lung function (Exploratory Aim 3.b). Across aims, we will use detailed characterization of PM chemical components to capture their emission sources. Exposure assessment will also be informed by indoor measurements at 356 of the NAS participants' homes. EVs have increasingly recognized roles in health and disease. Therefore, our research may yield a model that could be eventually applied to additional respiratory risk factors and other age-related ailments.

 描述（由适用提供）：生物标志物是细胞，生化或分子改变，可以在人体组织中易于和无创测量，并且直接或间接地在疾病途径中。空气颗粒污染，也称为颗粒物（PM），引起肺部和全身性炎症和急性减少肺功能和加速肺老化。反映高危暴露和对肺功能的临床前影响的生物标志物的有限可用性极大地限制了有效的靶向预防机会。为了解决这一差距，我们的长期目标是确定反映环境影响并预测肺功能受损的风险的新型生物标志物。我们将利用有关细胞外囊泡（EVS）的作用的实验和临床证据 - i。动物和人类研究表明，PM会影响电动汽车从肺和其他相关组织中释放到血液中。特别是，PM导致EV包含的miRNA的释放，它们是可以控制受体细胞中基因表达的关键生物活性分子。然而，迄今为止，作为将PM暴露与其对肺功能的不良影响的机械路径的一部分，EV生物标志物上尚无数据可用。在该提案中，我们将利用两个精心型纵向同伙的资源，规范性衰老研究（NAS，n = 750）和该地区Augsburg（KORA）的合作健康研究，我们的复制伙伴队列（n = 750 n = 750 in ped sud sed Replication Setit集合）。在NAS和KORA中，我们都可以从约10年的随访中连续访问血液样本，暴露数据和肺功能测量。我们假设血液电动汽车的数量，大小和miRNA货物是根据对环境PM的短期和/或长期暴露而修改的（AIM 1）；并且在血液样本中与肺功能测试的血液样本中肺功能较低的个体（AIM 2.A）和/或在最新的肺功能测试（AIM 2.B）中收集了长达10年（AIM 2.B）的血液样本（AIM 2.a）和/或中，EV数量，大小和miRNA货物发生了变化。我们将建立并公开提供有关血液电动汽车及其miRNA的组织/细胞形式的参考数据集；我们将使用此数据集估算链接PM的EV封装的miRNA的来源（探索性AIM 3.A）；我们将使用因果建模来确定EV生物标志物是否影响血液使者RNA的表达，与炎症标记以及预测直通介导或修饰PM对肺功能的影响（探索性AIM 3.B）。在整个目标中，我们将使用PM化学成分的详细表征来捕获其排放源。 NAS参与者家中356室的室内测量值也将告知暴露评估。电动汽车在健康和疾病中越来越认识到作用。因此，我们的研究可能会产生一个模型，该模型最终可以应用于其他呼吸危险因素和其他与年龄有关的疾病。