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

 描述（由申请人提供）：生物标志物是细胞、生物化学或分子改变，可以在人体组织中轻松且非侵入性地测量，并且直接或间接参与疾病途径。空气颗粒物污染，也称为颗粒物（PM），会导致肺部和全身炎症，以及肺功能的急性降低和加速肺老化。反映风险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靶向预防的机会。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风险的新型生物标志物。我们将利用实验和临床证据对细胞外囊泡（EV）的作用-即，人类细胞主动释放到血液中的微小的膜结合囊泡-以及它们作为炎症反应输送者的microRNA（miRNAs）的生物活性货物。动物和人类研究表明，PM诱导EV从肺和其他相关组织释放到血流中。特别是，PM导致EV封装的miRNA的释放，其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，没有关于EV生物标志物的数据，作为将PM暴露与其对肺功能的不良影响联系起来的机制路径的一部分。在本提案中，我们将利用两个表型良好的纵向队列的资源，规范性衰老研究（NAS，n=750）和奥格斯堡地区合作健康研究（KORA），我们的复制伙伴队列（在拟议的复制集中n=750）。在NAS和KORA中，我们可以从约10年随访的连续访视中获得重复采集的血液样本、暴露数据和肺功能测量结果。我们假设血液EV的数量、大小和miRNA货物在短期和/或长期暴露于环境PM时发生改变（目标1）;而电动车的数量大小在肺功能测试的同时，在具有较低肺功能的个体的血液样本中，（目标2.a）和/或在最近一次肺功能检查前长达10年收集的系列样本中（目标2.b）。我们将建立并公开一个关于血液EV及其miRNA起源的组织/细胞类型的参考数据集;我们将使用该数据集来估计将PM与肺功能受损联系起来的EV封装的miRNA的来源。（探索性目标3.a）;我们将使用因果模型来确定EV生物标志物是否影响血液信使RNA表达，是否与炎症标志物有关，并预测-通过调解或修改-PM对肺功能的影响（探索性目标3.b）。在所有目标中，我们将使用PM化学成分的详细表征来捕获其排放源。暴露评估还将通过在356个NAS参与者家中进行的室内测量进行。电动汽车在健康和疾病方面的作用越来越受到认可。因此，我们的研究可能会产生一个模型，最终可以应用于其他呼吸危险因素和其他与年龄相关的疾病。

 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.