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

 描述(由申请人提供)：生物标记物是细胞、生化或分子的改变，可以在人体组织中轻松和非侵入性地测量，并直接或间接地发生在疾病的途径中。空气颗粒物污染，也称为颗粒物(PM)，会导致肺部和全身炎症，肺功能急剧下降，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可获得性有限，极大地限制了有效靶向预防的机会。为了解决这一差距，我们的长期目标是识别反映环境影响和预测肺功能受损风险的新生物标志物。我们将利用实验和临床证据来研究细胞外小泡(EV)--即由人类细胞主动释放到血液中的微小的膜结合的小泡--及其具有生物活性的microRNAs(MiRNAs)作为炎症反应的传输者的作用。动物和人体研究表明，PM诱导EV从肺和其他相关组织释放到血液中。特别是，PM导致EV包裹的miRNAs的释放，这些miRNAs是关键的生物活性分子，可以控制受体细胞中基因的表达。然而，到目前为止，还没有关于EV生物标志物的数据，作为将PM暴露与其对肺功能的不利影响联系起来的机制途径的一部分。在这项提案中，我们将利用两个表型良好的纵向队列的资源，即标准化老龄化研究(NAS，n=750)和奥格斯堡地区合作卫生研究(KORA)，我们的复制伙伴队列(拟议的复制集合中的n=750)。在NAS和KORA中，我们都可以从连续访问中获得重复收集的血样、暴露数据和超过10年的随访中的肺功能测量。我们假设，EV的数量、大小和miRNA载量会因短期和/或长期暴露于周围PM而改变(目标1)；在肺功能测试的同时(目标2.a)和/或在最近一次肺功能测试前10年收集的系列样本中，EV的数量、大小和miRNA载量在肺功能较低的个体中发生改变(目标2.b)。我们将建立并公开一个关于EV及其miRNAs来源的组织/细胞类型的参考数据集；我们将使用该数据集来估计EV包裹的将PM与肺功能受损联系起来的miRNAs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的表达，是否与炎症标志物相关联，并通过中介或修饰来预测PM对肺功能的影响(探索性目标3.b)。在AIMS中，我们将使用PM化学成分的详细表征来捕获其排放源。暴露评估还将通过对356名NAS参与者家中的室内测量来提供信息。电动汽车在健康和疾病方面的作用得到越来越多的认可。因此，我们的研究可能会产生一个模型，最终可能会应用于其他呼吸道风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.