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

 描述(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。在过去的二十年里，科学研究一再表明，环境空气颗粒物污染，也被称为颗粒物(PM)，会导致肺部和全身炎症，以及肺功能下降和加速肺老化。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。我们将利用最近的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--及其生物活性的microRNAs(MiRNAs)作为炎症反应的新载体的作用。最近来自动物和人类研究的证据表明，PM诱导EV从肺和其他相关组织的细胞释放到血液中。特别是，PM暴露会导致EV包裹的miRNAs的释放，这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，到目前为止，还没有大量的、表型良好的人群中的数据来说明EV作为将PM暴露与其对肺功能的不利影响联系起来的途径的一部分的潜在作用。在这项建议中，我们利用了标准化老龄化研究(NAS)队列(n=750)的独特性质，在20多年的跟踪调查中，我们重复收集了多达7次访问的血液样本、暴露数据和肺功能测量。所有发现都将在KORA(n=750)中独立验证，这是一个在研究设计、暴露水平和参与者特征方面与NAS非常相似的队列。我们假设EV的数量、大小和miRNA载量会随着短期和/或长期暴露于周围PM而改变(目标1)；EV的数量、大小和miRNA载量反映了采血时和/或随后的系列检查中肺功能的下降(目标2)。我们将使用高级统计建模来整合暴露、EVS和肺功能受损路径中的一组炎症标志物；我们将建立并公开关于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)。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。由于我们可以利用来自NAS和KORA队列的大量现有的、随时可用的资源和数据，我们将能够经济高效地概括一个赠款周期内20多年的后续行动的数据。

 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. Over the past two decades, scientific research has repeatedly shown that ambient air particulate pollution, also known as particulate matter (PM), induces lung and systemic inflammation, as well as 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 recent 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 novel conveyors of inflammatory responses. Recent evidence from animal and human studies has shown that PM induces the release of EVs into the bloodstream from cells in the lung and other relevant tissues. In particular, PM exposure 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 in large, well-phenotyped populations are available to address the potential roles of EVs as part of the paths linking PM exposure to its adverse effects on lung function. In this proposal, we exploit the unique nature of the Normative Aging Study (NAS) cohort (n=750) in which we have repeated collections of blood samples, exposure data and lung function measures in up to 7 visits conducted over 20+ years of follow up. All findings will be independently validated in KORA (n=750), a cohort remarkably similar to the NAS for study design, exposure levels, and participants' characteristics. 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 reflect reduced lung function at the time of blood sampling and/or over subsequent serial visits (Aim 2). We will use advanced statistical modeling to integrate a panel of inflammation markers in the paths linking exposure, EVs, and impaired lung function; 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). Across all aims, we will use detailed characterization of PM chemical components to capture their emission sources. As we can leverage a wealth of extant, ready-to-use resources and data from the NAS and KORA cohorts, we will be able to cost- effectively recapitulate data from more than two decades of follow up over a single grant cycle.