Air pollution and high density lipoprotein structure and function

描述（由申请方提供）：心血管疾病是全球发病和死亡的最常见原因。有证据表明，空气污染会增加心血管疾病的风险，更好地了解这种关系的生物学原因可能会带来实质性的好处。与吸烟和一些饮食风险因素不同，个人（特别是儿童）在日常生活中基本上无法选择是否暴露于空气污染，这使得空气污染成为政策制定者公共卫生研究的重要主题。改善空气污染和心血管疾病之间的生物途径的特征可以通过更直接的空气质量管理政策来改善健康，更好地识别风险群体，减少对有害副作用的干预措施的需求。一些实验室研究报告称，颗粒物（PM）与人内皮细胞中的氧化磷脂反应，导致与血管炎症相关的促炎、促氧化、未折叠蛋白反应途径的表达，以及功能失调的高密度脂蛋白（HDL）的产生。这种PM诱导的功能失调的HDL失去了其心脏保护的品质，甚至可能成为动脉粥样硬化。我们的提案将进一步描述这种潜在的CVD途径，并探索暴露于一系列与交通有关的空气污染物（<2.5μm的颗粒物，二氧化氮，氮氧化物和炭黑）是否与人类HDL的变化有关。为了广泛地研究这个话题，我们将在两种不同的环境中研究与交通相关的空气污染物（TRAP）的暴露，并研究一套先进的HDL测量。首先，我们将研究空气污染暴露之间的横向关系，（使用基于EPA和特定队列监测的有效时空土地利用回归模型估计）和HDL颗粒数（HDL-P，HDL颗粒数的测量与CVD事件的相关性比HDL胆固醇更强）（梅萨航空），一个多种族的男性和女性队列。其次，我们将研究空气污染与亚临床动脉粥样硬化进展（以冠状动脉钙为指标）之间的关系是否由HDL-P介导，采用传统和因果中介分析框架来评估直接和间接影响。第三，我们将使用混合模型来检查是否控制暴露于空气污染的柴油机废气从人类暴露轨迹从发现中心的影响HDL的功能和蛋白质组学质量。在这项研究中，我们研究了短期暴露于柴油机废气对HDL抗氧化指数（HOI）以及HDL蛋白质组的影响，这两种指标都是HDL结构和功能的指标。了解TRAP和HDL结构和功能之间的关系将有助于阐明TRAP影响CVD的潜在生物学机制。

DESCRIPTION (provided by applicant): Cardiovascular disease is most common cause of morbidity and mortality worldwide. Evidence suggests that air pollution increases the risk of CVD, and better understanding of the biological causes of this relationship could have substantial benefits. Unlike smoking and some dietary risk factors, individuals (particularly children) are largely unable to choose whether or not to be exposed to air pollution in their daily life, making air pollution a crucial subject of public health research for policy makers. Improved characterization of the biological pathway between air pollution and CVD could improve health by allowing for more directed air quality management policies, and better identification of at risk groups, reducing the need for interventions with harmful side effects. Several laboratory studies report that particulate matter (PM) reacts with oxidized phospholipids in human endothelial cells, resulting in expression of pro-inflammatory, pro-oxidant, unfolded protein response pathways related to vascular inflammation, and the creation of dysfunctional high-density lipoproteins (HDL). This PM-induced dysfunctional HDL loses its cardio-protective qualities and may even become atherogenic. Our proposal will further characterize this potential CVD pathway, and explore whether exposure to a suite of traffic-related air pollutants (particulate matter <2.5μm, nitrogen dioxide, oxides of nitrogen, and black carbon) is associated with changes in HDL in humans. To broadly examine this topic, we will examine exposure to traffic-related air pollutants (TRAP) in two different settings, and examine a suite of advanced HDL measurements. First, we will examine the cross-sectional relationship between air pollution exposure (estimated using a validated spatiotemporal land-use regression model based on EPA and cohort- specific monitoring) and HDL particle number (HDL-P, a measure of HDL particle number more strongly associated with CVD events than HDL cholesterol) in the Multi-Ethnic Study of Atherosclerosis Air Pollution study (MESA Air), a multiethnic cohort of men and women. Second, we will examine whether the relationship between air pollution and progression of subclinical atherosclerosis (as measured by coronary artery calcium) is mediated by HDL-P, employing traditional and causal mediation analysis frameworks to assess direct and indirect effects. Third, we will use mixed models to examine whether controlled exposure to air pollution to diesel exhaust from a human exposure trail from the DISCOVER center effects functional and proteomic qualities of HDL. In this study, we examine the effect of a short-term exposure to diesel exhaust on HDL anti- oxidant index (HOI), as well as the HDL proteome, both measures of HDL structure and function. Understanding the relationship between TRAP and HDL structure and function will help to elucidate the underlying biological mechanisms by which TRAP affects CVD.