Air pollution and high density lipoprotein structure and function

描述（由申请人提供）：心血管疾病是世界范围内最常见的发病和死亡原因。有证据表明，空气污染增加了患心血管疾病的风险，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（尤其是儿童）在很大程度上无法选择在日常生活中是否暴露于空气污染中，这使得空气污染成为政策制定者公共卫生研究的一个重要主题。改进空气污染与心血管疾病之间的生物途径特征，可以通过制定更有针对性的空气质量管理政策、更好地确定风险群体、减少对具有有害副作用的干预措施的需要，从而改善健康。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发生反应，导致与血管炎症相关的促炎、促氧化、未折叠的蛋白质反应途径的表达，并产生功能失调的高密度脂蛋白（HDL）。这种pm诱导的功能失调HDL失去了其心脏保护特性，甚至可能成为动脉粥样硬化。我们的研究将进一步表征这一潜在的心血管疾病途径，并探索暴露于一系列交通相关的空气污染物（<2.5μm的颗粒物、二氧化氮、氮氧化物和黑碳）是否与人类高密度脂蛋白的变化有关。为了广泛地研究这一主题，我们将研究在两种不同的环境下暴露于交通相关的空气污染物（TRAP），并研究一套高级HDL测量方法。首先，我们将在多民族动脉粥样硬化空气污染研究（MESA air）中研究空气污染暴露（使用基于EPA和队列特定监测的经过验证的时空土地利用回归模型进行估计）与HDL颗粒数（HDL- p， HDL颗粒数与心血管事件的相关性比HDL胆固醇更强）之间的横断面关系。MESA air是一项多民族男性和女性研究。其次，我们将研究空气污染与亚临床动脉粥样硬化（以冠状动脉钙测量）进展之间的关系是否由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来自DISCOVER中心的人体暴露轨迹的空气污染对HDL的功能和蛋白质组质量是否有影响。在这项研究中，我们研究了短期暴露于柴油废气对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的结构和功能。了解TRAP与HDL结构和功能之间的关系将有助于阐明TRAP影响心血管疾病的潜在生物学机制。

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.