Air Pollution and Cardiovascular Diseases: Identification of Novel Biomarkers

空气污染和心血管疾病：新型生物标志物的鉴定

• 批准号: 8893819
• 负责人: Jesus Antonio Araujo
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893819
• 关键词: Address; Affect; Air; Air Pollutants; Air Pollution; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apolipoprotein E; Aromatic Polycyclic Hydrocarbons; Atherosclerosis; Behavior; Bilateral; Biological; Biological Markers; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chemicals; China; Cities; Clinical; Data; Developed Countries; Developing Countries; Development; Diesel Exhaust; Environment; Environmental Exposure; Environmental Health; Environmental Tobacco Smoke; Epidemiologic Studies; Event; Exhibits; Exposure to; Food; Future; Generations; Goals; Health; High Density Lipoproteins; Human; Joints; Knockout Mice; Knowledge; Lead; Light; Link; Lipid Peroxidation; Lipids; Los Angeles; Lung; Measures; Mediator of activation protein; Metabolism; Mus; Myocardial Infarction; Myocardial Ischemia; Natural experiment; Oxidation-Reduction; Particulate; Particulate Matter; Pathway interactions; Plasma; Pollution; Population; Property; Reporting; Research; Research Institute; Sampling; Source; Students; Sudden Death; Testing; Time; Tissues; Travel; Universities; Urine; atherogenesis; cardiovascular health; experience; food consumption; global environment; healthy volunteer; human subject; improved; innovation; novel; oxidation; particle; programs; public health intervention; public health relevance; ultrafine particle; uptake; urinary

 DESCRIPTION (provided by applicant): Animal studies support the notion that exposures to ambient fine particulate matter (PM2.5) lead to increased cardiovascular ischemic events and enhanced atherosclerosis. While epidemiological studies have reported similar associations in human population, limited biomarkers have been identified and validated in humans. We have identified novel measures of biological effects in mice that have the potential of being important biomarkers for cardiovascular diseases in human subjects. There is a critical knowledge gap as to what extent biomarkers identified in animal models can be applied to human subjects. Lack of such knowledge is an important problem because until novel and reliable biomarkers are available, there is a gap in our ability of detecting health effects before the presentation of cardiovascular clinical events such as myocardial infarction or sudden death. Our long-term goal is to better understand the links between air pollution, polycyclic aromatic hydrocarbon (PAH) exposures, and cardiovascular diseases. The objective of this application is to identify novel and sensitive biomarkers of cardiovascular health effects, in association to air pollution exposures. The central hypothesis is that subacute exposure to ambient particulate PAHs will result in lipid peroxidation and dysfunctional HDL in association with endogenously generated PAH oxidative metabolites. Guided by preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) To determine to what extent the exposure to particulate PAHs affects the total levels and proportions of PAH metabolites in human subjects. We will characterize personal exposures to PAHs from various sources including air, food, and second hand smoke (SHS), and determine PAH metabolites in the urine of 40 healthy subjects travelling between Los Angeles and Beijing; and 2) To evaluate to what extent exposures to particulate PAHs lead to enhancement of lipid peroxidation in the blood and the generation of dysfunctional HDL. We will assess various measures of lipid oxidation and HDL functionality in the blood of the same human subjects over time. This will be the first systematic study to assess the applicability of novel cardiovascular biomarkers identified in experimental animals among human subjects and one of the first studies conducted in China addressing the link between environmental exposure and biological effects. The rationale for the proposed research is that the identified and validated novel biomarkers will justify and enable future larger studies among populations at lower exposure levels in the US. The proposed research is innovative because it represents a new and substantive departure from the status quo by conducting a natural experiment in which a panel of healthy subjects will experience a dramatic exposure contrast in ambient PM2.5 within a well-defined timeframe. The proposed research is significant because it is the first step in a continuum of research that will identify novel biomarkers, link environmental exposure to biological effects, and eventually lead to the discovery of the pathways to atherosclerosis, thus justifying public health interventions.

 描述(由申请人提供)：动物研究支持暴露于环境中的细颗粒物(PM2.5)会导致心血管缺血事件增加和动脉粥样硬化加重的观点。虽然流行病学研究已经报告了在人类群体中类似的关联，但有限的生物标记物已经在人类中被识别和验证。我们已经确定了小鼠生物效应的新方法，这些方法有可能成为人类心血管疾病的重要生物标记物。在动物模型中确定的生物标记物可以在多大程度上应用于人类受试者，这方面存在严重的知识差距。缺乏这样的知识是一个重要的问题，因为在新的和可靠的生物标志物出现之前，我们在心血管临床事件(如心肌梗死或猝死)出现之前检测健康影响的能力存在差距。我们的长期目标是更好地了解空气污染、多环芳烃(PAH)暴露和心血管疾病之间的联系。这项应用的目的是识别与空气污染暴露相关的对心血管健康影响的新的和敏感的生物标记物。中心假设是，亚急性暴露于周围颗粒物多环芳烃将导致脂质过氧化和高密度脂蛋白功能障碍，并与内源性多环芳烃氧化代谢产物有关。在初步数据的指导下，这一假设将通过追求两个具体目标来检验：1)确定暴露于颗粒性多环芳烃对人体内多环芳烃代谢物的总水平和比例的影响程度。我们将分析个人从空气、食物和二手烟(SHS)等不同来源暴露于多环芳烃的特征，并测定40名来往洛杉矶和北京之间的健康受试者尿中多环芳烃的代谢物；以及2)评估暴露于颗粒性多环芳烃会在多大程度上导致血液中脂质过氧化的增强和功能失调的高密度脂蛋白的产生。随着时间的推移，我们将评估同一受试者血液中脂质氧化和高密度脂蛋白功能的各种指标。这将是第一次评估在实验动物中发现的新型心血管生物标记物在人类受试者中的适用性的系统研究，也是中国进行的首批解决环境暴露与生物效应之间联系的研究之一。这项拟议研究的基本原理是，已识别和验证的新型生物标志物将证明未来在美国较低暴露水平的人群中进行更大规模的研究是合理的，并使其成为可能。这项拟议的研究具有创新性，因为它通过进行一项自然实验，让一组健康的受试者在明确定义的时间框架内体验环境中PM2.5的强烈暴露对比，从而代表了对现状的新的实质性偏离。这项拟议的研究意义重大，因为它是一系列研究的第一步，这些研究将确定新的生物标记物，将环境暴露与生物效应联系起来，最终导致发现动脉粥样硬化的途径，从而证明公共卫生干预是合理的。