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）：动物研究支持这样的观点，即暴露于环境细颗粒物 (PM2.5) 会导致心血管缺血事件增加和动脉粥样硬化加剧。虽然流行病学研究报告了人群中的类似关联，但在人类中鉴定和验证的生物标志物有限。我们已经确定了小鼠生物效应的新方法，有可能成为人类心血管疾病的重要生物标志物。关于动物模型中识别的生物标志物在多大程度上可以应用于人类受试者，存在着关键的知识差距。缺乏此类知识是一个重要问题，因为在出​​现新颖且可靠的生物标志物之前，我们在出现心肌梗塞或猝死等心血管临床事件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。该应用的目的是识别与空气污染暴露相关的心血管健康影响的新颖且敏感的生物标志物。中心假设是，亚急性暴露于环境颗粒状多环芳烃将导致脂质过氧化和高密度脂蛋白功能障碍，与内源性生成的多环芳烃氧化代谢物相关。在初步数据的指导下，该假设将通过两个具体目标进行检验：1）确定颗粒状多环芳烃暴露在多大程度上影响人类受试者中多环芳烃代谢物的总水平和比例。我们将描述个人从空气、食物和二手烟 (SHS) 等各种来源接触 PAH 的情况，并测定往返于洛杉矶和北京之间的 40 名健康受试者尿液中的 PAH 代谢物； 2) 评估颗粒状多环芳烃的暴露在多大程度上会导致血液中脂质过氧化的增强以及功能失调的高密度脂蛋白的产生。随着时间的推移，我们将评估同一人类受试者血液中脂质氧化和高密度脂蛋白功能的各种指标。这将是第一个系统研究，旨在评估在实验动物中发现的新型心血管生物标志物在人类受试者中的适用性，也是在中国进行的首批研究环境暴露与生物效应之间联系的研究之一。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并支持未来在美国暴露水平较低的人群中进行更大规模的研究。拟议的研究具有创新性，因为它代表了对现状的新的实质性偏离，通过进行一项自然实验，一组健康受试者将在明确的时间范围内经历环境 PM2.5 的巨大暴露对比。拟议的研究意义重大，因为它是连续研究的第一步，该研究将识别新的生物标志物，将环境暴露与生物效应联系起来，并最终发现动脉粥样硬化的途径，从而证明公共卫生干预措施的合理性。