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）：动物研究支持以下观点：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增强。虽然流行病学研究报告了人类群体中的类似关联，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措施，这些措施有可能成为人类受试者心血管疾病的重要生物标志物。关于在动物模型中鉴定的生物标志物在多大程度上可以应用于人类受试者，存在关键的知识缺口。缺乏这样的知识是一个重要的问题，因为直到新的和可靠的生物标志物是可用的，有一个缺口，我们的能力检测健康影响之前，提出心血管临床事件，如心肌梗死或猝死。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。本申请的目的是确定与空气污染暴露相关的心血管健康影响的新的和敏感的生物标志物。中心假设是，亚急性暴露于环境颗粒多环芳烃将导致脂质过氧化和功能失调的HDL与内源性产生的多环芳烃氧化代谢产物。在初步数据的指导下，这一假设将通过追求两个具体目标进行测试：1）确定暴露于颗粒多环芳烃在多大程度上影响人类受试者体内多环芳烃代谢物的总水平和比例。我们将描述个人暴露于多环芳烃的各种来源，包括空气，食物，和二手烟（SHS），并确定多环芳烃代谢物在尿液中的40名健康受试者之间的洛杉矶和北京; 2）评估在何种程度上暴露于颗粒多环芳烃导致血液中脂质过氧化作用的增强和功能失调的HDL的产生。我们将评估同一人类受试者血液中脂质氧化和HDL功能随时间的各种测量。这将是第一项评估在人类受试者中实验动物中发现的新型心血管生物标志物适用性的系统性研究，也是中国首次开展的解决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，确定和验证的新型生物标志物将证明并使未来在美国较低暴露水平的人群中进行更大规模的研究成为可能。拟议的研究是创新的，因为它代表了一种新的和实质性的偏离现状，通过进行一项自然实验，其中一组健康受试者将在明确定义的时间范围内在环境PM2.5中经历戏剧性的暴露对比。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志物，将环境暴露与生物效应联系起来，并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。