Air Pollution and Cardiovascular Diseases: Identification of Novel Biomarkers

点击翻译按钮获取中文摘要

 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.