The overall aim of this project is to gain insight into the inflammatory, oxidative and endothelial controlmechanisms underlying the cardiovascular effects of short- and long-term exposure to traffic-associated fineparticulate matter (PM). This will be accomplished by investigating in a human population the differentialsusceptibility to PM effects associated with specific genetic polymorphisms that involve these keymechanistic pathways.
The aim will be addressed by making efficient use of an ongoing cohort study ofatherosclerotic cardiovascular disease, the Multi-ethnic Study of Atherosclerosis (MESA), and several MESAancillary studies for which PM and traffic exposure data, genotyping data, and data on multiple relevantcardiovascular endpoints are being collected.
The specific aims of this project are to gain insight into themechanisms underlying the cardiovascular effects of traffic-associated PM by: 1) making use of the MESAcohort to determine whether specific genetic polymorphisms in key pathways regulating inflammation,oxidative stress, and endothelial function modify: a) the long-term exposure effects of traffic-associated PMon the development and progression of atherosclerosis using measures that include arterial wall thicknessand coronary artery calcium, and b) the short-term exposure effects of these PM components on functionalcardiovascular and mechanistic endpoints, including carotid distensibility, pulse wave measures, endothelialfunction, and plasma markers of inflammation and endothelial activation; 2) validating the findings fromSpecific Aim 1 on a newly genotyped sample of MESA participants; and 3) making use of the toxicologicalfindings from Center Project 5 on novel genetic polymorphisms of interest by investigating the modifyingeffects of these additional polymorphisms on long-term and short-term PM exposure effects, and validatingthese findings on the newly genotyped human population sample. This project integrates across all projectsof this center through the choice of both the specific genetic polymorphisms to be investigated in commonwith other projects, and the specific cardiovascular endpoints to be studied. Further integration is evident inthe use of findings from other center projects to guide the choice of polymorphisms to study.Because it employs a representative human population sample of several U.S. ethnic groups to study apervasive and important inhalational exposure and a common disease, this project has direct public healthrelevance. It is currently not known which sources and chemical components of PM are most responsible forits cardiovascular effects, or which of several plausible mechanisms underlie these effects. By contributingto our understanding of mechanisms and the identification of exposure sources of most concern, this projectcan allow more directed and efficient public health policies to be considered.
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