Extensive evidence has indicated that air pollution contributes to the risk and severity of atherosclerotic disease. However, the mechanism by which PM2.5 exaggerates atherosclerosis remains hard to explain given that there is very little evidence for systemic translocation of particles from the lungs. The overall objective (immediate career goal) of this K99/R00 grant application is to identify a mechanism by which air pollution induces systemic and vascular lipid abnormalities and inflammation. Our pilot study suggests the involvement of oxidized lipids and pattern recognition receptor CD36 in transmitting the adverse vascular effect of PM2.5. This grant application will further our investigation of how PM2.5 initiates systemic and vascular inflammation using multidisciplinary methods that will significantly propel the principle investigator's career towards ultimate goal (to be an independent scientist working in an interdisciplinary research area of environmental science, cardiovascular biology, and lipidology): In K99 phase (Aim 1), the oxidized lipid profile in response to air pollution and cell types responsible for air pollution-induced lipid oxidation willbe examined in vivo using an exposure system that concentrates ambient air pollution allowing for chronic exposure experiments at environmentally relevant concentrations, followed by lipodomic analysis under the supervision of an internationally recognized leader in oxidative lipidomics, while incorporating unique animal models. By utilizing techniques acquired in the K99 phase, R00 phase (Aim 2) will test the hypothesis that increased lipid oxidation in plasma lipoproteins up-regulates monocyte CD36 subsequently promoting oxidized lipid accumulation and inflammasome activation in atherosclerotic plaques. The successful completion of the project will provide innovative insights into the molecular mechanism underlying how air pollutants mediated adverse systemic and/or vascular effects. It will also identify novel therapeutic targets for atherosclerosis and air pollution prevention. To achieve the proposed goals, the investigator has assembled a strong mentoring team consisting of Dr. Sanjay Rajagopalan (mentor), an internationally recognized expert in environmental cardiology, Dr. Valerian E. Kagan (co-mentor), an internationally recognized leader in oxidative lipidology, and Dr. Shyam S. Biswal, an internationally recognized expert in environmental toxicant-induced oxidative stress. The investigator will obtain training in lipidomic approaches (CyTOF-MS, ESI-MS, MALDI-MS, and flow cytometric detection of cellular/mitochondrial ROS), advanced knowledge in oxidative lipidology and Nrf2 biology, and lab management during the award period. Overall, the excellent environment at the University of Maryland School of Medicine, Johns Hopkins University, and University of Pittsburgh will facilitate the successful completion of the proposed research and assure a successful transition of the investigator to independence.
Although ambient air pollution has been well-known as a major contributor to the risk and severity of atherosclerotic cardiovascular disease, the mechanism of how PM2.5 mediates systemic/vascular effects remains unclear given that there is very little evidence for high-level of systemic translocation of particles from the lungs. Our recent findings suggest an involvement of oxidized lipids and macrophage scavenger receptor CD36 in air pollution-induced adverse vascular effects. In this grant application, we will further our investigation on how air pollution mediates systemic and vascular effects by testing the generation of oxidized lipids as well as the mechanism and functional consequence of CD36 up-regulation upon air pollution exposure.
