Role of Lipid Oxidation in Air Pollution-Induced Atherosclerosis

 描述（由申请人提供）：大量证据表明，空气污染有助于动脉粥样硬化疾病的风险和严重程度。然而，PM2.5加剧动脉粥样硬化的机制仍然很难解释，因为几乎没有证据表明颗粒物从肺部全身移位。此次K99/R 00资助申请的总体目标（近期职业目标）是确定空气污染诱导全身和血管脂质异常和炎症的机制。我们的初步研究表明，氧化脂质和模式识别受体CD 36参与传递PM2.5的不良血管效应。这项拨款申请将进一步我们的研究如何PM2.5启动全身和血管炎症使用多学科的方法，这将显着推动主要研究者的职业生涯走向最终目标（成为一名独立的科学家，从事环境科学、心血管生物学和脂质学的跨学科研究）：在K99阶段（目标1），将使用暴露系统在体内检查对空气污染和负责空气污染诱导的脂质氧化的细胞类型的氧化脂质谱，该暴露系统集中环境空气污染，允许在环境相关浓度下进行慢性暴露实验，随后在国际公认的氧化脂质组学领导者的监督下进行脂质组学分析，同时结合独特的动物模型。通过利用在K99期获得的技术，R 00期（Aim 2）将检验血浆脂蛋白中脂质氧化增加上调单核细胞CD 36随后促进氧化脂质积累和动脉粥样硬化斑块中炎性小体活化的假设。该项目的成功完成将为空气污染物如何介导不良全身和/或血管效应的分子机制提供创新见解。它还将确定动脉粥样硬化和空气污染预防的新治疗靶点。为了实现提出的目标，研究者组建了一个强大的指导团队，由Sanjay Rajagopalan博士（导师）、国际公认的环境心脏病学专家Valerian E.卡根（共同导师），在氧化脂质学国际公认的领导者，和博士Shyam S。Biswal是国际公认的环境毒物诱导氧化应激专家。研究者将获得脂质组学方法（CyTOF-MS，ESI-MS，MALDI-MS和细胞/线粒体ROS的流式细胞术检测）的培训，氧化脂质学和Nrf 2生物学的先进知识，以及在奖励期间的实验室管理。总体而言，马里兰州大学医学院、约翰霍普金斯大学和匹兹堡大学的良好环境将促进拟议研究的成功完成，并确保研究者成功过渡到独立。

 DESCRIPTION (provided by Applicant): 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.