Role of Lipid Oxidation in Air Pollution-Induced Atherosclerosis

脂质氧化在空气污染引起的动脉粥样硬化中的作用

• 批准号: 9353420
• 负责人: Xiaoquan Rao
• 金额: $ 9.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353420
• 关键词: 7-ketocholesterol; Air Pollutants; Air Pollution; Alveolar; Alveolar Macrophages; Animal Model; Aorta; Applications Grants; Area; Arterial Fatty Streak; Atherosclerosis; Award; Binding; Biology; Blood Circulation; Blood Vessels; Blood capillaries; Bone Marrow; C57BL/6 Mouse; CASP1 gene; CD36 gene; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Chronic; Crystal Formation; Data; Deposition; Detection; Ecology; Endothelium; Environment; Epithelium; Generations; Goals; IDL lipoproteins; Inflammasome; Inflammation; Interdisciplinary Study; Interleukin-1 beta; International; Intervention; Investigation; Knockout Mice; Knowledge; Ligands; Lipids; Lipoproteins; Low-Density Lipoproteins; Lung; Maryland; Mass Spectrum Analysis; Mediating; Mentors; Methods; Mitochondria; Molecular; Morbidity - disease rate; Mus; Oxidative Stress; Oxides; Pathogenicity; Pattern recognition receptor; Phase; Phosphorylcholine; Pilot Projects; Plasma; Play; Pollution Prevention; Production; Regulation; Research; Research Personnel; Risk; Role; Scientist; Severities; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Supervision; System; Techniques; Testing; Toll-like receptors; Toxic Environmental Substances; Training; Transplantation; Universities; Up-Regulation; Valerian; Very low density lipoprotein; air filter; ambient air pollution; ambient particle; capillary; career; cell type; cohesion; experience; experimental study; extracellular; in vivo; innovation; insight; macrophage; macrophage scavenger receptors; medical schools; monocyte; mortality; multidisciplinary; new therapeutic target; novel; overexpression; oxidation; oxidized lipid; particle; public health relevance; receptor; response; uptake; vascular inflammation

 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.

 描述（由申请人提供）：大量证据表明，空气污染会增加动脉粥样硬化疾病的风险和严重程度。然而，鉴于很少有证据表明 PM2.5 会加剧动脉粥样硬化，其机制仍难以解释。这项 K99/R00 拨款申请的总体目标（近期职业目标）是确定空气污染导致全身和血管脂质异常的机制。我们的初步研究表明，氧化脂质和模式识别受体 CD36 参与了 PM2.5 的不良血管效应的传递。这项拨款申请将进一步研究 PM2.5 如何引发全身性和血管炎症，这将有助于我们使用多学科方法。显着推动主要研究者的职业生涯迈向最终目标（成为环境科学、心血管生物学和脂质学跨学科研究领域的独立科学家）：在K99阶段（目标1），氧化脂质谱针对空气污染和导致空气污染引起的脂质氧化的细胞类型，将使用集中环境空气污染的暴露系统进行体内检查，允许在环境相关浓度下进行长期暴露实验，然后在国际公认的监督下进行脂质组学分析氧化脂质组学领域的领导者，同时结合独特的动物模型，通过利用在 K99 阶段获得的技术，R00 阶段（目标 2）将检验血浆脂蛋白中脂质氧化增加上调的假设。单核细胞 CD36 随后促进动脉粥样硬化斑块中氧化脂质积累和炎性小体激活，该项目的成功完成将为空气污染物介导不良全身和/或血管影响的分子机制提供创新见解，还将确定动脉粥样硬化的新治疗靶点。为了实现拟议的目标，研究者组建了一支强大的指导团队，由国际公认的环境心脏病学专家 Sanjay Rajagopalan 博士（导师）组成， Valerian E. Kagan 博士（共同导师）是国际公认的氧化脂质学领域的领导者，Shyam S. Biswal 博士是国际公认的环境毒物诱导的氧化应激专家。研究者将获得脂质组学方法 (CyTOF) 的培训。 -MS、ESI-MS、MALDI-MS 和细胞/线粒体 ROS 的流式细胞术检测）、氧化脂质学和 Nrf2 生物学方面的先进知识，以及总体而言，马里兰大学医学院、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。