Impact of Biomass Burning Aerosol and Humic-like Substances on Iron Homeostasis and Atherosclerosis

项目总结/摘要 野火烟雾暴露被认为是导致发病率增加和每年339，000人死亡的原因， 对心血管（CV）效应知之甚少。众所周知，空气中的细颗粒物（PM2.5） 污染成分与发病率和死亡率密切相关，主要是由于缺血性CV疾病。 将这些影响扩展到野火产生的生物质燃烧气溶胶（BBA）是不可直接转化的 由于大多数关于PM2.5 CV毒性的研究都是针对城市PM2.5，而城市PM2.5在化学成分上存在显著差异， 和毒理学特征进行比较。一些人认为，与非BBA相比，BBA表现出更高的CV毒性。 荒地来源，这可能是由于BBA组分破坏肺Fe稳态的能力。 BBA富含大气类腐殖物质（HULIS），复杂的水溶性有机物， 已被证明破坏肺铁稳态，导致功能性铁缺乏，可导致铁 超负荷、氧化应激和炎症反应。重要的是，没有任何研究都调查了 BBA或HULIS暴露对动脉粥样硬化进展的影响。我们的中心假设是BBA，HULIS在 特别是，破坏肺和全身组织中的Fe稳态，导致炎症增加， 动脉粥样硬化恶化在此K99/R 00 MOSAIC应用中，我们建议使用实验室生成的BBA 在细胞培养和受控的体内吸入暴露中。在目标1中，小鼠肺泡上皮和肺泡 巨噬细胞培养物将暴露于BBA和HULIS，以评估铁稳态、氧化性和细胞内环境的变化。 应激、炎症和促动脉粥样硬化代谢物。我们将使用Hepcidin Knockout（HKO）小鼠作为模型 肺泡上皮细胞和肺泡巨噬细胞铁超载。目的2探索体内BBA暴露是否 在高脂饮食的低密度脂蛋白受体敲除（Ldlr-KO）小鼠中加剧动脉粥样硬化病变 以及肺和全身组织中的铁超载是否起作用。目标1拟通过以下方式完成： 在K99阶段，候选人在Jesus Araujo博士的指导下。目标2将独立于 由候选人在R 00阶段任命后的教师职位促进。除此之外 研究，这K99/R 00马赛克将提供进一步的培训和职业发展的支持， 候选人申请人的长期目标是成为一所一流大学的独立教师， 污染毒理学研究为实现这一目标，我们提出了K99阶段的三个培训目标：（1）提高 生物医学教育，（2）培养体外方法技能，（3）获得生物统计学培训。Araujo博士的 加州大学洛杉矶分校大卫格芬医学院的实验室是成功完成K99的理想环境 研究以及实现培训目标和准备候选人飞碟过渡到独立。 在R 00阶段的支持将有助于候选人向独立过渡，同时推动 候选人和NIH的多样性目标。

PROJECT SUMMARY/ABSTRACT Wildfire smoke exposure is thought to be responsible for increased morbidity and 339,000 annual deaths, but little is known about cardiovascular (CV) effects. It is well known that fine particulate matter (PM2.5) is the air pollution component most strongly linked to morbidity and mortality, mostly due to ischemic CV diseases. Extending these effects to biomass burning aerosol (BBA) generated from wildfires is not directly translatable since most studies on CV toxicity of PM2.5 investigate urban PM2.5 which has significant differences in chemical and toxicological profiles compared to BBA. Some suggest BBA exhibits higher CV toxicity compared to non- wildland sources, which may be due to the ability of BBA components to disrupt pulmonary Fe homeostasis. BBA are enriched in atmospheric humic-like substances (HULIS), complex water-soluble organics that have been shown to disrupt pulmonary Fe homeostasis resulting in a functional Fe deficiency that can lead to Fe overload, oxidative stress, and in inflammatory response. Importantly, no study has every investigated the impact of BBA or HULIS exposure on the progression of atherosclerosis. Our central hypothesis is BBA, and HULIS in particular, disrupts Fe homeostasis in pulmonary and systemic tissues leading to increased inflammation and worsened atherosclerosis. In this K99/R00 MOSAIC application, we propose to use laboratory generated BBA in cell culture and controlled in vivo inhalation exposures. In Aim 1, murine alveolar epithelial and alveolar macrophage cultures will be exposed to BBA and HULIS for assessment of changes in Fe homeostasis, oxidative stress, inflammation, and proatherogenic metabolites. We will employ Hepcidin Knockout (HKO) mice as models of Fe overload in alveolar epithelial cells and alveolar macrophages. Aim 2 explores if in vivo BBA exposure exacerbates atherosclerotic lesions in low density lipoprotein receptor knockout (Ldlr-KO) mice on a high fat diet and whether Fe overload in pulmonary and systemic tissues play a role. Aim 1 is proposed to be completed by the candidate under the mentorship of Dr. Jesus Araujo during the K99 phase. Aim 2 will be independently facilitated by the candidate during the R00 phase following appointment to a faculty position. In addition to this research, this K99/R00 MOSAIC will provide support for further training and career development for the candidate. The applicant's long-term goal is to be an independent faculty at a tier-1 university and continue air pollution toxicology research. To achieve this, we propose three training goals for the K99 phase: (1) Enhance Biomedical Education, (2) Develop Skills in In Vitro Methods and (3) Acquire Training in Biostatistics. Dr. Araujo's lab at the David Geffen School of Medicine at UCLA is an ideal environment for successful completion of K99 research as well as achieving training goals and preparing the candidate for saucerful transition to independence. Support in the R00 phase will facilitate the candidate's transition to independence simultaneously advancing the candidate's and NIH diversity goals.