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

生物质燃烧气溶胶和腐殖质类物质对铁稳态和动脉粥样硬化的影响

基本信息

批准号：
10740774
负责人：
David H Gonzalez
金额：
$ 9.75万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-14 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740774
关键词：
Acceleration Aerosols Air Pollution Alveolar Alveolar Macrophages Animal Model Appointment Arterial Fatty Streak Atherosclerosis Atmosphere Biological Markers Biology Biomass Biometry Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cells Cessation of life Chelating Agents Chemicals Chemistry Circulation Complex Diet Education Environment Epithelial Cells Etiology Exhibits Experimental Designs Experimental Models Exposure to Faculty Frequencies Generations Goals Health High Fat Diet Homeostasis Human In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inhalation Inhalation Exposure Interdisciplinary Study Iron Iron Chelation Iron Overload Irrigation Ischemia Knock-out Knockout Mice Knowledge Laboratories Lesion Letters Link Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Lung Macrophage Mediating Mediator Medical emergency Mentorship Methods Modeling Morbidity - disease rate Mus Oxidative Stress Participant Pathogenicity Pathway interactions Phase Policies Positioning Attribute Production Pulmonary Inflammation Reactive Oxygen Species Research Scheme Science Smoke Source System Temperature Testing Tissue Harvesting Tissues Toxic effect Toxicology Training Transition Elements United States National Institutes of Health Universities Water Wildfire Work air filter alveolar epithelium atherogenesis atmospheric chemistry atmospheric processes cardiovascular effects cardiovascular risk factor career development cell type climate change comparison control cytokine fine particles hazard hepcidin in vivo indexing insight iron deficiency medical schools mortality skills smoke inhalation

项目摘要

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.

项目概要/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，但人们对心血管（CV）的影响知之甚少。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，主要是由于缺血性心血管疾病。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 毒性的研究都调查城市 PM2.5，其化学成分存在显着差异与 BBA 相比的毒理学特征。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 成分能够破坏肺铁稳态。 BBA 富含大气类腐殖质 (HULIS)，这是一种复杂的水溶性有机物，具有已被证明会破坏肺铁稳态，导致功能性铁缺乏，从而导致铁超负荷、氧化应激和炎症反应。重要的是，没有研究调查过其影响 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 是特别是，破坏肺部和全身组织中的铁稳态，导致炎症增加和动脉粥样硬化恶化。在此 K99/R00 MOSAIC 应用中，我们建议使用实验室生成的 BBA 细胞培养物和受控体内吸入暴露。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 Fe 稳态、氧化的变化压力、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中铁过载的影响。目标 2 探讨体内 BBA 暴露是否高脂肪饮食会加剧低密度脂蛋白受体敲除 (Ldlr-KO) 小鼠的动脉粥样硬化病变以及肺和全身组织中铁超载是否发挥作用。建议完成目标 1 K99阶段在Jesus Araujo博士指导下的候选人。目标2将独立由候选人在任命为教职后的 R00 阶段期间提供协助。除此之外研究中，这款 K99/R00 MOSAIC 将为进一步培训和职业发展提供支持候选人。申请人的长期目标是成为一级大学的独立教师并继续空气污染毒理学研究。为此，我们提出K99阶段的三个培训目标：（1）增强生物医学教育，(2) 培养体外方法技能，(3) 获得生物统计学培训。阿劳若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并为候选人顺利过渡到独立做好准备。 R00 阶段的支持将促进候选人向独立过渡，同时推进候选人和 NIH 的多样性目标。