Estrogen receptor signaling, inflammation and ozone toxicity

雌激素受体信号传导、炎症和臭氧毒性

基本信息

批准号：
10301740
负责人：
Ley C Smith
金额：
$ 11.79万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301740
关键词：
Acute Air Pollutants Anti-Inflammatory Agents Antioxidants Area Award Bioenergetics Bioinformatics Biology Cardiopulmonary Carnitine Palmitoyltransferase I Cell membrane Child Data Development Development Plans Disease Down-Regulation Elderly Environment Environmental Exposure Environmental Health Equilibrium Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogens Exposure to Faculty Failure Fatty Acids Fellowship Flow Cytometry Funding Genes Genetic Transcription Genus Hippocampus Glycolysis Goals Guidelines Impairment Individual Inflammation Inflammation Process Inflammatory Response Inhalation Injury Institution Knock-out Knowledge Lead Long-Chain-Acyl-CoA Dehydrogenase Lung Lung Inflammation Lung diseases Macrophage Activation Mediating Membrane Mentors Metabolism Mitochondria Modeling Morbidity - disease rate Mus Nuclear Oxidative Phosphorylation Oxidative Stress Ozone PPAR gamma Pathogenesis Pathway interactions Phenotype Play Positioning Attribute Receptor Signaling Regulation Reporting Research Research Personnel Resolution Role Scientist Signal Pathway Signal Transduction Technical Expertise Testing Toxic effect Training Transgenic Mice United States National Institutes of Health Universities Up-Regulation acyl-CoA oxidase burden of illness career development cytotoxic differential expression fatty acid oxidation lung injury macrophage next generation novel novel strategies oxidation ozone exposure programs receptor response single-cell RNA sequencing tenure track tissue injury tissue repair toxicant transcription factor transcriptome sequencing wound healing

项目摘要

Project Summary Abstract Macrophages contribute to ozone toxicity by regulating both the initiation and resolution of lung inflammation; these processes are mediated by distinct macrophage subpopulations broadly classified as proinflammatory/cytotoxic (M1) and anti-inflammatory/wound repair (M2) macrophages. M1 and M2 macrophage activation is controlled, in part, by intracellular metabolism; thus, while high glycolytic capacity is associated with M1 activity, increases in fatty acid oxidation and mitochondrial oxidative phosphorylation are required for M2 macrophage activation. New data suggest that ozone toxicity is due to impaired M2 activation and a failure to resolve inflammation, however, mechanisms are not known. A preliminary RNA-seq analysis of lung macrophages collected after ozone exposure revealed significant enrichment of the estrogen receptor signaling pathway among differentially expressed genes. This was associated with down-regulation of PPARγ expression, a transcription factor known to promote M2 phenotype and resolution of inflammation by shifting intracellular metabolism to fatty acid oxidation. Estrogen has been shown to regulate PPARγ expression by activating estrogen receptor alpha (ESR1) located at the cell membrane, and to promote macrophage anti- inflammatory activity by shifting metabolism to fatty acid oxidation; we speculate that this pathway is important in macrophage responses to ozone. We hypothesize that ozone interferes with extra-nuclear ESR1 signaling in macrophages and downstream activation of PPARγ; this leads to impaired fatty acid oxidation and M2 macrophage activation resulting in aberrant resolution of inflammation and increased tissue injury. Three aims are proposed to test this hypothesis. In the first two aims (K99 period of this award), we will analyze the effects of ozone on macrophage bioenergetics and the role for ESR1 signaling in macrophage immunometabolism and phenotypic activation. Aim 3 (R00 award period) will focus on 1) elucidation of mechanisms by which ozone interferes with extra-nuclear ESR1 signaling, 2) the role of extra- nuclear ESR1 in macrophage bioenergetics and phenotype in response to ozone and how this influences lung injury, and 3) developing strategies to mitigate ozone-induced lung injury by rescuing extra-nuclear ESR1 signaling. Results of these studies will provide novel data on mechanisms underlying macrophage responses to inhaled ozone and represent a significant departure from the co-primary mentor’s areas of emphasis. The career development plan will be performed at Rutgers University, a first-class institution with a strong training environment and will consist of technical training and professional development activities. These will provide the candidate with conceptual knowledge and training required to achieve his long-term goal of becoming an established investigator at an academic research institution directing an independent research program focused on elucidating cellular signaling networks controlling toxicant-induced lung disease and training the next generation of environmental health scientists.

项目概要摘要巨噬细胞通过调节肺部炎症的发生和消退来导致臭氧毒性；这些过程由不同的巨噬细胞亚群介导，大致分为：促炎/细胞毒性 (M1) 和抗炎/伤口修复 (M2) 巨噬细胞 M1 和 M2。因此，巨噬细胞的活化部分受到细胞内代谢的控制，而高糖酵解能力则受到影响。与 M1 活性相关，脂肪酸氧化和线粒体氧化磷酸化的增加 M2 巨噬细胞激活所需的新数据表明，臭氧毒性是由于 M2 激活受损所致。以及无法解决炎症，但初步的 RNA-seq 分析尚不清楚。臭氧暴露后收集的肺巨噬细胞显示雌激素受体显着富集差异表达基因之间的信号通路与 PPARγ 的下调有关。表达，一种已知可通过转移促进 M2 表型和炎症消退的转录因子细胞内脂肪酸氧化代谢已被证明雌激素可通过调节 PPARγ 表达。激活位于细胞膜上的雌激素受体α（ESR1），并促进巨噬细胞抗通过将代谢转变为脂肪酸氧化来抑制炎症活动；我们推测该途径很重要我们勇敢地承认臭氧会干扰核外 ESR1。巨噬细胞中的信号传导和 PPARγ 的下游激活会导致脂肪酸受损；氧化和 M2 巨噬细胞激活导致炎症异常消退提出了三个目标来检验这一假设（K99 时期）。该奖项），我们将分析臭氧对巨噬细胞生物能量学的影响以及 ESR1 信号传导的作用巨噬细胞免疫代谢和表型激活的目标 3（R00 奖励期）将重点关注 1)。阐明臭氧干扰核外 ESR1 信号传导的机制，2）核外的作用巨噬细胞生物能学和表型中的核 ESR1 对臭氧的反应及其对肺的影响损伤，以及 3) 制定通过拯救核外 ESR1 来减轻臭氧引起的肺损伤的策略这些研究结果将为巨噬细胞反应机制提供新的数据。吸入臭氧，这与联合主要导师的重点领域有很大不同。职业发展计划将在实力雄厚的一流学府罗格斯大学进行环境，将包括技术培训和专业发展活动。具有实现成为一名长期目标所需的概念知识和培训的候选人在学术研究机构设立研究员，指导独立研究项目专注于阐明控制毒物引起的肺部疾病的细胞信号网络并培训下一代环境健康科学家。