Estrogen receptor signaling, inflammation and ozone toxicity

雌激素受体信号传导、炎症和臭氧毒性

• 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
• 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

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.

项目摘要摘要 巨噬细胞通过规范肺注射的倡议和解决方案来促进臭氧毒性。 这些过程是由明显的巨噬细胞亚群介导的 促炎/细胞毒性（M1）和抗炎/伤口修复（M2）巨噬细胞。 M1和M2 巨噬细胞激活部分通过细胞内代谢控制。因此，尽管高糖酵解能力是 与M1活性相关，脂肪酸氧化和线粒体氧化磷酸化的增加是 M2巨噬细胞激活所必需的。新数据表明，臭氧毒性是由于M2激活受损引起的 然而，无法解决炎症，机制尚不清楚。初步的RNA-seq分析 臭氧暴露后收集的肺巨噬细胞显示出雌激素受体的显着富集 不同表达基因之间的信号通路。这与PPARγ下调有关 表达，一种已知促进M2表型和通过转移促进炎症的分辨率的转录因子 细胞内代谢对脂肪酸氧化。雌激素已显示通过 激活位于细胞膜的雌激素受体α（ESR1），并促进巨噬细胞抗 通过将代谢转移到脂肪酸氧化来炎症活动；我们推测该途径很重要 在巨噬细胞对臭氧的反应中。我们假设臭氧会干扰核外ESR1 巨噬细胞中的信号传导和PPARγ的下游激活；这导致脂肪酸受损 氧化和M2巨噬细胞激活，导致异常炎症和 组织损伤增加。提出了三个目的来检验这一假设。在前两个目标中（K99时期 该奖项），我们将分析臭氧对巨噬细胞生物能学的影响以及ESR1信号传导的作用 在巨噬细胞免疫代谢和表型激活中。 AIM 3（R00奖）将重点关注1） 阐明臭氧干扰核外ESR1信号传导的机制，2） 巨噬细胞生物能和表型的核ESR1响应臭氧，这如何影响肺 伤害和3）制定策略来减轻臭氧引起的肺损伤，从而营救核外ESR1 信号。这些研究的结果将提供有关巨噬细胞反应基础机制的新数据 融合臭氧并代表着与联合主要导师的重点领域的重大不同。 职业发展计划将在罗格斯大学（Rutgers University 环境，将包括技术培训和专业发展活动。这些将提供 具有概念知识和培训所需的候选人，以实现自己的长期目标 指挥独立研究计划的学术研究机构的成立研究者 专注于阐明控制有毒物质诱导肺部疾病的细胞信号网络，并训练 下一代环境健康科学家。