Key Events in Modulation of Lung Infection Susceptibility by Nanomaterials

纳米材料调节肺部感染易感性的关键事件

• 批准号: 9770860
• 负责人: Brian D. Thrall
• 金额: $ 38.96万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770860
• 关键词: Academy; Address; Affect; Air Pollution; Alveolar Macrophages; Animals; Bacteria; Benchmarking; Biological; Biological Assay; Biometry; Cell physiology; Clinical; Communities; Data; Development; Dose; Elderly; Engineering; Event; Exposure to; Gene Activation; Gene Expression Regulation; Genetic Transcription; Goals; Health; Health Hazards; Human; Immune; Impairment; In Vitro; Individual; Infection; Inhalation; Inhalation Exposure; Link; Lung; Lung infections; Macrophage Activation; Measures; Mediating; Messenger RNA; Methods; Modeling; Modernization; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; National Institute of Environmental Health Sciences; Natural Immunity; Outcome; Oxidation-Reduction; Oxidative Stress; Particulate; Pathway Analysis; Pathway interactions; Phagocytes; Phagocytosis; Pneumococcal Infections; Pneumonia; Predisposition; Protein S; Proteins; Proteomics; Regulation; Regulatory Pathway; Research; Risk; Set protein; Signal Transduction; Site; Source; Streptococcus pneumoniae; Stress; Structure; Systems Biology; Techniques; Testing; Toxic effect; Translating; Ultrafine; Welding; Work; adverse outcome; aged; base; clinical predictors; clinically relevant; cost; cytotoxic; dosimetry; environmental agent; environmental particulate; exposed human population; genetic regulatory protein; hazard; improved; in vitro Assay; in vivo; innate immune function; insight; macrophage; molecular marker; nano; nanomaterials; nanoscale; nanotoxicology; novel; outcome prediction; particle; pathogen; predictive signature; predictive test; success; tool; transcriptome sequencing; young adult

PROJECT SUMMARY We have shown that some types of engineered nanomaterials (ENMs) induce oxidative stress, alter macrophage gene regulation and phagocytic function, and increase the susceptibility of mice to Streptococcus pneumonia, the leading cause of community-acquired pneumonia. Increased risks of pneumonia are a major health outcome associated with human exposure to ultrafine environmental particulates, particularly in the elderly. Our goal is to develop and test a framework for prediction of ENM effects on infection susceptibility, using mechanism-based in vitro assays of macrophage function. We hypothesize exposure to ENMs compromises innate immune function and enhances susceptibility to lung infections through redox-mediated signaling mechanisms that alter macrophage polarization and impair phagocytic clearance of pathogens. We also propose that protein S-glutathionylation (SSG), a major form of protein oxidative modification that regulates multiple aspects of innate immunity, contribute as molecular initiative events for ENM toxicity. Aim 1 will use novel redox protoemics methods to identify the protein targets of SSG induced by ENMs and the major pathways that are most sensitive to these modifications. Aim 2 will identify macrophage transcriptional pathways impacted by ENMs and how exposure to ENMs modulate phagocytic activity toward S. pneumonia. We will investigate how the most robust SSG modifications and mRNA pathways affected by ENMs are co- regulated, and develop sensitive assays to quantify these markers in vitro and in vivo. Aim 3 will test whether in vitro assays for macrophage function and pathway markers identified in Aims 1-2 accurately predict whether inhalation exposure to ENMs modulates lung infections in both young and aged mice challenged with S. pneumonia. Advanced nanomaterial dosimetry models will be used to derive equivalent human exposure levels that would be required to induce these effects. The ability to accurately predict adverse outcomes of ENMs from mechanism-based in vitro studies will transform hazard and risk approaches for emerging ENMs, and addresses a broader human health problem associated with environmental particulate exposures.

项目摘要 我们已经表明，某些类型的工程纳米材料（ENM）会诱导氧化应激，改变 巨噬细胞基因调节和吞噬功能，并增加小鼠对链球菌的敏感性 肺炎，社区获得性肺炎的主要原因。肺炎的风险增加是主要的 与人类接触超细环境颗粒有关的健康结果，特别是在 老年。我们的目标是开发和测试一个预测ENM对感染敏感性影响的框架， 使用基于机制的巨噬细胞功能的体外测定。我们假设接触ENM 通过氧化还原介导的损害先天免疫功能并增强对肺部感染的敏感性 改变巨噬细胞极化并损害病原体的吞噬清除的信号传导机制。我们 还提出蛋白S-谷胱甘肽化（SSG），这是蛋白质氧化修饰的一种主要形式 调节先天免疫的多个方面，是ENM毒性的分子倡议事件。目标1 将使用新型的氧化还原原始方法来识别ENM诱导的SSG的蛋白质靶标和主要 对这些修饰最敏感的途径。 AIM 2将识别巨噬细胞转录 受ENM影响的途径以及ENMS暴露如何调节吞噬活性对肺炎链球菌。 我们将调查如何共同进行ENM影响的最健壮的SSG修饰和mRNA途径 调节并开发敏感测定，以在体外和体内量化这些标记。 AIM 3将测试是否 在AIMS 1-2中鉴定的巨噬细胞功能和途径标记的体外测定1-2准确地预测 吸入对ENM的吸入调节受到S.的年轻小鼠和老年小鼠的肺部感染。 肺炎。先进的纳米材料剂量测定模型将用于导致等效的人类暴露 引起这些影响所需的水平。准确预测不利结果的能力 来自基于机制的体外研究的ENM将改变新兴ENM的危害和风险方法， 并解决了与环境颗粒暴露有关的更广泛的人类健康问题。