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
基本信息
- 批准号:9770860
- 负责人:
- 金额:$ 38.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcademyAddressAffectAir PollutionAlveolar MacrophagesAnimalsBacteriaBenchmarkingBiologicalBiological AssayBiometryCell physiologyClinicalCommunitiesDataDevelopmentDoseElderlyEngineeringEventExposure toGene ActivationGene Expression RegulationGenetic TranscriptionGoalsHealthHealth HazardsHumanImmuneImpairmentIn VitroIndividualInfectionInhalationInhalation ExposureLinkLungLung infectionsMacrophage ActivationMeasuresMediatingMessenger RNAMethodsModelingModernizationModificationMolecularMolecular TargetMorbidity - disease rateMusNational Institute of Environmental Health SciencesNatural ImmunityOutcomeOxidation-ReductionOxidative StressParticulatePathway AnalysisPathway interactionsPhagocytesPhagocytosisPneumococcal InfectionsPneumoniaPredispositionProtein SProteinsProteomicsRegulationRegulatory PathwayResearchRiskSet proteinSignal TransductionSiteSourceStreptococcus pneumoniaeStressStructureSystems BiologyTechniquesTestingToxic effectTranslatingUltrafineWeldingWorkadverse outcomeagedbaseclinical predictorsclinically relevantcostcytotoxicdosimetryenvironmental agentenvironmental particulateexposed human populationgenetic regulatory proteinhazardimprovedin vitro Assayin vivoinnate immune functioninsightmacrophagemolecular markernanonanomaterialsnanoscalenanotoxicologynoveloutcome predictionparticlepathogenpredictive signaturepredictive testsuccesstooltranscriptome sequencingyoung adult
项目摘要
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.
项目概要
我们已经证明,某些类型的工程纳米材料 (ENM) 会诱发氧化应激,改变
巨噬细胞基因调节和吞噬功能,增加小鼠对链球菌的易感性
肺炎,社区获得性肺炎的主要原因。肺炎风险增加是一个主要因素
与人类暴露于超细环境颗粒物相关的健康结果,特别是在
老年。我们的目标是开发和测试一个框架来预测 ENM 对感染易感性的影响,
使用基于机制的巨噬细胞功能体外测定。我们假设接触 ENM
通过氧化还原介导损害先天免疫功能并增强对肺部感染的易感性
改变巨噬细胞极化并损害病原体吞噬清除的信号机制。我们
还提出蛋白质 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,作为 ENM 毒性的分子主动事件做出贡献。目标1
将使用新的氧化还原蛋白质组学方法来鉴定 ENM 诱导的 SSG 的蛋白质靶点和主要
对这些修饰最敏感的途径。目标 2 将识别巨噬细胞转录
受 ENM 影响的途径以及接触 ENM 如何调节肺炎链球菌的吞噬活性。
我们将研究受 ENM 影响的最强大的 SSG 修饰和 mRNA 通路如何共同作用
监管,并开发灵敏的测定法来量化这些体外和体内标记物。目标 3 将测试是否
目标 1-2 中确定的巨噬细胞功能和通路标记物的体外测定可准确预测是否
吸入暴露于 ENM 可以调节受到金黄色葡萄球菌攻击的年轻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推导等效的人体暴露量
诱导这些效应所需的水平。准确预测不良后果的能力
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,
并解决与环境颗粒物暴露相关的更广泛的人类健康问题。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brian D. Thrall其他文献
356 - A General Proteomics Approach for Site-Specific Quantification of Cysteine Redox Modifications and Its Application for Profiling S-Glutathionylation in Macrophages
- DOI:
10.1016/j.freeradbiomed.2013.10.782 - 发表时间:
2013-11-01 - 期刊:
- 影响因子:
- 作者:
Dian Su;Matthew J Gaffrey;Jia Guo;Therese R.W. Clauss;Brian D. Thrall;Richard d Smith;Wei-Jun Qian - 通讯作者:
Wei-Jun Qian
Brian D. Thrall的其他文献
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{{ truncateString('Brian D. Thrall', 18)}}的其他基金
Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
整合结构活动、生物动力学和反应进行 ENP 风险评估
- 批准号:
8464706 - 财政年份:2010
- 资助金额:
$ 38.96万 - 项目类别:
Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
整合结构活动、生物动力学和反应进行 ENP 风险评估
- 批准号:
8675237 - 财政年份:2010
- 资助金额:
$ 38.96万 - 项目类别:
PROTEOMIC ANALYSIS OF THE HMEC MITOGENIC RESPONSE
HMEC 有丝分裂反应的蛋白质组学分析
- 批准号:
7721391 - 财政年份:2008
- 资助金额:
$ 38.96万 - 项目类别:
Sytems Analysis of Nanoparticle Biocompatibility
纳米粒子生物相容性的系统分析
- 批准号:
7497144 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
Sytems Analysis of Nanoparticle Biocompatibility
纳米粒子生物相容性的系统分析
- 批准号:
8070832 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
Sytems Analysis of Nanoparticle Biocompatibility
纳米粒子生物相容性的系统分析
- 批准号:
7341333 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
Sytems Analysis of Nanoparticle Biocompatibility
纳米粒子生物相容性的系统分析
- 批准号:
8324443 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
Sytems Analysis of Nanoparticle Biocompatibility
纳米粒子生物相容性的系统分析
- 批准号:
7673833 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
PROTEOMIC ANALYSIS OF THE HMEC MITOGENIC RESPONSE
HMEC 有丝分裂反应的蛋白质组学分析
- 批准号:
7602867 - 财政年份:2007
- 资助金额:
$ 38.96万 - 项目类别:
PROTEOMIC ANALYSIS OF THE HMEC MITOGENIC RESPONSE
HMEC 有丝分裂反应的蛋白质组学分析
- 批准号:
7359107 - 财政年份:2006
- 资助金额:
$ 38.96万 - 项目类别:
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