Investigating a Model for PM-Induced Exacerbation of Autoimmunity
研究 PM 诱发的自身免疫恶化模型
基本信息
- 批准号:10266063
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAir PollutionAmericanAreaAromatic Polycyclic HydrocarbonsAryl Hydrocarbon ReceptorAtmosphereAutoimmuneAutoimmune DiseasesAutoimmunityCell Differentiation processCellsCessation of lifeChemicalsClinicalComplexCytochrome P450DataDendritic CellsDevelopmentDiagnosisDiesel ExhaustDietary InterventionDietary SupplementationDiseaseDustEnvironmental ExposureEnzymesExperimental Autoimmune EncephalomyelitisExposure toFaceGeneral PopulationGeneticGoalsGrantHealthImmuneImmunityIn VitroIncidenceInhalationKnowledgeLeadLigandsMediatingMetabolismMilitary PersonnelModelingMultiple SclerosisMusNull LymphocytesOccupational ExposureParticulate MatterPathogenicityPathologicPatientsPlayPollutionPopulationPreventionProcessRecommendationReference StandardsRegulationResearch PriorityRestRiskRisk FactorsRoleSamplingSecondary toSeveritiesSeverity of illnessSiteSmokeSourceT cell differentiationT cell responseT-LymphocyteTestingTranslatingVeteransactive dutyaryl hydrocarbon receptor ligandautoreactive T cellbaseburn pitdietarydietary supplementsdisorder preventionepidemiology studyexperimental studyhigh riskin vivo Modelinterestmilitary servicemilitary veteranmouse modeloral supplementationparticleparticle exposurepersistent symptompreventpreventive interventionremediationresponserisk predictiontreatment strategy
项目摘要
Epidemiologic studies strongly support that exposure to airborne pollution increases the incidence and severity
autoimmunity, a diagnosis that encompasses more than 80 different disease processes and affects more than
20 million Americans. Patients typically suffer chronic symptoms that leave them ill for the rest of their lives.
Surprisingly, despite the fact that inhaled particulate matter (PM) is well accepted as a risk for autoimmunity,
the specific exposures that cause disease and the mechanisms involved are not known. This is likely because
of the complexity of pollution that is generated by numerous sources with variable chemical composition, and
the diverse genetic background of populations that are exposed. This lack of understanding has made efforts
at regulation, remediation, and avoidance unsuccessful. Veterans may be at particularly high risk, as military
personnel are exposed to high levels of PM from diesel engines and other sources. In addition, some unique
exposures that may be particularly pathologic are found at sites of deployment, including burn pit exposures.
Our group has spent the last few years examining the ability of different samples of PM to enhance an effector
response and increase immunity. We have recently found that in a mouse model of experimental autoimmune
encephalomyelitis (EAE), two Standard Reference Materials (SRMs) from diesel exhaust particles (DEP)
significantly increased severity of disease. Analysis of the organic fractions of these samples show aryl
hydrocarbon receptor (AHR)-dependent ability for enhancement of effector Th17 cell differentiation by these
samples. In addition, analysis of polycyclic aromatic hydrocarbon (PAH) mixtures from these samples suggest
this fraction may be central to the increased effector response in T cells. These findings have led us to
generate the hypothesis that exposure to military service or deployment-related PM can increase self-
reactive T-cell responses in an AHR-dependent manner, resulting in more severe autoimmune disease.
We will explore the following aims: Aim 1: Identify DEP-mediated effects on T cells that lead to an
increase in EAE clinical severity. We will test the hypothesis that DEP exposure in the B6-EAE model
enhances disease severity by increasing the pathogenic potential of anti-MOG T cells, either directly through T
cells or indirectly through DCs. This aim focuses on effects on immune cells irrespective of a role for the AHR
Aim 2: Determine the contribution of the AHR, metabolism, and the PAHs in PM-driven autoimmune
exacerbation. We will test the hypothesis that both DEPs aggravate EAE via the AHR, and will explore the
importance of metabolism and PAH content.
Aim 3: Screen source samples of military service or deployment-related PM for immune-altering
activity. We will expose mice undergoing EAE to four samples relevant to military exposures, testing the
hypothesis that aggravation of autoimmunity is source dependent.
Aim 4: Determine the capacity of dietary interventions to mitigate DEP-mediated aggravation of
disease in the B6-EAE model. We will test the hypothesis that dietary ligands can specifically reduce the
effects of inhaled pollution on autoimmunity.
We anticipate that PM will aggravate EAE through a direct effect on the AHR in T cells. We further predict that
exposures unique to the military will aggravate disease, and oral supplementation with dietary AHR ligands will
mute the aggravation of disease seen after PM exposure. This grant directly addresses the priority research
area of interest regarding military service or deployment-related occupational exposures. Results from this
grant will provide a rational for understanding which military environmental exposures are most pathogenic and
aid in remediation, avoidance, and treatment strategies.
流行病学研究强烈支持暴露于空气污染会增加发病率和严重程度
自身免疫,一种诊断,包括80多个不同的疾病过程,影响超过
两千万美国人。患者通常患有慢性症状,使他们终生患病。
令人惊讶的是,尽管吸入的颗粒物(PM)被公认为自身免疫的风险,
引起疾病的具体接触和所涉机制尚不清楚。这可能是因为
污染的复杂性是由多种不同化学成分的污染源产生的,
暴露人群的多样遗传背景。这种缺乏了解的情况使人们努力
在监管、补救和规避方面都不成功。退伍军人可能处于特别高的风险,因为军事
人员暴露于来自柴油发动机和其他来源的高水平PM。此外,一些独特的
在部署部位发现可能特别病理性的暴露,包括烧伤坑暴露。
我们的团队在过去的几年里一直在研究不同的PM样品增强效应器的能力
提高免疫力和反应。我们最近发现,在实验性自身免疫小鼠模型中,
脑脊髓炎(EAE),柴油机排气颗粒(DEP)的两种标准参考物质(SRM)
疾病严重程度显著增加。对这些样品的有机部分的分析显示芳基
这些化合物增强效应Th 17细胞分化的烃受体(AHR)依赖性能力
样品此外,从这些样品中分析多环芳烃(PAH)混合物表明,
该部分可能是T细胞中增加的效应子应答的中心。这些发现使我们
产生的假设,暴露于军事服务或部署相关的PM可以增加自我-
以AHR依赖性方式的反应性T细胞应答,导致更严重的自身免疫性疾病。
我们将探索以下目标:目标1:确定DEP介导的对T细胞的作用,导致T细胞的凋亡。
EAE临床严重程度增加。我们将检验B6-EAE模型中DEP暴露的假设
通过增加抗MOG T细胞的致病潜力来增强疾病的严重程度,
细胞或间接通过DC。这一目标的重点是对免疫细胞的影响,无论AHR的作用如何
目的2:确定AHR,代谢和多环芳烃在PM驱动的自身免疫性疾病中的作用
加重我们将检验两种DEP均通过AHR加重EAE的假设,并将探讨
代谢和PAH含量的重要性。
目标3:筛选军事服务或部署相关PM的免疫改变源样本
活动我们将使经历EAE的小鼠暴露于与军事暴露相关的四种样品,测试
假设自身免疫的加重是来源依赖性的。
目的4:确定饮食干预减轻DEP介导的
B6-EAE模型中的疾病。我们将检验这一假设,即饮食配体可以特异性地减少
吸入污染对自身免疫的影响。
我们预期PM会通过直接影响T细胞中的AHR而加重EAE。我们进一步预测,
暴露于军队特有的环境中会加重疾病,口服补充饮食中的AHR配体会
使暴露于PM后所见的疾病恶化消失。该补助金直接用于优先研究
与军事服务或部署相关的职业暴露有关的感兴趣领域。结果从这个
格兰特将提供一个合理的理解,军事环境暴露是最致病的,
帮助补救、避免和治疗策略。
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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Joshua D Mezrich其他文献
Joshua D Mezrich的其他文献
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{{ truncateString('Joshua D Mezrich', 18)}}的其他基金
Investigating a Model for PM-Induced Exacerbation of Autoimmunity
研究 PM 诱发的自身免疫恶化模型
- 批准号:
9974282 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Investigating a Model for PM-Induced Exacerbation of Autoimmunity
研究 PM 诱发的自身免疫恶化模型
- 批准号:
10477272 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Pollution Aggravates Autoimmunity Through the Aryl Hydrocarbon Receptor
污染通过芳基烃受体加剧自身免疫
- 批准号:
8872438 - 财政年份:2015
- 资助金额:
-- - 项目类别:
A Novel mechanism for Environmentally Induced Airway Disease
环境诱发气道疾病的新机制
- 批准号:
8818368 - 财政年份:2014
- 资助金额:
-- - 项目类别:
A Novel mechanism for Environmentally Induced Airway Disease
环境诱发气道疾病的新机制
- 批准号:
9185978 - 财政年份:2014
- 资助金额:
-- - 项目类别:
A Novel mechanism for Environmentally Induced Airway Disease
环境诱发气道疾病的新机制
- 批准号:
8976608 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Surgery Summer Research Experience for Medical Students
医学生外科暑期研究经历
- 批准号:
9073123 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Surgery Summer Research Experience for Medical Students
医学生外科暑期研究经历
- 批准号:
10614513 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Surgery Summer Research Experience for Medical Students
医学生外科暑期研究经历
- 批准号:
9267453 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Surgery Summer Research Experience for Medical Students
医学生外科暑期研究经历
- 批准号:
9923619 - 财政年份:2006
- 资助金额:
-- - 项目类别:
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