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Mechanisms of Particulate Matter Induced Dendritic Cell Activation

颗粒物诱导树突状细胞激活的机制

基本信息

批准号：
8294888
负责人：
Marsha Wills-Karp
金额：
$ 53.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294888
关键词：
A/J Mouse Adoptive Transfer Air Airborne Particulate Matter Allergic Antigen Presentation Antigens Aromatic Hydrocarbons Asthma Attention Baltimore Breathing CD4 Positive T Lymphocytes Cell physiology Cells Child Childhood Asthma Chronic Complex Mixtures Data Dendritic Cells Dendritic cell activation Development Disease Disease susceptibility Endotoxins Environment Environmental Risk Factor Epidemiology Epithelial Cells Epithelium Exposure to Extrinsic asthma Fungal Components Genetic Genetically Engineered Mouse Goals Health Human ITGAM gene ITGAX gene In Vitro Inbreeding Individual Intervention Life Lung Mediating Metals Molecular Morbidity - disease rate Mouse Strains Mus Myelogenous Onset of illness Oxidants Oxidative Stress Oxidative Stress Pathway Particulate Matter Pathway interactions Pattern recognition receptor Phenotype Play Predisposition Prevalence Process Production Recruitment Activity Regulation Relative (related person)Research Design Research Personnel Resistance Role Signal Transduction Societies Source Stress Surface Symptoms T cell differentiation T-Lymphocyte Testing Translations airway hyperresponsiveness airway inflammation allergic response base chemokine clinical application cytokine dectin 1 environmental particulate eosinophilic inflammation immunogenic immunogenicity in vivo inhibitor/antagonist inner city insight novel pollutant programs respiratory response

项目摘要

Numerous studies have shown a strong association between exposure to airborne particulate matter (PM) and indicators of asthma. However, the mechanisms underlying this association remain unknown. Utilizing murine strains of mice, we have demonstrated that exposure to real world particulate matter induces allergic responses in some strains (A/J) of mice, while not in others (C3H/HeJ). Our preliminary studies suggest that PM exposure may confer susceptibility to asthma symptoms by altering dendritic cell (DC) phenotype and function. Specifically, we have made the novel observation that PM alters the relative proportion of immunogenic myeloid DC to tolerogenic plasmacytoid DC recruited to the lungs of susceptible A/J mice. Although the mechanisms by which AUB regulates DC function are unknown, our preliminary data suggests the following hypothesis: that ambient PM induces the allergic response via activation of dendritic cells through synergistic oxidant and pattern recognition receptor- dependent (PRRs) pathways. To test this hypothesis, we propose the following aims: 1) To determine the molecular mechanisms by which PM-induces epithelial cell chemokine production and DC recruitment, we will test the hypothesis that PM induces epithelial cell chemokine production and DC recruitment and maturation via oxidative stress pathways; 2) To determine the exact mechanisms by which PM alters DC cell phenotype, maturation and T cell stimulatory ability in vitro, we will evaluate the contribution of oxidative stress and pattern recognition receptor pathways (TLRs and dectin-1) to PM- induced alterations in DC phenotype (DC subset, costimulatory molecule expression, cytokine production, stimulation of CD4+T cells) in susceptible and resistant murine strains using a combination of approaches (i.e. pharmacological inhibitors, genetically engineered mice); and 3) To determine the contribution of AUB-activated DC subsets to susceptibility to the development of allergic airway responses in murine strains (A/J, C3H) in vivo, we will test the hypothesis that genetic differences in activation of oxidant and/or pattern recognition receptors (TLRs, dectin-1) contribute to altered activation of DC and subsequent development of the AUB-induced allergic phenotype. Taken together with the results of the other projects, the results of this proposal will provide a better understanding of how exposures to environmental particulate matter may exacerbate and/or induce airway inflammation and respiratory morbidity with the ultimate goal of translation of information into clinical applications or intervention strategies that can be used to reduce the morbidity of childhood asthma.

大量研究表明，暴露于空气中的颗粒物之间存在很强的联系