PM Adjuvant Effects, Dendritic Cells and Hierarchical, Oxidative Stress Response

PM 佐剂效应、树突状细胞和分层氧化应激反应

• 批准号: 7888353
• 负责人: Andre Elias Nel
• 金额: $ 36.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7888353
• 关键词: Acids; Adjuvant; Adoptive Transfer; Adverse effects; Air Pollutants; Allergic; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigens; Antioxidants; Asthma; Biological; Biological Assay; Biological Markers; Bone Marrow; Cell Maturation; Cell physiology; Chemicals; Collaborations; Core Facility; Dendritic Cells; Development; Diesel Exhaust; Disease susceptibility; Drug Metabolic Detoxication; Enzyme Induction; Enzymes; Equilibrium; Extrinsic asthma; Figs - dietary; Goals; Human; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-4; Intervention Studies; Lead; Liquid substance; Mediating; Modeling; Modification; Mus; Myelogenous; Nasal Lavage Fluid; Nose; Nutraceutical; Organic Chemicals; Outcome; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Pathway interactions; Phase; Principal Investigator; Production; Property; Proteome; Proteomics; Research; Sulforaphane; T-Cell Activation; Testing; Therapeutic Intervention; Thioctic Acid; Transgenes; Transgenic Mice; Transgenic Organisms; Xenobiotics; allergic airway disease; allergic airway inflammation; ambient particle; biological adaptation to stress; chemokine; cytokine; exposed human population; human subject; in vivo; inflammatory marker; novel; particle; particle exposure; programs; promoter; receptor; response; transcription factor; ultrafine particle; uptake

Relevance: The goal of this application is to understand the pathway by which participate air pollutants (a.k.a. particulate matter or PM) lead to worsening of allergic asthma by impacting dendritic cells (DC) in the immune system (IS). This research is relevant to understanding how air pollutants contribute to the development of asthma, and proposes rational therapy to block the impact of of PM on asthma through the use of a novel class of antioxidants. The principal hypothesis is that PM and adsorbed redox cycling organic chemicals alter DC function to favor Th2 skewing of the IR. The proposal is that oxidative stress perturbs DC activities such as antigen presentation, cellular maturation, cytokine production and/or co-stimulatory activity that are key for T-cell activation and Th2 differentiation. A pathway that is regulated by the transcription factor, Nrf2, protects against the pro-inflammatory and adjuvant effects of PM. Nrf2 accomplishes this by inducing the expression of a battery of phase II antioxidant enzymes that exert anti-inflammatory effects. Aim 1 will determine in a DC adoptive transfer model the mechanism(s) by which oxidative stress promotes Th2 skewing in vitro and in vivo. Diesel exhaust particles, ambient ultrafine particles and pro-oxidative PM chemical fractions will be used to determine their effect on DC immunoregulatory properties, including antigen uptake, antigen presentation, maturation, cytokine/chemokine production, transgenic T-cell activation, and co-stimulatory activity. In vivo skewing of the IR will be further expored in transgenic mice that express a nlL-4-GFP transgene knocked into the IL-4 promoter. Aim 2 will determine whether the Nrf2-mediated antioxidant defense pathway, by modification of DC function, regulates PM-induced oxidative stress and asthma. This will be accomplished by comparing wild type with Nrf2-deficient animals. This study will determine whether interference in phase II enzyme expression leads to exaggerated PM effects on DC antigen presenting activity and whether Nrf2 deficiency promotes Th2 skewing and allergic inflammation in vivo. Proteome analysis will be conducted to reveal in vivo oxidative stress markers in the BAL fluid that can used to study PM oxidative stress effects. In collaboration with Projects 2 & 3, proteome analysis will also be conducted on human nasal lavage fluid to develop a comprehensive understanding of the allergic inflammatory effects of DEP in the nose, including the dynamic equilibrium between pro-and antioxidant pathways. Aim 3 will determine whether Nrf2-mediated phase II enzyme expression during treatment with alpha-lipoic acid and sulfurophane protects against PM oxidative stress effects and asthma exacerbation in vivo and modulation of DC function in vitro.

相关性：该应用程序的目的是了解参与空气污染物的途径 （又称颗粒物或PM）通过影响树突状细胞（DC）导致过敏性哮喘恶化 免疫系统（IS）。这项研究与了解空气污染物如何促进 哮喘的发展，并提出合理疗法，以阻止PM对哮喘的影响 使用一种新型的抗氧化剂。 主要假设是，PM和吸附的氧化还原循环有机化学改变了DC功能以偏爱 Th2偏差IR。提议是氧化应激使DC活性（如抗原） 表现，细胞成熟，细胞因子产生和/或共刺激性活性是T细胞的关键 激活和Th2分化。由转录因子NRF2调节的途径可保护 针对PM的促炎和辅助作用。 NRF2通过诱导表达来实现这一目标 发挥抗炎作用的II期抗氧化剂酶的电池。 AIM 1将在DC中确定 收养转移模型的氧化应激在体外和IN中促进Th2偏斜的机制 体内。柴油排气颗粒，环境超细颗粒和促氧化PM化学部分将是 用于确定其对直流免疫调节特性的影响，包括抗原摄取，抗原 表现，成熟，细胞因子/趋化因子产生，转基因T细胞激活和共刺激性 活动。在表达NLL-4-GFP的转基因小鼠中，IR的体内偏斜将进一步经过 转基因撞到IL-4启动子中。 AIM 2将确定NRF2介导的抗氧化剂是否 防御途径，通过修改直流功能，调节PM诱导的氧化应激和哮喘。这 将通过将野生型与NRF2缺陷动物进行比较来完成。这项研究将确定是否 II期酶表达的干扰会导致PM对DC抗原的影响夸大 活性以及NRF2缺乏症是否促进了体内Th2偏斜和过敏性炎症。蛋白质组 将进行分析以揭示BAL流体中可以用于研究的体内氧化应激标志物 PM氧化应激效应。与项目2和3合作，还将进行蛋白质组分析 人类鼻腔灌洗液，以对过敏性炎症作用有全面的理解 鼻子中的dep，包括抗氧化通路之间的动态平衡。目标3意志 确定在用α-硫酸和 硫烷可预防体内PM氧化应激效应和哮喘恶化和调节 在体外DC功能。