Phenotyping/Epigenetic studies of PAH-associated Treg impairment in asthma

哮喘中 PAH 相关 Treg 损伤的表型/表观遗传学研究

• 批准号: 8296218
• 负责人: Kari C. Nadeau
• 金额: $ 49.49万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296218
• 关键词: Acute; Address; Age; Air Pollutants; Air Pollution; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Asthma; Biological; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; Cell physiology; Cells; Child; Chronic; Chronic Disease; Complex; Coupled; CpG Islands; DNA Methylation; Data; Defect; Development; Environment; Environmental Exposure; Environmental Health; Environmental Policy; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Etiology; Exposure to; Functional disorder; Generations; Genes; Genetic; Goals; Health; Health Policy; Human; Immune; Immune system; Immunity; Immunologics; Immunophenotyping; Impairment; In Vitro; Individual; Inflammation; Inflammatory Response; Interleukin-13; Interleukin-4; Lead; Life; Link; Measurement; Measures; Mediating; Memory; Methods; Methylation; Modification; Molecular; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Prevention; Production; Public Health; Publishing; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Research; Risk Management; Role; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic Intervention; Time; Work; allergic airway disease; cell type; cohort; functional disability; high risk; in vivo; innovation; insight; mRNA Expression; meetings; migration; novel; phenanthrene; pollutant; protein expression; public health relevance; response; tool; transcription factor

DESCRIPTION (provided by applicant): Asthma is the most frequent chronic disease in children, who are at high risk for adverse health consequences associated with ambient air pollution exposure. Recent studies have shown that the links between air pollution and asthma are complex and that air pollution may play a significant role in the etiology of asthma. The overall goal of this project is to further understand the link between exposure indicators and asthma outcomes by studying immune system changes in subjects exposed to elevated levels of polycyclic aromatic hydrocarbons (PAH). This application addresses an important gap in asthma immunopathogenesis by analyzing regulatory T cells (Treg), a cell type that inhibits effector T-cell responses, in asthmatic and non- asthmatic children concurrently with quantifying their in vivo exposure to ambient air pollution. This project's central hypothesis is that Treg function is impaired by PAH, which allows amplification of the T helper 2 (Th2) mediated inflammatory response and the promotion of asthma. The specific aims are 1) to determine Treg subset function, including both suppressive function and chemotactic function to human bronchial epithelial cells, 2) to define Treg memory and naive phenotypes, which we predict will be associated with acute and chronic PAH exposure, respectively, and 3) to measure epigenetic modifications in the Foxp3 gene in purified Treg subsets in each of subject. We will then compare the resultant data from each specific aim to individual exposure estimates and health outcomes in the asthmatic and non-asthmatic children exposed to high levels vs. low levels of PAH. This work will build on a cohort that we have been studying to determine the in vivo effects of high levels of ambient air pollution in children, as part of P20 Children's Environmental Health Center/Fresno Asthmatic Children's Environment Study (FACES). FACES is a cohort in which multiple detailed environmental exposures and health outcomes have been measured over the past 9 years. Repeated measurements over time of individual estimate exposure levels, blood sample results, and health outcome data from each subject will be compared. Together, these studies will: i) define the extent to which Treg dysfunction in asthma is due to PAH, ii) test whether PAH can lead to subsequent Th2-mediated inflammation in asthma, and iii) determine if PAHs are associated with epigenetic changes in Foxp3, a key transcription factor involved in Treg function and development. If the aims of the study are met, we expect that immunological indicators linked to environmental exposure and health outcomes will elucidate the role and mechanism of air pollution in asthma. This link is theoretically understood, circumstantially clear but heretofore not yet proven. The results are expected to have real-time, public health relevance to environmental policy and risk management because when it is completed, the study will have helped to develop tools to assess the effects of air pollution on immunologic mechanisms that underlie asthma and to determine possible targets for new asthma therapy. PUBLIC HEALTH RELEVANCE: Asthma is the leading serious chronic illness of children in the U.S. for which an estimated 6.8 million children under age 18 currently have asthma. Our proposed research findings could provide biologic plausibility to the association between the increase in asthma and ambient air pollution exposure.

描述（由申请人提供）：哮喘是儿童中最常见的慢性疾病，儿童因暴露于环境空气污染而导致不良健康后果的风险很高。最近的研究表明，空气污染与哮喘之间的联系很复杂，空气污染可能在哮喘的病因学中发挥着重要作用。该项目的总体目标是通过研究暴露于高水平多环芳烃 (PAH) 的受试者的免疫系统变化，进一步了解暴露指标与哮喘结果之间的联系。该应用通过分析哮喘和非哮喘儿童的调节性 T 细胞 (Treg)（一种抑制效应 T 细胞反应的细胞类型），同时量化他们体内暴露于环境空气污染的情况，解决了哮喘免疫发病机制中的一个重要空白。该项目的中心假设是 PAH 会损害 Treg 功能，从而放大辅助性 T 2 (Th2) 介导的炎症反应并促进哮喘。具体目标是 1) 确定 Treg 子集功能，包括对人支气管上皮细胞的抑制功能和趋化功能，2) 定义 Treg 记忆和幼稚表型，我们预测它们将分别与急性和慢性 PAH 暴露相关， 3) 测量每个受试者纯化的 Treg 亚群中 Foxp3 基因的表观遗传修饰。然后，我们将比较每个特定目标的结果数据与暴露于高水平和低水平 PAH 的哮喘和非哮喘儿童的个体暴露估计和健康结果。这项工作将建立在我们一直在研究的一个队列的基础上，以确定高水平环境空气污染对儿童体内的影响，作为 P20 儿童环境健康的一部分 中心/弗雷斯诺哮喘儿童环境研究 (FACES)。 FACES 是一个在过去 9 年中测量了多种详细环境暴露和健康结果的队列。随着时间的推移，将对每个受试者的个人估计暴露水平、血液样本结果和健康结果数据进行重复测量。总之，这些研究将：i) 确定 PAH 导致哮喘中 Treg 功能障碍的程度，ii) 测试 PAH 是否会导致随后的哮喘中 Th2 介导的炎症，以及 iii) 确定 PAH 是否与哮喘中的表观遗传变化相关。 Foxp3，参与 Treg 功能和发育的关键转录因子。 如果研究的目标得以实现，我们预计与环境暴露和健康结果相关的免疫学指标将阐明空气污染在哮喘中的作用和机制。这种联系在理论上是可以理解的，情况也很清楚，但迄今为止尚未得到证实。研究结果预计将与环境政策和风险管理具有实时的公共卫生相关性，因为研究完成后将有助于开发工具来评估空气污染对哮喘免疫机制的影响，并确定可能的影响新哮喘治疗的目标。 公共卫生相关性：哮喘是美国儿童的主要严重慢性疾病，目前估计有 680 万 18 岁以下儿童患有哮喘。我们提出的研究结果可以为哮喘增加与环境空气污染暴露之间的关联提供生物学合理性。