Project 1 for the Air pollution disrupts Inflammasome Regulation in HEart And Lung Total Health (AIRHEALTH) Study

空气污染扰乱心肺总体健康 (AIRHEALTH) 研究中的炎症小体调节项目 1

• 批准号: 10269334
• 负责人: Kari C. Nadeau
• 金额: $ 55.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10269334
• 关键词: ATAC-seq; Acute; Address; Age; Air; Air Pollution; Apoptosis; Area; Asthma; Automobile Driving; Biological Assay; Blood specimen; Body mass index; Cardiac; Cardiopulmonary; Cells; Characteristics; Chronic; Chronic lung disease; Clinical; DNA Methylation; Data; Development; Disease; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Ethnic Origin; Exposure to; Goals; Health; Heart; Heart Diseases; Heterogeneity; Histones; Human; Immune; Immune system; Incubated; Individual; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Ligands; Link; Liquid substance; Lung; Lung diseases; Measures; Mediating; Medical; Modification; Outcome; Oxidative Stress; Participant; Particulate Matter; Pathogenesis; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Pollution; Population; Post-Translational Protein Processing; Public Health; Pulmonary Pathology; Pulmonary alveolar structure; Pulmonary function tests; Regulation; Risk; Sampling; Signal Transduction; Structure of parenchyma of lung; Techniques; Testing; Time; Tissues; Underserved Population; Validation; Visit; alveolar epithelium; chemokine; cohort; cytokine; cytotoxicity; data sharing; experience; exposed human population; high dimensionality; immune activation; improved; inflammatory marker; inhibitor/antagonist; novel; novel strategies; patient population; prevent; response; sex; stem cells; transcriptome; transcriptome sequencing; transcriptomics

ABSTRACT: PROJECT 1 Air pollution, particularly particulate matter <2.5µm (PM2.5) comprising a variety of organic molecules produced by combustion, is a significant driver of chronic lung disease (e.g., asthma). PM2.5 enters pulmonary alveoli during chronic and acute PM2.5 exposure, releasing proinflammatory and vasoactive factors that contribute to pulmonary pathology. Recently, the cytokine IL-1β and the inflammasome pathway have been implicated in mechanisms underlying air-pollution-induced immune system activation and inflammation. Our proposal, for the first time, brings together a unifying hypothesis that pollution mediated heart and lung disease occurs through a shared IL-1β inflammasome pathway. This is not to say other factors are not relevant and we will concurrently test oxidative stress and other pathways through high dimensional, rigorous, and validated assays. We have shown that epigenetic modifications such as DNA methylation during air pollution exposure indicate extent of exposure and can be linked to lung diseases. Although such advances have been made in pollution-caused lung diseases, specific mechanisms of action have been elusive, driving an unmet need for new approaches to protect individuals at risk and to reduce the detrimental effects of PM2.5 exposure. We hypothesize that air pollution exposure induces circulating and cellular cytokines such as IL-1β and other pathways through epigenetic mechanisms and immune cell activation, leading to direct and indirect activation of lung epithelial cells, contributing to chronic lung disease. We will perform immune, and epigenetic studies in blood samples derived from highly characterized cohorts with individual estimate exposures to air pollution. We collected samples over time; therefore, we have samples from cohorts in a clean air environment (i.e. health control). Our project on stem-cell-derived lung tissues harmonizes with studies on stem-cell-derived cardiac tissues, along with novel aims specific to mechanisms in immune and lung tissue. We will share data across all Projects and Cores to synergize findings across immune, lung, and heart areas of study to achieve our overarching goal of uncovering the mechanisms of IL-1β and other pathways dysregulation in inflammation- associated cardiopulmonary pathology in response to chronic and acute air pollution exposure. Understanding the contribution of IL-1β and other markers will likely lead to the development and application of new ways to prevent and treat diseases associated with public health issues associated with air pollution, like asthma. Our study includes longitudinal and repeat measures within our cohorts of individuals (same individual over time is tested) with diverse ethnicities, some of which represent underserved populations. Our analyses will control for confounders (age, sex, body mass index, medications, other) and will address heterogeneity by similar matching of characteristics of the cohorts (two test cohorts and validation cohort).

摘要：项目1 空气污染，特别是颗粒物<2.5µm（PM2.5），包括产生的各种有机分子 通过燃烧，是慢性肺病的重要驱动因素（例如，哮喘）。PM2.5进入肺泡 在慢性和急性PM2.5暴露期间，释放促炎和血管活性因子， 肺部病理学最近，细胞因子IL-1β和炎性体途径已经被牵连在 空气污染引起的免疫系统激活和炎症的潜在机制。我们的建议，对于 第一次，汇集了一个统一的假设，即污染介导的心脏和肺部疾病的发生 通过共同的IL-1β炎性体途径。这并不是说其他因素不相关，我们将 同时测试氧化应激和其他途径，通过高维，严格和验证， 测定。我们已经证明，在空气污染暴露期间，表观遗传修饰，如DNA甲基化， 表明暴露程度，并可能与肺部疾病有关。虽然这些进步在 污染引起的肺部疾病，具体的作用机制一直难以捉摸，推动了未满足的需求， 保护处于风险中的个人并减少PM2.5暴露的有害影响的新方法。我们 假设空气污染暴露诱导循环和细胞细胞因子如IL-1β和其他 通过表观遗传机制和免疫细胞活化途径，导致直接和间接活化 肺上皮细胞的分裂，导致慢性肺部疾病。我们将进行免疫和表观遗传学研究， 血液样本来自高度特征化的队列，每个队列估计暴露于空气污染。我们 随着时间的推移收集的样本;因此，我们有来自清洁空气环境（即健康）中的队列的样本 对照）。我们的干细胞来源的肺组织项目与干细胞来源的心脏组织的研究相协调。 组织，沿着新的目标，特别是在免疫和肺组织的机制。我们将共享所有数据 项目和核心，以协同研究的免疫，肺和心脏领域的发现，以实现我们的 首要目标是揭示炎症中IL-1β和其他通路失调的机制- 慢性和急性空气污染暴露的相关心肺病理学。理解 IL-1β和其他标志物的贡献可能会导致新方法的开发和应用， 预防和治疗与空气污染相关的公共卫生问题相关的疾病，如哮喘。我们 这项研究包括我们的个人队列中的纵向和重复测量（同一个人随着时间的推移， 测试）与不同的种族，其中一些代表服务不足的人口。我们的分析将控制 混杂因素（年龄、性别、体重指数、药物、其他），并将通过类似的方法解决异质性问题 组群特征的匹配（两个测试组群和验证组群）。