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: 10684167
• 负责人: Kari C. Nadeau
• 金额: $ 103.49万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 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/10684167
• 关键词: ATAC-seq; Acute; 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 Cells; Epithelium; 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; Proliferating; 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; antagonist; chemokine; cohort; cytokine; cytotoxicity; data sharing; ethnic diversity; experience; exposed human population; high dimensionality; immune activation; improved; inflammatory marker; inhibitor; novel; novel strategies; patient population; prevent; response; sex; stem cells; synergism; 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，特别是产生的含有各种有机分子的颗粒物&2.5微米(PM2.5) 通过燃烧，是慢性肺部疾病(如哮喘)的重要驱动因素。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和炎症体途径被认为与 空气污染导致免疫系统激活和炎症的潜在机制。我们的建议， 第一次，汇集了一个统一的假设，即污染导致了心肺疾病 通过共享的IL-1β炎症小体途径。这并不是说其他因素不相关，我们会 同时通过高维、严格和有效的方式测试氧化应激和其他途径 化验。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 表明接触的程度，并可能与肺部疾病有关。尽管这些进展已经在 由污染引起的肺部疾病，具体的作用机制一直难以捉摸，推动了对 保护处于危险中的个人和减少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因子，如IL-1，β和其他 通过表观遗传机制和免疫细胞激活导致直接和间接激活的途径 肺上皮细胞，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，个人估计暴露在空气污染中。我们 随着时间的推移收集样本；因此，我们从清洁空气环境(即健康)的队列中获得样本 控制)。我们关于干细胞来源的肺组织的项目与干细胞来源的心脏组织的研究相一致 组织，以及针对免疫和肺组织机制的新目标。我们将在所有人之间共享数据 项目和核心，以协同免疫、肺和心脏研究领域的研究结果，以实现我们的 首要目标是揭示IL-1β和其他途径在炎症中的失调机制- 慢性和急性空气污染暴露的相关心肺病理。理解 IL-1、β和其他标志物的贡献可能会导致新的方法的开发和应用 预防和治疗与空气污染有关的公共卫生问题，如哮喘。我们的 研究包括在我们的个人队列中进行纵向和重复测量(随着时间的推移，相同的个人是 经过测试)，有不同的族裔，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、药物和其他)，并将通过类似的 队列特征的匹配(两个测试队列和验证队列)。