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，特别是特别<2.5µm（PM2.5），完成了多种有机分子 结合结合是慢性肺部疾病（例如哮喘）的重要驱动力。 PM2.5进入肺肺泡 在慢性和急性PM2.5暴露期间，释放促炎和血管活性因子有助于 肺病理。最近，在 空气污染引起的免疫系统激活和注射的机制。我们的建议，是 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发生 通过共享的IL-1β炎性体途径。这并不是说其他​​因素无关紧要，我们会 同时通过高维，严格且经过验证的氧化应激和其他途径 测定。我们已经表明，在空气污染暴露期间的表观遗传修饰，例如DNA甲基化 表示暴露的程度，可以与肺部疾病有关。尽管已经取得了这样的进步 污染引起的肺部疾病，特定的作用机制是难以捉摸的，驱动了对 保护有风险的个体并减少PM2.5暴露的有害影响的新方法。我们 假设空气污染暴露会诱导循环和细胞细胞因子，例如IL-1β和其他 通过表观遗传机理和免疫核管激活的途径，导致直接和间接激活 肺上皮细胞，导致慢性肺部疾病。我们将进行免疫和表观研究 从高度特征的同类中得出的血液样本，并带有个人估计暴露于空气污染。我们 随着时间的推移收集样品；因此，我们在干净的空气环境中有来自同类的样本（即健康 控制）。我们关于干细胞衍生的肺组织的项目通过对干细胞衍生的心脏的研究进行协调 组织，以及针对免疫组织和肺组织机制的新颖目的。我们将共享所有数据 在免疫，肺和心脏研究领域协同研究的项目和核心，以实现我们 揭示IL-1β机制和其他途径失调的总体目标 - 响应慢性和急性空气污染暴露的相关心肺病理。理解 IL-1β和其他标记的贡献可能会导致开发和应用新方法 预防和治疗与与空气污染相关的公共卫生问题相关的疾病，例如哮喘。我们的 研究包括我们个体同类中的纵向和重复措施（随着时间的流逝，同一个人是 经过多种种族的测试，其中一些代表了服务不足的人群。我们的分析将控制 混杂因素（年龄，性别，体重指数，药物等），将通过类似 匹配队列特征（两个测试队列和验证队列）。