Air pollution disrupts Inflammasome Regulation in HEart And Lung Total Health (AIRHEALTH)

空气污染扰乱心肺总体健康中的炎症小体调节 (AIRHEALTH)

• 批准号: 10460326
• 负责人: Kari C. Nadeau
• 金额: $ 212万
• 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 2023-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460326
• 关键词: Acute; Adolescent; Affect; Age; Air Pollution; Asthma; Automobile Exhaust; Biological; Biological Markers; Biotechnology; Blood; Blood Pressure; Blood Vessels; Cardiac; Cardiac health; Cardiopulmonary; Cardiovascular Diseases; Cells; Child; Chronic; Clinical; Complex; Data; Dependence; Development; Diesel Exhaust; Disease; Ensure; Environmental Exposure; Environmental Pollution; Epithelial; Equipment; Ethnic Origin; Exposure to; Fire - disasters; Future; Gender; Goals; Health; Heart; Heart Diseases; Human; Immune; Immune System Diseases; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Investigation; Knowledge; Ligands; Link; Lung; Lung diseases; Mentors; Modeling; Molecular; Monitor; Outcome; Particulate Matter; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Policies; Pollution; Program Research Project Grants; Proteomics; Public Health; Pulmonary Heart Disease; Regulation; Research Personnel; Resources; Sampling; Shapes; Sum; System; Systems Biology; Testing; Tissues; Toxic effect; Training; Wildfire; air treatment; antagonist; blood pressure elevation; cardiopulmonary system; clinical application; clinical investigation; cohort; data sharing; disorder risk; effective therapy; experimental study; fine particles; forest; global health; heart cell; immunopathology; improved; induced pluripotent stem cell; inflammatory marker; innovation; lung health; multidisciplinary; novel; personalized medicine; pollutant; prevent; programs; response; success; synergism

ABSTRACT: OVERALL COMPONENT Exposure to air pollution from automobile exhaust and forest fires is a significant, rapidly growing global public health burden that contributes to cardiopulmonary pathogenesis. Produced by epithelial and inflammatory cells, interleukin-1 beta (IL-1β) is key to this inflammatory response within blood, lung, cardiac, and vascular tissues, and primarily associated with acute and chronic inflammation upon exposure to pollutants. Accordingly, understanding the mechanisms of the IL-1β and other pathways will significantly benefit cardiopulmonary health since therapies are available to block this pathway and since knowledge of direct mechanisms of how air pollution leads to cardiopulmonary diseases is needed to shape policy in public health. Our central objective is to test distinct but intertwined mechanistic aspects of IL-1β and other pathway regulation in inflammation-associated cardiopulmonary pathology linked to air pollution. We will test the hypothesis that the immunopathology of cardiovascular and pulmonary diseases are linked to IL-1β and/or other pathways, as we have preliminary data demonstrating activation of IL-1β and inflammasome, and other pathways in air pollution exposure, particularly PM2.5. We understand there are other pathways other than IL-1β involved and to this end, we have proposed unbiased, agnostic experiments in all projects and cores, especially the systems biology approach of project 2. Furthermore, our data show the link of immune pathways to clinical outcomes, such as increase systolic blood pressure, in young children and adolescents exposed to air pollution. We have created synergy and dependency of all the projects and cores since we use all the same samples from the same cohorts, we share data to be able to create composite biological biomarkers to link pathology to disease (i.e. asthma or increased blood pressure). As an example of our innovation together, we have proposed using induced pluripotent stem cells (iPSCs) in both lung and heart models (Projects 1 and 3) to screen and identify agents that block IL-1β and other pathway effects. Our aims are: 1. Describe the mechanisms underlying heart, lung, and immune diseases associated with air pollution (PM2.5) exposure. We will identify and characterize biomarkers of acute and chronic environmental exposure to air pollution that predict cardiopulmonary diseases. 2. Ensure the efforts of the three scientific projects and project cores will be synergistic, coordinated, and integrated. We describe specifically how the three projects and cores are synergistic and how we will integrate our study findings with other efforts to investigate IL-1β and other pathways. 3: Provide a highly interactive, collaborative, and multi-disciplinary team of investigators and resources to support our goals. We describe our multi-disciplinary facilities and investigators that will contribute to the overall success of the PPG, called AIRHEALTH. If our program and overall aims are met, we will define the mechanistic links of lung and heart diseases with IL-1β and other pathways, which will likely lead to clinical app. of biologicals and other drugs in individuals exposed to acute and/or chronic air pollution.

摘要：整体成分暴露于汽车排气和森林火灾中的空气污染是一种 大量，迅速增长的全球公共卫生伯恩（Burnen）有助于心肺发病机理。 由上皮细胞和炎症细胞产生，白介素-1β（IL-1β）是这种炎症反应的关键 在血液，肺，心脏和血管组织中，主要与急性​​和慢性炎症有关 暴露于污染物后。根据了解IL-1β和其他途径的机制 显着使心肺健康受益，因为可以阻止这种途径，并且 需要了解空气污染如何导致心肺疾病的直接机制才能形成 公共卫生政策。我们的核心目的是测试IL-1β和 与空气污染相关的炎症相关心肺病理学中的其他途径调节。我们将 检验以下假设，即心血管和肺部疾病的免疫病理与IL-1β有关 和/或其他途径，因为我们的初步数据表明IL-1β和炎症体的激活，以及 空气污染暴露的其他途径，尤其是PM2.5。我们了解除了还有其他途径 涉及IL-1β，为此，我们在所有项目和核心中提出了无偏的不可知实验， 特别是项目2的系统生物学方法。此外，我们的数据显示了免疫途径的链接 暴露于空气的幼儿和青少年，临床结果，例如增加收缩压 污染。我们已经创建了所有项目和核心的协同作用和依赖性，因为我们使用所有相同的 来自同一队列的样本，我们共享数据以创建复合生物学生物标志物以链接 疾病病理学（即哮喘或血压升高）。作为我们共同创新的一个例子，我们 已经提出在肺和心脏模型中使用诱导多能干细胞（IPSC）（项目1和3） 筛选和识别阻断IL-1β和其他途径效应的药物。我们的目标是：1。描述 与空气污染相关的心脏，肺和免疫疾病的机制（PM2.5）暴露。 我们将确定并表征急性和慢性环境暴露于空气污染的生物标志物 预测心肺疾病。 2.确保三个科学项目和项目核心的努力 将是协同的，协调的和整合的。我们特别描述了三个项目和核心 是否协同以及我们将如何将研究结果与其他研究IL-1β和其他努力相结合 途径。 3：提供一个高度互动，协作和多学科的调查员团队 支持我们的目标的资源。我们描述了我们的多学科设施和调查人员 促进了PPG的整体成功，称为AirHealth。如果我们的计划和整体目标得到满足，我们 将通过IL-1β和其他途径定义肺和心脏病的机械联系，这可能会导致 到临床应用。暴露于急性和/或慢性空气污染的个体中的生物制剂和其他药物。