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

摘要：总体来说，汽车尾气和森林火灾造成的空气污染是一种 重大的、快速增长的全球公共卫生负担导致心肺疾病的发病。 由上皮细胞和炎症细胞产生的白介素1β(IL-1β)是这种炎症反应的关键 在血液、肺、心脏和血管组织内，主要与急性和慢性炎症有关 暴露在污染物中。因此，了解IL-1β和其他途径的机制将 显著有益于心肺健康，因为有治疗方法可以阻断这一途径，而且由于 需要了解空气污染如何导致心肺疾病的直接机制 公共卫生政策。我们的中心目标是测试不同但相互交织的IL-1β和 与空气污染有关的炎症相关心肺病理中的其他途径调节。我们会 检验心血管和肺部疾病的免疫病理与IL-1β有关的假设 和/或其他途径，因为我们有初步数据表明IL-1β和炎症体的激活，以及 空气污染暴露的其他途径，特别是PM2.5。我们知道还有其他途径，除了 参与了IL-1β，为此，我们建议在所有项目和核心中进行无偏见的、不可知的实验， 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之间的联系 对暴露在空气中的儿童和青少年的临床结局，如增加收缩压 污染。我们创建了所有项目和核心的协同和依赖关系，因为我们使用的都是相同的 来自相同队列的样本，我们共享数据以便能够创建复合生物标记物来链接 病理与疾病(如哮喘或血压升高)的关系。作为我们共同创新的典范，我们 已经提出在肺和心脏模型中使用诱导多能干细胞(IPSCs)(项目1和3) 筛选和鉴定阻断IL-1、β和其他途径作用的药物。我们的目标是：1.描述 与空气污染(PM2.5)暴露相关的心肺和免疫疾病的潜在机制。 我们将识别和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.确保三大科学工程和工程核心的努力 将是协同、协调和整合的。我们具体描述了三个项目和核心是如何 是协同的，以及我们将如何将我们的研究结果与其他研究IL-1、β和其他 小路。3：提供一个高度互动、协作和多学科的调查团队和 支持我们目标的资源。我们描述了我们的多学科设施和调查人员 为名为AIRHEALTH的PPG的全面成功做出贡献。如果我们的计划和总体目标都达到了，我们 将确定肺病和心脏病与IL-1β和其他途径的机制联系，这可能会导致 到临床应用程序。暴露在急性和/或慢性空气污染中的个人的生物制品和其他药物。

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.