Identifying Multidimensional Omics Profiles Associated with Cardiovascular and Pulmonary Responses to Chronic and Acute Air Pollution Exposure (Project 2) for AIRHEALTH Study

确定与慢性和急性空气污染暴露的心血管和肺部反应相关的多维组学概况（项目 2），用于空气健康研究

• 批准号: 10460331
• 负责人: MICHAEL P. SNYDER
• 金额: $ 50.85万
• 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/10460331
• 关键词: ATP phosphohydrolase; Acute; Air Pollution; Biochemical; Biological Assay; Biological Markers; Blood; Blood specimen; Cardiac; Cardiovascular system; Cell physiology; Cells; Chronic; Complex; Data; Disease; Drug Targeting; Engineering; Exposure to; Functional disorder; Gene Expression; Gene Proteins; Glucokinase; Health; Heart; Heart Diseases; Heat-Shock Proteins 70; Immune; Immune response; Immune signaling; Immune system; Individual; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; Link; Lung; Lung diseases; Mass Spectrum Analysis; Mediator of activation protein; Metabolic; Methods; Molecular; Participant; Pathologic; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Plasma; Play; Pollution; Proteins; Proteome; Proteomics; Regulation; Reporting; Role; Sampling; Signal Transduction; Structure; Systems Biology; Testing; Time; Tissues; Transcript; Work; cohort; cytokine; differential expression; experimental study; gene network; heart cell; innovation; laboratory experiment; lipid biosynthesis; lipid metabolism; liquid chromatography mass spectrometry; metabolome; metabolomics; molecular modeling; programs; protein metabolite; response; small molecule; synergism; therapy development; transcriptome; transcriptome sequencing

ABSTRACT: PROJECT 2 Lung and cardiac diseases are complex disorders with underlying chronic inflammation, which can be induced or worsened by exposure to air pollution. Thus, understanding the molecular mechanisms by which air pollution activates the immune system and inflammation is essential to developing therapies. The recently reported association of the pro-inflammatory cytokine, IL-1β, with air pollution-linked pulmonary and cardiovascular inflammation presents the hypothesis that IL-1β could be the common mediator of downstream inflammatory immune responses linked to air pollution. Project 1 directly tests the hypothesis that IL-1β or other pathways are induced by air pollution, and examines the effect of air pollution and IL-1β or other pathways on immune cell and lung cell function using blood samples from three well-characterized cohorts that had been exposed to air pollution. Project 3 tests the hypothesis that IL-1β or other pathways are involved in immune signaling in cardiovascular tissue by directly by studying engineered heart cells' function after exposure to plasma samples from the same three cohorts. In Project 2, we will synergize and harmonize our studies with Projects 1 and 3 by developing hypotheses using specific systems biology approaches to understand the molecular circuitry induced by IL-1β in response to chronic and acute air pollution. There will be no redundancy with Project 1 and 3 or core laboratory experiments because we plan to perform unique-omics level experiments on blood samples from the three cohorts. We hypothesize that IL-1β or other pathways induce a gene/protein/metabolite expression response that plays a role in the pathophysiology of air pollution-linked immune system activation. Our results in Project 2 could provide a comprehensive, global view of IL-1β−related and IL-1β non-related responses in blood, lung, and/or cardiac tissues with fine-scale characterization of time-dependent and cytokine- specific response patterns. To characterize this response, we will perform assays to identify abundances of transcripts, proteins, and metabolites in samples from the three cohorts exposed to air pollution. We plan to identify networks of molecules associated or not associated with IL-1β pathways, which are differentially expressed in chronic versus acute air pollution. Our aims are Aim 1. to determine whether IL1α, IL1β, and IL36γ and other markers are upregulated in individuals exposed to air pollution vs healthy control (e.g. cohort with no air pollution exposure time point) in blood, lung, and cardiac tissues; Aim 2. to determine whether ATPases, glucokinase, HSP70, and MAPkinases and other pathways are upregulated in air pollution exposure in blood sample; and Aim 3. to determine whether the metabolites associated with lipid metabolism and lipogenesis are upregulated in air pollution exposure. We expect that our data will generate hypotheses about pathological mechanisms that can be shared collaboratively with Projects 1 and 3 and the core HEMC to test biomarkers and drug targets for the PPG

摘要：项目 2 肺病和心脏病是具有潜在慢性炎症的复杂疾病，可诱发 或因暴露于空气污染而恶化。因此，了解空气污染的分子机制 激活免疫系统，炎症对于开发治疗方法至关重要。最近报道的 促炎细胞因子 IL-1β 与空气污染相关的肺和心血管疾病的关系 炎症提出了这样的假设：IL-1β 可能是下游炎症的常见介质 免疫反应与空气污染有关。项目 1 直接检验 IL-1β 或其他途径是 空气污染诱发的疾病，并检测空气污染和IL-1β或其他途径对免疫细胞和免疫细胞的影响 使用来自暴露于空气的三个特征明确的队列的血液样本来检测肺细胞功能 污染。项目 3 测试了 IL-1β 或其他途径参与免疫信号传导的假设 心血管组织通过直接研究工程心脏细胞在暴露于血浆样本后的功能 来自相同的三个队列。在项目2中，我们将与项目1和3协同和协调我们的研究 通过使用特定的系统生物学方法提出假设来了解分子电路 IL-1β 诱导慢性和急性空气污染。项目 1 不会出现冗余， 3 或核心实验室实验，因为我们计划对血液样本进行独特的组学水平实验 来自三个队列。我们假设 IL-1β 或其他途径诱导基因/蛋白质/代谢物 表达反应在空气污染相关免疫系统激活的病理生理学中发挥作用。 我们在项目 2 中的结果可以提供 IL-1β 相关和 IL-1β 非相关的全面、全局视图 血液、肺和/或心脏组织中的反应，具有时间依赖性和细胞因子相关的精细特征 具体的反应模式。为了表征这种反应，我们将进行测定以确定丰度 暴露于空气污染的三个队列样本中的转录本、蛋白质和代谢物。我们计划 识别与 IL-1β 通路相关或不相关的分子网络，这些分子网络有差异 表现为慢性与急性空气污染。我们的目标是目标 1. 确定 IL1α、IL1β 和 IL36γ 是否 和其他标记物在暴露于空气污染的个体中与健康对照者（例如没有健康对照的队列）相比上调 血液、肺和心脏组织中的空气污染暴露时间点；目标 2. 确定 ATP 酶是否 血液中葡萄糖激酶、HSP70和MAP激酶等途径在空气污染暴露中上调 样本;目标 3. 确定与脂质代谢和脂肪生成相关的代谢物是否 空气污染暴露上调。我们期望我们的数据能够产生关于病理学的假设 可以与项目 1 和 3 以及核心 HEMC 协作共享以测试生物标志物的机制 和 PPG 的药物靶点