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: 10269335
• 负责人: MICHAEL P. SNYDER
• 金额: $ 50.86万
• 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/10269335
• 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; Genes; 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; 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 肺和心脏疾病是具有潜在慢性炎症的复杂疾病， 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 激活免疫系统和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 IL-1β可能是下游炎症反应的共同介质， 与空气污染有关的免疫反应。项目1直接检验了IL-1β或其他途径是 研究了空气污染和IL-1β或其他途径对免疫细胞的影响， 肺细胞功能，使用来自三个暴露于空气中的特征良好的队列的血液样本 污染项目3检验了IL-1β或其他途径参与免疫信号传导的假设， 直接通过研究工程心脏细胞暴露于血浆样本后的功能来研究心血管组织 来自同一三个队列。在项目2中，我们将使我们的研究与项目1和项目3协同一致 通过使用特定的系统生物学方法来理解分子电路， IL-1β对慢性和急性空气污染的反应。项目1不会有冗余， 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 从三个队列中。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，在空气污染相关的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非相关的全面的全球观点。 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的精细尺度表征， 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 转录本，蛋白质和代谢物的样本从三个队列暴露于空气污染。我们计划 识别与IL-1β通路相关或不相关的分子网络，这些分子网络与IL-1β通路的表达有差异。 表现为慢性和急性空气污染。我们的目标是目标1。以确定IL 1 α、IL 1 β和IL 36 γ是否 和其他标志物在暴露于空气污染的个体中相对于健康对照（例如，没有 空气污染暴露时间点）在血液，肺和心脏组织;目的2。为了确定ATP酶， 葡萄糖激酶、HSP 70和MAP激酶等途径在空气污染暴露中上调 目标3;目标3。以确定与脂质代谢和脂肪生成相关的代谢物是否 在空气污染暴露中上调。我们希望我们的数据能产生关于病理学的假设， 可以与项目1和3以及核心HEMC合作共享的机制，以测试生物标志物 和PPG的药物靶点