Cardiovascular Response to CAP Microbial Components in Controlled Human Exposures

在受控人体暴露中对 CAP 微生物成分的心血管反应

• 批准号: 8805972
• 负责人: DIANE R GOLD
• 金额: $ 26.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805972
• 关键词: Accounting; Adult; Air Pollution; Bacteria; Bioinformatics; Biological Markers; Blood; Blood Pressure; Blood Vessels; Caliber; Cardiac; Cardiovascular system; Cells; Cessation of life; Cities; Climate; Clinic; Communities; Complex; Cross-Over Studies; Data; Diabetes Mellitus; Endotoxins; Exposure to; Future; Genes; Genetic Crossing Over; Gram-Negative Bacteria; Guanosine; Health; Heart; Human; Humidity; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Measures; Mediating; Metagenomics; Methods; Mexico; Microbe; Molecular; Mononuclear; Myocardial; Myocardial Infarction; North America; Outcome; Oxidative Stress; Pathway Analysis; Pathway interactions; Pattern; Pattern recognition receptor; Physiological; Play; Pollution; Production; Proteobacteria; Publishing; Randomized; Relative (related person); Risk Factors; Rodent; Role; Sampling; Seasons; Sentinel; Soil; Taxon; Techniques; Temperature; Testing; Toxic effect; Ultrafine; Up-Regulation; Vascular Endothelial Growth Factors; Weather; White Blood Cell Count procedure; Whole-Genome Shotgun Sequencing; ambient particle; base; biological adaptation to stress; brachial artery; burden of illness; cardiovascular health; cardiovascular risk factor; cytokine; defined contribution; exposed human population; fungus; improved; innovation; microbial; microbial community; microbiome; particle; particle exposure; pathogen; premature; public health relevance; rRNA Genes; response; secondary outcome; weather patterns

DESCRIPTION (provided by applicant): Ambient particle pollution, which can be a trigger for myocardial infarction, has been estimated to be the 13th leading cause of premature death and one of the top ten contributors to the global burden of disease world- wide. Despite evidence that ambient particles carry variable amounts of the gram-negative bacterial component endotoxin, the contribution of microbial communities on pollution particles to their inflammatory and cardiovascular effects is poorly defined. Studies suggest that the warm season is lengthening in North America with climate influences on patterns of airborne microbes. We have published and preliminary data demonstrating associations of the endotoxin component of concentrated ambient particles (CAPs) with increased systemic inflammation, oxidative stress and blood pressure in our completed randomized cross-over controlled human exposure study of 55 Toronto adults. Up to forty-percent of the increase in leukocyte count attributed to particle mass could be attributed to its endotoxin content. Endotoxin may be a sentinel marker for a complex array of microbial exposures with other pathogen-associated-molecular patterns (PAMPs) that stimulate human innate immune inflammation potentially relevant to cardiovascular outcomes. Leveraging on our Toronto study, we will combine 16S,18S, ITS rRNA gene and selective whole genome shotgun sequencing with innovative bioinformatic methods to characterize the bacterial and fungal communities on coarse, fine and ultrafine CAP exposures, at the phylum and genus level (Aim 1). We will evaluate how the relative abundance of microbial taxa on CAPS is influenced by ambient temperature and humidity levels in the two weeks prior to testing (Aim 4). We will test the hypothesis that increased abundance of gram-negative phylum Proteobacteria on CAPs will be associated with increased blood pressure, brachial artery narrowing and, secondarily, with increases in intermediate biomarkers of vascular stimulation(vascular endothelial growth factor), systemic inflammation (e.g., white blood cell count), and oxidative stress (e.g., 8-hydroxy-deoxy-guanosine), and will assess the relative contribution of individual bacterial genera within Proteobacteria to these associations (Aim 2). We will evaluate whether the most abundant fungal taxa on CAPs are independently associated with our outcomes (Aim 3). Finally, we will apply bioinformatic methods to our metagenomic data to quantify the relative abundance of synthesis pathways for active components of PAMPS, and explore how pathway abundance influences blood pressure, inflammation and oxidative stress. Understanding the microbial contributions to particle toxicity will help define mechanisms whereby particle pollution increases cardiovascular risk, and will inform regulators estimating the benefits of controlling particle pollution to improve cardiovascular health.

描述（由申请人提供）：环境颗粒污染可能是心肌梗死的触发因素，据估计是过早死亡的第13大主要原因，也是全球疾病负担的十大贡献者之一。尽管有证据表明，周围的颗粒物携带不同量的革兰氏阴性细菌成分内毒素，污染颗粒物上的微生物群落对炎症和心血管效应的贡献还很难确定。研究表明，由于气候对空气微生物模式的影响，北美的温暖季节正在延长。我们已发表的初步数据表明，在我们完成的55名多伦多成人随机交叉对照人体暴露研究中，浓缩环境颗粒（CAP）的内毒素组分与全身炎症、氧化应激和血压升高相关。高达40%的白细胞计数增加归因于颗粒 质量可归因于其内毒素含量。内毒素可能是一系列复杂的微生物暴露与其他病原体相关的分子模式（PAMP），刺激人类先天性免疫炎症可能与心血管疾病的结果的前哨标记。利用我们的多伦多研究，我们将结合联合收割机16 S，18 S，ITS rRNA基因和选择性全基因组鸟枪测序与创新的生物信息学方法，以表征细菌和真菌群落的粗，细和超细CAP暴露，在门和属的水平（目标1）。我们将评估CAPS上微生物分类群的相对丰度如何受到测试前两周内环境温度和湿度水平的影响（目标4）。我们将检验这样的假设，即CAP上革兰氏阴性门变形菌的丰度增加将与血压升高、肱动脉狭窄相关，其次与血管刺激的中间生物标志物（血管内皮生长因子）、全身性炎症（例如，白色血细胞计数）和氧化应激（例如，8-羟基-脱氧-鸟苷），并将评估变形菌门内个别细菌属对这些关联的相对贡献（目标2）。我们将评估CAP上最丰富的真菌分类群是否与我们的结果独立相关（目标3）。最后，我们将生物信息学方法应用于我们的宏基因组数据，以量化PAMPS活性成分合成途径的相对丰度，并探索途径丰度如何影响血压，炎症和氧化应激。了解微生物对颗粒毒性的贡献将有助于确定颗粒污染增加心血管风险的机制，并将告知监管机构估计控制颗粒污染对改善心血管健康的益处。