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: 8995662
• 负责人: DIANE R GOLD
• 金额: $ 26.38万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995662
• 关键词: Accounting; Adult; Air Pollution; Bacteria; Bioinformatics; Biological Markers; Blood; Blood Pressure; Blood Vessels; Caliber; Cardiac; Cardiac health; 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; 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; 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; 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）：环境颗粒污染可能引发心肌梗塞，据估计是导致过早死亡的第 13 大原因，也是造成全球疾病负担的十大因素之一。尽管有证据表明环境颗粒携带不同数量的革兰氏阴性细菌成分内毒素，但污染颗粒上的微生物群落对其炎症和心血管影响的贡献尚不清楚。研究表明，随着气候对空气微生物模式的影响，北美的暖季正在延长。在我们对 55 名多伦多成年人进行的随机交叉对照人体暴露研究中，我们已经发表了初步数据，证明浓缩环境颗粒 (CAP) 的内毒素成分与全身炎症、氧化应激和血压增加之间的关联。白细胞计数增加的百分之四十归因于颗粒 质量可能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分子模式（PAMP）的前哨标记，这些模式刺激人类先天免疫炎症，可能与心血管结果相关。利用我们的多伦多研究，我们将结合 16S、18S、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，在门和属水平上表征粗、细和超细 CAP 暴露下的细菌和真菌群落（目标1).我们将评估测试前两周内环境温度和湿度水平如何影响 CAPS 上微生物类群的相对丰度（目标 4）。我们将检验以下假设：CAP 上革兰氏阴性变形菌门丰度的增加与血压升高、肱动脉狭窄有关，其次与血管刺激中间生物标志物（血管内皮生长因子）、全身炎症（例如炎症）的增加有关。 、白细胞计数）和氧化应激（例如 8-羟基脱氧鸟苷），并将评估单个细菌属的相对贡献变形菌与这些关联（目标 2）。我们将评估 CAP 上最丰富的真菌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，并将告知监管机构评估控制颗粒污染以改善心血管健康的益处。