Project 2: Near-Roadway Air Pollution, Adipose Inflammation, and Metabolic Conse

项目 2：近车道空气污染、脂肪炎症和代谢问题

• 批准号: 8875810
• 负责人: ROB S MCCONNELL
• 金额: $ 0.41万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875810
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Age; Air Pollution; Animal Model; Animals; Biochemical Markers; Biology; Biopsy; Biopsy Specimen; Birth; Body fat; Body mass index; Breathing; Caliber; California; Carbon; Cardiovascular Diseases; Child; Child health care; Childhood; Communities; Conceptions; Data; Data Set; Dental crowns; Development; Diet; Disease; Drug or chemical Tissue Distribution; Environmental Health; Exposure to; Fatty acid glycerol esters; Flow Cytometry; Gene Expression; Genes; Growth; Health; Hepatic; Human; Incubated; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Insulin Signaling Pathway; Intervention; Lead; Life; Link; Literature; Liver diseases; MMP9 gene; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metals; Meteorology; Modeling; Morbidity - disease rate; Mus; NF-kappa B; NFKB Signaling Pathway; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Overweight; Participant; Particulate Matter; Pathway interactions; Physical activity; Play; Pollution; Prevalence; Procedures; Property; Recording of previous events; Recruitment Activity; Risk; Role; Sample Size; Sampling; Schools; Signaling Pathway Gene; Statistical Models; Structure; Techniques; Tissues; Transition Elements; Ultrasonography; Visceral; Work; air filter; base; cohort; cytokine; design; environmental chemical; inflammatory marker; innovation; insulin sensitivity; land use; macrophage; monocyte; mortality; mouse model; non-alcoholic fatty liver; novel; obesity in children; particle; pollutant; subcutaneous; trafficking; type 2 diabetes in children; young adult

Childhood obesity rates have increased for four decades, leading to increased prevalence of non-alcoholic fatty liver disease and type 2 diabetes in children and to substantial morbidity and mortality due to associated metabolic disease in adults. Emerging evidence indicates that the inflammatory profile of adipose tissue is an important determinant of the development of systemic inflammation, insulin resistance and metabolic disease in obese populations. Recent experimental work suggests that inhaled ambient particulate matter less than 5 pm in aerodynamic diameter {PMzs) causes similar metabolic effects in obese mice. New results from our Children's Health Study {CHS) show that near-roadway air pollution {NRAP) is strongly associated with childhood obesity and growth trajectory of body mass index. This project will investigate the mechanisms underlying NRAP associations with adipose tissue distribution and systemic metabolic outcomes in a subset of overweight and obese subjects understudy in Project 1 {PI). Associations of NRAP PM exposure with adipose tissue inflammation and insulin resistance, and the role of adipose tissue inflammation in the systemic metabolic effects of exposure, will be studied using deep subcutaneous abdominal adipose tissue {SAT) obtained by an innovative biopsy procedure from 60 overweight CHS participants. The subjects will be selected to represent the extremes of NRAP exposure occurring in Southern California and will be a subset of PI participants. The CHS was designed to evaluate the health effects of air pollution and the cohort (n=4560) has been followed prospectively over the course of childhood from age 6-18 years. Lifetime exposure to NRAP PM2.5 elemental carbon {EC) and transition metals (Fe and Cu) composition from birth to age 18 will be estimated from geocoded residential and school address history. A validated model of exposure has been developed using a unique historical data set of measurements of these pollutants in CHS communities and traffic distance, volume, meteorology and other land use variables. EC and these metals were selected for study because their known pro-inflammatory effects and steep near-roadway gradients make them likely causal components responsible for inflammatory and metabolic effects ofthe NRAP pollution mixture. In preliminary results generated for this application using a separate convenience sample of 36 obese young adults, modeled exposure to cruder markers ofthe NRAP mixture was associated with SAT inflammatory profile and with inflammatory gene expression. These results suggest that exposure to NRAP is associated with adipose tissue inflammation, which could play a critical role in promoting systemic inflammation, insulin resistance, and the metabolic risk associated with obesity. To our knowledge, these relationships have not previously been studied in humans. For this project, CHS participants from the extremes of lifetime cumulative NRAP exposure over childhood will be recruited as they reach age 18. Associations of EC and metals with inflammatory {Ml) macrophages determined by flow cytometry in SAT and with inflammatory cytokine and adipokine release from fat biopsies incubated ex vivo will be assessed. Based on preliminary results and relevant literature, the impact of exposure on expression of selected genes involved in inflammation and in insulin sensitivity will be investigated in macrophages and adipocytes, respectively. Innovative statistical modeling techniques will be used to examine the inflammatory mechanisms underlying NRAP effects on body fat, adipose inflammation, and metabolic outcomes. This analysis will use additional data on MRI hepatic and abdominal visceral adipose distribution, systemic inflammation and insulin resistance from P I , and covariates from the entire CHS cohort.

儿童肥胖率增加了四十年，导致非酒精性的患病率增加 儿童的脂肪肝病和2型糖尿病以及由于相关的大量发病率和死亡率 成人的代谢疾病。新兴的证据表明脂肪组织的炎症特征是 全身炎症，胰岛素抵抗和代谢疾病的发展的重要决定因素 在肥胖的人群中。最近的实验工作表明，吸入的环境颗粒物小于5 空气直径（PMZ）中的PM在肥胖小鼠中引起类似的代谢作用。我们的新结果 儿童健康研究（CHS）表明，近公路空气污染（NRAP）与 儿童肥胖和体重指数的生长轨迹。该项目将调查机制 与脂肪组织分布和全身代谢结果的基本NRAP关联 超重和肥胖的受试者在项目1 {PI）中进行了研究。 NRAP PM与脂肪的相关性 组织炎症和胰岛素抵抗，以及脂肪组织炎症在全身性的作用 暴露的代谢作用将使用深层皮下腹部脂肪组织（SAT）进行研究 通过60位超重CHS参与者的创新活检程序获得。受试者将是 被选为代表南加州发生的NRAP暴露极端的极端 PI参与者。 CHS旨在评估空气污染和队列的健康影响（n = 4560） 从6-18岁开始的童年期间，一直在遵循。终生暴露于NRAP PM2.5元素碳（EC）和过渡金属（Fe和Cu）从出生到18岁 根据地理编码的住宅和学校地址历史估算。经过验证的暴露模型已经 使用CHS社区中这些污染物的独特历史数据集开发 交通距离，数量，气象和其他土地使用变量。 EC和这些金属被选择 研究是因为他们已知的促炎作用和陡峭的近距离梯度使他们可能 负责NRAP污染混合物的炎症和代谢作用的因果成分。在 使用单独的36个肥胖年轻的便利样本为本应用产生的初步结果 成人，建模为NRAP混合物的Cruder标记的模型与SAT炎症有关 轮廓和炎症基因表达。这些结果表明，接触NRAP是相关的 使用脂肪组织炎症，这可能在促进系统性炎症，胰岛素中起关键作用 抗性以及与肥胖相关的代谢风险。据我们所知，这些关系还没有 以前是在人类中研究的。 对于这个项目，CHS参与者来自终生累积NRAP暴露于儿童时期的参与者 招募18岁。EC和金属与炎症（ml）巨噬细胞的关联 由SAT中的流式细胞仪和炎症活检中的炎症细胞因子和脂肪因子释放确定 将评估孵育的离体。基于初步结果和相关文献， 将研究参与炎症和胰岛素敏感性的选定基因表达的暴露 在巨噬细胞和脂肪细胞中。创新的统计建模技术将用于 检查NRAP对体内脂肪，脂肪炎症和 代谢结果。该分析将使用有关MRI肝和腹部内脏脂肪的其他数据 P I的分布，全身炎症和胰岛素抵抗，以及整个CHS队列的协变量。