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

40年来，儿童肥胖率一直在上升，导致非酒精性肥胖的患病率增加 儿童脂肪肝和2型糖尿病以及相关疾病的大量发病率和死亡率 成人的代谢性疾病。新出现的证据表明，脂肪组织的炎症状态是一种 全身性炎症、胰岛素抵抗和代谢性疾病发展的重要决定因素 在肥胖人群中。最近的实验研究表明，吸入的环境颗粒物小于5 空气动力学直径的PM在肥胖小鼠中也会产生类似的代谢效应。来自我们的新结果 儿童健康研究(CHS)显示，近道路空气污染(NRAP)与 儿童肥胖与体重指数的增长轨迹。这个项目将研究这些机制 NRAP与脂肪组织分布和全身性代谢结果的关系 在项目1中，超重和肥胖的受试者作为替补。NRAP PM暴露与脂肪的关系 组织炎症与胰岛素抵抗以及脂肪组织炎症在全身疾病中的作用 暴露对代谢的影响，将使用腹部深层皮下脂肪组织(SAT)进行研究 通过创新的活组织检查程序从60名超重的CHS参与者中获得。主题将是 被选为代表发生在南加州的NRAP暴露的极端情况，将是 PI参与者。社区卫生服务旨在评估空气污染和队列(n=4560)对健康的影响。 从6岁到18岁，在整个童年过程中都被前瞻性地跟踪。终生接触NRAP PM2.5元素碳(EC)和过渡金属(Fe和Cu)从出生到18岁的组成将是 根据地理编码的住宅和学校地址历史估计。一个经过验证的暴露模型已经被 使用CHS社区和社区中这些污染物的测量的唯一历史数据集开发 交通距离、流量、气象等土地利用变量。EC和这些金属被选为 研究是因为它们已知的促炎作用和陡峭的近道路坡度使它们可能 对NRAP污染混合物的炎症和代谢影响负责的原因成分。在……里面 使用36名肥胖青年的单独便利样本为该应用程序生成的初步结果 模拟暴露于NRAP混合物的粗略标志物的成年人与SAT炎症有关 并伴有炎性基因表达。这些结果表明，接触NRAP与 对于脂肪组织炎症，这可能在促进全身炎症中发挥关键作用，胰岛素 抵抗力，以及与肥胖相关的代谢风险。据我们所知，这些关系并没有 之前已经在人类身上进行了研究。 在这个项目中，来自儿童时期终生累积NRAP暴露的社区卫生服务参与者将 到18岁时应被征召入伍。EC和金属与炎性巨噬细胞的关系 流式细胞术检测SAT及脂肪活检中炎性细胞因子和脂肪因子的释放 将对体外孵化进行评估。根据初步结果和相关文献， 将调查与炎症和胰岛素敏感性有关的选定基因的表达情况。 分别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对体脂、脂肪炎症和 代谢结果。这项分析将使用更多关于MRI肝脏和腹部内脏脂肪的数据 来自PI的分布、全身炎症和胰岛素抵抗，以及整个CHS队列的协变量。

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.