Metabolomic Signatures Linking Air Pollution, Obesity and Diabetes

项目概要/摘要 紧急证据表明，暴露于区域空气污染物（AP）和近道路空气污染物 （NRAP）与肥胖和2型糖尿病的发展有关。先前的研究表明， 产前和生命早期暴露于AP可能在儿童肥胖的病因学中起关键作用。但 AP暴露与肥胖和糖尿病之间的联系机制尚不清楚。发病机制研究 AP相关的肥胖和糖尿病病因学的研究是迫切需要的。代谢组学技术提供了 流行病学家和临床医生提供了一个前所未有的机会来检查代谢途径， 暴露和疾病特征。在这份提案中，候选人建议确定关键的代谢途径 儿童期AP暴露与体脂、异位脂肪和糖尿病特征之间的潜在联系， 葡萄糖浓度和胰岛素抵抗通过代谢组学方法。研究涉及K99和 R 00阶段包括两个重要的发育期（新生儿和青春期）。因此本 工作可以阐明加速和/或改变疾病进程的AP暴露的关键时期， 将有可能为我们提供新的分子靶点，用于早期干预和预防肥胖， 糖尿病在K99指导阶段，候选人将对靶向代谢组学的新测量进行配对， 氨基酸和脂肪酸与现有的AP暴露数据和肥胖症和糖尿病表型， 正在进行的前瞻性儿童健康研究（CHS）的子研究，该研究正在检查代谢健康， 在南加州的AP暴露的影响。靶向代谢组学将用于确定 氨基酸和脂肪酸代谢与区域AP和NRAP累积暴露相关 从产前到青春期，以及200 CHS青少年的代谢疾病特征。此外，本发明还 将分析特定的代谢物如酰基肉毒碱和脂肪酸，以检查假设的 联系空气污染和肥胖和代谢紊乱的机制，如炎症激活和瘦素 阻力K99阶段的拟议培训目标，包括个人指导， 教学课程和研究研讨会，会议和讲习班，旨在提高候选人的 四个基本领域的知识和技能，包括1）接触评估和环境 流行病学，2）代谢组学，3）代谢组学数据和中介分析的特定统计建模， （4）职业发展。在K99阶段完成拟议的培训将确保 候选人成功进行K99/R 00研究项目，并为未来的过渡做好准备 独立的环境健康科学家在R 00阶段，候选人将应用培训， 在K99阶段进行的一项前瞻性出生队列研究中开发的技能， 环境和社会压力风险（MADRES）研究。候选人将使用非目标 代谢组学，以发现与产前AP暴露和新生儿相关的新代谢组学特征， 在来自MADRES的250份脐带血样本中，随后，靶向代谢组学将 在来自MADRES的250名新生儿的独立组的脐带血样本中进行分析， 复制先前鉴定的代谢组学特征。这两个K99/R 00项目将填补我们 了解连接产前和慢性AP暴露的代谢途径， 儿童肥胖和代谢紊乱。根据拟议的项目和期间获得的基本培训， 在K99阶段，候选人将被定位为开始她的独立学术生涯， 新的研究，以破译与环境暴露有关的疾病病因，并发现新的 早期干预和预防肥胖和糖尿病的细胞和分子靶点。

PROJECT SUMMARY / ABSTRACT The emergent evidence indicates that exposures to regional air pollutants (AP) and near-roadway air pollutants (NRAP) are associated with the development of obesity and type 2 diabetes. Previous studies suggest that prenatal and early life exposures to AP may play critical roles in the etiology of childhood obesity. However, the mechanism linking AP exposures and obesity and diabetes is unknown. Studies investigating the pathogenesis of the AP-related obesity and diabetes etiology are urgently needed. Metabolomics technology provides epidemiologists and clinicians an unprecedented opportunity to examine the metabolic pathways linking exposures and disease traits. In this proposal, the candidate proposes to identify key metabolic pathways underlying the associations of childhood AP exposures with body fat, ectopic fat and diabetes traits such as glucose concentrations and insulin resistance via the metabolomics approach. Studies involved in the K99 and R00 phases encompass two important developmental periods (neonatal and adolescence). Therefore, this work may elucidate the critical periods of AP exposures that accelerate and/or alter the course of disease, and will potentially inform us with novel molecular targets for early intervention and prevention of obesity and diabetes. In the K99 mentored phase, the candidate will pair new measurement of targeted metabolomics of amino acids and fatty acids with existing AP exposure data and obesity and diabetes phenotypes in an ongoing substudy of the prospective Children’s Health Study (CHS), which is examining the metabolic health impacts of AP exposure in Southern California. Targeted metabolomics will be used to identify pathway(s) of amino acid and fatty acid metabolism that are associated with cumulative exposures to regional AP and NRAP from prenatal to adolescence, as well as metabolic disease traits in 200 CHS adolescents. Additionally, specific metabolites such as acylcarnitines and fatty acids will be analyzed to examine the hypothesized mechanism linking air pollution and obesity and metabolic disorders, such as inflammatory activation and leptin resistance. The proposed training objectives during the K99 phase, which includes personal mentorship, didactic courses and research seminars, meetings, and workshops, are designed to enhance the candidate’s knowledge and skills in four essential areas including 1) exposure assessment and environmental epidemiology, 2) metabolomics, 3) statistical modeling specific to metabolomics data and mediation analysis, and 4) career development. The accomplishment of the proposed training in the K99 phase will ensure the candidate to successfully conduct the K99/R00 research projects and to be well-equipped for future transition into an independent environmental health scientist. In the R00 phase, the candidate will apply the training and skills developed during the K99 phase on a prospective birth cohort study, the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Study. The candidate will use the non-targeted metabolomics to discover novel metabolomic signatures related with prenatal AP exposures and neonatal and infant adiposity among 250 cord blood samples from the MADRES. Subsequently, targeted metabolomics will be analyzed in the cord blood samples from an independent group of 250 newborns from the MADRES to replicate previously identified metabolomic signatures. Both K99/R00 projects will fill critical gaps in our understanding of the metabolic pathways linking prenatal and chronic AP exposures and the development of childhood obesity and metabolic disorders. With the proposed projects and essential training obtained during the K99 phase, the candidate will be positioned to initiate her independent academic career and to carry out novel research to decipher the disease etiology related with environmental exposures, and to discover new cellular and molecular targets for early intervention and prevention of obesity and diabetes.