Metabolomic Signatures Linking Air Pollution, Obesity and Diabetes

项目摘要/摘要 新出现的证据表明，接触地区性空气污染物(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。此前的研究表明， 产前和早期暴露于AP可能在儿童肥胖的病因学中起关键作用。然而， AP暴露与肥胖和糖尿病之间的联系机制尚不清楚。对发病机制的研究 对AP相关肥胖和糖尿病病因学的研究是迫切需要的。代谢组学技术为 流行病学家和临床医生有一个前所未有的机会来检查连接代谢途径的 暴露和疾病特征。在这项提案中，候选人建议确定关键的代谢途径 儿童AP暴露与体脂、异位脂肪和糖尿病特征之间的关联 通过代谢组学方法研究葡萄糖浓度和胰岛素抵抗。与K99有关的研究 R00阶段包括两个重要的发育期(新生儿和青春期)。因此，这 工作可能阐明加速和/或改变病程的AP暴露的关键时期，以及 将有可能为我们提供早期干预和预防肥胖的新分子靶点 糖尿病。在K99指导阶段，候选人将配对新的靶向代谢组学测量 存在AP暴露数据的氨基酸和脂肪酸与肥胖和糖尿病的表型 正在进行的未来儿童健康研究(CHS)的子研究，该研究正在检查代谢健康 AP暴露对南加州的影响。靶向代谢组学将用于确定途径(S) 与区域性AP和NRAP累积暴露相关的氨基酸和脂肪酸代谢 从产前到青春期以及200名CHS青少年的代谢性疾病特征。另外， 特定的代谢物，如酰基肉碱和脂肪酸将被分析以检验假设 空气污染与肥胖和代谢紊乱的联系机制，如炎症激活和瘦素 抵抗。K99阶段的拟议培训目标，其中包括个人指导， 授课课程和研究研讨会、会议和研讨会旨在提高候选人的 四个基本领域的知识和技能，包括1)暴露评估和环境 流行病学，2)代谢组学，3)特定于代谢组学数据的统计建模和中介分析， 4)职业发展。在K99阶段完成拟议的培训将确保 成功开展K99/R00研究项目并为未来过渡做好准备的候选人 成为一名独立的环境健康科学家。在R00阶段，应聘者将应用培训和 在K99阶段在预期出生队列研究、母体和发育研究中培养的技能 环境和社会应激源的风险(MADRES)研究。应聘者将使用非定向的 代谢组学：发现与产前AP暴露和新生儿和新生儿相关的新代谢组学特征 马德雷地区250份脐带血样本中婴儿肥胖症的调查随后，靶向代谢组学将 在马德雷地区250名新生儿的脐带血样本中进行分析 复制先前识别的代谢组特征。这两个K99/R00项目将填补我们在 了解与产前和慢性AP暴露有关的代谢途径以及 儿童肥胖和代谢紊乱。在以下期间获得拟议项目和基本培训 在K99阶段，候选人将开始她的独立学术生涯并进行 破译与环境暴露有关的疾病病因的新研究，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.