Metabolomic Signatures Linking Air Pollution, Obesity and Diabetes

空气污染、肥胖和糖尿病之间的代谢组学特征

• 批准号: 9920725
• 负责人: Zhanghua Chen
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920725
• 关键词: Adolescence; Adolescent; Adult; Affect; Air; Air Pollutants; Air Pollution; Amino Acids; Area; Biological; Birth; Birth Weight; Blood; Blood specimen; Body fat; Brain; California; Child; Child Health; Childhood; Chronic; Cohort Studies; Data; Development; Diabetes Mellitus; Disease; Dual-Energy X-Ray Absorptiometry; Early Intervention; Educational workshop; Ensure; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemic; Epidemiologist; Etiology; Exposure to; Fasting; Fatty Acids; Fatty acid glycerol esters; Future; Glucose; Goals; Growth; Health; Inflammatory; Insulin Resistance; Interleukin-6; International; Interruption; Knowledge; Leptin; Leptin resistance; Life; Link; Liver; Longevity; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Mediation; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Molecular Target; Mus; Neonatal; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Phase; Phenotype; Pilot Projects; Play; Positioning Attribute; Prevention; Prospective cohort; Research; Research Project Grants; Risk; Role; Sampling; Sampling Studies; Scientist; Serum; Statistical Models; TLR2 gene; TNF gene; Technology; Testing; Training; Transportation; Umbilical Cord Blood; Visceral; Work; acylcarnitine; amino acid metabolism; career; career development; cellular targeting; critical period; cytokine; design; early life exposure; environmental stressor; fatty acid metabolism; glucose metabolism; improved; infant adiposity; meetings; metabolomics; neonate; novel; obesity development; obesity in children; obesity prevention; obesity risk; prenatal; prenatal exposure; prospective; skills; social stressor; subcutaneous; trait

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.

项目概要/摘要 新出现的证据表明，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 型糖尿病的发生有关。先前的研究表明 产前和生命早期接触 AP 可能在儿童肥胖的病因学中发挥关键作用。然而， AP 暴露与肥胖和糖尿病之间的联系机制尚不清楚。发病机制研究 迫切需要了解与 AP 相关的肥胖和糖尿病的病因。代谢组学技术提供 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的代谢途径 暴露和疾病特征。在该提案中，候选人提出确定关键的代谢途径 儿童期 AP 暴露与身体脂肪、异位脂肪和糖尿病特征（例如 通过代谢组学方法葡萄糖浓度和胰岛素抵抗。涉及 K99 和 R00 阶段包含两个重要的发育时期（新生儿期和青春期）。因此，这 这项工作可能会阐明 AP 暴露加速和/或改变病程的关键时期，以及 可能会为我们提供早期干预和预防肥胖的新分子靶标 糖尿病。在 K99 指导阶段，候选人将配对目标代谢组学的新测量 氨基酸和脂肪酸与现有的 AP 暴露数据以及肥胖和糖尿病表型 前瞻性儿童健康研究 (CHS) 正在进行的子研究，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识别途径 与局部 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 青少年的代谢疾病特征。此外， 将分析特定代谢物，例如酰基肉碱和脂肪酸，以检验假设的 空气污染与肥胖和代谢紊乱（例如炎症激活和瘦素）之间的联系机制 反抗。 K99 阶段拟议的培训目标，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能力 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) 针对代谢组学数据和中介分析的统计模型， 4）职业发展。 K99阶段拟议培训的完成将确保 成功开展 K99/R00 研究项目并为未来转型做好充分准备的候选人 成为一名独立的环境健康科学家。在 R00 阶段，候选人将应用培训并 在前瞻性出生队列研究 K99 阶段开发的技能，即孕产妇和发育 环境和社会压力源风险 (MADRES) 研究。候选人将使用非目标 代谢组学发现与产前 AP 暴露以及新生儿和新生儿相关的新代谢组学特征 MADRES 的 250 份脐带血样本中的婴儿肥胖情况。随后，靶向代谢组学将 对来自 MADRES 的 250 名新生儿的独立组的脐带血样本进行分析 复制先前确定的代谢组学特征。 K99/R00 两个项目都将填补我们的关键空白 了解与产前和慢性 AP 暴露相关的代谢途径以及 儿童肥胖和代谢紊乱。通过拟议的项目和期间获得的必要培训 K99阶段，候选人将能够开始她的独立学术生涯并开展 破译与环境暴露相关的疾病病因学的新颖研究，并发现新的 早期干预和预防肥胖和糖尿病的细胞和分子目标。