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.

项目摘要 /摘要 紧急证据表明，暴露于区域空气污染物（AP）和近路空气污染物 （NRAP）与肥胖和2型糖尿病的发展有关。先前的研究表明 产前和早期生命暴露于AP可能在儿童对象的病因中起关键作用。但是， 将AP暴露和肥胖和糖尿病联系起来的机制尚不清楚。研究发病机理的研究 迫切需要与AP相关的肥胖症和糖尿病病因。代谢组学技术提供 流行病学家和临床医生是一个前所未有的机会，可以检查与联系的代谢途径 暴露和疾病特征。在此提案中，候选人的提议识别关键代谢途径 儿童AP的关联与体内脂肪，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阶段包括两个重要的发展时期（新生儿和青少年）。因此，这个 工作可能会阐明加速和/或改变疾病进程的AP暴露的关键时期，并 可能会告知我们新的分子靶标，以提早干预和预防肥胖和 糖尿病。在K99 Mendored阶段，候选人将对目标代谢组的新测量 现有AP暴露数据以及肥胖和糖尿病表型的氨基酸和脂肪酸 前瞻性儿童健康研究（CHS）正在进行的研究，该研究正在研究代谢健康 南加州的AP暴露的影响。靶向代谢组学将用于识别途径 氨基酸和脂肪酸代谢与累积暴露于区域AP和NRAP有关 从产前到青少年，以及200个CHS青少年的代谢性状。此外， 将分析特定的代谢产物，例如酰基肉碱和脂肪酸，以检查假设的 连接空气污染，肥胖和代谢性疾病的机制，例如炎症激活和瘦素 反抗。在K99阶段提议的培训目标，其中包括个人精神职位， 教学课程和研究中心，会议和讲习班旨在增强候选人的 四个基本领域的知识和技能，包括1）曝光评估和环境 流行病学，2）代谢组学，3）特定于代谢组学数据和中介分析的统计模型， 4）职业发展。在K99阶段实现拟议的培训将确保 候选人成功地开展K99/R00研究项目，并能够为将来的过渡设备齐全 进入独立的环境健康科学家。在R00阶段，候选人将应用培训， 在K99阶段开发的技能，在一项前瞻性出生队列研究中，母体和发展 环境和社会压力源（MADRES）研究的风险。候选人将使用非目标 代谢组学发现与产前AP暴露和新生儿和新生儿有关的新型代谢组学特征 Madres的250个脐带血样本中的婴儿肥胖。随后，有针对性的代谢组学将 在从马德里斯到一个独立的250名新生儿的独立组的脐带血样本中进行分析 复制先前确定的代谢组学特征。两个K99/R00项目都将填补我们的关键空白 了解将产前和慢性AP暴露以及发展的代谢途径的理解 儿童肥胖和代谢障碍。随着拟议的项目和在此期间获得的基本培训 K99阶段，候选人将被定位为启动她的独立学术生涯并进行 新的研究以解密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标。