Fetal Programming of Growth and Obesity: A Metabolomics Approach

项目摘要/摘要 K01职业发展奖提出了一个多学科的4年期培训计划，以提供 候选人朱业毅博士，拥有开始成功职业生涯所需的经验和资源 独立调查员，以阐明肥胖症和相关并发症的早期起源。儿童肥胖症 流行病仍然是一个紧迫的公共卫生优先事项。及早预防是遏制肥胖浪潮的关键。 然而，我们确定有希望的预防目标的能力受到了衡量 用常规工具检测整体代谢状态。几项人体研究，包括朱博士之前的工作， 这表明，怀孕期间的个人暴露，包括饮食因素，可能会在以后的生活中增加肥胖风险。 然而，潜在的代谢途径是难以捉摸的。为了填补这一重要的知识空白，朱博士将使用 一种新的整体框架，利用靶向和非靶向代谢组学方法， 最先进的电子健康记录(EHR)数据和生物信息学分析，通过以下方式调查机制 宫内环境可推断胎儿极端生长的风险[小于胎龄(SGA)或大于 胎龄(LGA)]和改变的婴儿生长轨迹和过度肥胖(体重/身长或身体- 年龄质量指数z-Score≥第85个百分位数)。这个应用程序利用了怀孕环境 和生活方式研究，在北加州的Kaiser Permanente，有独特的，强大的禁食资源 妊娠早期至中期血清标本采集、人体测量、多领域调查 数据(例如，饮食、体力活动、心理社会评估)和整个妊娠期和 后代的婴儿期。具体目标，将在150个LGA、150个SGA和150个适当的样本中进行检查 对于胎龄出生，是为了：检查候选(支链氨基酸， 肌醇、三甲胺N-氧化物、酰基肉碱和脂肪酸)和非靶向代谢物 妊娠中期胎儿生长极限(目标1)与婴儿生长轨迹和超重肥胖(0-2) 年(目标2)，并探索子宫内饮食因素的代谢特征(目标3)。研究结果可能 阐明与可修饰的胰岛素相关的潜在代谢途径和潜在的上游预防目标。 子宫暴露，如母亲的饮食因素，以减轻儿童肥胖症。朱博士非常适合 进行这项研究：1)她在流行病学、营养学和生物统计学方面有扎实的基础；2)这位K01将 大大扩展了她在代谢组学、生物信息学和相关生物学方面的高级培训内容 口译；3)她利用了一套精心协调的资源，包括一项多学科的 指导委员会、课程安排和应用学习与培训目标和 明确的目标。这个K01对于推进她成为独立人士的长期职业目标是必不可少的 具有组学和生物信息学专业知识以研究心脏代谢性疾病的早期起源的研究人员， 最终目标是为上游肥胖及其并发症的预防提供个性化护理。

PROJECT SUMMARY/ABSTRACT This K01 Career Development Award proposes a multidisciplinary 4-year training program to provide the candidate, Dr. Yeyi Zhu, with the experience and resources necessary to launch a successful career as an independent investigator to elucidate early origins of obesity and related comorbidities. The childhood obesity epidemic remains an urgent public health priority. Early prevention is critical to stemming the tide of obesity. Yet, our ability to identify promising prevention targets has been impeded by the difficulty in measuring the holistic metabolic status by conventional tools. Several human studies, including from Dr. Zhu's previous work, indicate that individual exposures including dietary factors in pregnancy may program obesity risk in later life. However, the underlying metabolic pathways are elusive. To fill this important knowledge gap, Dr. Zhu will use a novel holistic framework that leverages both targeted and untargeted metabolomics approach, the state-of- the-art electronic health records (EHR) data, and bioinformatics analytics to investigate the mechanisms by which the in-utero environment may infer risk of fetal growth extremes [small for gestational age (SGA) or large for gestational age (LGA)] and altered infant growth trajectories and excess adiposity (weight-for-length or body- mass-index-for-age z-score ≥85th percentile). This application takes advantage of the Pregnancy Environment and Lifestyle Study within Kaiser Permanente Northern California, with unique, robust resources of fasting serum specimens collection in early to mid-pregnancy, anthropometric measurements, multi-domain survey data (e.g., diet, physical activity, psychosocial assessments), and EHR data throughout the gestation and offspring infancy. The specific aims, to be examined in a sample of 150 LGA, 150 SGA, and 150 appropriate for gestational age births, are to: examine the associations between candidate (branch-chain amino acids, myo-inositol, trimethylamine N-oxide, acylcarnitines, and fatty acids) and untargeted metabolites in early to mid-pregnancy with fetal growth extremes (Aim 1) and infant growth trajectories and excess adiposity from 0-2 years (Aim 2), and explore metabolomic signatures for dietary factors in utero (Aim 3). Study findings may elucidate the underlying metabolic pathways and potential upstream preventive targets related to modifiable in- utero exposures, such as maternal dietary factors, to mitigate childhood obesity. Dr. Zhu is well suited to perform this research: 1) she has a solid foundation in epidemiology, nutrition, and biostatistics; 2) this K01 will significantly broaden her repertoire of advanced training in metabolomics, bioinformatics, and related biological interpretation; and 3) she has leveraged a carefully coordinated set of resources including a multidisciplinary mentorship committee, coursework, and applied learning closely aligned with the training objectives and specific aims. This K01 is essential to advance her long-term career objective of becoming an independent investigator with expertise in omics and bioinformatics to study early origins of cardiometabolic disease, with the ultimate goal to inform individualized care for upstream prevention of obesity and its comorbidities.