Fetal Programming of Growth and Obesity: A Metabolomics Approach

项目总结/摘要 这个K 01职业发展奖提出了一个多学科的4年培训计划，以提供 候选人Yeyi Zhu博士拥有成功开展职业生涯所需的经验和资源， 独立研究者阐明肥胖和相关合并症的早期起源。儿童肥胖 这一流行病仍然是一个紧迫的公共卫生优先事项。早期预防对于遏制肥胖的趋势至关重要。 然而，我们确定有希望的预防目标的能力由于难以衡量 整体代谢状态的常规工具。几项人体研究，包括朱博士之前的工作， 表明怀孕期间包括饮食因素在内的个体暴露可能会导致以后的肥胖风险。 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 子宫内环境可能推断出胎儿生长极端的风险[小于胎龄（SGA）或大于胎龄（SGA）] 胎龄（LGA）]和改变的婴儿生长轨迹和过度肥胖（身高比体重或体重）。 年龄质量指数z评分≥第85百分位数）。此应用程序利用怀孕环境 凯撒医疗机构北方加州的生活方式研究，拥有独特的，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）和整个妊娠期的EHR数据， 后代的幼年期具体目标，将在150 LGA，150 SGA和150适当的样本中进行检查 对于胎龄出生，是：检查候选（支链氨基酸， 肌醇，三甲胺N-氧化物，酰基肉毒碱和脂肪酸）和非靶向代谢物， 妊娠中期，胎儿生长极端（目标1）和婴儿生长轨迹以及0-2岁的过度肥胖 年（目标2），并探索子宫内饮食因素的代谢组学特征（目标3）。研究结果可能 阐明潜在的代谢途径和潜在的上游预防目标， 子宫内暴露，如母亲的饮食因素，以减轻儿童肥胖。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坚实的基础; 2）这个K 01将 大大拓宽了她在代谢组学、生物信息学和相关生物学方面的高级培训课程， 解释; 3）她利用了一套精心协调的资源，包括多学科的 指导委员会，课程和应用学习与培训目标密切相关， 明确的目标。这个K 01是必不可少的，以推进她的长期职业目标，成为一个独立的 具有组学和生物信息学专业知识的研究人员，研究心脏代谢疾病的早期起源， 最终目标是为肥胖及其合并症的上游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.