Preterm Birth, Maternal and Cord Blood Metabolome, and Child Metabolic Risk

 描述(申请人提供)：利用生命历程框架，我们建议对早产(PTB)和母婴代谢特征与儿童发育不良代谢结果的关系进行全面和系统的调查。Barker和其他人的开创性工作将胎儿生长受限与包括2型糖尿病(T2D)在内的成人慢性疾病联系起来。肺结核和后来的代谢风险之间的联系没有得到很好的研究，但具有重要的临床和公共卫生意义。在美国，肺结核的发病率很高， 影响到所有出生人口中的1/9和非洲裔美国人出生的1/6。肥胖症和T2D已成为流行病，影响到包括母亲和儿童在内的所有年龄段，特别是在贫困的少数群体中。这一建议是由我们最近在波士顿出生队列(BBC)上进行的研究推动的，该研究表明，早产儿程度与胰岛素水平升高之间存在显著的剂量-反应关系，这些胰岛素水平在出生时即可检测到，并持续到儿童早期(Wang等人，《美国医学会杂志》，2014)。我们的发现增加了肺结核是随后代谢风险的重要早期生命风险因素的可能性。我们建议在英国广播公司(BBC)上研究早产和足月母婴对(目标1为3,000对，目标2和目标3为1,200对)，以解决三个具体目标：目标1.我们将检验这样一种假设，即在从出生到15岁的关键发育窗口期间，肺结核与儿童不良代谢结果有关，包括超重或肥胖、全身和中枢肥胖的代用品、胰岛素和血糖水平升高、血脂异常以及血压和代谢/炎症生物标记物的升高。目的2.我们将研究肺结核与出生时评估的母体和脐带血代谢之间的相互关系。我们还将探讨母体因素如生活方式和饮食因素、肥胖、糖尿病、血脂异常和高血压对母体和脐带血代谢的影响。目的3.我们将检验这样一种假设，即肺结核和不良的母体和脐带血代谢组特征可以独立并共同增加儿童代谢风险；我们进一步假设，脐带血代谢组可能起中介作用，而母体代谢组可能改变结核病对儿童代谢结果的不利影响。我们将重点关注一组300种成熟和有效的代谢物，这些代谢物与肥胖、糖尿病和代谢风险有关。此外，我们将在我们的探索性分析中包括非靶向代谢物。这将是第一项将尖端代谢组学与预期出生队列相结合的大规模研究，以解决早产背景下以及美国高危、城市低收入少数群体背景下代谢性疾病的胎儿起源的关键问题。该项目的研究结果将对宫内代谢环境(母体代谢体)、早产和胎儿代谢状态(脐带血代谢体)是否以及如何共同影响儿童未来的代谢结果提供新的线索。

 DESCRIPTION (provided by applicant): Using a life-course framework, we propose to conduct a comprehensive and systemic investigation on preterm birth (PTB) and maternal and fetal metabolic characteristics in relation to child development of adverse metabolic outcomes. Seminal work by Barker and others has linked fetal growth restriction to adult chronic diseases including type 2 diabetes (T2D). The link between PTB and later metabolic risk is not well studied but of great clinical and public health importance. In the U.S., the rates of PTB are high, affecting 1 in 9 of all births and 1 in 6 African American births. Obesity and T2D have become epidemic, affecting all age groups including mothers and children, especially in poor minority populations. This proposal is motivated by our recent study in the Boston Birth Cohort (BBC), which demonstrated a significant dose-response relationship between degree of prematurity and elevated insulin levels that were detectable at birth and persistent through early childhood (Wang et al, JAMA, 2014). Our findings raise the possibility that PTB is an important early life risk factor of subsequent metabolic risk. We propose to study preterm and term mother-child pairs (n= 3,000 pairs for Aim 1 and 1,200 pairs for Aims 2 and 3) in the BBC, one of the largest NIH-funded urban low-income minority birth cohorts, to address three specific aims: Aim 1. We will test the hypothesis that PTB is associated with adverse child metabolic outcomes, including overweight or obesity, surrogates of total body and central adiposity, elevated insulin and glucose levels, abnormal lipid profiles, and elevated blood pressure and metabolic/inflammatory biomarkers during critical developmental windows from birth to age 15 years. Aim 2. We will examine the interrelationships between PTB and the maternal and cord blood metabolomes assessed at birth. We will also explore the impact of maternal factors such as lifestyle and dietary factors, obesity, diabetes, dyslipidemia, and hypertension on the maternal and cord blood metabolomes. Aim 3. We will test the hypothesis that PTB and unfavorable maternal and cord blood metabolome profiles can independently and jointly increase child metabolic risk; we further hypothesize that the cord blood metabolome may mediate, while the maternal metabolome may modify the adverse effect of PTB on child metabolic outcomes listed in Aim 1. We will focus on a panel of 300 well-developed and validated metabolites that have been implicated in obesity, diabetes, and metabolic risk. In addition, we will include non-targeted metabolites in our exploratory analyses. This would be the first large-scale study to integrate cutting-edge metabolomics with a prospective birth cohort to address critical questions about fetal origins of metabolic diseases in the context of preterm birth and in the setting of a U.S. high-risk, urban low-income, minority population. Findings from this project will shed new light on whether and how in-utero metabolic environments (maternal metabolome), prematurity, and the fetal metabolic state (cord blood metabolome) jointly influence future metabolic outcomes in children.