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

 描述（由申请人提供）：使用生命过程框架，我们建议对早产（PTB）以及与儿童发展不良代谢结果相关的母体和胎儿代谢特征进行全面和系统的研究。Barker和其他人的精液工作将胎儿生长受限与成人慢性疾病（包括2型糖尿病（T2 D））联系起来。PTB和后期代谢风险之间的联系尚未得到充分研究，但具有重要的临床和公共卫生意义。在美国，肺结核发病率高， 影响所有出生的九分之一和六分之一的非洲裔美国人出生。肥胖和T2 D已成为流行病，影响到包括母亲和儿童在内的所有年龄组，特别是在贫困的少数民族人口中。这一提议的动机是我们最近在波士顿出生队列（BBC）中进行的研究，该研究表明早产程度与出生时可检测到并持续至儿童早期的胰岛素水平升高之间存在显著的剂量反应关系（Wang et al，JAMA，2014）。我们的研究结果提高了PTB是随后代谢风险的重要早期生命危险因素的可能性。我们建议在英国广播公司（NIH资助的最大的城市低收入少数民族出生队列之一）研究早产和足月母婴对（目标1为3,000对，目标2和3为1,200对），以解决三个具体目标：目标1。我们将检验PTB与儿童不良代谢结果相关的假设，包括超重或肥胖、全身和中心性肥胖的替代物、胰岛素和葡萄糖水平升高、血脂异常、血压升高以及从出生到15岁的关键发育窗口期的代谢/炎症生物标志物。目标二。我们将研究PTB与出生时评估的母体和脐带血代谢组之间的相互关系。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组的影响。目标3：我们将检验PTB和不利的母体和脐带血代谢组谱可以独立和联合增加儿童代谢风险的假设;我们进一步假设脐带血代谢组可能介导，而母体代谢组可能改变PTB对目标1中列出的儿童代谢结局的不良影响。我们将重点关注一组300种已开发和验证的代谢物，这些代谢物与肥胖，糖尿病和代谢风险有关。此外，我们将在探索性分析中纳入非靶向代谢物。这将是第一个将尖端代谢组学与前瞻性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风险，城市低收入，少数民族人口背景下有关代谢疾病胎儿起源的关键问题。该项目的发现将为宫内代谢环境（母体代谢组）、早产和胎儿代谢状态（脐带血代谢组）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.