Longitudinal metabolic profiling throughout gestation in the plasma and urine of women who develop early-onset preeclampsia

 描述（由申请人提供）：先兆子痫是一种严重的疾病，影响所有怀孕的3-7%。它是全世界孕产妇和新生儿发病率和死亡率的主要原因。先兆子痫的特征是妊娠20周后新发高血压和蛋白尿。如果不及时治疗，它可能导致产妇癫痫发作，多器官衰竭和死亡。分娩是唯一的治疗方法，通常需要早产。尽管进行了广泛的调查，先兆子痫的病因是知之甚少。提高对这种疾病的认识可以显著改善孕妇的临床护理。最近代谢组学（即，代谢谱分析（metabolic profiling）是指对细胞代谢物如糖、氨基酸、有机酸、核苷酸和脂质的检查）已经成为了解复杂疾病如高血压和2型糖尿病的有前景的技术。这种方法也是有用的理解妊娠障碍，因为母体代谢产物代表了母体，胎儿和胎盘室之间的相互作用网络的输出。在先兆子痫妇女中进行的初步代谢分析实验已经证明了代谢物的改变;然而，这些研究有很大的局限性。具体而言，（1）在每项研究中，先兆子痫妇女中报告的代谢特征是独特的;（2）先兆子痫妇女的亚组被一起分析（即，早发性和晚发性疾病患者）;（3）每项研究中仅分析了妊娠期的一个时间点;（4）大多数研究缺乏尿液分析。我们在这里提出了第一个纵向的，全球的代谢分析产妇血浆和尿液在每个妊娠三个月的妇女谁开发早发性先兆子痫（需要交付前37周）。用于该分析的样品已经储存并准备使用。该队列共包括2105名妇女，其中56名发展为早发性先兆子痫。我们将使用完善的液相色谱串联质谱平台来表征早发性先兆子痫妇女和匹配对照的母体血液和尿液中的总体代谢特征。将分析每例患者在妊娠期之间的代谢物变化。此外，将按妊娠期分析先兆子痫患者和匹配对照之间的代谢物差异。然后，我们将评估代谢表型是否可以根据临床表型识别患者亚组，重点关注分娩时的胎龄、婴儿出生体重和异常实验室研究。这些实验将确定早发性先兆子痫妇女在整个妊娠期间的代谢特征，并将增强我们对疾病发病机制所涉及的途径的理解。最终，这些知识有可能导致新的先兆子痫的预测性测试和治疗。

 DESCRIPTION (provided by applicant): Preeclampsia is a severe disorder that affects 3-7% of all pregnancies. It is a leading cause of maternal and neonatal morbidity and mortality worldwide. Preeclampsia is characterized by new-onset hypertension and proteinuria after 20 weeks gestation. Left untreated, it can lead to maternal seizures, multi-organ failure, and death. Delivery is the only cure, which often necessitates preterm birth. Despite extensive investigation, the etiology of preeclampsia is poorly understood. Improved understanding of the disease could significantly improve clinical care for pregnant women. Recently metabolomics (i.e., metabolic profiling, meaning the examination of cellular metabolites such as sugars, amino acids, organic acids, nucleotides, and lipids) has emerged as a promising technique for understanding complex diseases, such as hypertension and type 2 diabetes. This approach is also useful for understanding disorders of pregnancy, since maternal metabolites represent the output of a network of interactions between maternal, fetal, and placental compartments. Initial metabolic profiling experiments in women with preeclampsia have demonstrated altered metabolites; however, these studies have significant limitations. Specifically, (1) the metabolic signatures reported in women with preeclampsia have been unique in each study; (2) subgroups of women with preeclampsia have been analyzed together (i.e., those with early- and late-onset disease); (3) only one time point in gestation has been analyzed in each study; (4) urine analysis is lacking from most studies. We propose here the first longitudinal, global metabolic profiling of both maternal plasma and urine in each trimester of pregnancy in women who developed early-onset preeclampsia (requiring delivery prior to 37 weeks). The samples for this analysis are already banked and ready for use. The cohort includes 2105 total women, 56 of whom developed early-onset preeclampsia. We will characterize the global metabolic profile in maternal blood and urine in women with early-onset preeclampsia and matched controls using well-established liquid chromatography tandem mass spectroscopy platforms. Changes in metabolites will be analyzed between trimesters for each patient. Additionally, differences in metabolites between preeclamptics and matched controls will be analyzed by trimester. We will then assess if the metabolic phenotype can identify subgroups of patients based on their clinical phenotypes with a focus on gestational age at delivery, infant birth weight, and abnormal laboratory studies. These experiments will define the metabolic profile throughout pregnancy in women who develop early-onset preeclampsia and will enhance our understanding of pathways involved in disease pathogenesis. Ultimately, this knowledge has the potential to lead to new predictive tests and treatments for preeclampsia.