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

 描述(申请人提供)：先兆子痫是一种严重的疾病，影响所有妊娠的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周后出现新发高血压和蛋白尿。如果不进行治疗，它可能会导致产妇癫痫发作、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，但对先兆子痫的病因了解甚少。提高对这种疾病的了解可以显著改善对孕妇的临床护理。最近，代谢组学(即代谢谱，即对糖、氨基酸、有机酸、核苷酸和脂类等细胞代谢物的检测)已经成为一种很有前途的理解复杂疾病的技术，如高血压和2型糖尿病。这种方法对于了解妊娠障碍也很有用，因为母体代谢物代表了母体、胎儿和胎盘之间相互作用的网络的输出。先兆子痫妇女的初步代谢谱实验显示代谢物发生了变化；然而，这些研究有很大的局限性。具体地说，(1)每项研究报告的子痫前期妇女的代谢特征都是独一无二的；(2)对子痫前期妇女亚组(即早发性和晚发性疾病)进行了共同分析；(3)每项研究只分析了妊娠的一个时间点；(4)大多数研究缺乏尿液分析。在这里，我们建议对早发性子痫前期(要求在37周前分娩)的妇女在怀孕每三个月内对母体血浆和尿液进行首次纵向、全球代谢谱分析。这项分析的样品已经储存好，可以使用了。该队列包括2105名女性，其中56人发展为早发性先兆子痫。我们将使用成熟的高效液相色谱串联质谱仪平台，研究早发性子痫前期妇女和配对对照组的母体血液和尿液中的全球代谢特征。代谢物的变化将在每个患者的三个月之间进行分析。此外，先兆子痫患者和匹配对照组之间的代谢物差异将通过三个月进行分析。然后，我们将评估代谢表型是否能根据临床表型识别患者的亚组，重点是分娩时的孕周、婴儿出生体重和异常的实验室研究。这些实验将确定早发性先兆子痫妇女在整个怀孕期间的代谢情况，并将增强我们对疾病发病机制的理解。最终，这些知识有可能导致对先兆子痫的新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.