Immune activating syncytiotrophoblast microvesicles and danger associated molecular patterns in preeclampsia risk

项目概要/摘要 尽管经过几十年的研究，先兆子痫仍然是一个严重的公共卫生负担。的唯一治疗方法 先兆子痫是分娩，这往往导致医源性早产。不幸的是，临床症状并不 表明进展为严重的孕产妇结局。因此，先兆子痫仍然是一个重要的贡献者， 产妇和婴儿发病率和死亡率。健康风险超出了怀孕，因为患有先兆子痫的妇女 在以后的生活中更有可能患上心血管疾病。非常需要改进 了解先兆子痫的病因并确定该综合征的异质性。如系统性 炎症和内皮功能障碍是先兆子痫的标志， 合体滋养层微泡（STBEV）被认为是监测胎盘健康的潜在生物标志物。 小型研究报告了诊断后先兆子痫患者血浆STBEV升高，STBEV引发炎症 和实验模型中的内皮功能障碍。然而，大规模的流行病学调查， STBEV及其对免疫激活成分的影响，如危险相关分子模式 （DAMP），在临床诊断前尚未在先兆子痫中进行。我们的长期目标是确定 可以区分病理生理学先兆子痫表型的生物标志物。目前的提案将涉及 文献中的空白，以促进我们对STBEV在先兆子痫中的理解。核心假设是， 循环STBEV导致更高水平的循环DAMP和抗血管生成分子， 先兆子痫的临床症状目前的提案将采用巢式病例对照研究设计， 从280名患有先兆子痫的妇女和560名患有先兆子痫的妇女中获得血浆和前瞻性收集的元数据。 产科和妊娠终点筛选队列中的对照组（通过发病率密度抽样选择）。 具体目的是：1）在临床治疗前确定患有先兆子痫的女性中STBEV是否升高 诊断. 2)确定母体/胎儿因素是否影响STBEV水平。3)确定之间的关系 STBEV和DAMP和抗血管生成分子的循环水平先前与先兆子痫有关。 4)确定STBEV是否可以改善先兆子痫表型识别。该研究设计是一种有效的 在先兆子痫诊断之前测量STBEV的方法。本研究的创新特点包括 测量STBEV的灵敏度比Knight开发的标准更高，样品量更少 等在1998年，描述了STBEV在先兆子痫中的作用，并利用潜在的混合物模型来识别 先兆子痫表型我们的建议是重要的，因为临床症状并不能确定妇女谁会 进展到严重的结果，确实需要诱导分娩（目前的治疗）。因此， 重新定义PE可能会减少不必要的住院、早产和错过预防的机会。 产妇和胎儿发病率和死亡率。

PROJECT SUMMARY/ABSTRACT Despite decades of research, preeclampsia remains a serious public health burden. The only treatment for preeclampsia is delivery, which often leads to iatrogenic preterm birth. Unfortunately, clinical symptoms do not indicate progression to severe maternal outcomes. Thus, preeclampsia remains a significant contributor to both maternal and infant morbidity and mortality. Health risks extend beyond pregnancy, as women with preeclampsia are more likely to develop cardiovascular disease later in life. There is a significant need to improve understanding of preeclampsia etiology and to define the heterogeneous nature of the syndrome. As systemic inflammation and endothelial dysfunction are hallmarks of preeclampsia, novel immune stimulating syncytiotrophoblast microvesicles (STBEVs) are implicated as potential biomarkers to monitor placental health. Small studies report elevated plasma STBEVs in preeclampsia after diagnosis and STBEVs trigger inflammation and endothelial dysfunction in experimental models. However, large scale epidemiologic investigations of STBEVs and their influence on immune activating components, such as danger associated molecular patterns (DAMPs), have not been conducted in preeclampsia prior to clinical diagnosis. Our long-term goal is to identify biomarkers that can distinguish pathophysiological preeclampsia phenotypes. The current proposal will address gaps in the literature to advance our understanding of STBEVs in preeclampsia. The central hypothesis is that circulating STBEVs lead to higher levels of circulating DAMPs and antiangiogenic molecules that trigger the clinical symptoms of preeclampsia. The current proposal will utilize a nested case-control study design and obtain plasma and prospectively collected metadata from 280 women who developed preeclampsia and 560 controls (selected by incidence density sampling) in the Screening for Obstetric and Pregnancy Endpoints cohort. The specific aims are to; 1) Determine if STBEVs are elevated in women with preeclampsia prior to clinical diagnosis. 2) Determine if maternal/fetal factors influence STBEV levels. 3) Determine the relationship between STBEV's and circulating levels of DAMPs and antiangiogenic molecules previously implicated in preeclampsia. 4) Determine if STBEVs can improve preeclampsia phenotype discrimination. This study design is an efficient approach to measure STBEVs prior to preeclampsia diagnosis. Innovative features of this study include measuring STBEVs with increased sensitivity and less sample volume than the standard developed by Knight et al in 1998, delineating the role of STBEV's in preeclampsia and utilizing latent mixture modelling to identify preeclampsia phenotypes. Our proposal is significant, as clinical symptoms do not identify women who will progress to severe outcomes and truly require induced delivery (current treatment). Thus, progression towards redefining PE may reduce unnecessary hospitalization, early delivery, and missed opportunities to prevent maternal and fetal morbidity and mortality.