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

项目摘要/摘要 尽管进行了数十年的研究，先兆子痫仍然是一个严重的公共卫生负担。唯一的治疗方法是治疗 先兆子痫是分娩，通常会导致医源性早产。不幸的是，临床症状不会 表明进展为严重的母体结局。因此，先兆子痫仍然是这两种疾病的重要因素。 母婴发病率和死亡率。健康风险不仅限于怀孕，因为患有先兆子痫的妇女 更有可能在晚年患上心血管疾病。有很大的需要改进 了解先兆子痫的病因，并确定该综合征的异质性。作为系统性的 炎症和内皮功能障碍是子痫前期的特征，新型免疫刺激 合体滋养细胞微囊泡(STBEV)被认为是监测胎盘健康的潜在生物标志物。 小规模研究报告诊断后先兆子痫患者血浆STBEV升高，STBEV引发炎症 以及实验模型中的内皮功能障碍。然而，大规模的流行病学调查显示 STBEV及其对免疫激活成分的影响，如危险相关的分子模式 (DAMPS)，在临床诊断之前没有在先兆子痫中进行过。我们的长期目标是确定 可以区分病理生理学的子痫前期表型的生物标志物。目前的提案将解决 文献中的空白，以促进我们对先兆子痫的STBEV的理解。中心假设是 循环中的STBEV会导致更高水平的循环阻尼和抗血管生成分子，从而触发 先兆子痫的临床症状。目前的方案将采用嵌套式病例对照研究设计和 获取血浆并前瞻性收集280名患有先兆子痫的妇女和560名妇女的元数据 产科和妊娠终点队列筛查中的对照(通过发病率密度抽样选择)。 具体目的是：1)确定先兆子痫患者的STBEV是否在临床前升高 诊断。2)确定母婴因素是否影响STBEV水平。3)确定两者的关系 STBEV和循环中的湿气和抗血管生成分子水平以前与先兆子痫有关。 4)确定STBEV能否改善子痫前期的表型辨别能力。这项研究设计是一种高效的 子痫前期诊断前STBEV测定方法的探讨这项研究的创新特点包括 与奈特开发的标准相比，测量STBEV的灵敏度更高，样本量更少 1998年，描述了STBEV在先兆子痫中的作用，并利用潜伏混合物模型来识别 先兆子痫表型。我们的建议意义重大，因为临床症状不能确定哪些女性会 进展为严重后果，确实需要引产(目前的治疗)。因此，朝着 重新定义PE可能会减少不必要的住院、早产和错失预防机会 孕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.