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

先兆子痫风险中免疫激活合体滋养层微泡和危险相关分子模式

基本信息

批准号：
10441912
负责人：
Brandie DePaoli Taylor
金额：
$ 54.9万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441912
关键词：
Abnormal placentation Address African American Age of Onset Angiogenesis Inhibitors Apoptosis Biological Biological Markers Blood Circulation Body mass index Calibration Cardiovascular Diseases Characteristics Clinical Clinical Management Data Detection Development Diagnosis Discipline of obstetrics Discrimination Endoglin Etiology Experimental Models Fetus Functional disorder Gestational Age Goals Growth HELLP Syndrome HMGB1 Protein Health Hospitalization Human Iatrogenesis Immune In Vitro Incidence Inflammation Injury Knowledge Lead Life Linear Regressions Literature Maternal Age Maternal Mortality Measures Metadata Mission Modeling Modification Molecular Monitor Morbidity - disease rate Mothers Mus Nature Nested Case-Control Study Organ Outcome PGF gene Pathogenesis Pathway interactions Pattern Phenotype Placenta Plasma Pre-Eclampsia Pregnancy Premature Birth Prevention Probability Prospective cohort Proteinuria Public Health Reporting Research Research Design Risk Role Sampling Stimulus Stress Symptoms Syncytiotrophoblast Syndrome Testing Toll-like receptors United States National Institutes of Health Weight Woman case control clinical Diagnosis cohort density disability early onset endothelial dysfunction epidemiology study extracellular vesicles fetal hazard improved indexing infant morbidity/mortality innovation insight maternal morbidity maternal outcome maternal risk microvesicles mortality novel novel marker pathophysiology of preeclampsia placental protein 13 potential biomarker pregnancy hypertension pressure prevent prospective response screening secondary outcome sex systemic inflammatory response targeted treatment

项目摘要

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.

项目摘要/摘要尽管进行了数十年的研究，但子痫前期仍然是一个严重的公共卫生负担。唯一的治疗方法子痫前期是分娩，通常会导致医源性早产。不幸的是，临床症状没有表明进展为严重的母亲结局。因此，子痫前期仍然是两者的重要贡献母亲和婴儿的发病率和死亡率。健康风险超出了怀孕，因为患有先兆子痫的女性更有可能在以后的生活中发展心血管疾病。需要改进了解先兆子痫的病因并定义综合征的异质性。作为系统性炎症和内皮功能障碍是先兆子痫的标志，新型免疫刺激合成肌细胞细胞微覆盖（STBEV）被认为是监测胎盘健康的潜在生物标志物。小型研究报告说，诊断后的先兆子痫和STBEV触发炎症的血浆STBEV升高实验模型中的内皮功能障碍。但是，大规模流行病学研究 STBEV及其对免疫激活成分的影响，例如危险相关的分子模式（潮湿），在临床诊断之前尚未在子痫前期进行。我们的长期目标是确定可以区分病理生理前启示性表型的生物标志物。当前的提议将解决文献中的差距可以促进我们对先兆子痫中Stbev的理解。中心假设是循环的STBEV导致触发较高水平的循环阻尼和抗血管生成分子子痫前期的临床症状。当前的建议将利用嵌套的情况对照研究设计和从280名患有先兆子痫和560的女性中获得血浆和前瞻性收集的元数据在筛选产科和妊娠终点队列中的对照（通过入射密度采样选择）。具体目标是； 1）确定临床前先兆子痫的女性中的STBEV是否升高诊断。 2）确定产妇/胎儿因素是否影响STBEV水平。 3）确定先前涉及前球的潮湿和抗血管生成分子的STBEV和循环水平。 4）确定STBEV是否可以改善子痫前期表型歧视。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。这项研究的创新特征包括比骑士制定的标准，测量具有提高灵敏度和样品体积的STBEV 等人在1998年，描述了STBEV在先兆子痫中的作用，并利用潜在混合物建模来识别子痫前期表型。我们的建议很重要，因为临床症状并未确定女性进展到严重的结果，并真正需要引起的递送（当前治疗）。因此，进展重新定义体育母亲和胎儿的发病率和死亡率。