PLACENTAL FUNCTION IN PREECLAMPSIA

先兆子痫是一种多系统疾病独特的人类怀孕。它是胎儿生长迟缓、与早产有关的婴儿发病率和死亡率以及产妇死亡的主要原因。 包括血管内皮细胞功能障碍在内的几种异常与先兆子痫的发病机制有关。 然而，对内皮细胞功能的机制知之甚少。本研究将子痫前期胎盘滋养层功能异常与中性粒细胞活化和内皮细胞功能障碍联系起来。 我们还讨论了潜在的细胞和分子机制，有助于改变内皮细胞功能的先兆子痫。 我们的中心假设是胎盘滋养层细胞经历氧化应激，导致中性粒细胞和内皮细胞功能紊乱。 这一过程，加上嗜酸性粒细胞-内皮细胞相互作用的改变，导致内皮细胞功能障碍。 该假设将通过3个特定目标下概述的实验进行验证：1）描述先兆子痫中胎盘滋养层功能障碍的特征; 2）阐明胎盘因子介导的中性粒细胞活化的机制; 3）阐明胎盘因子介导的内皮细胞功能障碍的细胞和分子机制。 在这项研究中，滋养层细胞和内皮细胞从正常和先兆子痫妊娠将被分离和用作测试模型。 提出实验来评估先兆子痫中滋养层异常，表征胎盘因子介导中性粒细胞活化，使用两种细胞类型的共培养物来检查滋养层-内皮细胞相互作用，并解决胎盘因子在调节内皮细胞转录因子和mRNA表达中的作用。 我们相信，从这个拟议的项目中获得的信息将扩大我们的知识先兆子痫的发病机制，并提供潜在的途径，治疗干预妇女患有这种疾病。

Preeclampsia is a multisystem disorder unique to human pregnancy. It is a leading cause of fetal growth retardation, infant morbidity and mortality associated with premature delivery, and maternal death. Several abnormalities, including vascular endothelial cell dysfunction, have been implicated in the pathogenesis of preeclampsia. However, the mechanisms that underlie the endothelial cell function are poorly understood. The studies outlined in this proposal relate the abnormal placental trophoblast function of preeclampsia with neutrophil activation and endothelial cell dysfunction. We also address potential cellular and molecular mechanisms that contribute to the altered endothelial cell function in preeclampsia. Our central hypothesis is that placental trophoblasts experience an oxidative stress that results in the disturbance of neutrophil and endothelial cell function. This process, coupled to alteration of neutrophil-endothelial interactions, leads to the endothelial cell dysfunction. This hypothesis will be tested by experiments outlined under 3 specific aims: 1) To characterize the placental trophoblast dysfunction in preeclampsia; 2) To elucidate the mechanisms of placental factor-mediated activation of neutrophils; 3) To elucidate the cellular and molecular mechanisms of placental factor-mediated endothelial cell dysfunction. In this study, trophoblasts and endothelial cells from both normal and preeclamptic pregnancies will be isolated and used as testing models. Experiments are proposed to assess trophoblast abnormalities in preeclampsia, to character placental factor(s) in mediating neutrophil activation, to examine trophoblast-endothelial cell interactions using co-cultures of the two cell types, and to address the role of placental factor(s) in regulating endothelial cell transcription factor and mRNA expression. We believe that the information obtained from this proposed project will extend our knowledge of the pathogenesis of preeclampsia and provide potential avenues for therapeutic intervention in women suffering from this disorder.