PLACENTAL FUNCTION IN PREECLAMPSIA

子痫前期是人类妊娠特有的多系统疾病。它是胎儿发育迟缓、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。几种异常，包括血管内皮细胞功能障碍，已牵连到子痫前期的发病机制。然而，内皮细胞功能的机制尚不清楚。本研究概述了子痫前期胎盘滋养细胞功能异常与中性粒细胞活化和内皮细胞功能障碍的关系。我们还讨论了可能导致子痫前期内皮细胞功能改变的细胞和分子机制。我们的中心假设是胎盘滋养细胞经历氧化应激，导致中性粒细胞和内皮细胞功能紊乱。这一过程，加上中性粒细胞与内皮相互作用的改变，导致内皮细胞功能障碍。这一假设将通过以下三个特定目的的实验来验证：1)表征子痫前期胎盘滋养细胞功能障碍；2)阐明胎盘因子介导的中性粒细胞活化机制；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。在本研究中，将从正常妊娠和子痫前期妊娠中分离出滋养细胞和内皮细胞作为测试模型。实验旨在评估子痫前期滋养细胞异常，表征胎盘因子介导中性粒细胞活化，通过两种细胞类型的共培养来检测滋养细胞与内皮细胞的相互作用，并探讨胎盘因子在调节内皮细胞转录因子和mRNA表达中的作用。我们相信从这个项目中获得的信息将扩展我们对先兆子痫发病机制的了解，并为患有这种疾病的妇女提供治疗干预的潜在途径。

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.