PLACENTAL FUNCTION IN PREECLAMPSIA

子痫前期是人类妊娠所特有的一种多系统疾病。它是导致胎儿发育迟缓、与早产相关的婴儿发病率和死亡率以及产妇死亡的主要原因。一些异常，包括血管内皮细胞功能障碍，已被认为与子痫前期的发病机制有关。然而，内皮细胞功能背后的机制却知之甚少。这项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激活和内皮细胞功能障碍的关系。我们还探讨了导致先兆子痫内皮细胞功能改变的潜在细胞和分子机制。我们的中心假设是胎盘滋养层细胞经历了氧化应激，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-内皮细胞相互作用的改变，导致内皮细胞功能障碍。这一假说将通过以下三个特定目标的实验来验证：1)描述子痫前期胎盘滋养细胞功能障碍的特征；2)阐明胎盘因子介导的中性粒细胞激活的机制；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，来自正常妊娠和子痫前期妊娠的滋养层细胞和内皮细胞将被分离并用作测试模型。本实验旨在评估先兆子痫患者滋养层细胞的异常，确定胎盘因子(S)在中性粒细胞激活中的作用，利用两种细胞共培养的方法检测滋养层细胞与内皮细胞的相互作用，并探讨胎盘因子(S)在调节内皮细胞转录因子和基因表达中的作用。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潜在的治疗干预途径。

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.