IN VIVO AND IN VITRO MODELS OF PRE-ECLAMPSIA PATHOLOGY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 先兆子痫是孕产妇和围产儿发病率和死亡率的主要原因，但病因不明。虽然确切的病理生理学当然是多因素的，但许多研究人员认为它代表了一种具有重要潜在免疫发病机制的微血管病变。因此，我们对发病机制的理解的改进可能会为其他血管疾病提供见解。症状出现的较晚，以及与其发病相关的各种情况，都削弱了我们研究这种疾病的能力。这种情况主要影响人类，建立动物模型一直难以捉摸。子痫前期动物模型的建立将增强我们对子痫前期病理生理学的理解，并有助于发展与这种疾病作斗争所需的诊断、预防和治疗方法。子痫前期动物模型应呈现部分或全部标志性特征，如胎盘炎症、变性、宫内生长受限、血管缺乏、高血压、蛋白尿和肾脏病理。由于先兆子痫是母胎界面局部缺陷的全身性表现，我们假设这些患者的血清应该提供与这些病理条件相关的因素的“蓝图”。虽然先兆子痫血清在体内没有表现出任何异常的先例，但我们的初步数据表明，一次注射。妊娠第10天血清浓度升高可引起C57Bl/6野生型小鼠血压升高、蛋白尿、宫内生长受限和可溶性Enoglin生成增加。此外，在Matrigel的三维培养系统中，子痫前期患者的血清也干扰了滋养层细胞和内皮细胞之间的串扰。为了解决我们的中心假设并扩展我们的初步数据，我们提出了以下具体目标。具体目标1旨在评估轻度或重度子痫前期血清在体内引起小鼠疾病特征的潜力。在特定的目标2中，我们将在体外三维培养系统中确定子痫前期血清介导的绒毛外滋养层细胞和内皮细胞之间串扰的破坏和挽救。这些研究将有助于体内和体外的实验模型，以更好地了解子痫前期的机制基础，并建立预测分析。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality but has an unknown etiology. While the precise pathophysiology is certainly multi-factorial, many investigators believe it represents a microvasculopathy with an important underlying immunopathogenesis. As such, improvements in our understanding of the pathogenesis may provide insights into other vascular disorders. The late onset of symptoms and the myriad conditions associated with its onset have impaired our ability to study this disease. This condition primarily affects humans and the establishment of an animal model has been elusive. The creation of a pre-eclamptic animal model would enhance our understanding of the pathophysiology of pre-eclampsia and contribute to the development of diagnostic, prophylactic and therapeutic modalities needed to combat this disorder. The pre-eclamptic animal model should present some or all of the hallmark features such as placental inflammation, degeneration, intrauterine growth restriction, vascular deficiency, high blood pressure, proteinuria, and kidney pathology. Since pre-eclampsia is a systemic manifestation of local defects at the maternal-fetal interface, we hypothesize that serum from these patients should provide a "blueprint" of the factors associated with these pathologic conditions. Although there is no precedent for pre-eclampsia serum to manifest any in vivo anomalies, our preliminary data demonstrates that a single injection i.p. of serum on gestational day 10 could induce elevated blood pressure, proteinuria, intrauterine growth restriction, and elevated production of soluble endoglin in wild type C57 Bl/6 mice. In addition, pre-eclampsia serum also disrupted cross talk between trophoblasts and endothelial cells as monitored in a three dimensional culture system on matrigel. To address our central hypothesis and to expand on our preliminary data, we propose the following specific aims. Specific Aim 1 is designed to assess the in vivo potential of pre-eclampsia serum from mild or severe condition to cause hallmark features of the disease in mice. In Specific Aim 2, we will determine pre-eclampsia serum-mediated disruption and rescue of cross-talk between extravillous trophoblasts and endothelial cells in an in vitro, three dimensional culture system. These studies will contribute to in vivo and in vitro experimental models to better understand mechanistic underpinnings of and to establish predictive assays for pre-eclampsia.