Decidual-Endothelial Tissue Factor and IUGR

描述（由申请人提供）：子宫胎盘循环血栓形成，导致低氧血症和炎症，是宫内生长受限（IUGR）、胎儿死亡、流产和先兆子痫的常见先兆。这些病理性产科疾病与获得性和遗传性血栓形成相关（如凝血因子V Leiden）。本申请的目的是阐明导致子宫胎盘血栓形成的生化机制。我们的中心假设是，凝血酶，血管内皮生长因子（VEGF）和肿瘤坏死因子-α（TNF α）异常诱导强有力的促凝血组织因子（TF）在人子宫内膜内皮细胞（HEECs）通过不同的，但潜在的协同信号转导途径。提出了三个具体目标来检验这一假设，其中我们将：1）评估凝血酶、VEGF和TNFa对HEEC TF表达的单独和相互作用的体外作用，并确定它们的分子调控位点。将在独特的内皮-基质细胞共培养系统中评估是否需要相邻的基质细胞来介导病理组织中缺氧诱导的HEEC TF表达。2)采用因子V Leiden突变的小鼠模型，以确定遗传性血栓形成倾向诱导的子宫胎盘血栓形成是否与蜕膜内皮细胞TF的诱导相关，以及这是否与胎儿和胎盘生长受限相关。此外，异常增强的TF表达的关键作用将通过将表达低TF水平的小鼠与携带因子V Leiden突变的小鼠杂交来证实。3)进行一项前瞻性队列研究，以确定在人类妊娠期间和妊娠后6-12周的不同时间点母体凝血酶生成增加是否可预测随后发生IUGR、流产、先兆子痫和死胎。此外，我们将在选定的患者人群中将两种敏感的凝血酶标记物的母体血浆水平与获得性或遗传性血栓形成倾向的存在相关联。

DESCRIPTION (provided by applicant): Thrombosis in the uteroplacental circulation with resultant hypoxemia and inflammation are common antecedents to intrauterine growth restriction (IUGR), fetal death, abruption and preeclampsia. These pathological obstetrical conditions are associated with acquired and inherited thrombophilias (e.g. Factor V Leiden). The goal of this application is to elucidate the biochemical mechanisms leading to uteroplacental thrombosis. Our central hypothesis is that thrombin, vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNFa) aberrantly induce the potent procoagulant tissue factor (TF) in human endometrial endothelial cells (HEECs) by acting on distinct but potentially synergistic signal transduction pathways. Three specific aims are proposed to test this hypothesis in which we will: 1) Evaluate the separate and interactive in vitro effects of thrombin, VEGF and TNFa on HEEC TF expression and determine their sites of molecular regulation. Whether adjacent stromal cells are required to mediate hypoxia-induced HEEC TF expression in pathological tissues will be assessed in a unique endothelial-stromal cell co-culture system. 2) Employ a murine model of the Factor V Leiden mutation to determine whether Inherited thrombophilia induced uteroplacental thrombosis is associated with induction of decidual endothelial cell TF and whether this is correlated with fetal and placental growth restriction. Furthermore, the pivotal role of aberrantly enhanced TF expression will be confirmed by crossbreeding mice expressing low TF levels with those carrying the Factor V Leiden mutation. 3) Conduct a prospective cohort study to determine whether increased maternal thrombin generation at various time points during human gestation and at 6-12 weeks post gestation predicts the subsequent occurrence of IUGR, abruption, preeclampsia and stillbirth. Additionally, we will correlate maternal plasma levels of two sensitive thrombin markers with the presence of acquired or inherited thrombophilias in the selected patient population.