Decidual-Endothelial Tissue Factor and IUGR

描述(由申请人提供)：子宫胎盘循环中的血栓形成和由此导致的低氧血症和炎症是宫内生长受限(IUGR)、胎儿死亡、早剥和先兆子痫的常见前驱症状。这些产科病理性疾病与获得性和遗传性血栓形成有关(例如，因子V莱顿)。这项应用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(TNFa)通过作用于不同但潜在协同的信号转导通路，在人子宫内膜内皮细胞(HEECs)中异常诱导强大的促凝血剂组织因子(TF)。为了验证这一假说，我们提出了三个具体的目标：1)评估凝血酶、血管内皮生长因子和肿瘤坏死因子在体外对HEEC TF表达的单独和相互作用的影响，并确定它们的分子调控部位。是否需要相邻的基质细胞在病理组织中介导缺氧诱导的HEEC TF表达，将在一个独特的内皮-基质细胞共培养系统中进行评估。2)利用因子V Leiden突变的小鼠模型，确定遗传性血栓形成引起的子宫胎盘血栓是否与蜕膜内皮细胞转铁蛋白的诱导有关，以及这是否与胎儿和胎盘生长受限有关。此外，Tf表达异常增强的关键作用将通过将表达低Tf水平的小鼠与携带因子V莱顿突变的小鼠杂交来证实。3)进行前瞻性队列研究，以确定在人类孕期不同时间点和孕后6-12周，母亲凝血酶生成增加是否预示着随后发生IUGR、早剥、先兆子痫和死产。此外，我们还将把母体血浆中两个敏感的凝血酶标志物水平与选定患者群体中是否存在获得性或遗传性血栓形成联系起来。

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.