Anti-Coagulation Factors and Placentation

项目概要/摘要 血绒膜胎座发生在许多哺乳动物物种中，包括灵长类动物和啮齿动物。它确保 这是母体和胚胎之间最密切的接触，需要专门的调整。 在这些调整中，需要广泛重塑母体子宫螺旋动脉。子宫 需要对血管进行修饰以将营养物输送到胎儿。血管重塑的核心 过程是滋养层细胞的特化群体，称为侵袭性滋养层细胞，并且在 人类绒毛外滋养层这些细胞从胎盘迁移到子宫， 子宫螺旋动脉的重建，有助于向胎盘和胎儿输送营养。 这一基本过程的中断会导致妊娠和胎盘形成疾病，包括"大出血"。 产科综合征"（先兆子痫、宫内生长受限、早产、胎盘早剥）。许多 这些疾病中的大多数与凝血病有关。在这项研究中，我们调查了两个角色， 抗凝因子，组织因子途径抑制物（TFPI）和血栓调节蛋白（THBD），作为 浸润性滋养细胞谱系发育和子宫螺旋动脉重塑。我们的研究计划使用 大鼠作为实验模型，因为它表现出深的子宫内滋养层浸润和广泛的 子宫螺旋动脉重构类似于人类胎盘形成。我们将利用大鼠和人类滋养层干细胞 细胞，以评估参与浸润性滋养层细胞系分化的分子机制。 关于TFPI和THBD保守参与胎盘形成的假设将使用大鼠在体内进行测试。 通过基因组编辑和通过慢病毒介导的滋养外胚层基因操作创建的模型。这 这项研究将有助于阐明控制侵袭性滋养层细胞谱系的分子途径， 子宫螺旋动脉重塑，为了解疾病的发病机制创造平台 影响胎座形成

PROJECT SUMMARY/ABSTRACT Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments. Among these adjustments is the need for extensive remodeling of the maternal uterine spiral arteries. Uterine vascular modifications are required for the delivery of nutrients to the fetus. Central to the vascular remodeling process is a specialized population of trophoblast cells referred to as invasive trophoblast cells and in the human, extravillous trophoblast. These cells migrate from the placenta into the uterus where they contribute to the restructuring of the uterine spiral arteries, which facilitate the delivery of nutrients to the placenta and fetus. Disruptions in this fundamental process lead to diseases of pregnancy and placentation, including the “Great Obstetrical Syndromes” (preeclampsia, intrauterine growth restriction, preterm birth, abruptio placentae). Many of these disorders are associated with coagulopathies. In this research proposal we investigate roles for two anti-coagulation factors, tissue factor pathway inhibitor (TFPI) and thrombomodulin (THBD), as a regulators of invasive trophoblast lineage development and uterine spiral artery remodeling. Our proposed research uses the rat as an experimental model because it exhibits deep intrauterine trophoblast invasion and extensive uterine spiral artery remodeling similar to human placentation. We will utilize rat and human trophoblast stem cells to evaluate molecular mechanisms involved in differentiation of the invasive trophoblast lineage. Hypotheses for the conserved involvement of TFPI and THBD in placentation will be tested in vivo using rat models created by genome editing and through lentiviral-mediated trophectoderm gene manipulation. This study will facilitate elucidation of molecular pathways controlling the invasive trophoblast cell lineage and uterine spiral artery remodeling and create a platform for understanding the pathogenesis of diseases impacting placentation.