Anti-Coagulation Factors and Placentation

项目摘要/摘要 血液胎盘存在于许多哺乳动物物种中，包括灵长类和啮齿动物。它确保了 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，需要对母体子宫螺旋动脉进行广泛的重塑。子宫 将营养物质输送给胎儿需要进行血管修饰。血管重塑的中心 过程是一种特殊的滋养层细胞群，称为侵袭性滋养层细胞，在 人的绒毛外滋养细胞。这些细胞从胎盘迁移到子宫，在那里它们对 子宫螺旋动脉的重组，这有助于将营养物质输送到胎盘和胎儿。 这一基本过程的中断会导致妊娠和胎盘疾病，包括“伟大的 产科综合征“(先兆子痫、胎儿宫内发育受限、早产、胎盘早剥)。许多 这些疾病中有许多与凝固性疾病有关。在这个研究方案中，我们调查了两个角色 抗凝血因子、组织因子途径抑制物(TFPI)和血栓调节蛋白(THBD)作为血管内皮细胞的调节因子 侵袭性滋养细胞谱系发育与子宫螺旋动脉重构。我们建议的研究使用 大鼠作为实验模型，因为它表现出宫内滋养细胞的深层侵袭和广泛的 子宫螺旋动脉重塑类似于人类胎盘。我们将利用大鼠和人的滋养层干细胞 评估侵袭性滋养层细胞系分化的分子机制。 TFPI和THBD保守参与胎盘形成的假说将在体内用大鼠进行验证 通过基因组编辑和慢病毒介导的滋养外胚层基因操作创建的模型。这 研究将有助于阐明控制侵袭性滋养细胞谱系和 子宫螺旋动脉重塑为了解疾病发病机制提供平台 影响胎盘形成。

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.