Anti-Coagulation Factors and Placentation

抗凝因子和胎盘植入

• 批准号: 10403684
• 负责人: MICHAEL J SOARES
• 金额: $ 49.67万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403684
• 关键词: Abruptio Placentae; Anticoagulation; Blood Coagulation Disorders; Blood Vessels; Cell Lineage; Cells; Coagulation Process; Development; Diagnostic; Disease; Embryo; Ensure; Exhibits; Experimental Models; Fetal Growth Retardation; Fetus; Health; Hemochorial Placental Development; Human; Lead; Modeling; Modification; Molecular; Nutrient; Pathogenesis; Pathway interactions; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Primates; Process; Rattus; Regulation; Research; Research Proposals; Rodent; Role; Route; Spiral Artery of the Endometrium; TFPI; Therapeutic; Thrombomodulin; Uterus; Vascular remodeling; genetic manipulation; genome editing; in vivo evaluation; insight; lentiviral-mediated; obstetrical syndromes; trophoblast; trophoblast stem cell

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.

项目概要/摘要 血绒胎盘发生在许多哺乳动物物种中，包括灵长类动物和啮齿类动物。 母体和胚胎室之间最密切的接触，需要专门的调整。 这些调整包括需要对母体子宫螺旋动脉进行广泛的重塑。 血管改造是向胎儿输送营养物质所必需的，这是血管重塑的核心。 该过程是一种特殊的滋养层细胞群，称为侵袭性滋养层细胞，并且在 人类绒毛外滋养层细胞从胎盘迁移到子宫，并在那里发挥作用。 子宫螺旋动脉的重组，有利于将营养物质输送到胎盘和胎儿。 这一基本过程的破坏会导致妊娠和胎盘疾病，包括“大 产科综合症”（先兆子痫、宫内生长受限、早产、胎盘早剥）。 这些疾病中的一些与凝血病有关。在本研究提案中，我们研究了两种疾病的作用。 抗凝因子、组织因子途径抑制剂（TFPI）和血栓调节蛋白（THBD），作为调节剂 我们提出的研究用途是侵袭性滋养层谱系发育和子宫螺旋动脉重塑。 大鼠作为实验模型，因为它表现出子宫内深层滋养层浸润和广泛的 我们将利用大鼠和人的滋养层干细胞进行类似于人类胎盘的子宫螺旋动脉重塑。 细胞来评估参与侵袭性滋养层谱系分化的分子机制。 TFPI 和 THBD 在胎盘形成中保守参与的假设将使用大鼠进行体内测试 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。 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和 子宫螺旋动脉重塑，为了解疾病发病机制搭建平台 影响胎盘。