Anti-Coagulation Factors and Placentation

抗凝因子和胎盘植入

• 批准号: 10632127
• 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/10632127
• 关键词: Abruptio Placentae; Anticoagulation; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Vessels; Cell Lineage; Cells; Coagulation Process; Development; Diagnostic; Disease; Embryo; Ensure; Exhibits; Experimental Models; Fetal Growth Retardation; Fetus; Health; Hemochorial Placental Development; Human; Invaded; 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; Villous; cell motility; 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.

项目摘要/摘要 血液体位置发生在许多哺乳动物物种中，包括素数和啮齿动物。它确保了 产妇和胚胎室之间的最亲密接触，需要专门的调整。 在这些调整中，需要大量重塑母体子宫螺旋动脉。 将营养物质递送到胎儿需要进行血管修饰。血管重塑的中心 过程是滋养细胞的专业人群，称为侵入性滋养细胞细胞 人类，额外的滋养细胞。这些细胞从斑点迁移到子宫中 子宫螺旋性动脉的修发性，可促进营养物质到斑点和胎儿的递送。 这种基本过程中的破坏导致怀孕和安置疾病，包括“伟大 产科综合征”（子痫前期，宫内生长限制，早产，突发性花生症）。 这些疾病与凝血病有关。在这项研究建议中，我们研究了两个 抗凝因子，组织因子途径抑制剂（TFPI）和血小子蛋白（THBD），作为调节剂 侵入性滋养细胞谱系发育和子宫螺旋动脉重塑。我们提出的研究用途 大鼠作为实验模型，因为它表现出深层宫内滋养细胞的入侵和广泛的 子宫螺旋动脉重塑类似于人类的位置。我们将利用大鼠和人类滋养细胞茎 细胞评估与侵入性滋养细胞谱系分化有关的分子机制。 将使用大鼠在体内测试TFPI和THBD在放置中配置参与的假设 由基因组编辑以及通过慢病毒介导的滋养剂基因操纵创建的模型。这 研究将有助于阐明控制侵入性滋养细胞细胞谱系和 子宫螺旋动脉重塑并创建一个平台来理解疾病的发病机理 影响位置。