REGULATION OF FETAL-PLACENTAL DEVELOPMENT IN THE PRIMATE

灵长类动物胎儿胎盘发育的调节

• 批准号: 7716055
• 负责人: Eugene D. Albrecht
• 金额: $ 26.36万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716055
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Glands; Angiopoietin-1; Area; Aromatase Inhibitors; Biochemical; Blood Vessels; Cell Adhesion Molecules; Communication; Computer Retrieval of Information on Scientific Projects Database; Development; Ensure; Enzymes; Estradiol; Estrogens; Fetal Development; Fetus; Funding; Goals; Grant; Growth; Growth and Development function; Homeostasis; Human; Hydrocortisone; In Vitro; Incidence; Institution; Integrins; Knowledge; Low Birth Weight Infant; Modeling; Molecular; Neonatal; Papio; Patient currently pregnant; Permeability; Physiological; Placenta; Placentation; Play; Pregnancy; Pregnant Women; Prematurity of fetus; Primates; Regulation; Research; Research Personnel; Research Proposals; Resources; Role; Sodium-Hydrogen Antiporter; Source; Spiral Artery of the Endometrium; Syncytiotrophoblast; Testing; United States National Institutes of Health; Villous; angiogenesis; cytotrophoblast; fetal; improved; in utero; in vivo; insight; mortality; neonatal morbidity; programs; trophoblast

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The high incidence of human neonatal morbidity and mortality associated with low birth weight and prematurity indicates need for more intensive study of the mechanisms underlying placental and fetal development. The long-term objective of this research proposal is to improve knowledge in this area by building on our previous in vivo studies in the pregnant baboon which demonstrate that estrogen plays an integrative role in placental-fetal communication by regulating maturation of the placenta and fetal adrenal gland. Study I will test the hypothesis that early in gestation estrogen stimulates vascular endothelial growth/permeability factor and/or angiopoietin-1/-2 formation by villous trophoblasts and thus placental angiogenesis, and concurrently regulates expression of integrins-adhesion molecules by extravillous cytotrophoblasts to restrain their invasion of uterine spiral arteries, and that via these actions estrogen coordinates angiogenesis and placentation to ensure fetal-placental development. The goals of Studies I and II are interwoven to test the hypothesis that estrogen acts on the newly vascularized placenta to regulate expression of sodium-hydrogen exchangers (NHE-1 and -3) and their regulatory factors in the syncytiotrophoblast, directly (NHE-1), and indirectly by regulating the 11beta-hydroxysteroid dehydrogenase enzymes and thus local cortisol levels (NHE-3) to ensure placental-fetal homeostasis. Studies II and III are integrated to test the hypothesis that estrogen acts on the fetal adrenal to promote development of the transitional zone and restrain growth and development of the fetal zone, and that this in utero programming governs adrenal maturation and function in adulthood. Molecular, histological, biochemical, and in vivo physiological parameters of placental trophoblast and fetal adrenal development will be determined in baboons in which estrogen levels are prematurely elevated by estradiol administration or suppressed by a specific aromatase inhibitor. The estrogen-depleted/-repleted pregnant baboon provides a unique primate model to investigate the effects of altered trophoblast function on fetal-neonatal maturation, studies which cannot be performed in pregnant women or with in vitro approaches. Completion of the proposed study will provide new insight into communication between the fetus and placenta and improve our knowledge of the regulation of fetal development and neonatal self-sufficiency.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 与低出生体重和早产相关的人类新生儿发病率和死亡率的高发生率表明需要对胎盘和胎儿发育的机制进行更深入的研究。这项研究计划的长期目标是通过我们之前对怀孕狒狒进行的体内研究来提高这一领域的知识，这些研究表明雌激素通过调节胎盘和胎儿肾上腺的成熟在胎盘-胎儿通讯中发挥整合作用腺。研究 I 将检验以下假设：妊娠早期雌激素刺激绒毛滋养层细胞的血管内皮生长/渗透因子和/或血管生成素-1/-2 形成，从而刺激胎盘血管生成，同时调节绒毛外细胞滋养层细胞整合素粘附分子的表达，以抑制血管生成。它们侵入子宫螺旋动脉，并且通过这些作用雌激素协调血管生成和胎盘着床以确保胎儿胎盘发育。研究 I 和 II 的目标相互交织，以检验雌激素作用于新血管化胎盘以直接调节合体滋养层中钠氢交换器（NHE-1 和 -3）及其调节因子（NHE-1）的假设。 ），并间接通过调节 11β-羟基类固醇脱氢酶，从而调节局部皮质醇水平 (NHE-3)，以确保胎盘-胎儿稳态。研究 II 和 III 相结合，检验了以下假设：雌激素作用于胎儿肾上腺，促进过渡区的发育并抑制胎儿区的生长和发育，并且这种子宫内编程控制着成年期肾上腺的成熟和功能。胎盘滋养层和胎儿肾上腺发育的分子、组织学、生化和体内生理参数将在狒狒中测定，其中雌激素水平因雌二醇给药而过早升高或被特定芳香酶抑制剂抑制。雌激素耗尽/充满的怀孕狒狒提供了一种独特的灵长类动物模型，用于研究滋养层功能改变对胎儿-新生儿成熟的影响，这些研究无法在孕妇或体外方法中进行。完成拟议的研究将为胎儿和胎盘之间的沟通提供新的见解，并提高我们对胎儿发育调节和新生儿自给自足的认识。