REGULATION OF FETAL-PLACENTAL DEVELOPMENT IN THE PRIMATE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。与低出生体重和早产相关的人类新生儿发病率和死亡率高表明需要对胎盘和胎儿发育的机制进行更深入的研究。本研究提案的长期目标是通过建立在我们之前在妊娠狒狒中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-胎儿通信中发挥综合作用。研究I将检验妊娠早期雌激素刺激绒毛滋养层细胞形成血管内皮生长/渗透因子和/或血管生成素-1/-2从而促进胎盘血管生成，同时调节绒毛外细胞滋养层细胞表达整合素-粘附分子以抑制其侵入子宫螺旋动脉的假设，并且通过这些作用雌激素协调血管生成和胎盘形成以确保胎儿-胎盘发育。研究I和II的目的交织在一起，以检验以下假设：雌激素作用于新生血管化胎盘，直接（NHE-1）调节钠氢交换器（NHE-1和NHE-3）及其在合体滋养层中的调节因子的表达，间接（NHE-3）通过调节11 β-羟基类固醇脱氢酶，从而调节局部皮质醇水平，以确保胎盘-胎儿体内平衡。研究II和III的整合，以测试的假设，雌激素作用于胎儿肾上腺，以促进过渡区的发展和抑制生长和发育的胎儿区，这在子宫内编程管理肾上腺成熟和功能在成年期。将在雌激素水平通过雌二醇给药过早升高或通过特定芳香酶抑制剂抑制的狒狒中测定胎盘滋养层和胎仔肾上腺发育的分子、组织学、生物化学和体内生理参数。雌激素耗尽/充满怀孕狒狒提供了一个独特的灵长类动物模型，以研究改变滋养层功能对胎儿-新生儿成熟的影响，研究不能在孕妇或体外方法进行。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和新生儿自给自足的调节的认识。灵长类动物中心提供了狒狒用于这个项目。

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. The primate center provided baboons used in this project.