REGULATION OF FETAL-PLACENTAL DEVELOPMENT IN THE PRIMATE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。人类新生儿发病率和死亡率与低出生体重和早产相关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在怀孕狒狒体内的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-胎儿交流中起着综合作用。研究1将验证妊娠早期雌激素刺激绒毛滋养细胞形成血管内皮生长/通透因子和/或血管生成素-1/ 2形成，从而促进胎盘血管生成，同时调节绒毛外细胞滋养细胞表达整合素-粘附分子，抑制其对子宫螺旋动脉的侵袭，通过这些作用雌激素协调血管生成和胎盘形成，确保胎儿-胎盘发育。研究I和II的目标相互交织，以验证雌激素作用于新血管化的胎盘，直接（NHE-1）或间接通过调节11β -羟基类固醇脱氢酶和局部皮质醇水平（NHE-3）调节合胞滋养细胞中钠-氢交换物（NHE-1和-3）及其调节因子的表达，以确保胎盘-胎儿稳态的假设。综合研究II和III来验证雌激素作用于胎儿肾上腺促进过渡区发育和抑制胎儿区生长发育的假设，并且这种子宫内编程控制着成年期肾上腺的成熟和功能。在雌性激素水平被雌二醇过早升高或被特定芳香酶抑制剂抑制的狒狒中，胎盘滋养细胞和胎儿肾上腺发育的分子、组织学、生化和体内生理参数将被确定。雌激素耗尽/充满的怀孕狒狒提供了一个独特的灵长类动物模型来研究滋养细胞功能改变对胎儿-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。这项研究的完成将为胎儿和胎盘之间的交流提供新的见解，并提高我们对胎儿发育和新生儿自给自足调节的认识。灵长类动物中心为这个项目提供了狒狒。

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.