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: 7349787
• 负责人: Eugene D. Albrecht
• 金额: $ 1.88万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349787
• 关键词: REGULATION; FETAL; PLACENTAL; DEVELOPMENT; PRIMATE

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。与低出生体重和早产有关的人类新生儿发病率和死亡率的高发生率表明有必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建立在我们之前对怀孕狒狒的活体研究的基础上，通过调节胎盘和胎儿肾上腺的成熟来证明雌激素在胎盘-胎儿沟通中起着整合的作用。研究I将验证这样一种假设：在妊娠早期，雌激素刺激绒毛滋养层细胞血管内皮生长/渗透因子和/或血管生成素-1/-2的形成，从而促进胎盘血管生成，并同时调节绒毛外细胞滋养层细胞整合素-黏附分子的表达，以抑制其对子宫螺旋动脉的侵袭，并通过这些作用协调血管生成和胎盘形成，以确保胎儿-胎盘发育。研究一和研究二的目标相互交织，以检验这一假说，即雌激素作用于新血管的胎盘，直接(NHE-1)和间接地通过调节11β-羟基类固醇脱氢酶(11β-羟基类固醇脱氢酶)和局部皮质醇水平(NHE-3)来调节合体滋养层细胞中钠氢交换器(NHE-1和-3)的表达，以确保胎盘-胎儿的动态平衡。研究二和研究三综合检验了雌激素作用于胎儿肾上腺以促进移行区的发育和抑制胎儿区的生长和发育的假说，以及这一假说在子宫内编程调节成年后肾上腺的成熟和功能。胎盘滋养层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，在这种情况下，雌激素水平被雌激素过早升高或被特定芳香酶抑制剂抑制。雌激素耗竭/繁殖的怀孕狒狒提供了一种独特的灵长类动物模型来研究滋养层功能改变对胎儿-新生儿成熟的影响，这是一项不能在孕妇身上或通过体外方法进行的研究。这项拟议研究的完成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知识。灵长类动物中心提供了这个项目中使用的狒狒。