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: 6181361
• 负责人: Eugene D. Albrecht
• 金额: $ 69.78万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6181361
• 关键词: adrenocorticotropic hormone; baboons; cell differentiation; cell proliferation; electron microscopy; embryo /fetus; enzyme activity; estrogens; growth /development; hormone receptor; hormone regulation /control mechanism; hydroxysteroids; hypothalamic pituitary adrenal axis; image processing; immunocytochemistry; in situ hybridization; insulinlike growth factor; placenta; polymerase chain reaction; pregnancy; radioimmunoassay; statistics /biometry; steroid hormone biosynthesis; trophoblast; western blottings

The relatively high incidence of human neonatal morbidity and mortality associated with low birth weight and prematurity require that there be a more intensive study of the mechanisms underlying placental and fetal development. Our present understanding of the factors regulating growth and morphological and functional maturation of the placenta in preparation for development of the fetus, is incomplete. The overall objective of the present proposal is to improve knowledge in this area by building on our previous in vivo studies in the pregnant baboon demonstrating that the placenta is an estrogen target tissue. Study I will test the hypothesis that estrogen regulates proliferation of mononucleated villous cytotrophoblasts and/or their morphological differentiation into syncytiotrophoblasts. The goals of Studies I and II are interwoven to test the hypothesis that as a result of estrogen- regulated morphological and functional differentiation of trophoblasts, the Il (3-hydroxysteroid dehydrogenase (1 1I3-HSD)- 1 and -2 enzymes, that catalyze cortisol (F) and cortisone (E) interconversion, undergo spatial orientation within the syncytiotrophoblast resulting in transplacental oxidation of bioactive F to bioinactive E, and thus derepression of F feedback on and maturation of the fetal hypothalamic-pituitary- adrenocortical axis (HPAA). Studies II and III are integrated to test the hypothesis that estrogen has two different effects on the fetal HPAA: an indirect one to enhance, via placental II beta- HSD, fetal pituitary ACTH release and thus maturation of the fetal adrenal definitive zone with de novo production of F critical to fetal lung maturation, and a direct negative action on the fetal zone to modulate ACTH receptor-mediated C19-steroid synthesis to ensure an appropriate level of estrogen production. In vivo physiological measurements of placental, fetal adrenal and lung function coupled with histo/anatomical, biochemical, and molecular parameters of trophoblast differentiation and fetal organ system development will be determined in baboons in which estrogen levels are prematurely elevated or suppressed by a highly specific aromatase inhibitor during gestation. The estrogen- depleted/-repleted pregnant baboon provides a novel and unique model to investigate the effects of altered trophoblast differentiation on maturation of fetal organ systems essential to neonatal survival, studies which could not be performed in pregnant women. The results derived from the proposed study will provide new insight into the communication that occurs between the fetus and placenta and ultimately improve our knowledge of the regulation of pregnancy maintenance and development of neonatal self-sufficiency.

人类新生儿发病率相对较高 与低出生体重和早产相关的死亡率需要 对潜在机制进行更深入的研究 胎盘和胎儿的发育。我们目前的理解 调节生长、形态和功能的因素 胎盘的成熟，为胎儿的发育做准备 胎儿，是不完整的。本提案的总体目标 是在我们以前的基础上提高这方面的知识 对怀孕狒狒的体内研究表明 胎盘是雌激素的靶组织。研究我将测试 雌激素调节单核细胞增殖的假说 绒毛细胞滋养细胞和/或其形态分化 进入合体滋养层。研究 I 和 II 的目标是 交织在一起以检验以下假设：由于雌激素 调控的形态和功能分化 滋养细胞，II（3-羟基类固醇脱氢酶（1 1I3-HSD）- 1 和 -2 酶，催化皮质醇 (F) 和可的松 (E) 相互转换，在空间内进行定向 合体滋养层导致胎盘氧化 生物活性 F 转变为生物非活性 E，从而抑制 F 反馈 胎儿下丘脑-垂体的发育和成熟- 肾上腺皮质轴（HPAA）。研究 II 和 III 被整合到 检验雌激素对雌激素有两种不同影响的假设 胎儿 HPAA：一种间接增强剂，通过胎盘 II β- HSD，胎儿垂体 ACTH 释放，从而成熟 胎儿肾上腺限定区，从头产生 F 临界区 影响胎儿肺的成熟，对胎儿有直接的负面作用 调节 ACTH 受体介导的 C19 类固醇合成的区域 以确保雌激素产生适当水平。体内 胎盘、胎儿肾上腺和肺的生理测量 功能与组织/解剖学、生化和 滋养层分化和胎儿器官的分子参数 系统开发将由狒狒决定，其中 雌激素水平过早升高或受到高度抑制 妊娠期间的特异性芳香酶抑制剂。雌激素—— 耗尽/充满的怀孕狒狒提供了一种新颖而独特的 研究滋养层改变的影响的模型 分化对胎儿器官系统的成熟至关重要 新生儿存活率，无法进行的研究 孕妇。拟议研究的结果将 提供对之间发生的沟通的新见解 胎儿和胎盘，并最终提高我们的知识 妊娠维持和发育的调节 新生儿自给自足。