CORTISOL AND PLACENTAL ESTROGEN IN PROSTANOID SYNTHESIS

描述：（根据申请人描述扫描）：胎儿糖皮质激素 (GC)在几个国家进行的研究中， 世界各地的实验室。然而，胎儿皮质醇 引发了母体和胎儿内分泌的相互作用 变化并不明显。特别是，增强子宫收缩的机制 前列腺素（PG）的合成和输出，并导致子宫增加 活动和出生仍有待确定。虽然长期以来人们都认为 皮质醇影响孕酮向雌激素的转化， 子宫PG产生的变化（间接途径），我们假设， 皮质醇还通过刺激PG产生的另一重要途径起作用 直接路径（Direct Path）我们建议进行研究，以探讨这两个方向， PG合成关键酶- PGH合成酶GC调控的间接途径 （PGHS）和决定POE 2确切混合的关键PGHS后酶 和PGF 2F 2a。假设：皮质醇，1）直接和2）间接 （通过雌激素）调节PG合成中四种关键酶的活性： PGHS、POE 2、异构酶（POES）、PGF 2a合酶（PGFS）和PG 9-酮还原酶 （PG 9 KR）在绵羊胎儿和母体胎盘、子宫内膜、子宫肌层和 以组织和区域特异性的方式启动和维持宫颈 分娩过程中的几个关键环节目前还不清楚 PGES、PGFS或PG 9 KR。具体目标：我们的两个具体目标涉及两个 我们的中心假设的组成部分：我们将使用长期工具 肾上腺切除胎羊，以评估皮质醇各自的作用 （i）直接和（ii）通过雌激素间接作用，调节 绵羊胎儿和母体胎盘中PGHS、PGES、PGFS和PG 9 KR的活性， 子宫内膜、子宫肌层和子宫颈以组织特异性和区域特异性的方式。 对妊娠绵羊和胎儿进行了慢性内固定的研究 广泛地作为分娩的主要模式。为了最大限度地获取信息， 我们已经开发了系统，在体内和体内询问模型， 体外水平。我们的方法是研究时间相关的和组织特异性的 妊娠动物中发生的事件， 确定直接和间接途径中的关键步骤。例如使用 雌激素受体拮抗剂ICI 182780通过以下途径解决雌激素的作用： 间接途径。皮质醇改变PG产生的途径 和雌激素都可能在绵羊和灵长类动物中起作用。有 大量证据表明胎儿肾上腺功能增加， 雌性激素在灵长类动物包括孕妇的妊娠后期。同时 对这两种途径的研究提供了理解 跨物种的分娩早产是围生儿死亡的主要原因 死亡率和发病率。更好地了解长期和长期的机制， 早产将提供基于证据的，合理的诊断和管理。

DESCRIPTION: (Scanned from the applicant's description): Fetal glucocorticoid (GC) induces premature labor in pregnant sheep in studies conducted in several laboratories throughout the world. However, pathways by which fetal cortisol triggers the subsequent interactive evolution of maternal and fetal endocrine changes are not clear. In particular, mechanisms that enhance uterine prostaglandin (PG) synthesis and output, and result in increased uterine activity and birth remain to be determined. While it has long been accepted that cortisol influences progesterone to estrogen conversion with resultant changes in uterine PG production (indirect pathway), we hypothesize that cortisol also acts by an important additional pathway stimulating PG production directly (direct pathway). We propose studies to examine both the direction and indirect pathways of GC regulation of key enzymes of PG synthesis- PGH synthase (PGHS) and the critical post PGHS enzymes that determine the exact mix of POE2 and PGF2F2a produced. HYPOTHESIS: cortisol, both 1) directly and 2) indirectly (through estrogen) regulates activity of four key enzymes in PG synthesis: PGHS, POE2, isomerase (POES), PGF2a synthase (PGFS), and PG 9-keto reductase (PG9KR) in ovine fetal and maternal placenta, endometrium, myometrium, and cervix in a tissue- and regional- specific manner to initiate and maintain the several critical processes involved in labor. Nothing is known of regulation of PGES, PGFS or PG9KR. SPECIFIC AIMS: our two specific aims relate to the two component parts of our central hypothesis: We will use chronically instrumented adrenalectomized fetal sheep to evaluate the respective roles of cortisol acting (i) directly and (ii) indirectly through estrogen, in regulation of activity of PGHS, PGES, PGFS, and PG9KR in ovine fetal and maternal placenta, endometrium, myometrium and cervix in a tissue- and regional- specific manner. The chronically instrumented pregnant sheep and fetus have been studied extensively as a major model of parturition. To maximize information obtained, we have developed systems to interrogate the model at both the in vivo and in vitro levels. Our approach is to investigate time-related and tissue-specific events in pregnant animals undergoing specific experimental perturbations to determine critical steps in the direct and indirect pathways. For example, use of the estrogen receptor antagonist ICI 182780 addresses estrogen's role via the indirect pathway. The pathways whereby PG production is altered by cortisol and by estrogen are likely to operate in both sheep and primates. There is considerable evidence for both increased fetal adrenal function and increased estrogen in late gestation in primates including pregnant women. Simultaneous study of both pathways provides information critical to understanding of parturition across species. Premature labor is the major cause of perinatal mortality and morbidity. Better understanding of the mechanisms of term and preterm labor will provide evidence based, rational diagnosis and management.