CORTISOL AND PLACENTAL ESTROGEN IN PROSTANOID SYNTHESIS

描述：(摘自申请者的描述)：胎儿糖皮质激素 在几项研究中，(GC)诱导怀孕绵羊早产 世界各地的实验室。然而，胎儿皮质醇的途径 触发母体和胎儿内分泌随后的互动进化 变化尚不清楚。特别是，增强子宫的机制 前列腺素(PG)的合成和输出，并导致子宫增加 活动和出生情况仍有待确定。虽然它早已被人们接受 皮质醇影响黄体酮向雌激素的转化 子宫PG产生的变化(间接途径)，我们假设 皮质醇还通过一个重要的额外途径刺激PG的产生。 直接(直接途径)。我们建议进行研究，以研究方向和 GC调节PG合成关键酶--PGH合成酶的间接途径 (PGHS)和决定POE2确切组合的关键的PGHS后酶 和PGF2F2a产生。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、POE2、异构酶(POES)、PGF2a合成酶(PGFS)和PG-9-酮还原酶 (PG9KR)在绵羊胎儿和母体胎盘、子宫内膜、子宫肌层和 以组织和区域特有的方式启动和维持宫颈 涉及到分娩的几个关键过程。我们对此一无所知。 PGES、PGFS或PG9KR。具体目标：我们的两个具体目标与这两个目标有关 我们的中心假设的组成部分：我们将使用慢性仪器 去肾上腺胎羊评价皮质醇的作用 (I)直接作用和(Ii)通过雌激素间接调节 绵羊胎儿和母体胎盘中PGHS、PGES、PGFs和PG9KR的活性 子宫内膜、子宫肌层和宫颈具有组织和区域特异性。 对慢性器质性妊娠绵羊和胎儿进行了研究。 广泛地作为一种主要的分娩模式。为了最大限度地获取信息， 我们已经开发了在体内和体内对模型进行审问的系统 体外水平。我们的方法是研究与时间相关的和特定于组织的 怀孕动物在经历特定实验扰动时发生的事件 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 间接途径。皮质醇改变PG产生的途径 而雌激素很可能在绵羊和灵长类动物身上起作用。的确有 大量证据表明胎儿肾上腺功能增加和 包括孕妇在内的灵长类动物妊娠晚期的雌激素。同时进行 对这两条途径的研究提供了对理解 跨物种分娩。早产是围产儿的主要原因 死亡率和发病率。更好地理解术语和术语的机制 早产将提供循证、合理的诊断和处理。

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.