MOLECULAR NEUROENDOCRINOLOGY OF THE FETAL HYPOTHALAMUS

前言：前列腺素(PGs)是几种 胎儿和母亲在促进和完成分娩方面的水平， 胎儿下丘脑-垂体-肾上腺-胎盘环(HPAPL)和 产妇的子宫问题。拟议的研究将确定 PGS作为激活剂和/或作为怀孕绵羊的分娩刺激剂。二 前列腺素H合成酶(PGHS)、构成同工酶PGHS-1和 诱导同工酶PGHS-2的同工酶。我们将研究 PG的确切作用和两者各自不同的功能 与促进分娩相关的同工酶。 假设1：胎盘是胎盘的主要来源 过去40天胎儿和母体循环中的前列腺素升高 绵羊妊娠：PGHS-1、PGHS-2两种亚型的作用 胎盘前列腺素产生的独立、明确定义的角色；假说 胎盘前列腺素在胎儿成熟过程中起着中心和独特的作用 下丘脑-垂体-肾上腺轴(HPAA)；假设3：胎盘PGs 在胎盘类固醇合成中发挥核心作用，特别是 17α羟基酶的功能；假说4：PGS发挥作用 在调节子宫肌层收缩转换为 宫缩既是子宫肌层的直接刺激因素，也是肌层的激活剂 收缩相关蛋白(CAPS)。 我们的四个具体目标与我们的假设和使用直接相关 用慢性仪器化妊娠绵羊评价PG改变的效果 在过去的40年中通过抑制PGHS和/或输注PGE/2发挥作用 妊娠天数(DGA)与胎儿胎盘HPAA的关系 类固醇合成和子宫肌层活性。 方法：于2：00行PGHS抑制和PGE/2输注。 妊娠的关键阶段，110天和140天，以及分娩。至 子宫组织直接前列腺素功能与继发性前列腺素的鉴别 通过胎儿HPAA介导的效应，去肾上腺的胎羊将被 研究使用或不使用PGE/2输注。以下端点将是 在mRNA和/或蛋白质和/或酶活性水平进行分析：1) 胎盘、子宫肌层、子宫内膜、胎儿下丘脑和脑垂体- 1和PGHS-2；2)胎儿下丘脑CRH、垂体POMC和循环 促肾上腺皮质激素、肾上腺类固醇生成酶和循环皮质醇；3)胎盘 17αOH；4)子宫肌层收缩活动和cAMP。 总结和理由：拟议的研究将提供更好的 理解PG在促进和 刺激分娩及其与母体和胎儿HPAA的交叉 并帮助制定预防和管理早产儿的策略 以及产后分娩。

INTRODUCTION: Prostaglandins (PGs) are key mediators involved at several fetal and maternal levels in the promotion and completion of parturition, the fetal hypothalamic-pituitary-adrenal-placental loop (HPAPL) and maternal uterine issues. The proposed studies will determine the role of PGs as activators and/or as stimulators of labor in pregnant sheep. Two forms of prostaglandin H synthase (PGHS), constitutive isozyme PGHS-1 and inducible isozyme PGHS-2, have been characterized. We will examine the precise role of PG and the separate and distinct function of both PGHS isozymes in association with the promotion of parturition. HYPOTHESES: Hypotheses 1: The placenta is the major source of the increased PGs in fetal and maternal circulation in the last 40 days gestation (dGA) of ovine pregnancy: the two isoforms of PGHS-1 PGHS-2 play separate, clearly defined roles for placental PG's production; Hypothesis 2: Placental PGs play central and distinct roles in maturation of fetal hypothalamic-pituitary-adrenal axis (HPAA); Hypothesis 3: Placental PGs play a central role in placental steroidogenesis, specifically the function of 17alpha hydroxylase (17alphaOH); Hypothesis 4: PGs play a central role in regulation of the switch of myometrial contractures to contractions both as direct stimulators and as activators of myometrial contraction associated proteins (CAPs). OUR FOUR SPECIFIC AIMS relate directly to our hypotheses and use chronically instrumented pregnant sheep to evaluate effects of altered PG function by inhibition of PGHS and/or infusion of PGE/2 in the last 40 days gestation (dGA) in relation to the fetal HPAA, placental steroidogenesis and myometrial activity. METHODS: PGHS inhibition and PGE/2 infusion will be performed at two critical stages of gestation, 110 and 140 dGA, and at labor. To differentiate direct PG function on uterine tissue from secondary PG effects mediated through fetal HPAA, adrenalectomized fetal sheep will be studied with or without PGE/2 infusion. The following endpoints will be analyzed at mRNA and/or protein, and/or enzyme activity levels: 1) placental, myometrial, endometrial, fetal hypothalamic and pituitary PGHS- 1 and PGHS-2; 2) fetal hypothalamic CRH pituitary POMC and circulating ACTH, adrenal steroidogenic enzymes and circulating cortisol; 3) placental 17alphaOH; 4) myometrial contraction activity and CAPs. SUMMARY AND RATIONALE: The proposed studies will provide a better understanding of the importance of PGs in processes that promote and stimulate parturition and their intersection with maternal and fetal HPAA and help to develop strategies for prevention and management of pre-term and post-term birth.