MOLECULAR NEUROENDOCRINOLOGY OF THE FETAL HYPOTHALAMUS

简介：前列腺素（PGs）是参与几个关键的介质， 在促进和完成分娩方面， 胎儿下丘脑-垂体-肾上腺-胎盘环（HPAPL）， 母亲的子宫问题拟议的研究将确定以下方面的作用： PGs作为妊娠绵羊分娩的激活剂和/或刺激剂。两 前列腺素H合酶（PGHS）、组成型同工酶PGHS-1和 诱导型同工酶PGHS-2。我们会研究 PG的确切作用和PGHS的单独和不同的功能 与促进分娩有关的同工酶。 假设：假设1：胎盘是主要的来源， 过去40天内胎儿和母体循环中PG增加 绵羊妊娠（dGA）：PGHS-1和PGHS-2的两种亚型发挥作用 胎盘PG产生的单独、明确定义的作用;假设 2：胎盘PG在胎儿的成熟中起着重要而独特的作用。 下丘脑-垂体-肾上腺轴（HPAA）;假设3：胎盘PG 在胎盘类固醇生成中发挥核心作用，特别是 17 α羟化酶（17 α OH）的功能;假设4：PGs发挥作用， 在调节子宫肌层挛缩转变为 收缩既作为直接刺激物又作为子宫肌层的激活物 收缩相关蛋白（CAPs）。 我们的四个具体目标直接关系到我们的假设和使用 长期仪器怀孕羊，以评估改变PG的影响 在过去的40年中，通过抑制PGHS和/或输注PGE/2来发挥功能 妊娠天数（dGA）与胎儿HPAA，胎盘 类固醇生成和子宫肌层活性。 方法：PGHS抑制和PGE/2输注将在2 妊娠的关键阶段，110和140 dGA，以及分娩时。到 区分子宫组织上的直接PG功能和继发性PG 通过胎儿HPAA介导的作用，肾上腺切除的胎羊将 研究有或没有PGE/2输注。以下终点 在mRNA和/或蛋白质和/或酶活性水平上分析：1） 胎盘、子宫肌层、子宫内膜、胎儿下丘脑和垂体PGHS- 1和PGHS-2; 2）胎儿下丘脑CRH垂体POMC和循环 ACTH、肾上腺类固醇生成酶和循环皮质醇; 3）胎盘 17 α OH; 4）子宫肌层收缩活性和CAP。 总结和依据：拟定的研究将提供更好的 了解PG在促进和 刺激分娩及其与母体和胎儿HPAA交叉 并帮助制定预防和管理早产儿的战略， 和过期分娩。

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.