INTRODUCTION: In Project I during PO1 years 6-10 we expanded our baboon studies to enable chronic fetal catheterizations to answer critical questions in both motor and fetus. We will now focus on regulation of fetal hypothalamic-pituitary-adrenal-placental loops (HPAPL) in the pregnant baboon and fetus and determine the critical regulatory mechanisms that drive the changes in estrogen that we studied in years 6 - 10. HYPOTHESES: We propose four hypotheses with four related specific aims: 1. Increased activity of the fetal baboon HPAPL occurs at term in a fashion that parallels and is analogous to the well established pattern in pituitary adrenal activity demonstrated to be central to the initiation of parturition in sheep. 2. Maternal CRH plays an endocrine role in regulating a) uterine blood flow, b) myometrial activity and c) duration of pregnancy. 3. Inhibition of prostaglandin (PG) synthesis between 0.7 of gestation and term by infusion of PGHS1 and PGHS2 inhibitors independents or together will alter material and fetal HPAPL function and myometrial activity. 4. There will be gestation and parturition related changes in the proportion, position, and receptor-type of stimulatory and inhibitor PG and CRH receptors and PGHS and CRH production in myometrium and decidua. Methods: We will use chronically instrumented maternal and fetal baboons from 122 dGA to term (175 dGA). We will address our Specific Aims 1) by longitudinal sampling: 2) using CRH, a bioneutralizing anti-CRH antibody; 3) using different PH synthesis inhibitors and 4) with a complete range of probes for PH and CRH receptors. RATIONALE: Most chronic in vivo studies on control of maternal and fetal HPAPL, parturition, and myometrial function have been performed in sheep. Studies in chronically instrumented non-human primates are few. Differences in fetal and maternal endocrinology and myometrial contractility between sheep and primates dictate that a clear understanding of control of human parturition awaits firm experimental data from non-human primates. Labor is a multi-factorial process with interconnected positive feed- forward and negative feedback loops. Project I interacts with Projects II and III to enable cross-species comparison of fundamental fetal and maternal neuroendocrine mechanisms and parturition. Prevention and management of pre-term labor and pre-term birth are critical issues in human obstetrics and both require a better understanding of the processes we propose to study in this important non-human primate model.
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