The overall goal of the experiments performed in this laboratory are to identify the mechanisms controlling the activity of the hypothalamus-pituitary-adrenal (HPA) axis in fetal sheep. Providing a more complete understanding of the activity of the HPA axis will be key to understanding fetal stress, homeostasis, and (in sheep and perhaps in other species) the control of parturition. In past years, we have investigated several of the physiological and endocrine mechanisms controlling the activity of the ovine fetal HPA axis. Recently, we have reported that estrogen potently stimulates the activity of the fetal HPA axis. The present proposal is to investigate this endocrine interaction more completely: to elucidate the role of brain prostanoids as mediators of this interaction. Specifically, we propose two general aims: 1) to elucidate the spontaneous (preparturient) effects of development and endogenous estrogens on brain prostanoids; and 2) to elucidate the effects of exogenous estrogen on brain prostanoids: to elucidate the influence of estrogen on prostaglandin endoperoxide synthase (PGHS) isoforms in the fetal central nervous system and to demonstrate that estrogen-stimulated prostaglandin synthesis mediates the effect of estrogen on fetal ACTH secretion. To achieve these aims, we will perform experiments using in vivo, biochemical, and molecular techniques designed to study the prostaglandin biosynthesis system at the mRNA, protein, and posttranslational processing levels. All of the experiments will be based on the study of the HPA axis control in chronically-catheterized fetal sheep. Experiments designed for the first aim will include the measurement of brain PGHS-1 and PGHS-2 abundance and brain prostanoid production in response to estrogen treatment of fetal sheep, and other experiments which will test the effect of blockade of endogenous estrogen synthesis on HPA control, expression of PGHS isoforms and generation of prostaglandins within the brain. Experiments designed for the second aim will reveal the number of days required for estrogen stimulation of HPA function. Experiments designed for the second aim will investigate the effect of exogenous (physiological) estrogen administration on PGHS-1 and PGHS-2 expression, posttranslational processing, and colocalization with either known forms of the estrogen receptor.
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