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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042135-04
Application #
6935190
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Higgins, Rosemary
Project Start
2002-09-27
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$291,211
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Gersting, Jason A; Schaub, Christine E; Wood, Charles E (2009) Development of prostaglandin endoperoxide synthase expression in the ovine fetal central nervous system and pituitary. Gene Expr Patterns 9:603-11
Wood, Charles E; Powers Fraites, Melanie; Keller-Wood, Maureen (2009) Blockade of PGHS-2 inhibits the hypothalamus-pituitary-adrenal axis response to cerebral hypoperfusion in the sheep fetus. Am J Physiol Regul Integr Comp Physiol 296:R1813-9
Schaub, Christine E; Wood, Charles E (2009) Blockade of estrogen action upregulates estrogen receptor-alpha mRNA in the fetal brain. Neonatology 96:115-9
Schaub, Christine E; Keller-Wood, Maureen; Wood, Charles E (2008) Blockade of estrogen receptors decreases CNS and pituitary prostaglandin synthase expression in fetal sheep. Neuroendocrinology 87:121-8
Wood, Charles E; Keller-Wood, Maureen (2008) Ontogeny of androgen receptor expression in the ovine fetal central nervous system and pituitary. Neurosci Lett 439:153-6
Wood, Charles E (2008) Cerebral hypoperfusion increases estrogen receptor abundance in the ovine fetal brain and pituitary. Neuroendocrinology 87:216-22
Schaub, Christine E; Gersting, Jason A; Keller-Wood, Maureen et al. (2008) Development of ER-alpha and ER-beta expression in the developing ovine brain and pituitary. Gene Expr Patterns 8:457-63
Gersting, Jason; Schaub, Christine E; Keller-Wood, Maureen et al. (2008) Inhibition of brain prostaglandin endoperoxide synthase-2 prevents the preparturient increase in fetal adrenocorticotropin secretion in the sheep fetus. Endocrinology 149:4128-36
Powers, Melanie J; Wood, Charles E (2007) Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion. Am J Physiol Regul Integr Comp Physiol 292:R1542-9
Keller-Wood, Maureen; Powers, Melanie J; Gersting, Jason A et al. (2006) Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation. Physiol Genomics 24:218-24

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