Maturation of pituitary adrenal function is poorly understood. This system is vital in the fetus, subserving a diverse series of roles from stimulating pulmonary surfactant production to modulating enzymes involved with the synthesis of neurotransmitters. In the present application, we will test the unifying hypothesis that input from the hypothalamus begins a maturational change of corticotrophs, which results in stimulation of fetal cortisol secretion and that fetal cortisol then enhances the developmental change in corticotroph phenotype and acts, as well, to increase ACTH receptor number on the fetal adrenal; these effects of cortisol increase fetal adrenal responsiveness to ACTH in late gestation. To test this hypothesis, we propose to: a) measure the proportion of corticotrophs which bind CRH or AVP, the binding sites for CRH and AVP and the message for CRH and AVP receptors at three stages of fetal development; b) determine if alterations in corticotroph phenotype are associated with alterations in the secretory profile for POMC and ACTH1-39 from individual corticotrophs; c) establish if input from the hypothalamus or changes in cortisol affect the change in corticotroph phenotype; and, d) determine if a physiological consequence of blocking the change in corticotroph phenotype is attenuation of the increase in adrenal responsiveness ordinarily seen close to term and if the mechanism of this attenuation in responsiveness is related to a reduction in ACTH receptor expression on fetal adrenal cells in late gestation. Fetal sheep are used for these experiments because we have defined the period in gestation when the functional alterations in corticotroph populations occur and we can surgically manipulate and study this model in utero. To accomplish our goal, we will employ florescent labelled ligand binding for the measurement of corticotroph phenotype, RNase protection assays for the measurement of steady-state CRH, AVP, and ACTH receptor message levels and immunoblot techniques for the studies of POMC secretion from single cells. To our knowledge, these will be the first studies to examine the factors promoting the maturational change in corticotroph phenotype in the fetus from a molecular, cellular, and whole animal basis simultaneously. Thus, the proposed studies will provide important, new information on the role of the hypothalamus and adrenal in the developmental regulation of corticotroph phenotype, the physiological consequences of changes in corticotroph phenotype and the mechanisms by which cortisol may influence corticotroph phenotype expression and adrenal responsiveness to ACTH. This information, when combined with results of our experiments to define the model for phenotype change, will help explain how the fetus prepares itself for birth and may be useful for the development of treatments to minimize the consequences of premature birth.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD011210-21A1
Application #
6041410
Study Section
Special Emphasis Panel (ZRG1-REB (01))
Program Officer
Ilekis, John V
Project Start
1978-09-29
Project End
2005-02-28
Budget Start
2000-05-09
Budget End
2001-02-28
Support Year
21
Fiscal Year
2000
Total Cost
$298,033
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Su, Yixin; Carey, Luke C; Rose, James C et al. (2013) Antenatal glucocorticoid exposure enhances the inhibition of adrenal steroidogenesis by leptin in a sex-specific fashion. Am J Physiol Endocrinol Metab 304:E1404-11
Su, Yixin; Carey, Luke C; Rose, James C et al. (2012) Leptin alters adrenal responsiveness by decreasing expression of ACTH-R, StAR, and P450c21 in hypoxemic fetal sheep. Reprod Sci 19:1075-84
Valego, Nancy K; Rose, James C (2010) A specific CRH antagonist attenuates ACTH-stimulated cortisol secretion in ovine adrenocortical cells. Reprod Sci 17:477-86
Carey, Luke C; Tatter, Stephen B; Rose, James C (2009) Cortisol infusion in late-gestation hypothalamo-pituitary disconnected sheep fetus restores pituitary cell responsiveness to arginine vasopressin. Am J Physiol Endocrinol Metab 296:E300-4
Su, Yixin; Rose, James C (2008) The impact of ACTH receptor knockdown on fetal and adult ovine adrenocortical cell function. Reprod Sci 15:253-62
Carey, Luke C; Tatter, Stephen B; Rose, James C (2007) Ontogeny and effects of hypothalamic pituitary disconnection on formation of inositol trisphosphate in fetal sheep pituitary cells. Endocrinology 148:1440-4
Carey, Luke C; Su, Yixin; Valego, Nancy K et al. (2006) Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep. Am J Physiol Endocrinol Metab 291:E214-20
Valego, Nancy K; Su, Yixin; Carey, Luke C et al. (2005) Hypothalamic-pituitary disconnection in fetal sheep blocks the peripartum increases in adrenal responsiveness and adrenal ACTH receptor expression. Am J Physiol Regul Integr Comp Physiol 289:R410-R417
Su, Yixin; Carey, Luke C; Valego, Nancy K et al. (2005) Developmental changes in adrenocorticotrophin (ACTH)-induced expression of ACTH receptor and steroid acute regulatory protein mRNA in ovine fetal adrenal cells. J Soc Gynecol Investig 12:416-20
Chen, Kai; Carey, Luke C; Liu, Jingfang et al. (2005) The effect of hypothalamo-pituitary disconnection on the renin-angiotensin system in the late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 288:R1279-87

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