EXCEED THE SPACE PROVIDED.
The aims of this proposal focus on regulation of adrenocortical glucocorticoid biosynthesis in the late gestation sheep fetus. In fetal sheep, plasma cortisol concentrations increase exponentially during the final three weeks of gestation (birth =148 days) resulting in delivery of a viable neonate.
Specific Aim 1 will determine POMC processing in anterior pituitary corticotropes as a function of corticotrope phenotype. POMC processing will be studied in corticotrope subpopulations expressing the CRF) receptor, AVP receptor (Vlb) or both receptors. Since disruption of the PVN neuroendocrine signal to the anterior pituitary prevents adrenocortical maturation, neuropeptide regulation of POMC processing will be examined. I hypothesize that 1) CRF induces processing of POMC to ACTH|.39 via prohormone convertase 1 (PCI) in CRP! receptor expressing corticotropes, 2) without CRF, POMC is not processed to ACTH|_39, 3) glucocorticoids suppress ACTH,.39 biosynthesis and 4) CRF attenuates glucocorticoid inhibition of POMC processing.
Specific Aim 2 will determine mechanisms via which fetal adrenocortical cells respond to ACTH^g, 22 kDa proACTH and POMC. In adults, ACTH,.39 regulates adrenocortical steroidogenesis via the MC2R. Our data demonstrates that MC2R, MC1R and MC5R are expressed in the adrenal cortex of fetal sheep. / hypothesize that MC2R, MC5R and MC1R display distinct pharmacological characteristics for ACTH and ACTH precursors, and that developmental changes in the expression of these receptors is critical for adrenocortical development. While the MC2R is highly selective for ACTH].39, the MC5R recognizes multiple melanocortin peptides and potentially ACTH-processing intermediates and presents a mechanism for the differential regulation of fetal adrenocortical regulation by ACTHi.39, POMC, 22 kDa pro ACTH.
Specific aim 3 is to identify the role of the agouti gene in adrenocortical maturation. We have found that the agouti gene-, which encodes for a potent antagonist (ASiP) of MC2R and MC1R but not MC5R, is expressed in ovine fetal adrenal cortex. / hypothesize that ASIP antagonizes ACTH,_39 stimulated steroidogenesis and that declining expression of AsiP during gestation allows adrenocortical maturation in the presence of low pM concentrations ofACTH/_3y. Despite advances in the treatment and survival rate of preterm infants, the prevalence of preterm birth (~ 10 %) has not declined in the U.S.A., Canada or other developed countries. Premature birth continues to be a major cause of infant mortality. Identifying mechanisms initiatingthe onset of normal term labor and delivery will lead to the development of better strategies for preventing premature birth. PERFORMANCE SITE ========================================Section End===========================================
| Myers, Dean A; Singleton, Krista; Hyatt, Kim et al. (2015) Long-Term Gestational Hypoxia Modulates Expression of Key Genes Governing Mitochondrial Function in the Perirenal Adipose of the Late Gestation Sheep Fetus. Reprod Sci 22:654-63 |
| Myers, Dean A; Ducsay, Charles A (2012) Adrenocortical and adipose responses to high-altitude-induced, long-term hypoxia in the ovine fetus. J Pregnancy 2012:681306 |
| Ducsay, Charles A; Mlynarczyk, Malgorzata; Kaushal, Kanchan M et al. (2009) Long-term hypoxia enhances ACTH response to arginine vasopressin but not corticotropin-releasing hormone in the near-term ovine fetus. Am J Physiol Regul Integr Comp Physiol 297:R892-9 |
| Monau, Tshepo R; Vargas, Vladimir E; King, Natalie et al. (2009) Long-term hypoxia increases endothelial nitric oxide synthase expression in the ovine fetal adrenal. Reprod Sci 16:865-74 |
