While the signaling processes that regulate parturition are almost certainly multifactorial, there is considerable teleological evidence that the fetal adrenal glands act to influence the timing of labor. Near term the human fetal adrenals commence cortisol production and increase production of dehydroepiandrosterone-sulfate (DHEA-S), which acts as substrate for placental estrogen production. Fetal derived cortisol increases placental corticotropin releasing hormone (CRH) that initiates an endocrine feed-forward cascade that does not end until labor and separation of the fetus from the placenta. Increasing evidence supports the idea that estrogens and placental CRH act on the myometrium to initiate the transition from a quiescent to responsive contractile state, while cortisol alters fetal membrane prostaglandin production. The proposed research will define the mechanisms through which CRH directly activates the fetal adrenal gland thus initiating this feedforward endocrine cascade that ends in labor. To achieve these goals three aims are proposed:
Specific Aim 1 will define the CRH receptors and signaling pathways that regulate fetal adrenal production of cortisol and DHEA-S. The goal of this aim is to define the CRH receptor isoform that regulates the fetal adrenal, determine the intracellular signaling pathways used by CRH to regulate cortisol and DHEA-S biosynthesis, determine the mechanism regulating adrenal expression of CRH receptors and define the pattern of CRH receptor expression. The goal of Specific Aim 2 is to define the chronic effects of CRH on the capacity of fetal adrenal cells to produce cortisol and DHEA-S. During most of gestation the fetal adrenal gland expresses little 3beta-hydroxysteroid dehydrogenase (HSD3B2) making cortisol production impossible. Elevated levels of CRH in the second half of gestation coincide with the initiation of fetal adrenal cortisol biosynthesis and expression of HSD3B2.
In Aim 2 we will determine CRH gene targets that promote fetal adrenal production of cortisol via activation of HSD3B2 gene transcription.
Specific Aim 3 will determine if CRH increases fetal adrenal responsiveness to ACTH leading to the dramatic activation of steroid production seen in the last weeks of gestation. This effect of CRH would explain what was thought to be the conflicting observation that circulating levels of ACTH do not increase during the last trimester when fetal adrenal steroidogenesis most increases. Completion of the goals set forth in this application will determine how CRH activates the fetal adrenal glands late in gestation and will provide important details into endocrine controls of normal and preterm labor.
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| Mendelson, Carole R; Montalbano, Alina P; Gao, Lu (2017) Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Biol 170:19-27 |
| Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576 |
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| Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C et al. (2015) Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Invest 125:2808-24 |
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