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My overall research interest is the physiologic adaptations to pregnancy. The laboratory is focusing on changes related to cortisol effects at the two receptors at which adrenal steroids (such as cortisol) bind: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These receptors mediate physiologic effects necessary for regulating blood glucose, blood pressure, fluid and electrolyte excretion, appetite, and mood. In the brain and pituitary, these receptors are also critical for the proper regulation of adrenal secretion through feedback effects. In particular, we are interested in the role of these receptors in two inter-related adaptations of pregnancy: changes in regulation of the blood pressure and fluid balance, and changes in feedback control of the hypothalmo-pituitary-adrenal (HPA) axis.There are three major ongoing projects in the laboratory. The first is to examine the interaction of progesterone with corticosteroid receptors, in particular the mineralocorticoid receptors (MR). We hypothesize that during pregnancy progesterone antagonizes cortisol action at MR in the hippocampus, which in turn reduces the feedback effect of cortisol and allows ACTH (and therefore cortisol) to chronically increase. We are looking at both physiologic changes in HPA function, changes in MR and GR pharmacology, and changes in corticosteroid-regulated genes and proteins in hippocampus, such as serotonin receptors. The model systems we use are pregnant and progesterone-treated ewes, and hippocampal cell cultures.
A second area of research involves examining the physiologic significance of the increased cortisol during pregnancy. In one project we are testing the hypothesis that the increase in maternal cortisol is necessary for normal maternal volume expansion and for normal fetal fluid homeostasis. In this project we use pregnant ewes to test the effect of altering maternal cortisol levels on the mother and on the fetus. We are also beginning a study to examine the ontogeny of MR and GR expression and action in the late gestation fetus. Although GR-related actions are known to be crucial for normal lung and GI development at the time of birth, we are interested in whether MR-mediated actions precede this and cause induction of genes important for normal fluid regulation and maturation in the fetus. This is related to the function of maternal cortisol because in both sheep and humans the maternal adrenal is the major source of cortisol in fetal blood in late gestation, before the fetal adrenal matures.
In another project we are testing the effects of increased cortisol on the mother. Our hypothesis is that the increased cortisol in pregnancy aids in balancing the vasodilator effects of estrogen. The estrogen effect is known to be mediated by eNOS, an endogenously produced vasodilator. We are examining the interaction between estrogens and cortisol on eNOS. In this project we also use a sheep model, and measure both in vivo vascular reactivity and tissue levels of eNOS protein and mRNA.