Cortisol at MR Mediate Fetal Physiologic/Genomic Effects

这些研究的总体目标是检验这样一种假设，即在大多数怀孕期间， 胎儿中的游离皮质醇通过高亲和力(皮质类固醇I型)矿质皮质激素发挥生理作用 糖皮质激素受体(GR)不是亲和力较低但容量较高的受体(MR)。这很好 确定分娩时胎儿肾上腺产生的高水平皮质醇是重要的 对于正常的器官成熟，这些作用是由GR介导的。胎儿MR的存在 早在妊娠中期的组织表明，可能有低浓度的皮质醇通过磁共振的影响， 甚至在胎儿成熟之前。我们将测试MR受体上的皮质醇作用是否介导 通过肺和/或肾脏中特定的MR靶基因对胎儿体积的影响，以及对下丘脑的影响 脑垂体-肾上腺功能通过海马体中的MR靶基因实现。糖皮质激素在人体内的相对活性 这些组织将与血浆皮质醇水平、11T羟类固醇脱氢酶活性有关 和还原酶活性(1ll3HSD)，组织中MR和GR水平，以及改变基因的反式激活 表情。MR靶基因，包括早期反应基因SGK和K-RAS，以及更慢的诱导 将测试ENaC、Na/K ATPase和5HT1A、MR和GR基因。为了检验这一假设，实验 其目的是：1)定量测定MR的蛋白质、mRNA和内源性类固醇的相对占有率 和GR，以及肺、肾、心脏、海马区、脑干和脑组织中1I_HSD的活性。 妊娠晚期胎儿肾上腺成熟前后(120-140天)的脑垂体；2)试验 阻断胎儿MR受体对成人已知的MR介导的生理行为的影响， 肾功能和ACTH分泌，以及对胎儿肺液中可能的MR介导功能的影响 重吸收；3)测试MR占有率与这些生理效应之间的关系，以及 提出了在海马体、肾脏以及胎肺中MR作用的靶基因；4)比较 MR和GR联合占用对这些基因和生理行为的影响。

The overall goal of these studies is to test the hypothesis that for most of gestation, the concentrations of free cortisol in the fetus exert physiologic actions via the high affinity (corticosteroid type I) mineratocorticoid receptors (MR) rather than the lower affinity, but higher capacity, glucocorticoid receptors (GR). It is well established that the high levels of cortisol produced by the fetal adrenal at the time of delivery are important for normal organ maturation, and that these effects are mediated by GR. The presence of MR in fetal tissues as early as mid-gestation suggests that there may be effects of low concentrations of cortisol via MR, even before the time of fetal maturation. We will test whether cortisol action at MR receptors mediates effects on fetal volume through specific MR-target genes in the lung and/or kidney, and on hypothalamo- pituitary-adrenal function via MR-target genes in the hippocampus. The relative activity of corticosteroids in the tissues will be related to plasma levels of corticosteroids, activity of 11 t_ hydroxysteroid dehydrogenase and reductase activities (1ll3HSD), levels of MR and GR in the tissue, and transactivation to alter gene expression. MR target genes, including the early response genes, Sgk and K-Ras, and more slowly induced genes for ENaC, Na/K ATPase and 5HT1A, MR and GR will be tested. To test this hypothesis, experiments were designed to: 1) quantitate the protein, mRNA and relative occupancy by endogenous steroids of MR and GR, and activity of 1I_HSD in fetal tissues such as lung, kidney, heart, hippocampus, brainstem and pituitary in late gestation fetuses both before and after the time of fetal adrenal maturation (120-140d); 2) test the effect of blockade of fetal MR receptors on physiologic actions known in the adult to be MR-mediated, renal function and ACTH secretion, and on a possible MR-mediated function in the fetus, lung liquid reabsorption; 3) test for a relation between MR occupancy and these physiologic effects, and on the proposed target genes for MR action in hippocampus, kidney, and by analogy, fetal lung; 4) to compare the effect of combined MR and GR occupancy on these genes and physiologic actions.