Primate Fetal Adrenal Development: Impact on Physiological Processes After Birth

描述(申请人提供)：人类胎儿肾上腺经历了一种独特的皮质区特定的生长和发育模式，这对正常的出生后成熟和动态平衡是必不可少的，但这一过程的调节尚不清楚。以狒狒作为非人灵长类动物的翻译模型，并用芳香化酶抑制剂来曲唑抑制妊娠后半期胎盘雌激素水平，我们发现雌激素抑制胎盘生长和雄激素脱氢表雄酮(DHA)/DHA硫酸盐(DHA)的产生，尽管胎儿ACTH水平没有改变。初步研究表明，缺乏雌激素的狒狒怀孕所生的后代表现出葡萄糖不耐受/胰岛素抵抗。因此，我们认为雌激素抑制胎儿皮质区对ACTH的反应性，从而维持胎儿肾上腺雄激素和胎盘雌激素合成在生理水平，以确保出生后的动态平衡。然而，潜在的机制(S)尚不清楚。ACTH受体(R)与控制ACTHR运输和激活的黑素皮质素2受体辅助蛋白(MRAP)结合。促肾上腺皮质激素可刺激胎儿肾上腺表达胰岛素样生长因子-II，从而促进胎儿肾上腺生长。目的1验证雌激素抑制ACTHR和MRAP的表达/相互作用，从而抑制ACTHR和MRAP的表达，从而抑制：(A)IGF-II/IGFR和周期蛋白生长所需的周期蛋白；(B)狒狒胎儿肾上腺皮质胎儿区合成DHA/DHAS所需的腺苷环化酶和低密度脂蛋白(LDL)R及酶。为了实现目标1，将评估ACTHR信号、IGF-II/细胞周期和类固醇生成途径的组成部分，在未处理的狒狒的中期和近期获得的胎儿肾上腺中，以及在整个妊娠的后半段期间使用来曲唑雌二醇抑制/恢复雌激素的近足月狒狒。在体外对狒狒胎儿肾上腺的研究将阐明雌激素作用的潜在机制。最后，由于雌激素刺激和雄激素抑制胰岛素敏感性/葡萄糖代谢，目标2将测试这一假设，即胎盘雌激素水平在妊娠后半期直接升高，和/或通过抑制胎儿肾上腺皮质区雄激素分泌，发育计划胎儿胰岛素靶组织(即骨骼肌)内的胰岛素受体信号通路组件，导致出生后胰岛素敏感性/葡萄糖动态平衡。为了实现目标2，雌激素充足或雌激素缺乏的狒狒怀孕的后代将被抚养到成年，并确定胰岛素敏感性和胰岛素受体信号通路的组成部分，以阐明潜在的机制。从这项研究中获得的知识有望转化为人类，并在围产期和发育内分泌学方面取得以下新的概念性进展：(A)雌激素调节胎儿肾上腺皮质的生长和发育，(B)雌激素直接和/或通过控制胎儿肾上腺皮质发育，编程胰岛素敏感性，从而在出生后实现葡萄糖稳态。

DESCRIPTION (provided by applicant): The human fetal adrenal undergoes a unique pattern of cortical zone-specific growth and development which is essential for normal postnatal maturation and homeostasis, but the regulation of this process is unclear. Using the baboon as a nonhuman primate translational model, and the aromatase inhibitor letrozole to suppress placental estrogen levels during the second half of pregnancy, we have shown that estrogen represses fetal zone growth and production of the androgens dehydroepiandrosterone (DHA)/DHA sulfate (DHAS), although fetal ACTH levels were unaltered. Preliminary studies show that offspring delivered from estrogen-deprived baboon pregnancies exhibit glucose intolerance/insulin resistance. We propose, therefore, that estrogen represses responsivity of the fetal cortical zone to ACTH, thereby maintaining fetal adrenal androgen and thus placental estrogen synthesis at physiological levels to ensure homeostasis after birth. The underlying mechanism(s), however, are unknown. ACTH receptor (R) binds to melanocortin 2 receptor accessory protein (MRAP) which controls ACTHR trafficking and activation. ACTH stimulates fetal adrenal expression of insulin-like growth factor (IGF)-II which promotes fetal adrenal growth. Aim 1 will test the hypothesis that estrogen represses expression/interaction of ACTHR and MRAP and consequently expression of: (a) IGF-II/IGFR and the cyclins required for growth of and (b) adenylate cyclase and the low density lipoprotein (LDL)R and enzymes required for DHA/DHAS synthesis by the fetal zone of the baboon fetal adrenal cortex. To accomplish Aim 1, components of the ACTHR signaling, IGF-II/cell cycle and steroidogenesis pathways will be assessed in fetal adrenals obtained at midgestion and near term in untreated baboons and near term in baboons treated throughout the second half of gestation with letrozole ¿ estradiol to suppress/restore estrogen. In vitro studies with baboon fetal adrenals will elucidate mechanisms underlying estrogen action. Finally, since estrogen stimulates and androgens inhibit insulin sensitivity/glucose metabolism, Aim 2 will test the hypothesis that the elevated levels of placental estrogen during the second half of gestation directly, and/or by restraining fetal adrenocortical zone androgen secretion, developmentally program components of the insulin receptor signaling pathway within insulin target tissues, i.e. skeletal muscle, of the fetus leadin to insulin sensitivity/glucose homeostasis after birth. To accomplish Aim 2, offspring from estrogen-replete or estrogen-deprived baboon pregnancies will be reared to adulthood and insulin sensitivity and components of the insulin receptor signaling pathway determined to elucidate underlying mechanisms. The knowledge gained from this study is expected to translate to the human and make the following novel conceptual advances in perinatal and developmental endocrinology: (a) estrogen regulates fetal adrenocortical growth and development and (b) estrogen directly, and/or by controlling fetal adrenocortical development, programs insulin sensitivity and consequently glucose homeostasis after birth.