Primate Fetal Adrenal Development: Impact on Physiological Processes After Birth

灵长类动物胎儿肾上腺发育：对出生后生理过程的影响

• 批准号: 8502094
• 负责人: Eugene D. Albrecht
• 金额: $ 59.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502094
• 关键词: Adenylate Cyclase; Adrenal Cortex; Adrenal Glands; Adult; Androgens; Aromatase Inhibitors; Binding; Birth; Cell Cycle; Cholesterol; Corticotropin; Corticotropin Receptors; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; Dehydroepiandrosterone Sulfate; Development; Developmental Endocrinology; Endocrine Disruptors; Ensure; Enzymes; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Feedback; Fetal Development; Fetus; Glucose Intolerance; Growth; Growth and Development function; Homeostasis; Hormonal; Human; Hydrocortisone; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor II; Insulin-Like-Growth Factor I Receptor; Knowledge; Letrozole; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lyase; Mediating; Melanocortin 2 Receptor; Mixed Function Oxygenases; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Organ; Papio; Pathway interactions; Pattern; Perinatal; Perinatal Exposure; Phenotype; Physiological; Physiological Processes; Pregnancy; Premature Birth; Primates; Process; Production; Program Development; Proteins; Receptor Signaling; Regulation; Research; Risk; Role; Serum; Side; Signal Pathway; Signal Transduction; Skeletal Muscle; Steroid biosynthesis; Study models; Testing; Tissues; Translating; blood glucose regulation; dehydroepiandrosterone; fetal; glucose metabolism; in utero; insulin sensitivity; nonhuman primate; novel; offspring; postnatal; prevent; programs; protein expression; public health relevance; receptor binding; trafficking; uptake

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.

描述（由申请人提供）：人胎儿肾上腺经历了一种独特的皮质区特异性生长和发育模式，这对正常的出生后成熟和体内平衡至关重要，但该过程的调控尚不清楚。使用狒狒作为非人灵长类动物的翻译模型，芳香化酶抑制剂来曲唑抑制胎盘雌激素水平在怀孕的后半段，我们已经表明，雌激素抑制胎儿区的生长和生产的雄激素脱氢表雄酮（DHA）/DHA硫酸盐（DHAS），虽然胎儿ACTH水平不变。初步研究表明，从雌激素缺乏的狒狒怀孕分娩的后代表现出葡萄糖耐受不良/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，以确保出生后的稳态。然而，其潜在机制尚不清楚。促肾上腺皮质激素受体（R）与黑皮质素2受体辅助蛋白（MRAP）结合，后者控制促肾上腺皮质激素受体的运输和激活。ACTH刺激胎儿肾上腺胰岛素样生长因子（IGF）-II的表达，促进胎儿肾上腺生长。目的1将检验雌激素抑制ACTHR和MRAP的表达/相互作用，并因此抑制以下表达的假设：（a）IGF-Ⅱ/IGFR和生长所需的细胞周期蛋白，以及（B）腺苷酸环化酶和低密度脂蛋白（LDL）R和狒狒胎儿肾上腺皮质的胎儿区合成DHA/DHAS所需的酶。为了实现目标1，将在未给药狒狒的孕中期和近足月以及在整个妊娠后半期用来曲唑？雌二醇治疗以抑制/恢复雌激素的狒狒的近足月获得的胎肾上腺中评估ACTHR信号传导、IGF-II/细胞周期和类固醇生成途径的组分。狒狒胎儿肾上腺的体外研究将阐明雌激素作用的机制。最后，由于雌激素刺激胰岛素敏感性/葡萄糖代谢，而雄激素抑制胰岛素敏感性/葡萄糖代谢，因此目的2将检验以下假设：妊娠后半期胎盘雌激素水平升高直接和/或通过抑制胎儿肾上腺皮质区雄激素分泌，在胰岛素靶组织（即骨骼肌）内对胰岛素受体信号传导途径的组分进行发育程序，导致出生后胰岛素敏感性/葡萄糖稳态。为了实现目标2，将雌激素充足或雌激素缺乏的狒狒妊娠的后代饲养至成年，并确定胰岛素敏感性和胰岛素受体信号传导途径的组分以阐明潜在的机制。从本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，调节胰岛素敏感性，从而调节出生后的葡萄糖稳态。