Molecular Mechanisms of Adrenarche

描述(由申请人提供)：肾上腺是女性和青春期前儿童体内循环雄激素池的重要贡献者。与球状带(ZG)和束状带(ZF)不同，网状带(ZR)直到6岁左右才相对不活跃，此时该带扩大并显著增加DHEA-S的产生。这一事件被称为肾上腺，与阴毛和腋毛的生长以及青春期体臭和粉刺的发展有关。肾上腺早熟(PA)描述伴随着阴毛发育而产生的肾上腺雄激素的早期增加。许多研究表明，患有PA的儿童更有可能出现成人发病的疾病，包括胰岛素抵抗和多囊卵巢综合征(PCOS)。由于受这些疾病影响的成人人数众多，更好地了解PA作为未来疾病的潜在原因或早期指标具有高度的临床意义。我的实验室通过专注于肾上腺本身及其在肾上腺形成过程中所经历的变化来接近肾上腺的研究。在我们过去的资助期间，我们展示了肾上腺原始期肾上腺内的明显变化，这将使肾上腺产生一套新的生物活性雄激素。对人肾上腺静脉样本进行的类固醇代谢分析初步确定了一系列新的雄激素，包括112-羟基睾酮(11OHT)和11-酮睾酮(11kT)。11OHT和11kT代表了新的肾上腺特异性类固醇，因为它们的合成需要CYP11B1(112-羟基酶)，这是一种几乎只在人类肾上腺皮质表达的酶。我们提议的研究将检验这样一个总体假设，即肾上腺素是以产生生物活性雄激素为标志的，而生物活性雄激素在正常和早熟肾上腺的生理效应中发挥关键作用。我们将通过三个具体目标来解决这一目标：目标1将定义人类肾上腺生物活性雄激素代谢组和肾上腺发育过程中这些类固醇的水平。目标2将确定11OHT和11kT的肾上腺皮质生物合成途径。目标3将确定在肾上腺发育早期增加的生物活性雄激素。研究目标的完成将大大增加我们对导致青春期前肾上腺原发疾病的生化和表型表现的肾上腺产物的了解。这一新的肾上腺雄激素系列的定义也将为肾上腺失调提供新的生物标志物，这不仅可能对PA有影响，而且对肾上腺相关的高雄激素血症的女性也有意义。

DESCRIPTION (provided by applicant): The adrenal gland is a significant contributor to the circulating androgen pool in women and pre- pubertal children. Unlike the zona glomerulosa (ZG) and zona fasciculata (ZF), the zona reticularis (ZR) is relatively inactive until around 6 years of age when the zone expands and significantly increases the production of DHEA-S. This event is termed adrenarche, and is associated with the initiation of pubic and axillary hair growth as well as development of pubertal body odor and acne. Premature adrenarche (PA) describes an early rise in adrenal androgen production associated with concomitant development of pubic hair. Numerous studies now indicate that children with PA are more likely to have adult onset diseases that include insulin resistance and polycystic ovary syndrome (PCOS). Because of the large number of adults affected by these diseases, a better understanding of PA as a potential cause or early indicator of future disease has a high degree of clinical significance. My laboratory has approached the study of adrenarche by focusing on the adrenal itself and the changes it undergoes during the process of adrenarche. During our past funding period, we demonstrated distinct intra-adrenal changes during adrenarche that would allow the adrenal to produce a novel set of bioactive androgens. Preliminary steroid metabolomic analysis of human adrenal vein samples identified a series of novel androgens, including 112-hydroxytestosterone (11OHT) and 11- ketotestosterone (11KT). 11OHT and 11KT represent novel adrenal-specific steroids because their synthesis requires CYP11B1 (112-hydroxylase), an enzyme expressed almost solely in the human adrenal cortex. Our proposed research will test the overall hypothesis that adrenarche is marked by the production of bioactive androgens that play key roles in the physiologic effects of normal and premature adrenarche. We will address this goal through three specific aims: Aim 1 will define the human adrenal bioactive androgen metabolome and the levels of these steroids during adrenarche. Aim 2 will define the adrenocortical biosynthetic pathway for 11OHT and 11KT. Aim 3 will determine the bioactive androgens that increase during premature adrenarche. Completion of the study goals will significantly increase our understanding of the adrenal products that cause the biochemical and phenotypic manifestations of adrenarche during the pre-pubertal years. Definition of this novel series of adrenal androgens will also provide new biomarkers of adrenal dysregulation that may have implications not only in PA but also in women with adrenal-related hyperandrogenism.