Molecular Mechanisms of Adrenarche

肾上腺初现的分子机制

• 批准号: 8502466
• 负责人: William E Rainey
• 金额: $ 32.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502466
• 关键词: 11-ketotestosterone; 6 year old; Acne; Address; Adrenal Cortex; Adrenal Glands; Adult; Affect; Age; Age-Years; Aldosterone; Androgens; Axilla; Biochemical; Biological Markers; CYP11B1 gene; Child; Clinical; Dehydroepiandrosterone Sulfate; Development; Disease; Entire hair of pubis; Enzymes; Event; Funding; Future; Genes; Genomics; Goals; Growth; Hair; Hormones; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hyperandrogenism; Inorganic Sulfates; Insulin Resistance; Laboratories; Life; Mixed Function Oxygenases; Molecular; Monitor; Odors; Onset of illness; Pathway interactions; Pattern; Physiological; Play; Polycystic Ovary Syndrome; Process; Production; Research; Role; Sampling; Series; Serum; Source; Steroids; Testing; Time; Transcript; Unspecified or Sulfate Ion Sulfates; Veins; Woman; Zona Fasciculata; Zona Glomerulosa; Zona Reticularis; boys; clinically relevant; clinically significant; dehydroepiandrosterone; girls; hormone regulation; metabolomics; novel; premature; premature adrenarche; prepuberty

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.

描述（由申请人提供）：肾上腺是妇女和青春期前儿童循环雄激素库的重要贡献。与Zona glomerulosa（ZG）和Zona fasciculata（ZF）不同，Zona网状（ZR）一直相对不活跃，直到该区域扩展并显着增加DHEA-S的产生。该事件称为肾上腺素，与耻骨和腋毛生长以及青春期体气味和痤疮的发育有关。早产（PA）描述了肾上腺雄激素产生的早期升高与耻骨发育有关。现在的大量研究表明，患有PA的儿童更有可能患有成年发作疾病，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大量成年人，对PA作为潜在原因或未来疾病的早期指标的更好理解具有很高的临床意义。我的实验室通过着重于肾上腺本身及其在肾此内的肾上腺经历的变化来研究肾上腺素。在过去的融资期间，我们在肾上腺肾上腺中表现出明显的肾上腺内变化，这将使肾上腺产生一组新型的生物活性雄激素。人肾上腺静脉样品的初步类固醇代谢组学分析确定了一系列新型的雄激素，包括112-羟基睾丸激素（11OHT）和11-酮睾丸激素（11KT）。 11OHT和11KT代表了新型肾上腺特异性类固醇，因为它们的合成需要CYP11B1（112-羟化酶），这是一种几乎仅在人肾上腺皮质中表达的酶。我们提出的研究将检验以下总体假设：肾此制度的标志是生物活性雄激素的产生，这些雄激素在正常和过早肾上腺素级的生理效应中起着关键作用。我们将通过三个特定目标来解决这一目标：AIM 1将定义人类肾上腺生物活性雄激素代谢组以及肾上腺素期间这些类固醇的水平。 AIM 2将定义11OHT和11KT的肾上腺皮质生物合成途径。 AIM 3将确定在过早肾上腺素结构期间增加的生物活性雄激素。完成研究目标的完成将显着提高我们对肾上腺产物的理解，这些肾上腺产物会导致肾上腺素前几年的生化和表型表现。这一新型肾上腺雄激素的定义还将提供肾上腺失调的新生物标志物，不仅在PA中，而且对肾上腺相关的高雄激素主义女性也可能产生影响。