Molecular Mechanisms of Adrenarche

肾上腺初现的分子机制

基本信息

批准号：
8193425
负责人：
William E Rainey
金额：
$ 37.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/8193425
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Adrenarche denotes the progressive increase in adrenal androgen production that normally is detected around six years of age. Premature or exaggerated adrenarche appears to be a harbinger of adult diseases, thus increasing its clinical relevance. While DHEA and its sulfate are used to monitor adrenarche, these steroids have no androgenic bioactivity. In this proposal, we will define the bioactive androgens produced by the adrenal and define their role as markers of premature and normal adrenarche.

描述（由申请人提供）：肾上腺是女性和青春期前儿童循环雄激素库的重要贡献者。与球状带 (ZG) 和束状带 (ZF) 不同，网状带 (ZR) 在 6 岁左右之前相对不活跃，此时该区域会扩大并显着增加 DHEA-S 的产生。该事件被称为肾上腺初现，并且与阴毛和腋毛生长的开始以及青春期体臭和痤疮的发展有关。肾上腺早现 (PA) 是指肾上腺雄激素分泌过早增加，并伴有阴毛的发育。现在大量研究表明，患有 PA 的儿童更有可能患上成人发病的疾病，包括胰岛素抵抗和多囊卵巢综合征 (PCOS)。由于大量成年人受到这些疾病的影响，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。我的实验室通过关注肾上腺本身及其在肾上腺初现过程中所经历的变化来研究肾上腺初现。在我们过去的资助期间，我们展示了肾上腺初现期间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。对人肾上腺静脉样本的初步类固醇代谢组学分析发现了一系列新型雄激素，包括 112-羟基睾酮 (11OHT) 和 11-酮睾酮 (11KT)。 11OHT 和 11KT 代表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类肾上腺皮质中表达的酶。我们提出的研究将检验这样一个总体假设：肾上腺初现以生物活性雄激素的产生为标志，生物活性雄激素在正常和过早肾上腺初现的生理效应中发挥关键作用。我们将通过三个具体目标来实现这一目标：目标 1 将定义人类肾上腺生物活性雄激素代谢组以及肾上腺初现期间这些类固醇的水平。目标 2 将定义 11OHT 和 11KT 的肾上腺皮质生物合成途径。目标 3 将确定肾上腺初现过早期间增加的生物活性雄激素。研究目标的完成将显着增加我们对导致青春期前肾上腺初现的生化和表型表现的肾上腺产物的理解。这一系列新的肾上腺雄激素的定义也将提供肾上腺失调的新生物标志物，这可能不仅对 PA 产生影响，而且对患有肾上腺相关高雄激素血症的女性产生影响。公共卫生相关性：肾上腺初现是指肾上腺雄激素分泌逐渐增加，通常在六岁左右发现。过早或过度的肾上腺初现似乎是成人疾病的先兆，因此增加了其临床相关性。虽然 DHEA 及其硫酸盐用于监测肾上腺初现，但这些类固醇没有雄激素生物活性。在本提案中，我们将定义肾上腺产生的生物活性雄激素，并定义它们作为过早和正常肾上腺初现标志物的作用。