ANDROGEN PRODUCTION IN ADRENARCHE AND PCOS

肾上腺初现和多囊卵巢综合征中雄激素的产生

基本信息

批准号：
7036609
负责人：
WALTER L. MILLER
金额：
$ 33.29万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

项目摘要

Adrenarche is the peri-pubertal event when the human adrenal begins to make large amounts of 19-carbon steroids, especially dehydroepiandrosterone (DHEA). Children normally begin adrenarche at about age 8-9 before the onset of puberty. Clinical studies show that early, exaggerated adrenarche maybe an early sign of the polycystic ovary syndrome (PCOS), which affects 3-5 percent of women of reproductive age. PCOS women have increased secretion of C-19 androgens from both the adrenals and ovaries. The conversion of 17OH pregnenolone to DHEA by the 17,20 lyase activity of cytochrome p450c17 determines the amount of androgen produced in both tissues. P450c17 catalyzes both 17alpha-hydroxylase and 17,20 lyase activities. Each activity requires the donation of a pair of electrons from p450 oxidoreductase (OR). The mechanisms of the tissue-specific expression of P450c17 in the adrenal and gonad are unknown. When expressed in the zona fasciculata, P450c17 catalyzes 17alpha- hydroxylase but very little 17,20 lyase activity to produce cortisol. When it is expressed in the adrenal zona reticularis and in the gonad, it has high 17,20 lyase activity and catalyzes the formation of DHEA, the precursor of androgens and estrogens. At least two factors regulate the 17,20 lyase activity of P450c17 at a post-translational level: the presence of cytochrome b5, which allosterically fosters the interaction of P450cl7 with OR, and serine phosphorylation of P450c17, which increases 17,20 lyase activity by unknown mechanisms. We propose to elucidate the key transcriptional and post-translational mechanisms of regulation of P450c17 by pursuing four specific aims. Aim 1: Identify the factors required for tissue-specific basal transcription of the human p450c17 gene. Aims 2: Identify the kinase(s) responsible for P450c17 phosphorylation. Aim 3: Determine whether the degree of phosphorylation of P450c17 is regulated by dephosphorylation (phosphatases). Aim 4: Determine how P450c17 phosphorylation influences 17,20 lyase activity. Fulfillment of these four aims will greatly expand our understanding of the mechanisms by which androgen production is regulated in both health and disease and should provide novel insights into the mechanisms by which the adrenals and gonads of women with PCOS overproduce androgens.

肾上腺素是人肾上腺开始生产大量19碳类固醇，尤其是脱氢表雄酮（DHEA）时。儿童通常在青春期发作之前的8-9岁左右开始肾上腺素。临床研究表明，早期，夸张的肾上腺素可能是多囊卵巢综合征（PCOS）的早期迹象，这会影响3-5％的生殖年龄妇女。 PCOS妇女增加了肾上腺和卵巢中C-19雄激素的分泌。通过17,20个细胞色素P450C17的17,20石晶酶活性将17OH妊娠烯酮转化为DHEA，决定了这两种组织中产生的雄激素量。 P450C17催化17Alpha-羟化酶和17,20个裂解酶活性。每种活动都需要从P450氧化还原酶（OR）捐赠一对电子。肾上腺和性腺中P450C17组织特异性表达的机制尚不清楚。当在Zona fasciculata中表达时，P450C17催化17Alpha-羟化酶，但几乎没有17,20层裂解酶活性产生皮质醇。当它在肾上腺Zona网状和性腺中表达时，它具有高17,20裂解酶活性，并催化DHEA的形成，DHEA是雄激素和雌激素的前体。至少有两个因素在翻译后级别调节P450C17的17,20个裂解酶活性：细胞色素B5的存在，它们在变构中促进了P450CL7与OR的相互作用，以及P450C17的丝氨酸磷酸化，从而增加了17,20 Lyase活性，从而增加未知机制。我们建议通过追求四个具体目标来阐明P450C17调节的关键转录和翻译后机制。目标1：确定人P450C17基因组织特异性基础转录所需的因素。目标2：确定导致P450C17磷酸化的激酶。 AIM 3：确定P450C17的磷酸化程度是否通过去磷酸化（磷酸酶）调节。 AIM 4：确定P450C17磷酸化如何影响17,20裂解酶活性。实现这四个目标将大大扩展我们对健康和疾病中雄激素产生的机制的理解，并应提供新的见解，以了解PCOS过量生产雄激素的妇女的肾上腺肾上腺和性腺。