Molecular Mechanisms of Adrenarche

描述（由申请人提供）：肾上腺增生是指从肾上腺网状带产生的脱氢表雄酮和脱氢表雄酮s的显著增加，通常发生在6岁左右。肾上腺增生的表型结果是腋毛或腋毛和阴毛的发育，在8岁左右的女孩和男孩中都有发生。过早或过度的肾上腺素增高可能是成年期出现疾病的先兆，因此增加了其临床相关性。虽然诱导肾上腺素分泌的确切触发因素尚不清楚，但肾上腺雄激素产生的生化变化清楚地反映了肾上腺网状带中关键酶和辅助因子表达的变化。在本提案中，我们将重点关注肾上腺素分泌过程中这些关键酶和辅助因子的表达调控机制。在Specific Aim 1中，我们将使用微阵列分析来比较DHEA-S产生部位的网状带和皮质醇产生部位的束状带的转录谱。肾上腺素分泌的DHEA-S的增加至少部分反映了类固醇17a-羟化酶（CYP17）的C17-20裂解酶活性的增加，可能是继发于电子供体细胞色素b5表达的增加，以及dhea -硫转移酶（SULT2A1）的增加。初步数据已经确定了某些关键转录因子的差异，这些转录因子可能会改变DHEA-S产生酶的表达模式。在Specific Aim 2中提出的研究将集中在这些转录因子上调细胞色素b5和SULT2A1的作用，以及我们在微阵列研究中发现的作为网状带功能关键成分的其他基因。非细胞色素P450酶3b-羟基类固醇脱氢酶（HSD3B2）具有独特的能力，可以从通向DHEA-S的途径中去除前体，从而抑制肾上腺雄激素的生物合成。HSD3B2在束状带的皮质醇生成细胞中高水平表达，但一旦肾上腺素分泌开始，在网状肌中就不存在。在Specific Aim 3中，我们将定义阻断网状带中HSD3B2表达的分子机制。总的来说，拟议的研究将提供肾上腺皮质在肾上腺素分泌期间发生的分子改变的详细图片，并应阐明肾上腺内调节肾上腺雄激素产生的机制。

DESCRIPTION (provided by applicant): Adrenarche denotes the marked increase in DHEA and DHEA-S production from the adrenal zona reticularis that normally occurs at around 6 years of age. The phenotypic result of adrenarche is pubarche or the development of axillary and pubic hair that occurs in both girls and boys at about age 8. Premature or exaggerated adrenarche may be a harbinger of diseases that manifest in adulthood, thus increasing its clinical relevance. While the exact trigger that induces adrenarche remains poorly understood, the biochemical alterations in adrenal androgen production clearly reflect changes in the expression of key enzymes and cofactors in the adrenal zona reticularis. In this proposal, we focus on the mechanisms that regulate the expression of these key enzymes and cofactors during adrenarche. In Specific Aim 1, we will use microarray analyses to compare the transcription profiles of the zona reticularis at the site where DHEA-S is produced and the zona fasciculata, where cortisol is made. The increase in DHEA-S production seen at adrenarche at least partly reflects an increase in the C17-20 lyase activity of steroid 17a-hydroxylase (CYP17), presumably secondary to increased expression of the electron donor cytochrome b5, and an increase in DHEA-sulfotransferase (SULT2A1). Preliminary data already have identified differences in certain key transcription factors that may modify the expression pattern of the DHEA-S producing enzymes. Studies proposed in Specific Aim 2 will focus on the roles of these transcription factors to up-regulate cytochrome b5 and SULT2A1, as well as other genes identified in our microarray studies as key components of zona reticularis function. The noncytochrome P450 enzyme 3b-hydroxysteroid dehydrogenase (HSD3B2) has the unique ability to remove precursors from the pathway leading to DHEA-S thereby inhibiting adrenal androgen biosynthesis. HSD3B2 is expressed at high levels in cortisol-producing cells of the zona fasciculata but is absent in the reticularis once adrenarche is initiated. In Specific Aim 3, we will define the molecular mechanisms that block HSD3B2 expression in the zona reticularis. Collectively, the proposed studies will provide a detailed picture of the molecular alterations that occur in the adrenal cortex during adrenarche and should also elucidate the intra-adrenal mechanisms regulating adrenal androgen production.