Molecular Mechanisms of Adrenarche

描述（由申请人提供）：肾上腺初显是指通常发生在6岁左右的肾上腺网状组织中DHEA和DHEA-S的产生显著增加。肾上腺初长的表型结果是阴毛初长或腋毛和阴毛的发育，男孩和女孩都在8岁左右出现。过早或过度的肾上腺初显可能是成年期疾病的先兆，因此增加了其临床相关性。虽然诱导肾上腺初显的确切触发因素仍然知之甚少，但肾上腺雄激素产生的生化改变清楚地反映了肾上腺网状层中关键酶和辅因子表达的变化。在这个建议中，我们专注于肾上腺初显过程中调节这些关键酶和辅因子表达的机制。在具体目标1中，我们将使用微阵列分析来比较产生DHEA-S的网状内皮细胞和产生皮质醇的束状内皮细胞的转录谱。在肾上腺初显时观察到的DHEA-S产量增加至少部分反映了类固醇17 α-羟化酶（CYP 17）的C17-20裂解酶活性增加，推测继发于电子供体细胞色素b5表达增加和DHEA-磺基转移酶（SULT 2A 1）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生产酶的表达模式。在具体目标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SULT 2A 1的作用，以及在我们的微阵列研究中确定的其他基因作为网状内皮功能的关键组成部分。非细胞色素P450酶3b-羟基类固醇脱氢酶（HSD 3B 2）具有从导致DHEA-S的途径中去除前体的独特能力，从而抑制肾上腺雄激素生物合成。HSD 3B 2在皮质醇产生细胞的肾上腺束细胞中高水平表达，但一旦肾上腺初显开始，网状层中就不存在。在具体目标3中，我们将确定阻断网状内皮细胞中HSD 3B 2表达的分子机制。总的来说，拟议的研究将提供肾上腺初显期间肾上腺皮质中发生的分子改变的详细情况，还应阐明调节肾上腺雄激素产生的肾上腺内机制。

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.