Molecular Mechanisms of Adrenarche

描述(申请人提供)：肾上腺原是指肾上腺网状带的脱氢表雄酮和脱氢表雄酮-S的产量显著增加，通常发生在6岁左右。肾上腺的表型结果是耻骨或腋毛和阴毛的发育，在大约8岁的女孩和男孩中都会出现。过早或夸张的肾上腺可能是成年后出现的疾病的先兆，因此增加了其临床意义。虽然诱发肾上腺原癌的确切触发因素仍不清楚，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关键酶和辅因子表达的变化。在这项建议中，我们将重点放在肾上腺发育过程中调节这些关键酶和辅因子表达的机制上。在具体目标1中，我们将使用微阵列分析来比较产生脱氢表雄酮-S的网状带和产生皮质醇的束状带的转录图谱。脱氢表雄酮-S产量的增加至少部分反映了类固醇17a-羟基酶C17-20裂解酶(C17-20裂解酶)活性的增加，这可能是由于电子供体细胞色素b5表达增加和脱氢表雄酮-磺基转移酶(SULT2A1)增加所致。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脱氢表雄酮-S产生酶的表达模式。在特定目标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SULT2A1的作用，以及我们的微阵列研究中确定的其他基因，这些基因是网状带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(HSD3B2)具有从脱氢表雄酮-S途径中去除前体从而抑制肾上腺雄激素生物合成的独特能力。HSD3B2在束状带的皮质醇产生细胞中高水平表达，但在肾上腺起始时在网状肌中不表达。在具体目标3中，我们将确定阻止HSD3B2在网状带表达的分子机制。总的来说，拟议的研究将提供肾上腺始动过程中肾上腺皮质发生的分子变化的详细图景，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.