Molecular Mechanisms of Adrenarche

肾上腺初现的分子机制

• 批准号: 8010062
• 负责人: William E Rainey
• 金额: $ 10万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010062
• 关键词: 6 year old; 8 year old; Address; Adrenal Cortex; Adrenal Glands; Adult; Age; Aldosterone; Anabolism; Androgens; Axilla; Biochemical; Biological Models; CYP17A1 gene; Cell Culture Techniques; Cells; Coenzymes; Cytochrome P450; Cytochromes b5; DNA Methylation; Data; Dehydroepiandrosterone Sulfate; Development; Disease; Endocrine Physiology; Entire hair of pubis; Enzymes; Family; Family member; GATA6 transcription factor; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; Goals; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Immunohistochemistry; Inorganic Sulfates; Link; Lyase; Microarray Analysis; Mixed Function Oxygenases; Modeling; Molecular; Molecular Profiling; NR4A1 gene; Pathway interactions; Pattern; Process; Production; Regulation; Role; Secondary to; Signal Pathway; Site; Steroids; Time; Trans-Activators; Unspecified or Sulfate Ion Sulfates; Zinc Fingers; Zona Fasciculata; Zona Glomerulosa; Zona Reticularis; base; boys; clinically relevant; dehydroepiandrosterone; dehydroepiandrosterone sulfotransferase; electron donor; girls; insight; premature; protein expression; src-Family Kinases; transcription factor

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.

描述（由申请人提供）：肾上腺素法表示通常发生在6岁左右的肾上腺Zona网状网状物质的DHEA和DHEA-S产生显着增加。肾上腺素的表型结果是在大约8岁的男孩和男孩中发生的腋毛和阴毛的发展。过早或夸张的肾上腺素可能是在成年后表现出的疾病的预兆，从而增加了其临床相关性。虽然诱导肾上腺素的确切触发因素仍然尚不清楚，但肾上腺雄激素产生的生化改变显然反映了肾上腺Zona网状肾上腺素和辅助因子表达的变化。在此提案中，我们专注于调节肾上腺素期间这些关键酶和辅助因子表达的机制。在特定的目标1中，我们将使用微阵列分析比较生产DHEA-S的位点的Zona网状分析和制作皮质醇的Zona fasciculata。在肾上腺素结构上看到的DHEA-S产生的增加至少部分反映了类固醇17A-羟化酶（CYP17）的C17-20石油酶活性的增加，这可能是继发于电子供体细胞色素B5表达的继发性的，而DHEA-Sulfotransforperase（Sutt2A1A1）的表达增加。初步数据已经确定了某些关键转录因子的差异，这些因子可能会改变DHEA-S产生酶的表达模式。在特定目标2中提出的研究将重点介绍这些转录因子上调细胞色素B5和Sult2A1的作用，以及在我们的微阵列研究中确定的其他基因作为Zona neticularis功能的关键组成部分。非循环P450酶3B-羟基固醇脱氢酶（HSD3B2）具有从通往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。 HSD3B2在Zona fasciculata的皮质醇产生细胞中以高水平表达，但一旦开始肾上腺素，就没有在网状骨中表达。在特定的目标3中，我们将定义阻断Zona网状中HSD3B2表达的分子机制。总的来说，拟议的研究将提供详细的图景，说明肾上腺肾上腺皮质中发生的分子改变，还应阐明调节肾上腺雄激素产生的肾上腺内机制。