Adrenal Zonation and Androgen Synthesis
肾上腺分区和雄激素合成
基本信息
- 批准号:8831143
- 负责人:
- 金额:$ 6.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-06 至 2016-09-05
- 项目状态:已结题
- 来源:
- 关键词:11-ketotestosteroneAdrenal CortexAdrenal Gland TissueAdrenal GlandsAdultAnabolismAndrogensAndrostenedioneBiological MarkersBlood specimenBypassC19 steroidCYP11B1 geneCYP17A1 geneCYP21A2 geneCarbonCharacteristicsChildChronicClinicalCoenzymesCongenital adrenal hyperplasiaCorticotropinCushing SyndromeCytochromes b5DataEnzymesGeneticGlucocorticoidsGoalsGonadal structureHereditary DiseaseHumanHydrocortisoneHydroxyprogesteroneHydroxysteroid DehydrogenasesInorganic SulfatesLiquid ChromatographyMeasurementMeasuresMixed Function OxygenasesMonitorMutationOxidoreductasePathway interactionsPatientsProductionProteinsResearchRouteSerumSiteStanoloneSteroid 17-alpha-monooxygenaseSteroid 21-MonooxygenaseSteroidsTestosteroneTissuesUnspecified or Sulfate Ion SulfatesVirilismZona FasciculataZona GlomerulosaZona Reticulariscofactordehydroepiandrosteronefetalgirlsimprovednovelpublic health relevancetandem mass spectrometry
项目摘要
DESCRIPTION (provided by applicant): The most common form of congenital adrenal hyperplasia, 21-hydroxylase deficiency (21OHD), is also one of the most common genetic diseases. A hallmark characteristic of all patients with 21OHD is adrenal androgen excess. These androgens derive from accumulation of precursors, such as 17-hydroxyprogesterone (17OHP4), proximal to the defective enzymatic step, which are converted to testosterone (T) via accessible pathways involving steroid 17-hydroxylase/17, 20-lyase (CYP17A1) under the stimulation of cofactor protein cytochrome b5 (CYB5A). Dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and androstenedione (AD) are thought to be the major androgen precursors of adrenal origin. Although serum 17OHP4 has long been used to monitor treatment of CAH, it correlates poorly with DHEA and AD; furthermore, no good correlation between these routinely measured androgens and clinical evidence of androgen excess has been demonstrated. In addition, routine measurement of AD and T in adults with 21OHD can be confusing, because these steroids also derive from the gonads. A biomarker of androgen production unique to the adrenal gland would be a major advance in the management of 21OHD. We propose as biomarker candidate's 11b-hydroxylated 19- carbon steroids and their 11-keto metabolites, because 11b-hydroxylase (CYP11B1) is expressed only in the adrenal gland and not in the gonad. In addition, other androgens and precursors might be elevated in patients with 21OHD. Recent data has shown elevation of metabolites from the so-called "backdoor pathway" to dihydrotestosterone (DHT) in patients with 21OHD. These intermediates emerge via an enzymatic cascade initiated by the 5�-reduction of 17OHP4, which bypasses the intermediacy of DHEA, AD, or T to the most potent androgen, DHT. In addition, we hypothesize that the abundance of D4-androgens in these patients is facilitated by disrupted adrenal expression of androgenic enzymes and cofactors, conferring the adrenal a gonadal-like zone. The proposed studies aim to (1) determine the zonal distribution of key androgenic enzymes and cofactors within the adrenal cortex in patients with 21OHD and (2) to characterize in detail the adrenal androgen and intermediates in 21OHD, which derive via traditional and novel pathways, with the ultimate goal of identifying adrenal-specific biomarkers of androgen excess. In Aim 1, we will immunostain normal adrenal tissue and adrenal glands obtained from patients with 21OHD and ACTH-dependent Cushing syndrome for CYB5A and 3b-hydroxysteroid dehydrogenase type 2 (HSD3B2), two enzymes necessary for androgen synthesis, but normally expressed in different adrenal zones. We hypothesize that 21OHD and chronic ACTH stimulation disrupt the normal adrenal enzyme distribution, contributing to excessive androgen synthesis. In Aim 2, we will characterize steroid profiles using liquid chromatography-tandem mass spectrometry analysis of blood samples obtained from patients with classic and non-classic 21OHD and from normal controls.
描述(由申请人提供):先天性肾上腺增生症的最常见形式,21-羟化酶缺乏症(21 OHD),也是最常见的遗传性疾病之一。所有21 OHD患者的标志性特征是肾上腺雄激素过多。这些雄激素来源于前体的积累,如17-羟孕酮(17 OHP 4),接近有缺陷的酶促步骤,在辅因子蛋白细胞色素b5(CYB 5A)的刺激下,通过涉及类固醇17-羟化酶/17,20-裂解酶(CYP 17 A1)的可及途径转化为睾酮(T)。脱氢表雄酮(DHEA)及其硫酸盐(DHEAS)和雄烯二酮(AD)被认为是肾上腺来源的主要雄激素前体。虽然血清17 OHP 4长期以来一直用于监测CAH的治疗,但它与DHEA和AD的相关性很差;此外,这些常规测量的雄激素与雄激素过量的临床证据之间没有良好的相关性。此外,在21 OHD成人中常规测量AD和T可能会令人困惑,因为这些类固醇也来自性腺。一种肾上腺特有的雄激素产生生物标志物将是21 OHD治疗的一个重大进展。我们建议将11b-羟基化的19-碳类固醇及其11-酮代谢产物作为生物标志物候选物,因为11b-羟化酶(CYP 11B 1)仅在肾上腺中表达,而不在性腺中表达。此外,21 OHD患者的其他雄激素和前体可能升高。最近的数据显示,在21 OHD患者中,从所谓的“后门途径”到双氢睾酮(DHT)的代谢产物升高。这些中间体通过由17 OHP 4的5 β-还原引发的酶级联反应出现,该酶级联反应绕过DHEA、AD或T的中间作用,成为最有效的雄激素DHT。此外,我们推测,在这些患者中的D4-雄激素的丰度是促进破坏肾上腺表达的雄激素酶和辅因子,赋予肾上腺性腺样区。拟定的研究旨在(1)确定21 OHD患者肾上腺皮质内关键雄激素酶和辅因子的带状分布,(2)详细描述21 OHD中肾上腺雄激素和中间体的特征,这些中间体通过传统和新途径产生,最终目标是确定雄激素过多的肾上腺特异性生物标志物。在目标1中,我们将对正常肾上腺组织和从21 OHD和ACTH依赖性库欣综合征患者中获得的肾上腺进行CYB 5A和3b-羟基类固醇脱氢酶2型(HSD 3B 2)的免疫染色,这两种酶是雄激素合成所必需的,但通常在不同的肾上腺区表达。我们假设21 OHD和慢性ACTH刺激破坏了正常的肾上腺酶分布,导致雄激素过度合成。在目标2中,我们将使用液相色谱-串联质谱法分析从经典和非经典21 OHD患者和正常对照组中获得的血液样本来表征类固醇特征。
项目成果
期刊论文数量(0)
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Adina F Turcu其他文献
Is Screening for Primary Aldosteronism Always the Best Option?-Reply.
原发性醛固酮增多症筛查始终是最佳选择吗?-回复。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:39
- 作者:
Adina F Turcu;Suranut Charoensri;Linda Bashaw - 通讯作者:
Linda Bashaw
Adina F Turcu的其他文献
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{{ truncateString('Adina F Turcu', 18)}}的其他基金
11-Oxyandrogens and Aging: Health Implications
11-氧雄激素与衰老:健康影响
- 批准号:
10576446 - 财政年份:2023
- 资助金额:
$ 6.58万 - 项目类别:
Primary Aldosteronism Subtypes: Pathophysiology and Steroid Signatures
原发性醛固酮增多症亚型:病理生理学和类固醇特征
- 批准号:
10548823 - 财政年份:2021
- 资助金额:
$ 6.58万 - 项目类别:
Primary Aldosteronism Subtypes: Pathophysiology and Steroid Signatures
原发性醛固酮增多症亚型:病理生理学和类固醇特征
- 批准号:
10326386 - 财政年份:2021
- 资助金额:
$ 6.58万 - 项目类别:
The contemporary endocrinology of congenital adrenal hyperplasia
先天性肾上腺皮质增生症的当代内分泌学
- 批准号:
9085554 - 财政年份:2016
- 资助金额:
$ 6.58万 - 项目类别:
The contemporary endocrinology of congenital adrenal hyperplasia
先天性肾上腺皮质增生症的当代内分泌学
- 批准号:
9897565 - 财政年份:2016
- 资助金额:
$ 6.58万 - 项目类别:
The contemporary endocrinology of congenital adrenal hyperplasia
先天性肾上腺皮质增生症的当代内分泌学
- 批准号:
9276675 - 财政年份:2016
- 资助金额:
$ 6.58万 - 项目类别:
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