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

基本信息

批准号：
9897565
负责人：
Adina F Turcu
金额：
$ 16.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897565
关键词：
11-ketotestosterone 21-hydroxylase deficiency Adrenal Glands Adult Anabolism Androgen Receptor Androgens Androstenedione Biochemical Biological Markers Blood Blood Circulation CYP11B1 gene CYP17A1 gene CYP21A2 gene Carbon Caring Clinical Congenital adrenal hyperplasia Cosyntropin Cushing Syndrome Data Defect Development Diagnosis Disease Endocrinology Environment Enzymes Functional disorder Future Genetic Diseases Genetic study Glucocorticoids Goals Gonadal structure Hydrocortisone Hydroxyprogesterone Hyperaldosteronism In Vitro Individual Lead Link Liquid Chromatography Luciferases Measurement Measures Medical Mentored Clinical Scientist Development Award (K08)Mentorship Metabolic Diseases Methods Michigan Mixed Function Oxygenases Modeling Monitor Multicenter Trials Mutation Oxidoreductase Pathway interactions Patient Monitoring Patients Physicians Physiology Pregnanes Prevalence Production Reporter Research Research Design Resources Route Scientist Serum Stanolone Steroid 21-Monooxygenase Steroids Sulfate Talents Testing Testosterone Training Universities Virilism Work accurate diagnosis androgenic biomarker validation candidate marker dehydroepiandrosterone girls improved metabolomics novel overtreatment prospective public health relevance recessive genetic trait specific biomarkers steroid metabolism disorder tandem mass spectrometry treatment response

项目摘要

DESCRIPTION (provided by applicant): The proposed Mentored Clinical Scientist Development Award aims to support the development of a talented candidate into an independent physician-scientist, while advancing promising preliminary work to improve the diagnosis and management of congenital adrenal hyperplasia (CAH). CAH comprises a set of autosomal recessive genetic defects in cortisol biosynthesis, and 21-hydroxylase deficiency (21OHD) accounts for >95% of CAH cases. With a prevalence of 1:1000 in its nonclassic form, a defined monogenic origin, and circumscribed biochemical basis, 21OHD represents a paradigm for genetic disorders of metabolism. Scientific progress on steroid flux and physiology in 21OHD, however, has been stagnant for decades. Unreliable steroid intermediates and final products in major pathways identified in the 1950s are still used to diagnose and to monitor disease, which hampers efforts to provide optimal medical care and to develop better treatments. These currently used biomarkers correlate poorly with clinical evidence of adrenal androgen excess and also derive from the gonad, further limiting their utility in adults with 21OHD. The long-term goals of the proposed research are 1) to develop improved methods to diagnose 21OHD, including nonclassic disease and 2) to define the steroids responsible for clinical manifestations of androgen excess in these patients, which will enhance treatment monitoring. For Aim 1, we hypothesize that a panel of steroid biomarkers upstream the enzymatic defect will accurately diagnose classic and nonclassic 21OHD in a single random blood draw. We will employ liquid chromatography-tandem mass spectrometry (LC-MS/MS) to comprehensively characterize steroids in patients with classic and nonclassic 21OHD compared to unaffected individuals. For Aim 2, we hypothesize that adrenal-specific 11-oxygenated androgens are primarily responsible for the androgen excess of 21OHD. With the help of LC-MS/MS, we will generate a detailed characterization of the adrenal androgen precursors flux in patients with 21OHD, and by using an in vitro androgen receptor model linked to a luciferase reporter, we will define the active androgens in 21OHD. All studies will be conducted at the University of Michigan, which provides a rich and rigorous research environment, ideal mentorship and abundant resources for the completion of the proposed studies. Future directions include validation of the biomarkers emerging from these studies in prospective multicenter trials, by assessing their response to treatment. The candidate will pursue additional training in genetics, study design, and advanced steroid metabolomics, which will fully prepare her to become a lead scientist in CAH and other disorders of steroid metabolism.

描述（由申请人提供）：拟议的指导临床科学家发展奖旨在支持有才华的候选人发展成为一名独立的医师科学家，同时推进有前景的初步工作，以改善先天性肾上腺增生症（CAH）的诊断和治疗。包括皮质醇生物合成中的一组常染色体隐性遗传缺陷，21-羟化酶缺乏症 (21OHD) 占 CAH 病例的 95% 以上。 21OHD 的非经典形式的患病率为 1:1000，具有明确的单基因起源和有限的生化基础，代表了 21OHD 类固醇流动和生理学方面的科学进展几十年来一直停滞不前。 20 世纪 50 年代发现的主要途径中不可靠的类固醇中间体和最终产品仍然用于诊断和监测疾病，这阻碍了提供最佳医疗护理和开发更好治疗方法的努力。目前使用的这些生物标志物与肾上腺雄激素过多的临床证据相关性较差，并且也源自性腺，进一步限制了它们在 21OHD 成人中的应用。拟议研究的长期目标是 1) 开发诊断 21OHD 的改进方法，包括。 2) 定义导致这些患者雄激素过多临床表现的类固醇，这将加强治疗监测。对于目标 1，我们认为一组类固醇生物标志物位于男性的上游。酶缺陷将在单次随机抽血中准确诊断经典和非经典 21OHD。我们将采用液相色谱-串联质谱 (LC-MS/MS) 来全面表征经典和非经典 21OHD 患者与未受影响个体的类固醇特征。 2、我们承认肾上腺特异性11-氧化雄激素是导致21OHD雄激素过多的主要原因。 LC-MS/MS，我们将生成 21OHD 患者肾上腺雄激素前体通量的详细特征，并通过使用与荧光素酶报告基因连接的体外雄激素受体模型，我们将定义 21OHD 中的活性雄激素。该研究在密歇根大学进行，该大学为完成拟议的研究提供了丰富而严格的研究环境、理想和丰富的资源，未来的方向包括对这些研究中出现的生物标志物进行前瞻性验证。多中心试验，通过评估他们对治疗的反应，候选人将接受遗传学、研究设计和高级类固醇代谢组学方面的额外培训，这将为她成为 CAH 和其他类固醇代谢疾病的首席科学家做好充分准备。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Clinical Impact of [68 Ga]-DOTATATE PET/CT for the Diagnosis and Management of Ectopic Adrenocorticotropic Hormone - Secreting Tumours.

[68 Ga]-DOTATATE PET/CT 对异位促肾上腺皮质激素分泌肿瘤的诊断和治疗的临床影响。

DOI：
发表时间：
2019
期刊：
影响因子：
3.2
作者：
Wannachalee, Taweesak;Turcu, Adina F;Bancos, Irina;Habra, Mouhammed Amir;Avram, Anca M;Chuang, Hubert H;Waguespack, Steven G;Auchus, Richard J
通讯作者：
Auchus, Richard J

Real-World Effectiveness of Mineralocorticoid Receptor Antagonists in Primary Aldosteronism.

盐皮质激素受体拮抗剂在原发性醛固酮增多症中的实际疗效。