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（由适用提供）：拟议中的指导临床科学家发展奖旨在支持将才华横溢的候选人发展成独立的身体科学家，同时促进有望的初步工作，以改善先天性肾上腺增生（CAH）的诊断和管理。 CAH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％。 21OHD以其非古典形式的患病率为1：1000，其定义的单基因起源和限制的生化基础代表了代谢遗传疾病的范式。然而，在21OHD中立体通量和生理学的科学进步已经停滞了数十年。在1950年代确定的主要途径中的不可靠的立体中间体和最终产品仍用于诊断和监测疾病，这阻碍了提供最佳医疗服务并开发更好的治疗方法的努力。这些目前使用的生物标志物与超过肾上腺雄激素的临床证据相关，并源自性腺，进一步限制了他们在21OHD成年人中的效用。拟议的研究的长期目标是1）开发改进的方法来诊断21OHD，包括非经典疾病，以及2）定义这些患者超过雄激素临床表现的立体素质，这将增强治疗监测。对于AIM 1，我们假设在单个随机抽血中，酶促缺陷上游的一组立体生物标志物将准确诊断经典和非经典21OHD。与未受影响的个体相比，我们将采用液相色谱倾斜质谱法（LC-MS/MS）来全面地表征经典和非经典21OHD患者的立体体。对于AIM 2，我们假设肾上腺特异性11-氧化雄激素主要是雄激素过量的21OHD。在LC-MS/MS的帮助下，我们将在21OHD患者中对肾上腺雄激素前体通量的详细表征，并通过使用与荧光素酶报告基因相关的体外雄激素受体模型，我们将在21OHD中定义活性雄激素。所有研究都将在密歇根大学进行，该大学提供了丰富而严格的研究环境，理想的心态和丰富的资源，以完成拟议的研究。未来的方向包括通过评估预期多中心试验中从这些研究中出现的生物标志物的验证，通过评估其对治疗的反应。候选人将在遗传学，研究设计和高级类固醇代谢组学方面进行其他培训，这将使她完全准备成为CAH和其他类固醇代谢疾病的主要科学家。

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）

Mineralocorticoid Receptor Antagonists Decrease the Rates of Positive Screening for Primary Aldosteronism.

DOI：
10.4158/ep-2020-0277
发表时间：
2020-12
期刊：
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
影响因子：
0
作者：
Tezuka Y;Turcu AF
通讯作者：
Turcu AF

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

DOI：
10.3389/fendo.2021.625457
发表时间：
2021
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Tezuka Y;Turcu AF
通讯作者：
Turcu AF

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors.

DOI：
10.1210/clinem/dgab598
发表时间：
2022-01-01
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Schröder MAM;Turcu AF;O'Day P;van Herwaarden AE;Span PN;Auchus RJ;Sweep FCGJ;Claahsen-van der Grinten HL
通讯作者：
Claahsen-van der Grinten HL

Clinical significance of 11-oxygenated androgens.