The contemporary endocrinology of congenital adrenal hyperplasia

 描述(由申请者提供)：建议的导师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内科科学家，同时推进有前途的前期工作，以改进先天性肾上腺增生症(CAH)的诊断和管理。CAH包括一组皮质醇生物合成的常染色体隐性遗传缺陷，21-羟基酶缺乏症(21OHD)占CAH病例的95%。21OHD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，代表了遗传性新陈代谢障碍的范例。然而，在21OHD的类固醇通量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年代确定的主要途径中不可靠的类固醇中间体和最终产品仍被用于诊断和监测疾病，这阻碍了提供最佳医疗保健和开发更好治疗方法的努力。这些目前使用的生物标记物与肾上腺雄激素过剩的临床证据相关性很差，而且也来自性腺，进一步限制了它们在患有210HD的成年人中的应用。这项拟议研究的长期目标是1)开发改进的方法来诊断21OHD，包括非经典疾病；2)确定导致这些患者雄激素过多的临床表现的类固醇，这将加强治疗监测。对于目标1，我们假设酶缺陷上游的一组类固醇生物标志物将在一次随机抽血中准确诊断典型和非典型21OHD。我们将使用LC-MS/MS(LC-MS/MS)来综合表征典型和非典型21OHD患者与未受影响的患者的类固醇激素。对于目标2，我们假设肾上腺特异的11-氧合雄激素是210HD雄激素过剩的主要原因。在LC-MS/MS的帮助下，我们将生成210HD患者肾上腺雄激素前体流量的详细特征，并使用与荧光素酶报告相连接的体外雄激素受体模型，我们将确定210HD中活跃的雄激素。所有研究将在密歇根大学进行，密歇根大学为完成拟议的研究提供了丰富而严谨的研究环境、理想的导师和丰富的资源。未来的方向包括在预期的多中心试验中验证从这些研究中出现的生物标记物，通过评估它们对治疗的反应。应聘者将接受遗传学、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和其他类固醇代谢紊乱的首席科学家做好充分准备。

 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.