The contemporary endocrinology of congenital adrenal hyperplasia

 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独立的医生-科学家，同时推进有前途的初步工作，以改善先天性肾上腺增生症（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，并且21-羟化酶缺乏症（21 OHD）占CAH病例的>95%。21 OHD的非经典型患病率为1：1000，具有明确的单基因起源和限定的生化基础，代表了代谢遗传性疾病的范例。然而，关于21 OHD中类固醇通量和生理学的科学进展几十年来一直停滞不前。1950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志物与肾上腺雄激素过多的临床证据相关性很差，并且也来自性腺，进一步限制了它们在21 OHD成人中的应用。拟议研究的长期目标是：1）开发诊断21 OHD（包括非经典疾病）的改进方法; 2）确定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，我们假设酶缺陷上游的一组类固醇生物标志物将在单次随机抽血中准确诊断经典和非经典21 OHD。我们将采用液相色谱-串联质谱法（LC-MS/MS）来全面表征经典和非经典21 OHD患者与未受影响的个体相比的类固醇。对于目标2，我们假设肾上腺特异性11-氧合雄激素是21 OHD雄激素过量的主要原因。在LC-MS/MS的帮助下，我们将生成21 OHD患者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连接的体外雄激素受体模型，我们将定义21 OHD中的活性雄激素。所有研究将在密歇根大学进行，该大学为完成拟议的研究提供了丰富而严格的研究环境，理想的导师和丰富的资源。未来的方向包括通过评估这些研究对治疗的反应，在前瞻性多中心试验中验证这些研究中出现的生物标志物。候选人将在遗传学，研究设计和先进的类固醇代谢组学方面进行额外的培训，这将使她为成为CAH和其他类固醇代谢疾病的首席科学家做好充分准备。

 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.