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

基本信息

批准号：
10326386
负责人：
Adina F Turcu
金额：
$ 70.2万
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：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326386
关键词：
ATP1A1 gene Address Adrenal Gland Diseases Adrenal Gland Neoplasms Adrenal Glands Affect Aldosterone Bilateral Biological Markers Blood Blood Tests Cardiac Cardiovascular system Cells Classification Clinical Common Neoplasm Community Practice Corticotropin Costs and Benefits Cosyntropin Data Data Analyses Detection Dexamethasone Diagnosis Diagnostic Disease Essential Hypertension Fingerprint Functional disorder General Practitioners Genes Genomics Genotype Goals Heterogeneity High Prevalence Histologic Hormonal Hybrids Hyperaldosteronism Hypertension Image Immunohistochemistry Ion Channel Ion Pumps Kidney Lesion Life Mass Spectrum Analysis Measures Medical Methods Mineralocorticoid Receptor Morbidity - disease rate Mutate Mutation Operative Surgical Procedures Patients Peripheral Pharmacology Phenotype Potassium Potassium Channel Primary Health Care Procedures Production Protocols documentation Provider Public Health Research Resistant Hypertension Sampling Serum Somatic Mutation Source Standardization Steroids Techniques Temperature Testing Tissues Variant Veins adenoma adrenal hypertension antagonist biomedical referral center cardiovascular risk factor cost design hypertension treatment medical specialties mortality next generation sequencing novel peripheral blood personalized care prevent response standard of care tool tumor voltage

项目摘要

ABSTRACT Primary aldosteronism (PA) is the most common adrenal disorder and the most common cause of endocrine hypertension. PA is associated with cardiovascular morbidity and mortality that are disproportionately higher compared to those observed in patients with similar degree of essential hypertension. The two major types of PA are unilateral PA (typically an aldosterone producing adenoma, APA, ~40% of PA cases), which can be cured with surgery, and bilateral hyperaldosteronism (BHA, ~60% of PA cases), which requires life-long targeted medical therapy. Despite its high prevalence and serious cardio-renal complications, PA is underdiagnosed, in part because the steps for diagnosis and subtyping are complicated, costly, and invasive. Adrenal imaging is inaccurate in identifying the source(s) of excessive aldosterone production. Consequently, the current standard-of-care for PA subtyping is adrenal vein sampling (AVS), which is an invasive, technically challenging, and poorly standardized procedure, with availability limited to tertiary referral centers. The overall objectives of this application are: 1) to define the steroid synthetic capacity of various APAs by implementing comprehensive histologic, genomic and steroid profiling analyses of APA tissue; 2) combine baseline and dynamic blood tests to define the steroid signatures of PA subtypes in peripheral blood. This approach will eliminate the need for AVS in over 60% PA patients (BHA). Two specific aims have been designed to address critical gaps in the care of PA patients. • In Aim 1, we will probe the working hypothesis that APAs with distinct underlying aldosterone-driver somatic mutations have specific steroid fingerprints. We will implement CYP11B2 immunohistochemistry-guided next-generation sequencing (NGS) to characterize the somatic mutations underlying APAs. In parallel, we will use state-of-the-art mass spectrometry to define the steroid profiles of APAs from: (a) optimal cutting temperature (OCT)-embedded APA tissue; (b) blood from the adrenal veins draining these tumors; and (c) peripheral blood. • In Aim 2, we will test the working hypothesis that panels of steroid biomarkers measured in peripheral blood can distinguish APAs from both BHA and essential hypertension. We will implement baseline and dynamic testing (ACTH stimulation and Dexamethasone suppression) to identify differences between the steroid signatures of PA subtypes. Mass spectrometry will be used to quantify steroids in patients with PA and essential hypertension. This approach will directly address the critical clinical need to simplify PA diagnosis and subtyping and will take essential steps towards our long-term goal, of expanding personalized PA treatment and maximizing the number of cured PA cases.

抽象的原发性醛固酮增多症 (PA) 是最常见的肾上腺疾病，也是导致肾上腺皮质功能减退症的最常见原因。 PA 与心血管发病率和死亡率不成比例地相关。与具有相似程度的原发性高血压的患者相比更高。 PA 类型为单侧 PA（通常为产生醛固酮的腺瘤，APA，约占 PA 病例的 40%），可可以通过手术治愈，双侧醛固酮增多症（BHA，约占 PA 病例的 60%）需要终生治疗尽管 PA 的患病率很高且存在严重的心肾并发症，但它仍然是一种有针对性的药物治疗。诊断不足，部分原因是诊断和分型步骤复杂、昂贵且具有侵入性。肾上腺成像无法准确识别所检查的醛固酮生成过多的来源。目前 PA 亚型分型的护理标准是肾上腺静脉采样 (AVS)，这是一种侵入性的技术具有挑战性且标准化程度差的程序，仅限于三级转诊中心。本申请的总体目标是：1) 定义各种 APA 的类固醇合成能力通过对 APA 组织进行全面的组织学、基因组和类固醇分析分析 2) 结合；基线和动态血液测试，以确定外周血中 PA 亚型的类固醇特征。该方法将消除超过 60% PA 患者 (BHA) 的 AVS 需求。解决 PA 患者护理中的关键差距 • 在目标 1 中，我们将探讨 APA 的工作假设。具有独特的潜在醛固酮驱动体细胞突变具有特定的类固醇指纹，我们将实施。 CYP11B2 免疫组织化学引导的下一代测序 (NGS) 来表征体细胞与此同时，我们将使用最先进的质谱法来定义类固醇。来自以下的 APA 概况：(a) 最佳切割温度 (OCT) 包埋的 APA 组织；(b) 来自肾上腺的血液；引流这些肿瘤的静脉；以及 (c) 外周血在目标 2 中，我们将检验小组的工作假设。外周血中测量的类固醇生物标志物可以区分 APA 与 BHA 和必需的我们将实施基线和动态测试（ACTH 刺激和地塞米松）。抑制）来鉴定 PA 亚型的类固醇特征之间的差异。用于量化 PA 和原发性高血压患者的类固醇。这种方法将直接解决这一问题。临床需要简化 PA 诊断和分型，并将采取必要步骤实现我们的长期目标目标是扩大个性化 PA 治疗并最大限度地提高 PA 治愈病例数。