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

• 批准号: 10548823
• 负责人: Adina F Turcu
• 金额: $ 69.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10548823
• 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; Caring; 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; Mass Spectrum Analysis; Measures; Medical; Methods; Mineralocorticoid Receptor; Morbidity - disease rate; Mutate; Mutation; Operative Surgical Procedures; Patients; Peripheral; Phenotype; Potassium; Potassium Channel; Procedures; Production; Protocols documentation; Provider; Public Health; Quality of life; 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; pharmacologic; prevent; response; standard of care; tool; tumor; voltage; ATP1A1 gene; Address; Adrenal Gland Diseases; Adrenal Gland Neoplasms; Adrenal Glands; Affect; Aldosterone; Bilateral; Biological Markers; Blood; Blood Tests; Cardiac; Cardiovascular system; Caring; 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; Mass Spectrum Analysis; Measures; Medical; Methods; Mineralocorticoid Receptor; Morbidity - disease rate; Mutate; Mutation; Operative Surgical Procedures; Patients; Peripheral; Phenotype; Potassium; Potassium Channel; Procedures; Production; Protocols documentation; Provider; Public Health; Quality of life; 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; pharmacologic; prevent; response; standard of care; tool; tumor; voltage

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 原发性醛固酮主义（PA）是最常见的肾上腺疾病，也是最常见的原因 内分泌高血压。 PA与心血管发病率和死亡率不成比例有关 与在具有相似程度的基本高血压患者中观察到的患者相比高。两个专业 PA的类型是单侧PA（通常是产生腺瘤的醛固酮，APA，约40％的PA病例），可以 用手术和双侧甲醛醛蛋白酶治愈（BHA，约60％的PA病例），这需要终身 有针对性的医疗疗法。尽管患病率很高和严重的心肾脏并发症，但PA是 诊断不足，部分原因是诊断和亚型的步骤是复杂，昂贵和侵入性的。 肾上腺成像在识别过度醛固酮产生的来源不准确。最后， 当前的PA亚型护理标准是肾上腺静脉抽样（AVS），这是一种侵入性的，从技术上讲 具有挑战性和标准化的程序不足，可用性仅限于三级推荐中心。 该应用程序的总体目标是：1）定义各种APA的类固醇合成能力 通过实施APA组织的全面组织学，基因组和类固醇分析分析； 2）结合 基线和动态血液检查以定义外周血中PA亚型的类固醇特征。这 方法将消除60％以上PA患者（BHA）中对AV的需求。设计了两个具体目标 解决PA患者护理中的关键差距。 •在AIM 1中，我们将探究APA的工作假设 具有独特的潜在醛固酮驱动器的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）以表征体细胞 APA的突变。同时，我们将使用最先进的质谱法来定义立体 APA的曲线来自：（a）最佳切割温度（OCT）填充的APA组织； （b）肾上腺的血液 排出这些肿瘤的静脉； （c）外周血。 •在AIM 2中，我们将测试面板的工作假设 在外周血中测得的立体生物标志物可以将APA与BHA和必需区分开 高血压。我们将实施基线和动态测试（ACTH刺激和地塞米松 抑制）确定PA亚型类固醇特征之间的差异。质谱将是 用于量化PA患者和原始高血压患者中的立体体。这种方法将直接解决 简化PA诊断和亚型的关键临床需求，并将采取重要步骤 目标，扩大个性化PA治疗并最大化治愈PA病例的数量。