Adrenal Origins of Aldosterone Excess

醛固酮过量的肾上腺起源

• 批准号: 9893404
• 负责人: William E Rainey
• 金额: $ 66.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9893404
• 关键词: Adrenal Glands; Adult; Age; Aldosterone; American; Amlodipine; Archives; Automobile Driving; Bilateral; CYP11B2 gene; Calcium; Calcium Channel; Calcium Channel Blockers; Cardiovascular Diseases; Cardiovascular system; Cell model; Cells; Cessation of life; Clinical; Cohort Studies; Collection; DNA; DNA Sequence Alteration; Development; Dihydropyridines; Disease; Disease Progression; Distal; Electrolyte Balance; Equilibrium; Formalin; Foundations; Funding; Gene Mutation; Gene Targeting; Genetic; Gold; Grant; High Prevalence; Human; Hyperaldosteronism; Hyperplasia; Hypertension; Immunohistochemistry; In Vitro; Kidney; Kidney Diseases; Life; Medical; Metabolic syndrome; Mineralocorticoid Receptor; Molecular; Mutation; Mutation Analysis; Nature; Operative Surgical Procedures; Paraffin Embedding; Pathogenesis; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Physiology; Play; Population; Potassium; Prevalence; Production; Receptor Activation; Renin; Renin-Angiotensin System; Research; Role; Sodium; Somatic Mutation; Source; Steroids; Testing; Therapeutic; Tissues; Zona Glomerulosa; adenoma; adrenal hypertension; blood pressure regulation; carbohydrate metabolism; cohort; driver mutation; exome sequencing; improved; next generation sequencing; novel therapeutics; renal damage; research and development; sex; side effect; targeted treatment; therapeutic target; voltage gated channel

Project Summary/Abstract Project background: This is a competing renewal R01 applicaton that proposes to study the cellular and genetic origins of the most common adrenal disease, primary aldosteronism (PA). The prevalence of PA is 6- 8% amongst all hypertensive patients suggesting that 1 in 40 American adults has PA. PA is hallmarked by renin-independent adrenal aldosterone production that results in excessive mineralocorticoid receptor (MR) activation. The two major subtypes of PA are unilateral aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA). While PA resulting from APA has a surgical cure, IHA requires life-long medical therapy using MR antagonists. There are no current therapeutic approaches that inhibit the disease- causing inappropriate aldosterone production in IHA patients. During the initial funding period of this grant, we made significant progress in defining genetic causes of PA. This includes the first in field use of a small cohort of IHA formalin-fixed paraffin-embedded (FFPE) adrenal tissues that showed a buildup of activating somatic mutations in CACNA1D (L-type calcium voltage-gated channel alpha 1D subunit). IHA CACNA1D mutations were found in aldosterone-producing cell clusters (APCC), a clonal adrenal dysplastic cellular entity that we initially described in the zona glomerulosa (ZG) of normal adrenals. These findings form the foundation for this competitive renewal application. Specific Aims. Aim 1 will define the aldosterone-driving somatic mutations that initiate dysregulation of aldosterone production in a large cohort of normal adrenals (˃ 400). Aim 2 will define the role of APCC and somatic gene mutations in bilateral adrenal IHA autonomous aldosterone production. Aim 3 will evaluate the potential for calcium channel blockers (CCBs) to specifically target and reduce autonomous aldosterone secretion in patients with IHA. Overall significance and clinical impact. Despite the high prevalence of PA, its clear impact on cardiovascular disease, and intriguing new genetic findings related to its cause, we know very little about the origin and progression of PA and particularly IHA. Because IHA results from bilateral adrenal disease, there is no surgical cure. Current strategies, although effective, do not target dysregulation of aldosterone release but instead target the MR, which can cause unfavorable off target side effects. The proposed research would significantly improve our understanding of the molecular mechanisms causing bilateral adrenal IHA and has the added potential of providing foundational research for the development of novel therapeutics that could directly inhibit IHA adrenal renin-independent aldosterone production.

项目摘要/摘要 项目背景：这是一个竞争的续签R01应用程序，提议研究细胞和 最常见的肾上腺疾病，原发性醛固酮（PA）的遗传起源。 PA的患病率为6- 在所有高血压患者中，有8％表明40名美国成年人中有1例患有PA。 PA是标志性的 肾素非依赖性肾上腺醛固酮产生，导致过量的盐皮质激素受体（MR） 激活。 PA的两个主要亚型是单侧醛固酮产生腺瘤（APA）和双侧 特发性大醛固酮（IHA）。虽然由APA产生的PA具有手术治疗，但IHA需要终身 使用MR拮抗剂的药物治疗。目前尚无治疗方法抑制疾病 - 在IHA患者中导致不适当的醛固酮产生。在这笔赠款的最初资助期间，我们 在定义PA的遗传原因方面取得了重大进展。这包括第一次在现场使用小队列 IHA Hormorin固定石蜡包裹（FFPE）肾上腺组织的含量，显示出激活体的积累 CACNA1D的突变（L型钙电源门控通道Alpha 1d亚基）。 IHA CACNA1D突变 在产生醛固酮的细胞簇（APCC）中发现，我们 最初在正常肾上腺的Zona肾小球（ZG）中进行了描述。这些发现构成了这一基础 竞争性更新申请。具体目标。 AIM 1将定义醛固酮驱动的躯体突变 在大量正常肾上腺中，启动醛固酮产生的失调（˃400）。 AIM 2意志 定义APCC和体细胞基因突变在双侧肾上腺IHA自主醛固酮中的作用 生产。 AIM 3将评估钙通道阻滞剂（CCB）专门针对目标的潜力和 减少IHA患者的自主醛固酮分泌。总体上重大和临床影响。 尽管PA的患病率很高，但它对心血管疾病的明显影响以及吸引了新的通用性 与其原因有关的发现，我们对PA，尤其是IHA的起源和进步知之甚少。 由于IHA是由双侧肾上腺疾病引起的，因此无法治愈手术。但是，当前的策略 有效，不要靶向醛固酮释放的失调，而是针对MR，这可能导致 不利目标副作用。拟议的研究将大大提高我们对 引起双侧肾上腺IHA的分子机制，并具有提供基础的潜力 研究开发新疗法的研究，可以直接抑制IHA肾上腺肾素无关的 醛固酮生产。