Adrenal Origins of Aldosterone Excess

醛固酮过量的肾上腺起源

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要项目背景：这是一个竞争性的更新R01应用程序，旨在研究蜂窝和最常见的肾上腺疾病原发性醛固酮增多症 (PA) 的遗传起源 PA 的患病率是 6-。 8% 的高血压患者表明，每 40 名美国成年人中就有 1 人患有 PA。不依赖于肾素的肾上腺醛固酮的产生导致盐皮质激素受体 (MR) 过多 PA 的两种主要亚型是单侧醛固酮腺瘤 (APA) 和双侧醛固酮腺瘤。特发性醛固酮增多症 (IHA) 虽然 APA 引起的 PA 可以通过手术治愈，但 IHA 需要终生治疗。使用 MR 拮抗剂进行药物治疗目前尚无抑制该疾病的治疗方法。 IHA 患者醛固酮分泌不当在本次拨款的初始资助期间，我们在确定 PA 的遗传原因方面取得了重大进展，其中包括首次在小范围的现场使用。 IHA 福尔马林固定石蜡包埋 (FFPE) 肾上腺组织，显示激活体细胞的积聚 CACNA1D（L 型钙电压门控通道 α 1D 亚基）突变。在产生醛固酮的细胞簇（APCC）中发现，这是一种克隆性肾上腺发育不良细胞实体，我们最初是在正常肾上腺的球状带（ZG）中描述的，这些发现构成了这一点的基础。具体目标 1 将定义醛固酮驱动的体细胞突变。导致大量正常肾上腺醛固酮产生失调（目标 2）。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目标 3 将评估钙通道阻滞剂 (CCB) 特异性靶向和生产的潜力。减少 IHA 患者自主醛固酮分泌的总体意义和临床影响。尽管 PA 的患病率很高，但它对心血管疾病有明显的影响，并且令人感兴趣的新遗传因素与其病因相关的发现，我们对 PA，尤其是 IHA 的起源和进展知之甚少。由于 IHA 是由双侧肾上腺疾病引起的，因此目前尚无手术治疗方法。有效，不是针对醛固酮释放失调，而是针对 MR，这可能会导致所提出的研究将显着提高我们对脱靶副作用的理解。引起双侧肾上腺 IHA 的分子机制，并具有提供基础基础的额外潜力研究开发可直接抑制肾上腺素依赖性 IHA 的新型疗法醛固酮的产生。