Adrenal Origins of Aldosterone Excess

项目总结/摘要 项目背景：这是一个竞争性的更新R 01应用程序，建议研究蜂窝和 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的患病率为6- 8%，这表明每40名美国成年人中就有1人患有PA。PA的特点是 非肾素依赖性肾上腺醛固酮产生，导致盐皮质激素受体（MR）过多 activation. PA的两种主要亚型是单侧产醛固酮腺瘤（阿帕）和双侧 特发性醛固酮增多症（IHA）。虽然阿帕导致的PA可以通过手术治愈，但IHA需要终身治疗 使用MR拮抗剂的药物治疗。目前还没有抑制这种疾病的治疗方法- 导致IHA患者不适当的醛固酮产生。在这项资助的初期，我们 在确定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一个小队列 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 CACNA 1D（L型钙电压门控通道α 1D亚基）突变。IHA CACNA 1D突变 在醛固酮生成细胞簇（APCC）中发现，APCC是一种克隆性肾上腺发育不良细胞实体， 最初描述于正常肾上腺的球状腺（ZG）。这些发现构成了这一基础 竞争性更新申请。具体目标。目标1将定义醛固酮驱动的体细胞突变 在大量正常肾上腺中引发醛固酮产生失调（10400）。目标2将 确定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 生产目的3将评估钙通道阻滞剂（CCB）特异性靶向和 减少IHA患者的自主性醛固酮分泌。总体意义和临床影响。 尽管PA的高患病率，其对心血管疾病的明显影响，以及有趣的新的遗传因素， 尽管我们对PA的病因和发病机制的研究发现不多，但我们对PA尤其是IHA的起源和进展知之甚少。 因为IHA是由双侧肾上腺疾病引起的，所以没有手术治愈的方法。目前的战略，虽然 有效，不针对醛固酮释放的失调，而是针对MR，这可能导致 不利的脱靶副作用。拟议的研究将大大提高我们对 导致双侧肾上腺IHA的分子机制，并具有提供基础治疗的额外潜力。 研究开发新的治疗方法，可以直接抑制IHA肾上腺肾素非依赖性 醛固酮生成。

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.