Adrenal Origins of Aldosterone Excess

醛固酮过量的肾上腺起源

• 批准号: 9225195
• 负责人: William E Rainey
• 金额: $ 45.15万
• 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 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225195
• 关键词: Adrenal Gland Adenoma; Adrenal Glands; Adult; Aldosterone; American; Bilateral; CYP11B2 gene; Calcium; Cardiovascular Diseases; Cell Line; Cell Proliferation; Cells; Clinical; DNA; Data; Development; Disease; Enzymes; Exhibits; Future; Gene Mutation; Genetic; High Prevalence; Homeostasis; Hyperaldosteronism; Hypertension; In Vitro; Lead; Mineralocorticoids; Mutation; Patients; Pharmacology; Prevalence; Process; Production; Renin; Renin-Angiotensin System; Research; Resistant Hypertension; Role; Secondary Hypertension; Somatic Mutation; Testing; Therapeutic; Tissues; Zona Glomerulosa; adenoma; base; cell growth; exome sequencing; improved; insight; molecular diagnostics; molecular targeted therapies; neoplastic cell; novel; public health relevance; therapeutic candidate; tumor

 DESCRIPTION (provided by applicant): The most common adrenal disease relates to excess mineralocorticoid production and is called primary aldosteronism (PA). Despite the common occurrence of PA (approximately 1 in 30 adults), little is known about its cellular origins. Recently, a set of somatic gene mutations that cause renin-independent aldosterone production were identified in adrenal adenomas. In vitro studies have confirmed that these mutations cause aldosterone production through effects on adrenal cell calcium homeostasis. This proposal will test the hypotheses: 1) that most adults have neoplastic cells bearing "first hit" somatic mutations that cause renin- independent aldosterone production; 2) PA results from the build up of these nests of cells or through additional "multi-hit" mutations that increase cell proliferatio, tumor development and excessive aldosterone synthesis. To test these hypotheses, two specific aims are proposed. Aim 1 will define the somatic mutations found in normal adrenals that exhibit adrenal aldosterone-producing cell clusters (APCC) and will test the hypothesis that APCC are dysplastic cells bearing somatic gene mutations that activate aldosterone production. Aim 2 will define the somatic gene mutations present in aldosterone-producing adenomas (APA) and test the hypothesis that APA share some mutations with APCC, but exhibit additional mutations that cause cell proliferation and tumor development. The impact of APCC and APA mutations on aldosterone production and cell proliferation will be determined using primary cultures of normal adrenal cells and the H295R adrenal cell line. Pharmacologic agents that inhibit aberrant mutation-stimulated aldosterone production will be defined. The proposed research will significantly improve our understanding of the mechanisms leading to mineralocorticoid excess and provide information needed for the future development of molecular diagnostics and targeted therapeutics to treat PA.

 描述（由适用提供）：最常见的肾上腺疾病与过量的盐皮质生产有关，被称为原代醛固酮（PA）。尽管PA发生了常见（大约30名成年人中的1个），但其细胞起源知之甚少。最近，在肾上腺腺瘤中鉴定出了一组引起肾素非依赖性醛固酮产生的体细胞基因突变。体外研究证实，这些突变通过对肾上腺细胞钙稳态的影响导致醛固酮产生。该提案将检验假设：1）大多数成年人的肿瘤细胞带有“首次命中”的体细胞突变，引起肾素独立的醛固酮产生； 2）PA是由这些细胞巢的积累或其他增加细胞增殖，肿瘤发育和过量醛固酮合成的“多击”突变产生的。为了检验这些假设，两个目标1将定义在暴露肾上腺醛固酮产生的细胞簇（APCC）的正常肾上腺中发现的体细胞突变，并将检验以下假设：APCC是具有体细胞基因突变的发育异常细胞，可激活醛固酮。 AIM 2将定义产生醛固酮腺瘤（APA）中存在的体细胞基因突变，并检验APA与APCC共享某些突变的假设，但暴露了导致细胞增殖和肿瘤发育的其他突变。 APCC和APA突变对醛固酮产生和细胞增殖的影响将使用正常肾上腺细胞和H295R肾上腺细胞系的原发性确定。将定义抑制异常突变刺激醛固酮产生的药理学剂。拟议的研究将显着提高我们对导致矿体皮质类动物超过的机制的理解，并提供未来分子诊断和有针对性治疗PA的靶向疗法所需的信息。