Adrenal Origins of Aldosterone Excess

醛固酮过量的肾上腺起源

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：最常见的肾上腺疾病与盐皮质激素分泌过多有关，称为原发性醛固酮增多症（PA），尽管 PA 很常见（大约每 30 名成人中就有 1 人），但最近对其细胞起源知之甚少。在肾上腺腺瘤中发现了一组导致不依赖肾素的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以下方式导致醛固酮产生。该提案将检验以下假设：1）大多数成年人的肿瘤细胞具有“首次打击”体细胞突变，导致肾素不依赖的醛固酮产生；2）PA是由这些细胞巢的形成引起的。或通过增加细胞增殖、肿瘤发展和醛固酮合成过多的额外“多重打击”突变来检验这些假设，提出了两个具体目标，即定义正常肾上腺中发现的体细胞突变。展示肾上腺醛固酮生成细胞簇 (APCC)，并将检验 APCC 是带有激活醛固酮生成的体细胞基因突变的发育不良细胞的假设。目标 2 将定义醛固酮生成腺瘤 (APA) 中存在的体细胞基因突变，并测试假设 APA 与 APCC 共有一些突变，但表现出导致细胞增殖和肿瘤发展的其他突变。APCC 和 APA 突变对醛固酮产生和细胞增殖的影响将通过以下方法确定。正常肾上腺细胞和 H295R 肾上腺细胞系的原代培养物将被确定，以抑制异常突变刺激的醛固酮产生。这项研究将显着提高我们对导致盐皮质激素过量的机制的理解，并为未来的发展提供所需的信息。治疗 PA 的分子诊断和靶向治疗。