Adrenal Origins of Aldosterone Excess

 描述(申请人提供)：最常见的肾上腺疾病与过量的盐皮质激素产生有关，被称为原发性醛固酮增多症(PA)。尽管PA常见(大约每30个成人中就有1个)，但对其细胞起源知之甚少。最近，在肾上腺腺瘤中发现了一组导致肾素非依赖性醛固酮产生的体细胞基因突变。体外研究已经证实，这些突变通过影响肾上腺细胞钙稳态而导致醛固酮的产生。这项提议将检验以下假设：1)大多数成年人的肿瘤细胞携带导致肾素非依赖性醛固酮产生的体细胞突变；2)PA是由这些细胞巢的建立或通过增加细胞增殖、肿瘤发展和过度的醛固酮合成而产生的。为了检验这些假设，本文提出了两个具体目标。目的1将定义在正常肾上腺中发现的显示肾上腺醛固酮产生细胞团(APCC)的体细胞突变，并将检验APCC是携带激活醛固酮产生的体细胞基因突变的发育不良细胞的假说。目的2定义产生醛固酮的腺瘤(APA)中存在的体细胞基因突变，并验证APA与APCC有共同的一些突变，但表现出导致细胞增殖和肿瘤发展的额外突变的假设。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肾上腺细胞系的原代培养来确定。将定义抑制异常突变刺激的醛固酮产生的药理药物。这项拟议的研究将显著提高我们对导致盐皮质激素过量的机制的理解，并为未来治疗PA的分子诊断学和靶向疗法的发展提供所需的信息。

 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.