Adrenal Origins of Aldosterone Excess

 描述（由申请人提供）：最常见的肾上腺疾病与盐皮质激素过多有关，称为原发性醛固酮增多症（PA）。尽管PA的常见发生率（约为30分之1），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引起非肾素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引起醛固酮产生。该提议将检验以下假设：1）大多数成人具有携带“首次命中”体细胞突变的肿瘤细胞，所述体细胞突变引起非肾素依赖性醛固酮产生; 2）PA由这些细胞巢的建立或通过增加细胞增殖、肿瘤发展和过量醛固酮合成的额外“多次命中”突变引起。为了检验这些假设，提出了两个具体目标。目标1将定义在正常肾上腺中发现的体细胞突变，这些肾上腺表现出肾上腺醛固酮产生细胞簇（APCC），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异常细胞的假设。目的2将定义醛固酮腺瘤（阿帕）中存在的体细胞基因突变，并验证阿帕与APCC共享一些突变，但表现出导致细胞增殖和肿瘤发展的额外突变的假设。APCC和阿帕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H295 R肾上腺细胞系的原代培养物来确定。将定义抑制异常突变刺激的醛固酮产生的药物。拟议的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，并为未来开发分子诊断和靶向治疗PA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.