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.
Mineralocorticoid excess is the most common adrenal disease, but little is known regarding the origins of this disorder. Recently, we and others identified a set of somatic mutations that cause aldosterone production in aldosterone producing tumors. These mutations share the ability to disrupt adrenal cell calcium homeostasis. Herein, we propose to test the hypotheses that mineralocorticoid excess develops as a result of somatic mutations that initially cause renin-independent aldosterone production followed by additional (secondary hit) mutations that increase cell proliferation and lead to tumor development. The proposed research will provide new insights into our understanding of adrenal disease and particularly mineralocorticoid excess.
| Omata, Kei; Satoh, Fumitoshi; Morimoto, Ryo et al. (2018) Cellular and Genetic Causes of Idiopathic Hyperaldosteronism. Hypertension 72:874-880 |
| Nanba, Kazutaka; Vaidya, Anand; Rainey, William E (2018) Aging and Adrenal Aldosterone Production. Hypertension 71:218-223 |
| Nanba, Kazutaka; Omata, Kei; Else, Tobias et al. (2018) Targeted Molecular Characterization of Aldosterone-Producing Adenomas in White Americans. J Clin Endocrinol Metab 103:3869-3876 |
| Sun, Na; Wu, Yin; Nanba, Kazutaka et al. (2018) High-Resolution Tissue Mass Spectrometry Imaging Reveals a Refined Functional Anatomy of the Human Adult Adrenal Gland. Endocrinology 159:1511-1524 |
| Omata, Kei; Yamazaki, Yuto; Nakamura, Yasuhiro et al. (2017) Genetic and Histopathologic Intertumor Heterogeneity in Primary Aldosteronism. J Clin Endocrinol Metab 102:1792-1796 |
| Yamazaki, Yuto; Nakamura, Yasuhiro; Omata, Kei et al. (2017) Histopathological Classification of Cross-Sectional Image-Negative Hyperaldosteronism. J Clin Endocrinol Metab 102:1182-1192 |
| Nanba, Kazutaka; Vaidya, Anand; Williams, Gordon H et al. (2017) Age-Related Autonomous Aldosteronism. Circulation 136:347-355 |
| Omata, Kei; Anand, Sharath K; Hovelson, Daniel H et al. (2017) Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals. J Endocr Soc 1:787-799 |
| Omata, Kei; Tomlins, Scott A; Rainey, William E (2017) Aldosterone-Producing Cell Clusters in Normal and Pathological States. Horm Metab Res 49:951-956 |
| Nanba, Kazutaka; Chen, Andrew X; Omata, Kei et al. (2016) Molecular Heterogeneity in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab 101:999-1007 |
Showing the most recent 10 out of 13 publications
