GenAdEx

Background and rationale: Adrenal steroids are main contributors to blood pressure and metabolic control and excessive aldosterone production as evident in primary aldosteronism (PA) is the most prevalent cause of secondary hypertension. Mainly based on translational studies, we could make major contributions towards the identification of genetic abnormalities in PA and the determinants of increased aldosterone production and nodule formation in the adrenal cortex. However, mechanisms that would explain the broader spectrum of endocrine autonomy in the adrenal cortex are lacking. Therefore, the overall objectives and specific aims of this proposal are to identify novel genetic contributors to primary aldosteronism and provide mechanistic insight into their mode of action. Further, to develop and characterize cellular and murine models of hyperaldosteronism and hypercortisolism that allow to investigate early steps and further evolution that result in steroid excess, and to investigate the molecular pathways leading to excessive steroid production, tumor formation and modification of the endocrine phenotype. The expected results from the working program include the identification of candidate genes within loci linked to PA by genome-wide association studies (GWAS) and investigation of their functional relevance by performing phenotypic and mechanistic studies in differentiated cell lines and dedicated animal models. We further expect to delineate the effect of modulation of calcium concentrations in the adrenal cortex of mice on their functional phenotype and to decipher a calcium signaling specific signature in the zona glomerulosa. We further expect to answer the question whether induction of specific somatic mutations identified in human tumor samples are sufficient to trigger the development of adrenocortical adenomas, to identify the cellular and molecular consequences on tumor formation and adrenal zonation induced by these mutations and, finally, to assess whether the pathophysiological effects of the somatic mutations are influenced by the differentiation status of affected cells. Thereby, the impact of these detailed genetic, molecular and functional studies will be the identification of mechanisms responsible for adrenocortical endocrine autonomy and tumor formation that will influence endocrine research and patients’ care, but might well have implication beyond for the understanding of the development of hypertension in the general population.