ANR-FNS - Appel à projets générique 2018 - FNS

Genetic and molecular contributors to adrenocortical hormone excess – GenAdEx

Genetic and molecular contributors to adrenocortical hormone excess

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. Recent studies have identified 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.

The overall objectives of this proposal are to identify novel genetic contributors to primary aldosteronism and provide mechanistic insight into their mode of action.

Adrenal steroids are main contributors to blood pressure and metabolic control and excessive aldosterone production as evident in primary aldosteronism is the most prevalent cause of secondary hypertension. The genetic contributors of around 90% of all aldosterone producing adenoma (APA) cases can currently be delineated. Despite these achievements, there has been only minor progress in translating this knowledge into clinical practice. Moreover, somatic mutations causative of APA have been also identified in a high proportion of adrenal glands from healthy kidney donors and from autopsy series. Due to the lack of animal models closely resembling the human phenotype, questions such as why some adrenal cells carrying APA-related somatic mutations develop into APAs while others do not; or which are the effects of aldosterone overproduction on the renal and cardiovascular system in this particular context remain understudied.<br />The main objectives of this joint proposal are the following<br />1. To identify novel genetic contributors of primary aldosteronism<br />2. To develop and characterize cellular and murine models of hyperaldosteronism and hypercortisolism that have been identified in human pathophysiology and that allow to investigate early steps and further evolution that result in steroid excess<br />3. To investigate the molecular pathways leading to excessive steroid production, tumor formation and modification of the endocrine phenotype.

The project develops the following tasks (only the tasks concerning the French partner are listed) :

1. Molecular pathways involved in adrenal zona glomerulosa structure and function and the development of PA
Task 1. Identification of candidate genes within loci linked to PA by GWAS in cell models
Task 2: Development of genetically modified mouse models

2. The role of calcium signaling in ZG structure and function
Task 1: To evaluate the effect of modulation of calcium concentrations in the adrenal cortex of mice using chemogenetic tools in cell and animal models
Task 2: To decipher a calcium specific signature in zona glomerulosa of the adrenal cortex by performing omics studies in adrenals from genetically modified mice

We conducted a genome-wide association study (GWAS) in patients with primary aldosteronism and identified different susceptibility loci. Two candidate genes located at the two main loci are expressed in human and murine adrenal cortex and in aldosterone-producing adenomas. Their overexpression in cell models significantly alters the steroidogenic properties of the cells. Thus, our work identifies for the first time risk loci for primary hyperaldosteronism and suggests that the two most frequent forms, aldosterone-producing adenoma and bilateral adrenal hyperplasia, may share common genetic susceptibility mechanisms leading to the development of aldosterone excess.

The project is now at month 30. Perspectives and future projects will be evaluated at the end of the program.

One multipartner manuscript is currently been submitted for publication.

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.

Project coordination

Maria-Christina ZENNARO (PARIS CENTRE DE RECHERCHE CARDIOVASCULAIRE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

PARCC PARIS CENTRE DE RECHERCHE CARDIOVASCULAIRE
UZH University of Zurich

Help of the ANR 346,910 euros
Beginning and duration of the scientific project: December 2018 - 48 Months

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