Current state of knowledge
Previous research in the field
During the past decade a dramatic change has occurred in our understanding of the pathogenic role of the steroid hormone aldosterone in disease states. Aldosterone and MR actions have been discovered in wide range of tissues including skin, eye, and heart. The impact of these findings is immense. Aldosterone has direct actions on several non-epithelial cells, e.g., vascular endothelial and smooth cells, cardiomyocytes, macrophages and other inflammatory cells and adipocytes. Aldosterone/MR activation has therefore been involved in the pathogenesis of several cardiovascular, renal, and metabolic diseases. Based on this innovative research (much of it undertaken in Europe), more specific MR antagonists have recently been approved for clinical use.
Recently, major breakthroughs have occurred in the identification of genetic factors and the molecular mechanisms involved in aldosterone related disorders, namely pseudohypoaldosteronism type 1 and primary aldosteronism. European teams which are partners in this COST Action contributed to these discoveries. The signalling pathways and molecular targets modulated by aldosterone and MR in the various target organs are still under intense investigation and the contribution of European teams has been crucial to these advances. Moreover, several unique animal models (transgenic mouse models) dedicated to the analysis of the pathophysiological role of aldosterone/MR have been generated by European teams in this COST Action.
Clinical studies have documented that antagonists of the MR, in addition to standard therapy, reduce
- cardiovascular morbidity and mortality in heart failure;
- left ventricular hypertrophy and proteinuria in hypertensives with or without diabetes mellitus;
- proteinuria in chronic kidney diseases.
However, widespread clinical use of MR antagonists to treat these diseases has not occurred for several reasons:
- not all patients show beneficial responses to MR blockade;
- it is difficult to determine which patients will respond;
- the adverse side effect profile of the available agents.
ADMIRE aims to tackle these challenges to increase the effective clinical use of MR antagonists.
This COST Action will represent an innovative approach to the research groups active in the field through:
1. Wide ranging membership
ADMIRE is the first dedicated European Action to organize this field, build capacity and consolidate the international competitiveness of the European teams.
Members of the Action have published extensively in the field and have experience ranging from molecular analysis of MR structure, cellular actions of aldosterone, pathophysiological roles, genetics of hyperaldosteronism and hypertension, clinical studies in cardiovascular, renal, endocrinology or metabolic diseases, clinical trials of MR antagonists in cardiovascular diseases. They have all made original contributions to the field and have uncovered new aspects of aldosterone and MR actions thus promoting excellence of European research.
ADMIRE currently has 18 EU countries within the Action and 2 international partner countries (Chile and Mexico)
2. Creating a European network
A network focused in this field will not only provide a stimulus for innovative breakthroughs to consolidate the leading position of European researchers in the field but will also facilitate the creation and improvement of laboratory training programmes and stimulate intra-European exchanges of young scientists to build up the future and strengthen trans-border European research. The proposed network will accelerate knowledge exchange and expertise between multidisciplinary teams and create a catalyst for rapid feedback and dissemination of research results among the consortium. This COST Action will also stimulate transfer of research outputs from bench to bedside and interactions between basic researchers and clinical teams. This will strengthen the quality of scientific publications and novel evidenced-based clinical trials. Of note, this European network will extend a previous smaller network – the European Section of Aldosterone Council (ESAC) which was established in France in the 1990s and extended since 2006 to Germany. The ESAC network’s objectives were less ambitious but allowed a dedicated symposium each year that was also open to non-French and non-German participants which has grown since 2009 to include Switzerland, Italy, the UK and Ireland. To stimulate participation of young researchers and students, a specific effort was made by ESAC-France and ESAC-Germany to financially support participants under 30 years. The ESAC network highlighted the need of a larger pan-European consortium to open up networking beyond the French-German teams. The ESAC network is a clear advantage for this COST Action since it can be seen as a successful embryonic structure to build up a larger network with more ambitious goals.
3. Innovative investigation tools
This COST action will allow researchers and clinicians to have access to advanced equipment and technology platforms (and associated expertise) such as magnetic resonance imaging, molecular modelling, in silico drug screening, high throughput target validation, animal models including transgenic mice and, most importantly, clinical biological resources established by the clinical teams but often under-used or not large enough if not combined with other complementary platforms in the same field (for example adrenal tumour or DNA/RNA/fluid biobanking).