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The role of the Calcium Sensing Receptor (CaSR) in health and disease, implications for translational medicine

Final Report Summary - MULTIFACETED CASR (The role of the Calcium Sensing Receptor (CaSR) in health and disease, implications for translational medicine.)

THE MULTIFACETED CASR (The role of the Calcium Sensing
Receptor (CaSR) in health and disease, implications for translational medicine)

Marie Curie Initial Training Network No. 264663 (see also Impressions from the Multifaceted CaSR).

Project Coordinator: Prof Enikö Kallay
Center of Pathophysiology, Infectiology & Immunology
Medical University Vienna

Background and Project Objectives
The calcium sensing receptor (CaSR) is the fundamental tool used by cells to detect subtle changes in extracellular calcium concentration and has been the subject of intense research activity since it was first cloned 20 years ago. The CaSR, a widely expressed cell-surface G-protein coupled receptor, is the main regulator of systemic calcium homeostasis, but beyond that, it controls diverse biological processes that include nutrient sensing, hormone secretion, gene expression, ion channel activity, modulation of inflammation, proliferation, differentiation, and apoptosis, and therefore represents a key molecule in functional physiology. Indeed, altered CaSR function is implicated in the development of major non-communicable disorders that include cardiovascular disease and cancer. The Multifaceted CaSR ITN established a European network of 15 Early Stage Researchers (ESRs) and one Experienced Researcher (ER) at seven host institutions: Medical University Vienna (MUW), University of Florence (UNIFI), Université de Picardie Jules Verne (UPJV), Cardiff University (CU), University of Oxford (UOXF), VU University Amsterdam (VUA) and AstraZeneca (AZ). The main purposes of this ITN were to:
1. Educate and train Early Stage Researchers to become excellent scientists, enable them to gain a holistic view of their specific research area, prepare them for the challenges of working in a highly competitive environment, be it in Academia or in Industry.
2. Generate a systems biology model for CaSR-dependent signalling in order to find innovative therapeutic approaches and interventions for the natural and synthetic ligands of the CaSR.
3. Establish long lasting interdisciplinary and intersectoral cooperation among basic, clinical and applied researchers, working on the CaSR to strengthen the European Research Area.

Main achievements
All ESRs were enrolled in PhD programmes and established Personal Development Plans. Network-specific training events comprised annual ITN meetings, workshops, an international conference (International Symposium on the Calcium Sensing Receptor), secondments to other host institutions, and participation in e-learning via a dedicated online platform. Network-wide training was supplemented by University-specific courses.
Three fellows, Rita Gato (ESR in Prof. Brandi’s group at Univ. Florence, IT), Martin Schepelmann (ESR in Prof Riccardi’s group at Cardiff University, UK) and Irfete Fetahu (ESR in Prof Kallay’s group at the Medical University of Vienna, Austria) have already been awarded a PhD degree from their universities. A. Aggarwal (MUW) und V. Babinsky (UOXF) have submitted their theses.
The Multifaceted CaSR fellows presented 102 ORAL or POSTER PRESENTATIONS at different national and international conferences, (excluding the ITN-only meetings) and they have received a total of 40 AWARDS. During the ITN-specific meetings each fellow presented their achievements (totally 33 oral presentations).
Until now, the Fellows have 23 scientific publications either published or accepted for publication; they are first authors in 11, co-authors in the rest. There are 10 first authorship manuscripts under revision or in preparation.
The Multifaceted CaSR ITN had three main scientific objectives:
1. Define the contribution that CaSR signalling makes to cell proliferation/differentiation in colon, parathyroid, and breast cells, and its impact on tumourigenesis.
2. Characterize the functional role of the CaSR in vascular calcification.
3. Identify and model major signalling routes and controlling proteins for CaSR-dependent signal transduction.

The results of the ITN’s scientific activities included:
1. Developing cell-based systems for the characterization of CaSR signalling and function. The first parathyroid cell-line that stably expresses parathyroid hormone (PTH) and the CaSR was established. This cellular model represents a key experimental tool for characterising the biological processes that regulate PTH secretion and parathyroid tumourigenesis. Six colon cancer cell lines were transfected to stably overexpress either the wild-type or a mutant CaSR. Moreover, CaSR-expressing cells that incorporate a combined Förster resonance energy transfer (FRET) G-protein sensor and intracellular calcium FRET sensor were generated to measure ligand-biased signalling by the CaSR. The development of this technology will facilitate the selection of drugs that act on specific CaSR signalling pathways, whilst minimising off-target effects.
2. Defining dual roles of the CaSR in the promotion and suppression of tumourigenesis. The CaSR was demonstrated to be a tumour suppressor within the colon: it influences the differentiation, proliferation and apoptosis of colonic cells, and loss of CaSR expression leads to tumour development. Moreover, alterations of CaSR expression within colonic tumours were revealed to involve gene-silencing mechanisms such as DNA methylation and CaSR-targeting microRNAs. In contrast to its role in the colon, the CaSR was shown to promote the metastasis of breast cancer. Indeed, mice injected with breast cancer cells that overexpressed the CaSR developed extensive metastases in bone.
3. Establishing a role for the CaSR in the maintenance of blood pressure and protection from vascular calcification. The use of tissue-specific CaSR knockout mouse models revealed that this receptor influences blood vessel tone and highlighted the possibility of developing CaSR-based therapeutics for blood pressure control. Furthermore, positive allosteric CaSR modulators, known as calcimimetics, were revealed to have a beneficial effect on vascular calcification, which represents a major cause of mortality in chronic kidney disease patients.
4. Developing a systems biology model for CaSR-dependent signalling. The combined use of cell-based experimental data and mathematical modelling led to the establishment of biophysical model for G-protein coupled receptors, which describes how receptor conformations may alter under the influence of ligand binding leading to the biased activation of intracellular signalling pathways.

The ESRs regularly presented their research at national and international scientific conferences, and played a major role in organising the first international symposium dedicated to research on the CaSR (Vienna, December 2012) and will be attending the 2nd International CaSR Symposium in San Diego, March 2015. They had a total of 102 contributions at these conferences and meetings. The Multifaceted CaSR ITN also issued an annual newsletter publicising the aims and achievements of the consortium, and utilised its website as a key tool for communication within the Network, as well as to the wider public, scientific, and medical communities (see attachment).

Research undertaken by the Multifaceted CaSR ITN has highlighted the CaSR as potential therapeutic target for cardiovascular disease and cancer, which are the leading causes of mortality in the EU, and account for around 40% and 29% of all deaths, respectively. The development of CaSR-based drugs may provide new therapeutic avenues for patients with major non-communicable diseases. Moreover, this ITN has developed new strategies and experimental tools for evaluating the impact of a single molecule within an entire organism, which will benefit researchers working in the field of molecular and cell biology. Finally, this ITN has demonstrated the importance of intersectoral multidisciplinary cooperation for the investigation of major diseases and to train and foster the development of young researchers.