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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CaSR Biomedicine (Calcium-Sensing Receptor (CaSR): Therapeutics for Non-Communicable Diseases)

Teaser

Summary

G-protein coupled receptors (GPCRs) are the largest family of cell-surface proteins in mammals and play crucial roles in almost every biological process. The calcium-sensing receptor (CaSR) is a GPCR that plays a key role in detecting calcium and regulating its concentration. It is present in a range of tissues such as the parathyroid glands, kidneys, intestine, pancreas, lungs, brain, and breast, where it has several functions from controlling the hormone release to preventing asthma and the development of tumours. However, a detailed understanding of how the CaSR modulates the function of individual cells within these tissues has not been established. It is also unclear whether changes in CaSR function contribute to the development and progression of diseases such as asthma, diabetes mellitus, Alzheimerâ€™s disease, and cancer.
The major non-communicable diseases: cancers, cardiovascular disease, diabetes, chronic respiratory disorders, and disorders of mental health represent a global health burden.
The CaSR Biomedicine consortium has brought together 13 groups from academic and non-academic institutions within eight EU countries to address the following scientific, training, and European objectives:
Scientific objectives: characterise the functions of the CaSR at a cellular level in a range of tissues such as the intestine, pancreas, lungs, brain, breast and muscle; investigate how CaSR function is altered in Alzheimerâ€™s disease, inflammatory lung disease, diabetes mellitus, sarcopaenia, and cancer; and develop innovative CaSR-based therapeutic approaches for these major diseases.
Training objectives: provide high quality state-of-the-art scientific training to 14 early-stage researchers (ESRs) who are based in academic and non-academic sectors.
European objectives: establish an EU-wide network of researchers working on the CaSR and a worldwide forum for CaSR research, as well as building links to communities studying the role of other GPCRs in health and disease.

Work performed

The scientific work undertaken by the CaSR Biomedicine consortium is divided into three work packages.
WP1 aims to characterise how the CaSR regulates the communication processes, known as signalling, within a cell, as these processes control the basic functions of the cell. This work package has focused on developing an experimental cell system for these studies, and successfully established genetically modified cells that have the CaSR present on the cell-surface. The ESRs investigate how these cells can modulate the amount of CaSR at the cell-surface, and also to develop a detailed understanding of how the CaSR interacts with other proteins within the cell to influence signalling. CaSR signalling is also being evaluated in abnormal cells, such as cancer cells. This work package has made a substantial breakthrough in demonstrating that the CaSR not only detects calcium, but could potentially also detect phosphate, high levels of which cause cardiovascular deaths in patients with chronic kidney disease.
This work package is also facilitating the identification of drugs that can target the CaSR by developing a detailed three-dimensional model of this receptor for use in computer simulation studies.
WP2 aims to investigate the role of altered CaSR function in major diseases of ageing such as Alzheimerâ€™s disease (AD), inflammatory lung disease, diabetes, and age-related muscle loss (known as sarcopaenia). These studies have demonstrated that the CaSR is present in nerve cells derived from AD patients and in muscle stem cells, dysfunction of which may potentially cause sarcopaenia. The CaSR is present at high levels within pancreatic islets and the ESRs investigate whether this receptor influences islet hormone secretion by regulating signalling or the growth of cells within individual islets.
A key aim of this work package is to evaluate whether drugs targeted against the CaSR may be used to treat major diseases of ageing. These studies have shown the effectiveness of a drug inhibiting the CaSR, known as a calcilytic, for treating allergic asthma in several mouse models of this disease. Indeed, the effectiveness of calcilytic treatment was similar to that of inhaled steroids, which are being currently used to treat patients with asthma.
WP3 aims to determine whether drugs targeting the CaSR may be used to treat cancers affecting the colon, breast and, nervous system. The ESRs have shown that mice transplanted with colon cancer cells containing a mutant CaSR that has reduced function, develop more aggressive cancers. Loss of CaSR function has also been shown in neuroblastoma, a rare childhood cancer of the nervous system. ESRs now assess whether drugs that upregulate CaSR function, known as calcimimetics, may be used to treat colorectal cancer and neuroblastoma. In contrast to the effect of reduced CaSR function in colorectal cancer and neuroblastoma, increased CaSR function has been previously shown to enhance the spread of breast cancers. An ESR is currently evaluating the use of calcilytic drugs to prevent the spread of breast cancers to other tissues. This work package is also developing new computer methods involving artificial neural networks to allow the automated detection of cells and tissues by microscopy.

Final results

A major goal of CaSR Biomedicine is to establish an overall understanding of the impact of the CaSR in health and disease. By the end of this project we aim to have established a biological and mathematical model of how the CaSR controls the communication processes within cells. We plan to have determined whether altered function of the CaSR contributes to diseases of ageing. We expect to understand whether the CaSR influences: the build-up of proteins within nerve cells that lead to AD; the ability of pancreatic islets to control blood glucose levels; the loss of muscle cells that causes weakness and frailty in elderly individuals; and the growth of tumours affecting breast, colon and the nervous system. We expect to have evaluated whether drugs targeting the CaSR have the potential to be repurposed for the treatment of AD, diabetes, chronic airways disease, sarcopaenia and cancer. Moreover, we plan to establish a computer model that will allow the high-throughput assessment of existing drugs that have the potential to act on the CaSR. The ultimate goal of this research is to reduce the socioeconomic burden of cancers and diseases of ageing by repurposing existing drugs rather than incurring the expense of developing new drugs for the treatment of these conditions.
This consortium also has a strong focus on nurturing emerging talent and allowing young scientists to gain transferable skills required for successful careers in academic or industrial biomedical research, or outside of research. To achieve this, all early-stage researchers are exposed to academic, industrial and clinical environments, and are trained in ethics, intellectual property rights, teaching, and entrepreneurship. Thus, CaSR Biomedicine enhances the professional competencies of young scientists far beyond the standard of conventional PhD programmes.
A further key impact of CaSR Biomedicine is to increase world-wide visibility of the participating researchers thus strengthening the European Research Area in the field of GPCR biology, as well as promoting links between academic research and the industrial biomedical sector.