Towards the clinical development of calcium-sensing receptor antagonists as novel therapeutics for inflammatory lung diseases
G protein-coupled receptors (GPCRs) have crucial roles in almost every physiological process from cardiac function, immune responses and neurotransmission to sensory functions comprising sight, taste and smell.
Aberrant GPCR activity or expression contributes to some of the most prevalent human diseases1 and GPCRs are the targets for >35% of all modern drugs. Their importance is reflected by the 2012 Nobel Prize in Chemistry awarded for “Studies of G-protein-coupled receptors”. One member of this superfamily, the calcium-sensing receptor (CaSR) has emerged as a promising new target for the treatment of major non-communicable diseases either via traditional pharmacotherapeutic approaches aimed at receptor activation or inhibition, or via alternative pharmacotherapeutic approaches that modulate receptor expression and trafficking. The CaSR plays a pivotal role in the control of systemic calcium metabolism and has been successfully targeted in the treatment of various human disorders of calcium metabolism using positive and negative allosteric modulators. The recent breakthrough that abnormal CaSR expression contributes to, and promotes, the pathogenesis of major non-communicable diseases such as asthma forms the basis of this research project (Iarova et al., Science TM 2015). We are looking for a self-funded PhD candidate with a strong interest in respiratory physiology or pharmacology to investigate the role of the CaSR in the pathogenesis of inflammatory lung diseases. Specifically, the PhD student will test the hypothesis that existing or novel negative CaSR allosteric modulators can be repurposed as a novel therapeutic for chronic obstructive pulmonary disease (COPD). The successful candidate will work alongside with an innovative, multidisciplinary and dynamic research team in the frame of the EU Horizon2020 Marie Sklodowska-Curie Action: “CaSR Biomedicine” ETN (Calcium Sensing Receptor (CaSR): therapeutics for Non-Communicable Diseases). The objectives of the project are to perform basic and applied multidisciplinary investigations into the role of the CaSR in airway function and pathology, and to provide experimental data demonstrating effects of CaSR antagonists on airway function in human bronchial epithelial and smooth muscle cells and in pre-clinical models of COPD.
Work generated by this project will significantly contribute to inform the design of the clinical drug testing in patients with COPD and other inflammatory lung disorders.