Projects

The calcium-sensing receptor (CaSR) has emerged as a promising new target for the treatment of major non-communicable diseases either via traditional pharmaco-therapeutic approaches aimed at receptor activation or inhibition, or via alternative pharmaco-therapeutic 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 allosteric modulators. The recognition that abnormal CaSR function, or expression contributes to, and promotes, the pathogenesis of major non-communicable diseases including Alzheimer’s disease (AD), cardiovascular disease (CVD), diabetes mellitus (DM), cancer, and sarcopenia; diseases that account for >25% of the global disease burden forms the basis of the research strategies that support the CaSR Biomedicine ETN described in this proposal.

The scientific objectives of CaSR Biomedicine:

• Identify major CaSR-mediated signalling routes and effector molecules to provide a comprehensive understanding of CaSR-dependent physiology.
  WP1: We will analyse the cell- and ligand-specific signalling pathways regulated by the CaSR by using quantitative, well-controlled, and standardised CaSR stimulation experiments. We will elucidate the molecular mechanisms that underlie biased signalling and conditional efficacy to aid the development of next generation CaSR therapeutics. Though focused on one receptor, CaSR Biomedicine will train the ESRs in state-of-the-art concepts in drug discovery, applicable across the GPCR superfamily and across all areas of biomedicine. (Project 1, Project 5, Project 7, Project 11, Project 13).
  
  
• Test the usability of CaSR-based therapeutic approaches for diseases of aging (Alzheimer’s disease, cardiovascular disease, diabetes mellitus, sarcopenia).
  WP2: We will examine the contribution of changes in CaSR expression or function for the pathophysiology of Alzheimer’s disease, cardiovascular disease, diabetes, sarcopenia, and will test CaSR targeting drugs as innovative therapeutic approaches for these major, age-related diseases. (Project 3, Project 6, Project 8, Project 12).
  
  
• Test CaSR-based therapeutic approaches for three types of cancer (neuroblastoma, colorectal cancer, breast cancer).
  WP3: We will examine the contribution of changes in CaSR expression, or function for the pathophysiology of neuroblastoma, breast and colon cancer, and will test CaSR modulators as innovative therapeutic approaches for delaying the onset of tumourigenesis, or preventing metastasis in these malignancies. (Project 2, Project 4, Project 10).
  
  
• Generate and validate algorithms for tissue segmentation used in advanced tissue cytometry.
  WP3: We will develop in vitro diagnostics (IVD)-compliant algorithms for automated detection of the CaSR. (Project 14).