Research
One of the most important questions in Biology is to understand how cells sense their environment. A major piece of this complex puzzle are the superfamily of G-protein coupled Receptors whose over 500 members make it the most abundant membrane protein family in mammals. By some estimates, GPCR's represent one third of all existing drug-targets, and only ~10% of GPCRs are known targets. This fact makes GPCRs extremely attractive for further study in order to understand how to exploit the other 90% for potential therapy.
A major challenge is to better understand how these receptors function in health and disease states so that we may increase the number of potential drug targets. My lab works on a variety of areas of GPCR function including:
1) GPCR oligomers: How does GPCR oligomerization impact function? Where are these complexes located and how at the molecular level are they organized? (eg. Tissue Areas, cell types, organelles, expression level, frequency, and stoichiometry) What is the physiological role of these heteromers and how do they function both at the cellular and physiological levels.
2) Molecular pharmacology of GPCRs: How does a drug interact with a GPCR? Can we design new drugs based on this knowledge and demonstrate their efficacy at a given GPCR for potential drug development?
3) GPCRs in cancer: Numerous GPCRs are upregulated in tumour cells. We have identified several of these and are currently studying how expression of these alters patient prognosis and how they might be used as biomarkers or as drug targets.
Drug Discovery
One of the major challenges to creating new drugs is reducing side effects and increasing the efficiency of a new drug. One way this can be achieved is by identifying new places where a drug can bind to a target of interest. This new region can be on an already known drug target or on a completely new one. These alternative drug sites, termed allosteric sites, act as rheostats, where they are able to turn down or turn up the bodies response. Once a location is identified, then rheostat molecules can be developed as new drugs. My lab works on identifying new sites for future such future molecules. Our work is on both known drug targets as well as on new drug targets. We currently are working on such sites for the treatment of obesity, neurodegenerative diseases, depression, inflammation after a heart attack and various cancer types.
G-protein coupled receptor oligomerization
The G-protein-receptor (GPCR) superfamily is subdivided in six classes (A to F). These receptors represent important drug targets, with ~30% of all drugs in the clinic targeting a GPCR. It is clear from structural data that GPCRs are not single on/off switches but instead have different ligand-modulated signalling states, and that higher-order oligomers are important for activity. Our own work has shown that these oligomers (homo and heteromers) have the potential to significantly alter downstream signalling pathways. However, how this is achieved will vary for the partner and most likely the physiological setting (expression levels, cell and tissue type, etc..). Our work and others have demonstrated that the consequences of protein-protein interactions between receptors can be allosteric in nature, or via altered trafficking. One stream of our research is focused on achieving a full understanding of these intricate protein complexes, their role in physiology and disease, and ultimately how to manipulate them for therapeutic interventions.
Research grants
Anti-Histamines as Novel Therapeutics in Pancreatic Cancer
PANCREATIC CANCER RESEARCH FUND (UK)
January 2023 - December 2025