Drug Discovery Biology Deputy Theme Leader

Viertel Senior Medical Research Fellow (2020-2025)
funded by The Cross Family and The Frank Alexander Charitable Trusts
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences

NHMRC RD Wright Career Development Fellow (2014-2019)
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences

NHMRC CJ Martin Overseas Biomedical Fellow (2008-2013)
Department of Pharmacology, University of Cambridge, UK
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences

It is important to understand signal organisation in cells because all physiological and pathological processes depend on cell signalling.

Cells contain the ‘machinery’ to receive an astoundingly diverse range of stimuli (light, odours, hormones, lipids) and relay this information to perform distinct and diverse functions (including sight, smell, cell migration and metabolism). Cells achieve this through large numbers of receptors expressed on the cell surface but interestingly, these receptors interact with a limited number of cell signalling pathways. This is well illustrated by the largest class of receptor proteins, the G protein-coupled receptors (GPCRs). In response to these stimuli, ~800 different GPCRs activate the same 4-5 canonical signalling pathways but initiate a variety of cell responses such as migration, contraction, gene transcription and metabolism. With >100 different types of GPCRs expressed on average on each cell, it has been difficult to rationalise how signalling can simultaneously coordinate a variety of cellular responses.

By measuring localised signals in live cells my team has shown that signals from GPCRs are highly localised and organised in both space and time. That is, the types of signals activated by the GPCR are dependent on receptor location and are often restricted to tightly regulated subcellular compartments. This is facilitated by their physical incorporation into extensive protein scaffolding networks. With our inter-disciplinary collaborators, this knowledge has driven cutting-edge drug development to target GPCRs in specific subcellular locations. This new generation of targeted therapeutics has much greater efficacy than current drugs which are designed to bind all receptors at the cell surface.

Our research is focussed on understanding how receptors control localised signalling, how this can be hijacked by disease, and how we can target these signals to gain greater therapeutic efficacy.

We do this by combining high resolution microscopy and cell biology with advanced mass spectrometry and drug delivery approaches. Current projects include characterising novel properties of GPCRs when incorporated into protein complexes, defining how GPCR signalling is altered in highly metastatic cancer cells to drive invasion, and understanding how intracellular binding proteins can affect activation of nuclear hormone receptors.