Dr. Brian Kwon Canada Research Chair in Spinal Cord Injury Professor, Department of Orthopaedics, Faculty of Medicine, University of British Columbia Spine Surgeon, Vancouver Spine Program, Vancouver General Hospital Associate Director, Clinical Research, ICORD Director, Vancouver Spine Research Program
‘Bench to Bedside and Back: Translational Research in Acute Spinal Cord Injury’
The term “translational research” is frequently invoked as a desirable / necessary endeavour to bring effective therapies to fruition in biomedical research. But what exactly is it? Why has it failed to deliver such therapies in so many areas of medicine? And importantly, what role can front-line clinicians / surgeons play in translational research? Here we use the backdrop of acute spinal cord injury to provide a perspective on the bidirectional flow of investigation and knowledge generation from both bench to bedside and bedside back to bench.
Dr. Michel Bouvier Chief Executive Officer, IRIC Principal Investigator, Molecular Pharmacology research unit, IRIC Professor, Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal Deputy Vice-Rector Research, Discovery, Creation and Innovation
Molecular and Structural Determinants of GPCR functional selectivity; Impacts for Drug Discovery
It is now clear that G protein-coupled receptors (GPCRs) are not uni-dimensional switches that turn ‘on’ or ‘off’ a single signaling pathway. Instead, each receptor can engage multiple signaling partners to form dynamic complexes that can engage various downstream effector systems that may or may not involve G protein activation. Individual ligands can have differential efficacies toward specific subsets of the signaling effector repertoire engaged by a given receptor. This phenomenon, known as ligand-biased signaling or functional selectivity, opens new opportunities for the development of new drugs with increased selectivity profiles and less undesirable effects. Yet, this pluridimensional nature of signaling efficacy presents a challenge to establish the complete signaling profile of drugs. To better assess multiple signaling outcomes and unravel the structural basis of GPCR functional selectivity, we developed a diversity of biosensors based on bioluminescence resonance energy transfer (BRET) that allow real-time monitoring of multiple GPCR effectors and downstream signaling events. We generated more than 40 BRET-based sensors that monitor a large diversity of signaling pathways with unprecedented spatio-temporal resolution in living cells. In addition we developed label-free approaches that permit assessing the integrated cellular responses and dissecting the relative contribution of the contributing signaling pathways. Their combined use with BRET sensors revealed unexpected signaling texture and provide a new tool-set to monitor signal transduction from the membrane to intracellular organelles including endosomes, opening new avenues for the screening and profiling of drug candidates with favorable functional selectivity. At the molecular level, molecular modeling and site-directed mutagenesis revealed that specific domains of receptors play crucial roles for the activation of selective pathways, providing insights into the rational design of biased ligands with desired signaling properties.
Tuesday April 11th, 2017 3:00pm - 4:00pm School of Medicine, Room 032A