Young researcher of the month
Our young researcher of the month is Amanda Mackenzie, Amanda has just completed her PhD in Pharmacology in Professor Graeme Milligan’s lab and is moving to the University of California, San Diego, to take up a postdoctoral position in the prestigious laboratory of Professor Roger Sunahara. This project will focus on the β1-adrenergic G protein coupled receptor in diabetes.
My PhD Project
GPCRs belong to a family of cell surface receptors that act to transduce extracellular cues via intracellular signal transduction cascades into biological responses. These responses include the ability to respond to light, odorants, stress and taste, for example. Because of their location at the cell surface, and their links to disease, GPCRs are historically the most successful group of proteins targeted by the pharmaceutical industry. However, many marketed pharmaceuticals act upon relatively few of the 900 strong members of the GPCR family, suggesting that there could be many more potential therapeutic targets remaining to be developed.
My PhD focussed on the identification of ligands for an ‘orphan’ GPCR named GPR35 (pictured) that had been associated with inflammatory bowel disease, type 2 diabetes, and coronary artery disease through genome-wide association studies. However, since GPR35 is an orphan GPCR – meaning that its endogenous ligand has not been discovered – very little information was known regarding the basic biological profile of this receptor. Historically, the effect of the endogenous ligand would impart information as to the receptor’s physiology, and for GPR35 this lack of information has resulted in significant challenges in understanding the receptor’s function.
Nevertheless, the first steps in characterizing a GPCR and its physiological role begins with the identification of potent and selective tool compounds that can be used to probe the receptor’s signalling. Over the last four years, we worked alongside industrial partners Novartis and the Medical Research Council Technology to identify potent compounds that could activate GPR35 in various functional outputs in vitro. We were fortunate in that we identified a number of chemically and pharmacologically diverse agonist molecules that could be used to probe the pharmacology and function of GPR35. Currently we have reported three of the most potent agonists of human GPR35; these will be invaluable to future research efforts that wish to probe the involvement of GPR35 in health and disease.
PhD Highlights
I have gained a breadth of knowledge during my time in Graeme’s lab, where I have thoroughly enjoyed developing projects and producing exciting data. My highlights outside of the lab include presenting my work at conferences in Heidelberg, Germany, and Experimental Biology 2013 in Boston. At EB2013 I had the opportunity to attend the keynote speeches of Brian Kobilka and Robert Lefkowitz. Kobilka and Lefkowitz were awarded the Nobel Prize in Chemistry (2012) for their pioneering work resulting in the publication the β2-adrenergic receptor crystal structure – the first hormone/neurotransmitter-regulated GPCR to be crystalized.
Pictures
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