Advancing new paradigms of adenosine receptor pharmacology for the treatment of ischemic heart disease
Adenosine receptor (AR) stimulation represents a powerful cardioprotective mechanism, however the transition of canonical AR agonists into the clinic has been severely hindered due to high doses causing adverse effects such as bradycardia and hypotension. New paradigms of AR pharmacology including allosterism, dimerization and biased agonism have considerable clinical potential as they present the opportunity to develop therapeutics that promote desired, but minimize unwanted, on-target signal transduction.
Available projects examine:
1. The structural basis of allosterism and biased agonism at adenosine receptors;
2. The mechanism of biased agonism in cardiomyocytes and cardiac fibroblasts;
3. The role of adenosine receptor dimerization in cardioprotection;
4. The ability of AR biased agonists to prevent cardiac ischemia-reperfusion injury and the progression to heart failure, in the absence of adverse effects.
To test our hypothesis, we have access to a novel and diverse pharmacological toolbox. Techniques applied may include molecular biology, high-throughput signalling assays, isolation of cardiomyocytes and cardiac fibroblasts, recombinant cell culture, computational modeling, fluorescent/radioligand binding, high-end fluorescence microscopy and ex vivo/in vivo models of cardiac ischemia-reperfusion.