Lygate Group - Realising the therapeutic potential of creatine and homoarginine in heart disease

I originally trained as a pharmacist, then moved into laboratory science via a Master of Research in Biological Sciences in Manchester and a PhD in Cardiovascular Physiology from University of Glasgow. I moved to Oxford in 2000 for my first post-doctoral position and have stayed ever since. I am currently Associate Professor of Cardiovascular Physiology in the Division of Cardiovascular Medicine and run the 'Cardiac Energetics and Integrative Physiology' research group funded by the British Heart Foundation.

My research aims to understand the contribution of cellular energy metabolism to cardiac function in health and disease. In particular, to explore the therapeutic potential of augmenting cardiac energetics in the setting of acute ischaemia and chronic heart failure. My personal expertise lies in assessing in vivo cardiac function and I am Head of the Murine Cardiac Phenotyping Laboratory within the Division of Cardiovascular Medicine. Our research paradigm is to identify a protein of interest from the literature or from cell-based experiments and collaborate with the transgenic core to create a genetically-modified model of altered protein function. We then determine the effect on global cardiac function using techniques similar to those available in the clinic, e.g. by echocardiography, ECG, heart catheterisation or MRI. Often, we are interested in how specific proteins alter the disease process, and we test this in clinically-relevant models of cardiac hypertrophy, ischaemia-reperfusion and heart failure. This provides proof-of-concept on whether tweaking a particular protein might provide therapeutic benefit. We then seek to explore physiological and pathophysiological regulation of our protein target, since this may identify pathways that modify protein function. For this, we use a wide variety of biochemical and molecular biology techniques (e.g. Western blot, HPLC, protein activity assays, radiolabel uptake, PCR, immunoprecipitation), cell culture studies (e.g. confocal microscopy, siRNA knockdown), and collaborate on non-biased approaches such as global gene array, proteomics, and metabolomics.  The creatine transporter (SLC6A8) is a key focus of our current research and we are collaborating with colleagues in Chemistry to identify small molecule modulators of the creatine transporter as the basis for novel treatments for ischaemia-reperfusion injury. Similar approaches are being applied to the creatine kinase and adenylate kinase enzymes, and to the metabolite homoarginine, which we recently found to improve cardiac function in a model of chronic heart failure.