Defining important functional paradigms that lead to inherited cardiomyopathies, in search of novel treatments.
We investigate the biological processes that cause the inherited heart muscle diseases (cardiomyopathies), and in particular focus on hypertrophic (HCM) and dilated (DCM) cardiomyopathy. HCM has a prevalence of 1 in 500 worldwide and is a common cause of sudden cardiac death.
As a group, we are interested in the molecular, cellular and physiological mechanisms that underlie the progression of the disease with an ultimate aim of identifying novel ways to treat the patients carrying disease-causing mutations in their DNA.
We have found that most disease causing variants are in genes that encode components of the contractile apparatus (sarcomere) of cardiomyocytes. We have established world leading in vitro and ex vivo model systems to interrogate the functional effect of HCM and DCM mutations in the actin thin filament (ie troponin and tropomyosin). We have also helped establish a paradigm describing the primary cause of disease, whereby HCM mutations are hypercontractile whilst DCM mutations are hypocontractile.
As a result of these findings, we now have several ongoing programmes of research, including:
1) How HCM or DCM mutations in cardiomyocytes can alter intracellular calcium handling and signalling due to altered buffering of calcium by the sarcomere. We accomplish this using both classical electrophysiology techniques and novel genetically encoded calcium sensors to establish the compartmentalisation of calcium flux in the mutant cells. In addition, we are investigating a huge array of potential downstream signalling networks activated by altered calcium handling using biochemical and imaging techniques.
2) Investigating potential treatments of patients with HCM using novel synthesised analogues of the green tea catechin EGCg. We have developed a novel screening strategy using high throughput in vitro ATPase assays to identify compounds that desensitise the sarcomere to calcium thus reducing its buffering capacity. We hope this work will identify a potent, non-toxic desensitiser that will benefit “at risk” HCM patients with overt cardiac remodelling from experiencing life limiting cardiac events.
We have several exciting research collaborations here in Oxford, and both nationally and globally. Together we hope to expand the boundaries of scientific knowledge and better understand inherited cardiac disease processes. We will achieve this by using novel and world leading research techniques developed right here in the Radcliffe Department of Medicine.
We are based at the West Wing of the John Radcliffe Hospital and the Wellcome Trust Centre for Human Genetics.