My group employs a multi-disciplinary approach to our research interests which are focused on the effects of cardiovascular disease on normal physiology. Studies embrace a wide range of sophisticated techniques from molecular biology and cell culture through to in vivo cardiovascular imaging and state-of-the-art functional assessment. The combination of transgenic technology with models which mimic human disease states associated with cardiovascular complications, such as diabetes and hypertension, provides a powerful tool for investigation of the mechanisms underlying the (mal)adaptive changes characterising such conditions. By relating molecular and cellular changes to alterations in cardiovascular structure and function, my group aims to promote detailed understanding of the pathogenesis of cardiovascular disease towards identification of novel therapeutic targets.
Much of my current research is focused around the role of oxidative stress and reactive oxygen species (ROS) in the development and progression of cardiovascular remodeling and dysfunction. Redox signalling plays an important role in numerous physiological processes and under disease conditions, oxidative stress occurs due to an imbalance between ROS production and endogenous antioxidant defence mechanisms. This has been linked to the pathophysiology of many cardiovascular diseases and selective targeting of the underlying pathways is an attractive therapeutic option with clear potential to improve the clinical management of such pathologies. Recent work by our group and others has identified a family of NADPH oxidases as an important cardiovascular source of ROS. We have demonstrated that NADPH oxidase activity and expression is increased in heart failure and that ROS derived specifically from this complex regulate several key processes underlying cardiovascular remodeling, such as hypertrophy, apoptosis, fibrosis, inflammation and contractile dysfunction. Interestingly, it appears that these different components may be subject to independent regulation by NADPH oxidases and much of our current work is directed towards the identification of underlying mechanisms and specific upstream activators or downstream targets of NADPH oxidases which may be selectively modulated for potential therapeutic benefit.
I am also interested in the novel cardiovascular actions of peptide hormones, such as glucagon-like peptide-1 (GLP-1) and obestatin. GLP-1 is an established therapy used for glycaemic control in type 2 diabetes, which is also known to exert wide-ranging cardiovascular effects, including modulation of heart rate, blood pressure, vascular tone and cardiac contractility. Importantly, GLP-1 has also been shown to confer beneficial actions on cardiovascular disease, in both the experimental and clinical setting, either in the presence or absence of diabetes. Recent data from my laboratory indicates that GLP-1 may attenuate adverse cardiac remodeling via differential regulation of several of the underlying processes, such as inflammation and extracellular matrix remodeling. My current research in this area is focused on identification of the precise actions of GLP-1 in both the normal and hyperglycaemic situation, which may support its use as a novel therapy for chronic heart failure in both diabetic and non-diabetic patients.
In the future, I plan to particularly focus on diabetes which is frequently associated with cardiovascular complications. Interestingly, NADPH oxidases are known to promote inflammation, apoptosis and necrosis in cardiovascular disease, particularly in the setting of ischaemia, to which the diabetic heart is especially susceptible. In this regard, I plan to explore whether modulation of NADPH oxidases and other signalling pathways may be beneficial in attenuating ischaemic injury by preventing cell death, modulating inflammatory cell activation or promoting haematopoietic stem cell recruitment and microvascular repair and regeneration.
Current Laboratory Members
British Heart Foundation, Diabetes UK, Medical Research Council