Channon Group: Cardiovascular functional genomics and redox signalling
We work to understand how early changes in cells of the cardiovascular system, such as endothelial cells and leukocytes, are related to cardiovascular disease, with a particular focus on redox biology.
As a group we bring together interdisciplinary expertise in biochemistry, vascular function, in vivo models of cardiovascular disease and immune cell biology to probe molecules involved in cardiovascular disease. Our work is split over 4 main themes:
The role of the endothelium and nitric oxide signalling in the development of vascular diseases
Endothelial nitric oxide synthase (eNOS) can promote both vascular health, through nitric oxide production, but also drive vascular inflammation though superoxide production. We have used both clinical studies and experimental models to demonstrate that its regulation by tetrahydrobiopterin defines this balance in vascular disease, and in particular the inflammation associated with atherosclerotic plaque formation. We are currently using targeted knockouts of GTPCH, the rate limiting enzyme controlling tetrahydrobiotperin production, to work out how tetrahydrobiopterin is involved in both normal function in the cardiovascular system and in cardiovascular diseases in vivo.
In studies of patients with diabetes and coronary artery disease, we have examined changes in endothelial function, and nitric oxide and tetrahydrobiopterin levels, and how these relate to the clinical features of disease. We have carried out clinical trials of treatments to increase tetrahydrobiopterin levels.
ROS-independent roles of tetrahydrobiopterin in cardiovascular disease
When studying the role of tetrahydrobiopterin in regulating NOS function it became clear to us that this molecule has important functions independent of NOS biology. We are now focused on studying this new biology using both cell lines and our targeted knockouts of GTPCH. We have found unexpected alterations in macrophage redox state that do not depend on nitric oxide synthase expression. Our most recent work has shown a role for endothelial tetrahydrobiopterin in controlling mitochondrial redox balance.
Leukocyte recruitment in cardiovascular inflammation
The recruitment and retention of monocytes is an important early step in cardiovascular inflammatory diseases. We have identified molecules and interventions that alter this process, resulting in beneficial effects in models of vascular inflammation. Altering chemokine-induced cell recruitment either through blockade of CC-chemokine function or through alteration of chemokine GPCR signal duration via RGS1 expression reduces atherosclerosis, angiotensin-II induced vascular inflammation and aneurysm formation. To probe monocyte macrophage biology in more detail we have characterised a novel GFP expressing macrophage reporter mouse, the hCD68GFP mouse. We are using this mouse in vascular inflammation models, allowing us to identify, adoptively transfer and recover specific monocyte and macrophage populations. We are using these green monocyte macrophages to look at cell recruitment in cardiovascular inflammation and metabolic disease.
Evaluating novel GWAS candidate genes in experimental models of cardiovascular disease
Human GWAS studies have identified multiple candidate genes, but in many cases the function of these genes and how they might affect disease is completely unknown. We are helping to translate these human studies into potential new therapies by identifying how these genes work. Using our experience in experimental models of cardiovascular disease and inflammation including atherosclerosis, aneurysm formation, angioplasty, and vein grafting, we are creating focused phenotyping platforms to identify functions for these genes using novel targeted gene knockouts.