SMC DEVELOPMENT, LINEAGE AND DISEASE
The group’s focus is on the role of the myogenic transcription factor, myocardin and transforming growth factor (TGF)-β and Notch signalling as well as other transcription factors and signalling cascades that interact with these pathways. We are also determining whether SMCs of different lineages respond differently to atherosclerotic mediators, whether these differences account for some of the regional heterogeneity in atherosclerosis development, and the underlying mechanisms responsible for the differential response.

MODELLING GENETIC DISORDERS USING PATIENT-DERIVED STEM CELLS
The aorta is the major vessel which carries blood from the heart to the rest of the body. In individuals with diseases such as Marfan, Loeys-Dietz and vascular Ehlers-Danlos syndromes, mutations can lead to the enlargement and rupture of the aorta – a life-threatening event. A major focal point for our group is to model these genetic disorders using inducible pluripotent stem cells (iPSCs). These stem cells can be derived from patients, which in turn can be differentiated into a variety of cells, including lineage-specific vascular smooth muscle cells (SMCs). SMCs are the major constituents of the aorta, and are thought to significantly contribute towards aortic disease. We are particularly interested in investigating the disease-causing mechanisms in genetic disorders leading to aortic aneurysm and dissection. Through our collaborations with various clinical scientists, we have a collection of patient-derived iPSCs. We have developed a variety of methods to phenotype and characterise SMCs, and have shown that our Marfan syndrome model captures the disease hallmarks observed in patient SMCs. Using these resources, we aim to tease out causal disease mechanisms, and identify novel treatments for these disorders.

MYOCARDIN AS A KEY REGULATOR OF VASCULAR DISEASE
We have carried out the first gain- and loss-of function studies in vivo to identify a new role for myocardin in regulating the vascular injury response and atherosclerosis. We have delineated some of the molecular mechanisms by which myocardin regulates SMC biology in these conditions and hypothesise that myocardin is a ‘guardian’ of vascular health. Further studies are under way to clarify the underlying mechanisms in more detail and to determine whether modulation of myocardin represents a novel approach to treating vascular diseases.