Mechanisms regulating smooth muscle cell mechano-signalling (WARRENU17SF)

Decreased aortic compliance is an independent risk factor for cardiovascular mortality and is associated with ageing and vascular disease, including atherosclerosis and hypertension. Aortic stiffening is ultimately driven by remodelling of the extracellular matrix. However, increased matrix stiffness enhances smooth muscle cell (SMC) contraction and recent studies have shown that enhanced SMC contraction contributes to aortic stiffening during ageing and hypertension. Therefore, understanding how SMCs sense and respond to changes in matrix stiffness may identify novel strategies for improving aortic compliance.

The LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, that couples the nucleus and actin cytoskeleton, directly transmits signals across the nuclear envelope and into the nucleus. Importantly, our previous findings implicate the LINC complex in the response of SMCs to matrix stiffness, however, the mechanisms regulating association between the LINC complex and the actin cytoskeleton remain poorly defined. In this project we propose to investigate how changes in matrix stiffness and mechanical signalling influence the association between the LINC complex and filamentous actin.

During this PhD the candidate will be trained in standard molecular biological, cell biological and biochemical techniques. In addition, the candidate will gain extensive experience in state-of-the-art biophysical, cell biological and imaging techniques including fluorescence recovery after photobleaching (FRAP), fluorescence resonance energy transfer (FRET) and traction force microscopy (TFM). The candidate will also gain hands on experience in fabricating hydrogels of defined stiffness and atomic force microscopy.