About the Project
Smooth muscle cells (SMC) are the major cellular component of the vascular wall. They can switch between a differentiated contractile phenotype (in health) to a dedifferentiated synthetic phenotype in cases of disease or injury, for example following SV bypass grafting. We have previously shown that T2D-SVSMCs exhibit a unique phenotype that presents with a mixture of contractile and synthetic features, which may impact on graft success. However, the signalling pathways leading to this mixed phenotype have not been fully characterised.
RhoA is a small GTPase that is involved in regulating diverse cellular functions including morphology, migration and SMC marker gene expression. One of the major downstream effectors of RhoA is Rho kinase (ROCK), which modulates the cytoskeleton. Inhibition of RhoA or ROCK can mimic T2D-SVSMC morphology in non-diabetic (ND) cells suggesting that RhoA-ROCK signalling plays an important role in regulating SMC phenotype. RhoA activity is inhibited in T2D-SVSMC through a hitherto unknown mechanisms. Potential routes for regulation include targeted degradation of RhoA messenger RNA by microRNAs (miRs) or destabilisation of RhoA protein via interaction with Rho guanine dissociation inhibitors (RhoGDIs), Rho GTPase activating proteins (RhoGAPs) and Rho guanine exchange factors (RhoGEFs). It is likely that a fine balance of RhoA regulators may define the final cellular phenotype.
To test our hypothesis, we will pursue an integrated programme of work that exploits our complimentary skills in diabetes (KR) and cardiovascular cell signalling mechanisms (TP) to achieve the following aims:-
1) Identify aberrant expression of key regulators of RhoA activity, e.g. RhoGDIs, RhoGEFs and RhoGAPs, and their impact on T2D-SVSMC (months 1-18)
2) Fully characterise the downstream impact of reduced RhoA on SMC phenotype and function using a dominant negative mutant in ND-SVSMC (months 12-24)
3) Restore T2D-SVSMC RhoA levels using factors identified in (1) and / or a constitutively active RhoA mutant, to try to reverse the T2D-SVSMC phenotype (months 20-36)
This suite of work will identify mechanisms responsible for deregulating RhoA signalling in SVSMC from clinical patients, and as such has translational potential to identify new therapeutics. It would suit a candidate with an MSc in Biology, Pharmacology or an allied subject.
Why not add a message here
Based on your current searches we recommend the following search filters.
Based on your current search criteria we thought you might be interested in these.