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Title: Inhibition of the Rho signalling activator GEF-H1 for the prevention of epithelial degeneration
Author: Mills, C. C.
ISNI:       0000 0004 7226 5219
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Pathological responses, involving the degeneration and malfunction of epithelial tissue, are major components of many clinically relevant diseases. In the eye, such epithelial degeneration is an important component of pathologies affecting the retinal pigment epithelium (RPE). RPE dysfunction can be recapitulated in primary cultures stimulated with TGF-β. We have previously identified the Rho signalling activator, GEF-H1, as a major driver of pathological fibrotic responses in RPE cells after TGF-β stimulation. GEF-H1 promotes epithelial to mesenchymal transition and cell migration. The purpose of this project was to generate inhibitors to block the function of GEF-H1, with the aim of preventing RPE disease. Inhibitors were designed either on RhoA sequences that contact GEF-H1 or the inhibitory C-terminal domain of GEF-H1. Potential inhibitors were tested for their ability to prevent the in vitro binding of GEF-H1 and RhoA, as well as changes to the actin cytoskeleton and promoter stimulation induced by GEF-H1 expression. From these screens two successful inhibitors were identified, made cell permeable and tested in primary RPE cells stimulated with TGF-β. The identified inhibitors are able to prevent αSMA expression and junction disruption in TGF-β stimulated RPE cells. As GEF-H1 is also a driver of endothelial cell dysfunction during inflammation, the inhibitors were further validated in endothelial cells stimulated by inflammatory factors. The identified inhibitors successfully prevented several pathogenic responses in activated endothelial cells. The findings from this project are the first step towards the therapeutic exploitation of GEF-H1.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available