Finding drugs to prevent damage to the cells that line the eye
Research details
- Type of funding: The Frankenburg PhD Studentship
- Grant Holder: Professor Maria Balda
- Institute: UCL Institute of Ophthalmology
- Region: London
- Start date: October 2012
- End Date: December 2015
- Priority:
- Eye Category:
Overview
Many severe conditions can lead to sight loss due to damage to the layers of cells that line the body (epithelial layers), inside and out. Age-related macular degeneration, diabetes, long-term inflammation and infection are all examples.
In the eye, the corneal epithelium is a clear layer that protects the eye from the environment. There is also a layer called the retinal pigment epithelium that forms a barrier between the blood and the light-sensitive part of the eye (the retina). Cells in this layer are vital for vision.
Prof Balda and team are using this research project to find a way to stop 2 key molecules from binding together. When they bind together it triggers a response that leads to epithelial damage. The first stage is finding molecules that can prevent them binding. These can then be tested to find out whether this prevents the damage. The team hopes that the results will lead to new treatments for several blinding conditions.-
Scientific summary
Inhibition of the Rho signalling activator GEF-H1 for the prevention of epithelial degeneration
Pathological responses involving degeneration and malfunction of epithelial cells and tissues are major components of many clinically relevant diseases and often lead to loss of functions of organs and tissues. In the eye, such epithelial degenerative defects are important components of diseases affecting the retinal pigment epithelium and the cornea, and can be induced by chronic inflammation and infections, mechanical traumas and very common diseases such as diabetes.
The researchers have previously identified the Rho signalling activator GEF-H1 as a diagnostic marker and major driver of pathological fibrotic responses in retinal pigment epithelial cells and a regulator of inflammatory responses in corneal epithelial cells. The aim of this project is to generate inhibitors of the Rho signalling activator GEF-H1 and to test them in retinal pigment and corneal epithelial cell disease models.
Small molecular inhibitors and inhibitory peptides are being selected using a combination of structural predictions, in silica screens, as well as in vitro and cell-based assays, designed to determine inhibitory efficiency as well as specificity. The potential to inhibit pathological responses of identified inhibitory molecules will then be tested in primary cultures of retinal pigment and corneal epithelial cells. The team thus expects that this studentship will be the first step towards the therapeutic exploitation of GEF-H1 and will enable inhibition of common pathological responses using specific inhibitory molecules.