Finding out what causes the swelling and fat build-up in TED
- Type of funding: PhD Studentship
- Grant Holder: Dr Maryse Bailly
- Institute: UCL Institute of Ophthalmology
- Region: London
- Start date: September 2014
- End Date: September 2019
- Priority: Causes
- Eye Category: Ocular inflammatory
Graves ophthalmopathy (also called thyroid eye disease or ‘TED’) is a condition that disfigures the face and has the potential to blind people. It affects around 400,000 people in the UK.
In TED, fat and muscle at the back of the eye become red and swollen (inflamed). This affects eye movements and can sometimes compress the cable that sends visual signals from eye to brain (the optic nerve).
The swelling also pushes the eye forward which makes the eyelid retract, and the cornea – the clear front surface of the eye – become exposed and damaged.
Although TED can partly be controlled with long-term steroid medication, this can have significant unwanted side effects. But we don’t yet know enough about the mechanics of TED to develop new treatments. One key question is how or why connective tissue cells at the back of the eye turn into fat and/or scar tissue in people with TED.The research team has used cells taken from TED patients and healthy controls to develop a laboratory model of cell behaviour. Their first results suggest that a family of proteins known as SFKs may be overactive in people with TED. So in this project they are finding out more about SFK and its ability to turn connective tissue into fat and scar tissue. They’re also looking for potential treatments that can reduce SFK activity. If they can do so in a lab dish then clinical trials may be possible relatively soon, as this type of drug is already available in the clinic (mostly as anti-cancer treatment).
The role of Src family kinases in thyroid eye disease: disease mechanisms and therapeutic potential
Thyroid eye disease (TED) is a disfiguring and potentially blinding disorder affecting patients with autoimmune thyroid disease, most commonly Graves’ disease. Clinical manifestations include extraocular muscle fibrosis and upper lid retraction, as well orbital fat inflammation and expansion, causing eye bulging. These pathological processes are thought to be mediated by transdifferentiation of resident fibroblasts into adipocytes and fibrotic cells within the orbit. However, neither the disease mechanisms nor the stimuli that regulate cell transdifferentiation are known, preventing any significant development in prevention and treatment.
The research team’s preliminary work on orbital fibroblasts isolated from TED patients has shown that TED fibroblasts display a characteristic dual profibrotic and adipogenic phenotype in vitro. Both the profibrotic matrix contraction profile and adipogenesis could be modulated by Src kinase family (SFK) inhibitors, suggesting that SFK activity may underlie TED pathogenesis. The aim of this project is thus to test the hypothesis that the specific dual phenotype of TED cells is due to an increase in SFKs activity, and characterise the kinase and downstream pathway(s) involved to identify new treatment options.