A novel pathway regulating adipogenesis in Thyroid Eye Disease: characterization of spontaneous lipogenesis and validation of novel therapeutic targets

Overview

Thyroid Eye Disease (TED) is a severe and potentially blinding disease of the tissues behind the eyeball, commonly affecting patients with thyroid problems. Fat and muscles in the orbit, the bony socket where the eye sits, swell and scar, perturbing eye movements and pushing the eye forward. This gives patient a staring “eye-bulging“ appearance, which creates significant social stigma, and leads to double vision, dry eyes and corneal damage, and may cause sight-threatening compression of the optic nerve. TED is poorly understood and treatment options are limited, often leaving patients with permanent disfigurement and double vision. Most of the swelling in TED results from the fat behind the eyeball expanding, as local cells, called fibroblasts, turn into fat cells. However, why and how those cells change is still unclear, preventing significant developments in prevention and treatment

To better understand how fibroblasts turn into fat in TED, our team has grown patient cells in soft gels made of collagen, an essential component of the tissues in the orbit. Under such conditions, fibroblasts from patients spontaneously produce fat, mirroring what happens in TED. Our preliminary study of the cell characteristics and the type of fat they make suggests that fibroblasts in TED do not produce fat as classically found in the main body (e.g. belly fat), but rather make fat from sugars (a process termed de novo lipogenesis) and/or absorb more fat from the circulation. This project aims to confirm these findings and identify how the cells do it on a molecular level.

TED affects an estimated 400,000 people in the UK. In over 90% of cases, expansion of orbital tissues and fat are responsible for most of the detrimental disease manifestations, and thus an understanding of how this happens is crucial to the development of suitable treatments. Through exploring novel mechanisms driving fat accumulation in orbital cells, this project will identify potential new therapeutic targets that may provide better disease management options for the patients.