We focus on identifying the molecules and mechanisms that govern the behaviour of cells of the ocular lens, in health, ageing and disease.
Our studies have identified a number of molecules that play key roles in both normal and pathological lens development and growth.
Using a range of in vitro (in test tube) and in vivo (in living organism) models, we are working to gain a better understanding of how these molecules are regulated in the eye. This includes a focus on:
This is fundamental to identifying new therapeutics for retarding or preventing cataract, one of the most common and costly age-related diseases.
The lens transmits and focuses light onto the retina of the eye. To do this, it needs to be transparent. This depends on the development and maintenance of highly ordered cellular architecture.
The lens consists of two forms of cells surrounded by a thick basement membrane:
Whilst the fibre cells make up the bulk of the lens and mostly determine its optical properties, epithelial cells play a key role in maintaining an appropriate physiological environment within the lens.
In addition, the epithelium contains the ‘stem cells’ that proliferate, migrate and differentiate into the new fibres that are progressively added throughout life.
Abnormal changes in lens’ cells leads to cataract, a growing cause of blindness worldwide. The only cure for cataract is surgery, the most commonly carried out surgical procedure in the world.
Unfortunately, complications after cataract surgery result from abnormal growth and differentiation of the lens epithelial cells and this too requires further surgical treatment.
Using a unique lens epithelial explant culture system that allows us to grow lens cells, we have identified members of the FGF growth factor family as inducers of lens cell proliferation, migration and differentiation; responses that are induced in a dose-dependent manner, similar to the effects of the ocular media that bathes the lens.
Based on this, we proposed that a gradient of FGF in the eye determines lens polarity and growth patterns. There is now compelling evidence to support this model and a major thrust of our research activity is aimed at elucidating FGF-induced signalling pathways in cells and the their modes of regulation.
In recent developments we have explored the intricate signalling pathways responsible for lens cell activity and most importantly how this can be tightly controlled.
We have shown that members of the transforming growth factor beta (TGFß) family induce aberrant growth and differentiation of lens epithelial cells, better known as an epithelial to mesenchymal transition (EMT), similar to a wound healing response. This progressively leads to disruption of normal cellular architecture and opacification of the lens.
Cataract is the most common cause of blindness in the world today. Although surgery is generally effective, in many countries it cannot keep pace with the growing demand. Moreover, complications such as aberrant growth and differentiation of lens epithelial cells left behind after cataract surgery (most commonly referred to as posterior capsule opacification, PCO), require further treatment and add to the cost of cataract management.
Because of its clinical significance it is vital to understand how TGFß is regulated in the eye and how it induces cataractous effects on the lens. This information is fundamental to understanding the molecular basis of cataract and devising strategies for prevention.
Our recent studies have identified different growth factor signalling regulators in the lens (including Sprouty, BMPs, and EGF receptor signalling) and our current research is aimed at better understanding their role in order to block the cataractous effects of TGFß.
Using our knowledge of factors that promote epithelial to fibre differentiation, we have identified interactions between lens epithelial and fibre cells that activate intrinsic programs that result in the self-assembly of the two forms of lens cells into functional lens-like spheroidal structures.
We have also started to better characterise the constituents of the lens basement membrane and show its importance for lens cells. We are working to elucidate the molecular basis of all these interactions, and the signalling pathways involved, as we feel this will provide the key to promoting regeneration of lens structure and function after cataract surgery.