Regulation of growth factor signaling in the eye and its implications for normal lens biology and pathology.

Summary

Fibroblast growth factors play an essential role in regulating lens cell behaviour. Antagonists of FGF receptor signalling, Sef and Sprouty, are expressed in the lens and are important for the tight control of FGF in normal lens biology and cataract.

Supervisor(s)

Associate Professor Frank J. Lovicu, Professor John McAvoy

Research Location

Bosch Institute (Anatomy)

Program Type

Masters/PHD

Synopsis

Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mechanisms involved in cataract formation. Following cataract surgery, for example, many patients develop aftercataract which results from residual lens cells. These residual cells, unlike those tightly regulated in the normal lens, divide and differentiate to form a secondary cataract. The aim of this project is to understand what molecules regulate the proliferation and differentiation of lens cells. Growth factors are key regulators of cell behaviour and our studies provide evidence that FGF growth factors play pivotal roles in the lens by influencing cell proliferation and differentiation. We have recently identified inhibitors of FGF in the lens, called Sprouty and Sef; molecules shown in other systems to block FGF signalling pathways. To understand how Sef and Sprouty regulate lens cell proliferation and differentiation, we plan to examine what regulates their expression, and more importantly their role in FGF-induced cell signalling in normal lens biology. We will use an established explant culture system to monitor the effect of these inhibitors on growth factor-induced cell proliferation and differentiation, as well as use transgenic mice to determine the role they play in situ. By understanding the molecular and cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.

Additional Information

Projects in our area of interest are customised to the student’s needs and interests. The laboratory is set up to conduct a range of biomedical related techniques, covering histology, PCR analysis, protein and gene screening and expression studies, to more advanced molecular biology techniques to generate transgenic mouse models. We extensively use a lens explant system to identify key molecules involved in regulating lens cell behaviour. We are set up for tissue culture, all aspects of tissue histology, from light microscopy to electron microscopy. We carry out expression studies using RT-PCR, Immunolabelling (Western blotting/Immunofluorescence) and In situ hybridization. We extend our in vitro findings to in vivo models using transgenic mice. We have a strong lens specific promoter that we use to overexpress genes of interest specifically in the lens. From this we characterise lens and ocular morphogenesis, obtaining and studying embryonic tissues throughout different stages of embryogenesis. With this we have developed different mouse models, including lines that develop cataract analogous to that found in humans. Using our promoter system we have several lines of Cre-recombinase expressing mice, which allow us to conditionally delete genes of interest specifically in the lens. We have a dedicated PC2 laboratory for our GMO studies as well as a conventional PC1 laboratory. We are equipped for a range of research listed above including equipment for sectioning tissues, PCR analysis, all aspects of microscopy (both upright and inverted fluorescent research microscopes with dedicated digital cameras for image capture).

Keywords

Blindness, Cataract, Posterior capsular opacification (PCO), Aftercataract, Vision impairment, Lens Development, Cell proliferation, Cell Differentiation, Growth Factors, FGF, TGF-ß, Signal transduction, Receptor Antagonists, Sef, Sprouty, Hearing & vision problems, Infertility & developmental problems, Cell biology, Genes in biology & medicine, The senses

Opportunity ID

The opportunity ID for this research opportunity is: 11

Other opportunities with Professor John McAvoy

• Studies on eye lens development and cataract