REGULATION OF GROWTH FACTOR SIGNALLING IN THE EYE AND ITS IMPLICATIONS FOR NORMAL LENS BIOLOGY AND PATHOLOGY.

Summary

Growth factors play an essential role in regulating lens cell behaviour in the eye. Diverse intracellular signalling pathways work in concert or oppose each other to promote and regulate normal cell behaviour. When these precise pathways are compromised, lens pathology in the form of cataracts pursues. This pathology can be derived from an epithelial to mesenchymal transition (EMT) of the normal lens epithelial cells to myofibroblastic cells, a conserved process found normally early development of organs, but manifesting later in life contributing to wound healing, fibrosis, and even cancer. Understanding growth factor signalling and identifying novel ways to modulate this will no doubt be instrumental in developing future non-invasive therapeutics.

Supervisor(s)

Professor Frank J. Lovicu

Research Location

Camperdown - School of Medical Sciences - Bosch Institute

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, migrate and transdifferentiate to form a secondary cataract. The aim of this project is to understand what molecules regulate the normal proliferation and differentiation of lens cells, as well as what leads to their trans-differentiation leading to pathology. Growth factors are key regulators of cell behaviour, and our studies provide evidence that factors such as FGF play pivotal roles in the lens by influencing cell proliferation and differentiation, while others such as TGF can lead to cell trans-differentiation and subsequent pathology. We have identified inhibitors of these factors and their signalling pathways in the lens, as we try to better understand how these processes are regulated. Using an established explant culture system to monitor the influence of growth factor-induced cell proliferation and differentiation, as well as transgenic mice models, we hope to better understand the molecular and cellular processes essential for normal lens development, and how disruptions of these processes lead to cataract formation. In doing so we hope to discover novel and naturally occurring treatments for the prevention and/or treatment of cataract.

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. With access to state of the art molecular and microscopy facilities, our lab is also are equipped for the 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).

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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