This project aims to elucidate factors that regulate differentiation and growth of the epithelial monolayer. There is growing evidence that members of the FGF, RA and Wnt families may play key roles in lens epithelial cell biology. Part one is directed at testing the hypothesis that FGF (a low dose), RA and Wnt regulate lens epithelial proliferation, adhesion and communication. The effects of these ligands on expression of lens epithelial phenotypic characteristics including key molecules, such as cadherins, integrins and connexons, will be investigated using RT-PCR, in-situ hybridisation and immunohistochemistry. Part two will test the hypothesis that FGF (a low dose), RA and Wnt stimulate signalling cascades which cooperate to stimulate expression of key epithelial transcription factors. This will investigate modulation of receptor expression and identification of signaling cascades activated by these ligands. Transcription factors studied will be Pax-6, Eya-1, Six-3, maf-B, AP2a, RAR/RXR and Foxe-3. Part three will test the hypothesis that TFGbeta-induced cataractous changes involve inhibition of FGF, RA and Wnt signalling, and down regulation of expression of key epithelial transcription factors. This will investigate how TGFbeta modulates expression of FGF, RA and Wnt receptors, signalling molecules and transcription factors (see above). Part four will test the hypothesis that reduced Pax-6 expression makes lens epithelial cells more susceptible tp TGFbeta-induced cataractous changes. The small eye (Sey) mouse will be investigated to determine if epithelial cells from this mutant are more sensitive to TGFbeta and, if so, the mechanism(s) involved. Understanding the molecular interactions that determine the lens epithelial phenotype is central to understanding the molecular basis of cataracts involving aberrant epithelial growth, including PCO.
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