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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY003177-25
Application #
6948461
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1991-09-30
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
25
Fiscal Year
2005
Total Cost
$100,000
Indirect Cost
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
Zhao, Guannan; Bailey, Charles G; Feng, Yue et al. (2018) Negative regulation of lens fiber cell differentiation by RTK antagonists Spry and Spred. Exp Eye Res 170:148-159
Dawes, L J; Shelley, E J; McAvoy, J W et al. (2018) A role for Hippo/YAP-signaling in FGF-induced lens epithelial cell proliferation and fibre differentiation. Exp Eye Res 169:122-133
Shu, Daisy Y; Wojciechowski, Magdalena C; Lovicu, Frank J (2017) Bone Morphogenetic Protein-7 Suppresses TGF?2-Induced Epithelial-Mesenchymal Transition in the Lens: Implications for Cataract Prevention. Invest Ophthalmol Vis Sci 58:781-796
Wojciechowski, Magdalena C; Mahmutovic, Leila; Shu, Daisy Y et al. (2017) ERK1/2 signaling is required for the initiation but not progression of TGF?-induced lens epithelial to mesenchymal transition (EMT). Exp Eye Res 159:98-113
McAvoy, J W; Dawes, L J; Sugiyama, Y et al. (2017) Intrinsic and extrinsic regulatory mechanisms are required to form and maintain a lens of the correct size and shape. Exp Eye Res 156:34-40
Shu, Daisy Y; Lovicu, Frank J (2017) Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. Prog Retin Eye Res 60:44-65
Das, Shannon J; Lovicu, Frank J; Collinson, Emma J (2016) Nox4 Plays a Role in TGF-?-Dependent Lens Epithelial to Mesenchymal Transition. Invest Ophthalmol Vis Sci 57:3665-73
Lovicu, F J; Shin, E H; McAvoy, J W (2016) Fibrosis in the lens. Sprouty regulation of TGF?-signaling prevents lens EMT leading to cataract. Exp Eye Res 142:92-101
Audette, Dylan S; Anand, Deepti; So, Tammy et al. (2016) Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression. Development 143:318-28
Sugiyama, Yuki; Shelley, Elizabeth J; Yoder, Bradley K et al. (2016) Non-essential role for cilia in coordinating precise alignment of lens fibres. Mech Dev 139:10-7

Showing the most recent 10 out of 87 publications