Cataract is the most common cause of blindness in the world today. Surgery is generally very effective in restoring sight;however, a common complication is the development of posterior capsule opacification. This is caused by aberrant growth and differentiation of lens cells. One way to prevent this costly complication is to promote normal patterns of lens cell growth and differentiation. In relation to fiber differentiation, evidence indicates that members of the Wnt growth factor family, through activation of the Wnt/planar cell polarity (PCP) signaling pathway, provide a critical component of a FGF- induced signaling cascade that is required for fiber differentiation. This project will test the hypothesis that Wnt/PCP signaling plays a critical role in directing the elongation, migration and alignment of lens fibers. In Part (a), investigations by RT-PCR, in situ hybridisation, immunolocalization and Western blotting, will determine expression patterns of members of the core Wnt/PCP signaling families, prickle, van gogh-like and scribble, during lens development. Part (b) will then manipulate expression of PCP signaling components in lens epithelial explants and in transgenic mice to determine their functional roles in fiber differentiation. Using siRNA, dominant-negative and conditional knockout strategies the functions of the PCP signaling components (identified in a) in promoting the elongation, directed migration and alignment of lens fibers, will be tested. These studies will provide vital new information about mechanisms and molecules that are required to promote the growth, differentiation and maintenance of lens cells and in so doing will address key objectives identified within the 'Lens and Cataract Program'of NEI.

Public Health Relevance

With approximately 20 million people affected, clouding of the lens (cataract) is the most common cause of blindness in the world today. Although surgery can initially be very effective in restoring sight, in the longer term complications are common and often result in the development of a secondary cataract. A central aim in our laboratory is to devise molecular strategies that (i) prevent the aberrant lens cell behaviour that occurs after surgery and (ii) promote normal patterns of lens cell growth and differentiation so that lens clarity is maintained.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY003177-29
Application #
7995948
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
1991-09-30
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
29
Fiscal Year
2011
Total Cost
$157,453
Indirect Cost
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
Das, Shannon J; Lovicu, Frank J; Collinson, Emma J (2016) Nox4 Plays a Role in TGF-β-Dependent Lens Epithelial to Mesenchymal Transition. Invest Ophthalmol Vis Sci 57:3665-73
McAvoy, J W; Dawes, L J; Sugiyama, Y et al. (2016) Intrinsic and extrinsic regulatory mechanisms are required to form and maintain a lens of the correct size and shape. Exp Eye Res :
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
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
Lovicu, F J; Shin, E H; McAvoy, J W (2016) Fibrosis in the lens. Sprouty regulation of TGFβ-signaling prevents lens EMT leading to cataract. Exp Eye Res 142:92-101
Zhao, Guannan; Wojciechowski, Magdalena C; Jee, Seonah et al. (2015) Negative regulation of TGFβ-induced lens epithelial to mesenchymal transition (EMT) by RTK antagonists. Exp Eye Res 132:9-16
Sugiyama, Yuki; Shelley, Elizabeth J; Badouel, Caroline et al. (2015) Atypical Cadherin Fat1 Is Required for Lens Epithelial Cell Polarity and Proliferation but Not for Fiber Differentiation. Invest Ophthalmol Vis Sci 56:4099-107
Dawes, L J; Sugiyama, Y; Lovicu, F J et al. (2014) Interactions between lens epithelial and fiber cells reveal an intrinsic self-assembly mechanism. Dev Biol 385:291-303
Dawes, Lucy J; Sugiyama, Yuki; Tanedo, Ana S et al. (2013) Wnt-frizzled signaling is part of an FGF-induced cascade that promotes lens fiber differentiation. Invest Ophthalmol Vis Sci 54:1582-90
Wang, Chunxiao; Dawes, Lucy J; Liu, Yizhi et al. (2013) Dexamethasone influences FGF-induced responses in lens epithelial explants and promotes the posterior capsule coverage that is a feature of glucocorticoid-induced cataract. Exp Eye Res 111:79-87

Showing the most recent 10 out of 82 publications