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 that remain in the capsular bag after surgery. Our approach to circumvent this problem is to identify the conditions required for normal growth and differentiation of residual lens cells and apply this new information to promote regeneration of normal lens structure and function. Our previous NEI-funded studies showed that members of the FGF growth factor family could induce fiber differentiation in vitro and subsequent studies by our group and others have now provided compelling evidence that fiber differentiation in vivo depends on FGF signaling. This knowledge is fundamental to devising strategies for lens regeneration after cataract surgery. However, if we are to successfully regenerate transparent lenses with normal focusing abilities, in addition to being able to initiate and promote fiber differentiation, we need to be able to recapitulate the coordinated cell behavior that is required to generate the exquisite three-dimensional organization of fibers (and epithelial cells) that is the central feature of normal lens morphogenesis. In our current NEI-funded project we have identified Wnt/Frizzled signaling through the planar cell polarity (Wnt-Fz/PCP) pathway as critical for promoting the precise alignment/orientation of fibers. We have also shown that epithelial cells provide a polarizing cue that aligns/orients elongating fibers. To exploit these novel findings this renewal application aims to elucidate the mechanism(s) whereby activation of Wnt-Fz/PCP signaling translates into polarized fiber cell behavior and establishes the global alignment/orientation of fibers that is critical for normal lens morphogenesis. In section 1 of the project we will use FGF to induce fiber differentiation in our well- characterized epithelial explant system to identify the mechanism whereby components of the Wnt-Fz/PCP signaling pathway organize the lens cell cytoskeleton and promote coordinated alignment/orientation. In section 2, using epithelial explants and complementary transgenic approaches we will both promote and inhibit Wnt bioavailability and/or Wnt signaling to determine if epithelial-derived Wnt ligand provides a directional cue that draws fibers to poles This project will provide vital new information about mechanisms and molecules that are required to promote the regeneration of lens structure and function and in so doing will address key objectives identified within the Lens and Cataract Program of the 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 behavior 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 #
4R01EY003177-31
Application #
8398913
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (02))
Program Officer
Araj, Houmam H
Project Start
1991-09-30
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
31
Fiscal Year
2013
Total Cost
$186,975
Indirect Cost
$13,850
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
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
Sugiyama, Yuki; Shelley, Elizabeth J; Wen, Li et al. (2013) Sfrp1 and Sfrp2 are not involved in Wnt/*-catenin signal silencing during lens induction but are required for maintenance of Wnt/*-catenin signaling in lens epithelial cells. Dev Biol 384:181-93
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
Shin, Eun Hye H; Basson, M Albert; Robinson, Michael L et al. (2012) Sprouty is a negative regulator of transforming growth factor ýý-induced epithelial-to-mesenchymal transition and cataract. Mol Med 18:861-73
Sugiyama, Yuki; McAvoy, John W (2012) Analysis of PCP defects in mammalian eye lens. Methods Mol Biol 839:147-56
Sugiyama, Yuki; Lovicu, Frank J; McAvoy, John W (2011) Planar cell polarity in the mammalian eye lens. Organogenesis 7:191-201
Lovicu, F J; McAvoy, J W; de Iongh, R U (2011) Understanding the role of growth factors in embryonic development: insights from the lens. Philos Trans R Soc Lond B Biol Sci 366:1204-18
Kallifatidis, Georgios; Boros, Jessica; Shin, Eun Hye H et al. (2011) The fate of dividing cells during lens morphogenesis, differentiation and growth. Exp Eye Res 92:502-11
Newitt, Peter; Boros, Jessica; Madakashira, Bhavani P et al. (2010) Sef is a negative regulator of fiber cell differentiation in the ocular lens. Differentiation 80:53-67

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