Corneal epithelial disorders produce irregular epithelial thickening that leads to visual loss, causes excessive corneal scarring, increases susceptibility to infection, and promotes development of corneal vascularization, a condition referred to as corneal surface disease. To understand the pathological consequences and develop appropriate treatment protocols for corneal diseases, elucidation of the pathways underlying the normal maintenance of corneal integrity and function, and the molecular mechanisms causing abnormalities is important. Corn1 mice develop a roughened, opaque corneal surface caused by hyperproliferation, and subsequent corneal neovascularization. Because these two events occur without external manipulation, corn1 mice offer a unique model to evaluate the regulatory factors responsible for epithelial and vascular proliferation as well as to identify the genes that control these processes. We have determined, by positional cloning, that the phenotypes in corn1 mice are caused by a mutation in destrin. Destrin, a member of the ADF/cofilin family, is an essential regulator of actin filament turnover, which acts by enhancing depolymerization of actin filament. The long-term goal of the proposed research is to determine the specific functions of destrin in corneal epithelial cells and to elucidate the mechanism responsible for neovascularization in corn1 mice. To achieve these goals, we propose to (1) determine the molecular cue and downstream molecular changes that drive the corneal epithelial cells to hyper-proliferate, and to (2) identify a series of molecular changes that links epithelial hyperproliferation and stromal neovascularization in corn1 mice. Information gained from this study may enhance our understanding of the processes at work in the corneal surface diseases, offer a useful tool for developing therapeutic interventions and provide insights into the regulatory mechanisms controlling corneal epithelial proliferation and inappropriate neovascularization.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016108-04
Application #
7345362
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
2005-01-01
Project End
2009-03-31
Budget Start
2008-01-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$276,919
Indirect Cost
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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