The cornea functions as the main refractive element of the visual system, contributing between 65-75 percent of the eye's total focusing power. Proper refraction of light depends on the smooth surface and transparency of the cornea and diseases affecting the cornea are a major cause of blindness worldwide. To understand the pathological consequences and develop appropriate treatment protocols for corneal diseases, it is important to elucidate the pathways underlying the normal maintenance of corneal integrity and function, and the molecular mechanisms causing abnormalities. Animal models for corneal diseases provide useful experimental systems for these purposes. Mice homozygous for the autosomal recessive corneal disease-1 (corn1) mutation develop a roughened, opaque corneal surface caused by hyperproliferation, and subsequent corneal neovascularization. We previously determined that deletion of destrin (Dstn), a major regulator of actin dynamics, is responsible for these corneal abnormalities. The long-term goal of this research is to determine the role proper regulation of actin dynamics play in the cornea. Our subsequent analyses of the mutant identified a series of gene expression changes downstream of the Dstn mutation and actin dynamics defects, which may underlie epithelial hyperproliferation and neovascularization in the cornea, and also the finding that the Dstn-corn1 mutation leads to an auto-inflammatory condition in the cornea. This information now allows us to build new hypotheses on the molecular pathways responsible for the corneal phenotypes in Dstn-corn1 mice, which we propose to test in this renewal application. Specifically, we propose to (1) test whether defects in actin dynamics lead to corneal abnormalities through transcription factor dependent pathways in Dstn-corn1 mice and (2) determine the role inflammatory cells and molecules play in the development of corneal abnormalities observed in Dstn-corn1 mice.

Public Health Relevance

Dstn mutant mice provide a unique model to study the abnormal corneal epithelial thickening and neovascularization. Proposed studies using this mouse model will further our understanding of molecules and pathways that are important for the proper function of the cornea, and identify defects that could lead to the observed corneal abnormalities. Findings from this study may enhance our understanding of the processes at work in the corneal surface diseases and lead to an understanding that is critical in defining therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016108-08
Application #
8244498
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2005-01-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$317,552
Indirect Cost
$103,712
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kawakami-Schulz, Sharolyn V; Verdoni, Angela M; Sattler, Shannon G et al. (2014) Serum response factor: positive and negative regulation of an epithelial gene expression network in the destrin mutant cornea. Physiol Genomics 46:277-89
Kawakami-Schulz, Sharolyn V; Sattler, Shannon G; Doebley, Anna-Lisa et al. (2013) Genetic modification of corneal neovascularization in Dstn (corn1) mice. Mamm Genome 24:349-57
Kawakami-Schulz, Sharolyn V; Verdoni, Angela M; Sattler, Shannon G et al. (2012) Differences in corneal phenotypes between destrin mutants are due to allelic difference and modified by genetic background. Mol Vis 18:606-16
Verdoni, Angela M; Ikeda, Sakae; Ikeda, Akihiro (2010) Serum response factor is essential for the proper development of skin epithelium. Mamm Genome 21:64-76
Verdoni, Angela M; Schuster, Keaton J; Cole, Brian S et al. (2010) A pathogenic relationship between a regulator of the actin cytoskeleton and serum response factor. Genetics 186:147-57
Verdoni, Angela M; Aoyama, Natsuyo; Ikeda, Akihiro et al. (2008) Effect of destrin mutations on the gene expression profile in vivo. Physiol Genomics 34:9-21
Verdoni, Angela M; Smith, Richard S; Ikeda, Akihiro et al. (2008) Defects in actin dynamics lead to an autoinflammatory condition through the upregulation of CXCL5. PLoS One 3:e2701