Retinal pigment epithelial (RPE) cells form a columnar, barrier epithelium at the back of the retina and do not normally divide in the mature animal. However, in some disease states, such as proliferative vitreoretinopathy (PVR), they gain access to, and proliferate in the vitreous. In PVR, cells in the vitreous elaborate membranous material containing extracellular matrix and cells. Contraction of these membranes results in traction forces that can detach the neural retina from the underlying RPE and cause blindness. RPE cells in the vitreous lose some of their normal properties and undergo a morphological transformation such that they have a more mesenchymal (fibroblast-like) appearance. These changes are also seen when RPE cells are cultured in the presence of vitreous in vitro. Little is known about biochemical changes involved, although a few gene products, including FGF-2, has been shown to be regulated by exposure to vitreous.
The aim of this application is to identify additional genes the expression of which is modulated by vitreous and to determine the role of the known and newly identified genes in the altered phenotype of the RPE cells upon vitreous-treatment. Using gene array technology, it is planned to examine a limited number of genes (approximately 1000) which are known to be regulated in neoplastic cells which also undergo epithelial-mesenchymal transformation as well as genes which are known to be involved in cell-cell interaction and those coding for growth factors, cytokines and their receptors. This makes it possible to examine the expression of many genes simultaneously. Since the gene sequence and protein sequence for each gene is known, and some information is available relating to each gene's function, the results should give insights into both what the changes are, and which ones might be important. This should facilitate the generation of hypotheses concerning the pathway of the epithelial-to-mesenchymal transformation, the possible nature of the vitreous components involved, and the implications of the results in retinopathies involving aberrant RPE cells, such as PVR. In future studies, beyond the scope of the current proposal, the information obtained will be used to investigate human epiretinal membranes removed during surgery, and to investigate changes in an animal model for PVR. The ultimate aim is the development of novel therapeutic approaches for PVR. This facilitated by the ability to deliver agents directly to the vitreous, which is separated from the blood stream by the blood-eye barrier.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY012711-01A1
Application #
6196193
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
2000-08-15
Project End
2004-07-31
Budget Start
2000-08-15
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$252,875
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Parapuram, Sunil K; Chang, Binyue; Li, Lei et al. (2009) Differential effects of TGFbeta and vitreous on the transformation of retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 50:5965-74
Ganti, Ramapriya; Hunt, Richard C; Parapuram, Sunil K et al. (2007) Vitreous modulation of gene expression in low-passage human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 48:1853-63
Hartung, Ren; Parapuram, Sunil K; Ganti, Ramapriya et al. (2007) Vitreous induces heme oxygenase-1 expression mediated by transforming growth factor-beta and reactive oxygen species generation in human retinal pigment epithelial cells. Mol Vis 13:66-78
Liou, Gregory I; Samuel, Sara; Matragoon, Suraporn et al. (2004) Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium. Mol Vis 10:383-91
Parapuram, Sunil K; Ganti, Ramapriya; Hunt, Richard C et al. (2003) Vitreous induces components of the prostaglandin E2 pathway in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 44:1767-74
Liou, Gregory I; Matragoon, Suraporn; Samuel, Sara et al. (2002) MAP kinase and beta-catenin signaling in HGF induced RPE migration. Mol Vis 8:483-93