Detachment of the neural retina from the adjacent retinal pigment epithelium (RPE) results in physical separation of the photo receptor cell layer from the apical surface of the RPE, an expansion of the interphotoreceptor space (ie the subretinal space), and a concomitant change in the biochemical composition of the interphotoreceptor matrix (IPM). It also initiates a complex series of cellular and molecular changes in both retinal and RPE cells (see Fisher and Anderson, 1994). It may impede the normal transfer of ions and metabolites, and liberate or activate endogenous regulatory factors. It triggers a progressive degeneration of photoreceptor cells, and it induces a rapid proliferative response in non-neuronal retinal cells that is highly similar to the reactive gliosis that accompanies brain injury. Prompt reapposition of the retina and RPE layers can result in the arrest and/or partial reversal of some of these abnormalities, although cellular recovery is incomplete and chronic visual deficits usually persist. There are no pharmacologic treatments that can prevent, arrest, or reduce the degenerative and proliferative changes that accompany detachment or other acquired retinal degenerations. Their eventual development, however, may be predictably linked to the identification of the molecular mechanisms responsible for maintaining normal retinal adhesion, sustaining photoreceptor cell survival, maintaining mitotic quiescence, and arresting reactive gliosis. This provides a compelling rationale to examine the functions of adhesion and regulatory molecules that are normally present in the retina, and that have the potential to influence the molecular events that accompany retinal injuries such as detachment. In this proposal, the focus is on three such molecules: the vitronectin receptor (VnR), an adhesion receptor from the integrin superfamily; and two growth factors, transforming growth factor-beta (TGF-(Beta), and basic fibroblast growth factor (bFGF), both of which are thought to regulate aspects of wound healing and scar formation in the brain. The subunit composition of the integrins expressed on the surfaces of cells bordering the IPM will be identified and characterized. The involvement of this integrin(s) and its IPM ligand(s) in retinal adhesion will be assessed using in vitro and in vivo adhesion assays. Second, the function(s) of TGF-Beta1, TGF-Beta2, TGF-Beta3 isoforms will be evaluated in the context of reactive gliosis induced by retinal detachment. Finally, the processing of bFGF by retinal cells will be compared under conditions designed to induce photoreceptor degeneration (i.e. detachment) and to elicit photoreceptor cell """"""""rescue"""""""". In pursuing these three aims, new insights should be gained into the retina's dynamic response to injury, and into the mechanisms responsible for maintaining normal retinal adhesion.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002082-21
Application #
2608553
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1977-09-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1999-11-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Santa Barbara
Department
Type
Organized Research Units
DUNS #
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Ozaki, S; Radeke, M J; Anderson, D H (2000) Rapid upregulation of fibroblast growth factor receptor 1 (flg) by rat photoreceptor cells after injury. Invest Ophthalmol Vis Sci 41:568-79
Anderson, D H; Hageman, G S; Mullins, R F et al. (1999) Vitronectin gene expression in the adult human retina. Invest Ophthalmol Vis Sci 40:3305-15
Lewis, G P; Fisher, S K; Anderson, D H (1996) Fate of biotinylated basic fibroblast growth factor in the retina following intravitreal injection. Exp Eye Res 62:309-24
Geller, S F; Lewis, G P; Anderson, D H et al. (1995) Use of the MIB-1 antibody for detecting proliferating cells in the retina. Invest Ophthalmol Vis Sci 36:737-44
Lewis, G P; Guerin, C J; Anderson, D H et al. (1994) Rapid changes in the expression of glial cell proteins caused by experimental retinal detachment. Am J Ophthalmol 118:368-76
Pfeffer, B A; Flanders, K C; Guerin, C J et al. (1994) Transforming growth factor beta 2 is the predominant isoform in the neural retina, retinal pigment epithelium-choroid and vitreous of the monkey eye. Exp Eye Res 59:323-33
Guerin, C J; Lewis, G P; Fisher, S K et al. (1993) Recovery of photoreceptor outer segment length and analysis of membrane assembly rates in regenerating primate photoreceptor outer segments. Invest Ophthalmol Vis Sci 34:175-83
Lewis, G P; Erickson, P A; Guerin, C J et al. (1992) Basic fibroblast growth factor: a potential regulator of proliferation and intermediate filament expression in the retina. J Neurosci 12:3968-78
Lewis, G P; Erickson, P A; Anderson, D H et al. (1991) Opsin distribution and protein incorporation in photoreceptors after experimental retinal detachment. Exp Eye Res 53:629-40
Hageman, G S; Kirchoff-Rempe, M A; Lewis, G P et al. (1991) Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix. Proc Natl Acad Sci U S A 88:6706-10

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