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From the The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
PURPOSE. The work from numerous laboratories has led to the idea that the growth factors such as platelet-derived growth factor (PDGF) contribute to proliferative vitreoretinopathy (PVR) in experimental models of the disease, as well as in humans. In support of this idea, the authors have previously reported that cells unable to respond to PDGF had a greatly reduced PVR potential, compared with PDGF-responsive versions of the same cells. The goal of this study was to test the effect of blocking the output of the PDGF receptor in an experimental model of PVR.
METHODS. Polymerase chain reaction–based site-directed mutagenesis was used to
generate point mutations in the human PDGF 
receptor (PDGFR)
cDNA, which resulted in single amino acid substitutions. These changes
were based on naturally occurring point mutations in the c-kit receptor
tyrosine kinase, which suppresses the function of wild-type c-kit. A
truncated PDGFR was also made, in which the receptor ended just
after the juxtamembrane domain. As with the point mutants, truncated
receptors have been shown to block the action of wild-type receptors.
All the PDGFR mutants were introduced into cells that naturally
express the wild-type receptor, and the PDGF-dependent output of the
resultant cell lines was determined. In addition, the PVR potential of
cell lines expressing the mutant receptors was tested in a PVR rabbit
model.
RESULTS. Although the mutants differed in their ability to suppress PDGF-dependent signaling of the wild-type receptor, each mutant effectively blocked cell cycle progression. When expressed in rabbit conjunctival fibroblasts, a cell line that effectively induces PVR, the mutant receptors blocked PVR to various degrees. The most effective receptor was the truncated mutant.
CONCLUSIONS. These data suggest that the PDGFR plays an important role in
PVR. In addition, these mutant receptors appear to have therapeutic
potential for prevention of this blinding
disease.
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