Our findings in the previous grant period included that platelet-derived growth factor (PDGF) receptors (PDGFRs) are present in epiretinal membranes of human proliferative vitreoretinopathy (PVR) donors, and that PDGFRs are required for development of PVR in a rabbit model of the disease. We will continue to investigate the role of PDGF in PVR as outlined in these specific aims: 1. To investigate why the alphaPDGFR is better at causing PVR than the betaPDGFR. In the rabbit model of PVR, cells expressing the alphaPDGFR induce PVR much more effectively than do the same cells expressing the betaPDGFR. We will identify the region(s) of the alphaPDGFR that enable the betaPDGFR to induce PVR by using chimeras of the alpha and betaPDGFRs. 2. Test the hypothesis that TGFbeta activates the alphaPDGFR via PDGF-CC. Activation of the PDGFR is a prerequisite for PVR in rabbits, and in this aim we will test whether our recently discovered unconventional, transforming growth factor beta (TGFbeta)-dependent route to activate the alphaPDGFR is dependent on PDGF-CC. 3. Identify factors that augment the PVR potential of retinal pigment epithelial cells (RPEs). While fibroblasts efficiently induce PVR in our rabbit model, RPE cells do not. This deficiency will be exploited to identify factors that elevate the PVR potential of RPE cells. 4. Screen epiretinal membranes from human PVR donors for expression of factors that promote PVR in the animal model. We will screen epiretinal membranes from human PVR donors for the expression of factors that are critical for PVR in the rabbit model (like alphaPDGFR, activated alphaPDGFR and ligands for this receptor). Together these studies will identify factors that promote PVR and elucidate the relationships between such factors. In addition, our finding will critically evaluate the relevance of the rabbit model to human disease. This information will guide future efforts to develop approaches to prevent and/or treat PVR in humans.
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