The specific aim of this proposal is to investigate the role of pharmacologic agents in the treatment of fibroproliferative vitreoretinal diseases. We plan to expand upon our prior study on the effects of fluoropyrimidines on intracellular processes including cellular proliferation and cell-mediated contraction, to include compounds that modify the interaction between the cells and their extracellular matrix. Heparin, low molecular weight heparin fragments and related synthetic compounds will be specifically evaluated with respect to their ability to inhibit cellular proliferation and cell-mediated contraction. Low molecular weight heparin fragments will be screened for populations which have lost their anticoagulation properties, but still retain their antiproliferative effects. The antiproliferative and anticontractile properties of heparin, commercially available heparin fragments and heparin fragments prepared in our laboratory will be compared. The most potent heparin fragments will be tested in vitro in combination with other members of the fluoropyrimidine and steroid family for additive or synergistic effects. The mechanism of action of heparin and its biologically active fragments in ocular call types will be explored, with emphasis upon cytoskeletal changes, effects on cell-substrate attachment, DNA synthesis and the rate of binding and internalization of heparin and its fragments. Heparin fragments will be tested first in the well established homologous fibroblast model of PVR in the rabbit, and dosages found effective will then be tested in a new, more realistic rabbit model of PVR following partial vitrectomy and diathermy. Drug combinations found effective in the in vitro experiments will also be evaluated using these PVR models. In vivo studies including electroretinograms and histology to determine the potential toxicity of heparin and heparin fragments and the rate of clearance of both intravitreally injected heparin and heparin fragments in the rabbit will be carried out. The anticontractile and antiproliferative properties of heparin should make it a useful agent for the treatment of ocular proliferative diseases.
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