Continued research on intraocular proliferation, an area of investigation targeted by the National Eye Council in its most recent 5-year plan, is proposed. Past work resulted in the validation of several different experimental models of proliferative vitreoretinopathy (PVR) induced by penetrating posterior ocular injury and has provided insight into the role of the macrophage in the pathogenesis of this condition. In these and other published studies it has been shown that the retinal pigment epithelium (RPE) is a key element of PVR pathogenesis. Ocular injury results in direct tissue damage with impairment of the blood/ocular barrier and leakage of serum and tissue factors that initiate an inflammatory response. Infiltrating leukocytes release cytokines which are known to affect migration, differentiation, and proliferation of many cell types including RPE and glial cells. Activation of these retinal cells followed by migration into the vitreous results in the membranes characteristic of PVR. Three hypotheses concerning these processes will be tested: (1) in the initial stage, RPE cells are """"""""activated"""""""" by cytokines and direct trauma; (2) the activated stage is characterized by increased RPE proliferation, phagocytosis, cytokine production, and immune competence; (3) the membrane stage develops when vitreous TGF-beta transforms the RPE cell to a migratory phenotype, followed by increased extracellular matrix formation and downregulation of the """"""""activated phenotype."""""""" These hypotheses will be tested with the following Specific Aims: (1) The effects and mechanism of action of selected cytokines on phenotype and function of cultured human RPE cells will be studied in vitro. (2.) The in vivo effects of these cytokines on RPE cell morphology and function will be determined in a new subretinal bleb system. (3) The modulating effects of these cytokines on """"""""wound healing"""""""" after direct RPE cell injury will be determined in a new """"""""scratched culture"""""""" model of RPE cell injury.
Showing the most recent 10 out of 61 publications
