VASCULAR CELL IMMATURITY IN RETINOPATHY OF PREMATURITY

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The incidence of retinopathy of prematurity (ROP) , a blinding disease, is increasing; there is no way to prevent the disease at this time. ROP is highly correlated with prematurity as well as 02 toxicity and the less differentiated front of the developing vasculature is affected in ROP, not the mature vessels. However, there has been little work on the role of retinal endothelial cells (RCE) in the disease process. This proposal addresses both the questions of pathogenesis and potential therapies. We will use an in vitro model of RCE differentiation to examine superoxide dismutase (SOD) as a partial reflection of the ability of RCE at different points in differentiation to help detoxify some free radical products of 02 metabolism; SOD may be an important enzyme in this detoxification and also in differentiation. In this model we will also examine the effect on SOD of agents which may alter differentiation. Although the in vitro model allows us to test the hypothesis that the degree of differentiation determines the levels of SOD in EC, we need the full complexity of in vivo conditions to further explore the pathogenesis of ROP and evaluate potential intervention. We have developed a mouse model of quantifiable oxygen-induced vasculopathy and will use this model to study SOD enzyme activity and basic fibroblastic growth factor (bFGF) localization by immunohistochemistry in whole retinas and also examine SOD and bFGF mRNA expression (by in situ hybridization). We will compare the findings in our ROP model to those found in normally developing murine retina. Furthermore, we will compare the effect of agents known to inhibit angiogenesis: (1) alpha-interferon, an agent known to inhibit proliferation of EC in culture and currently in clinical trials for treatment of vascular tumors and (2) AGM-1470, a very promising angiostatic agent now in clinical trials as an anti-tumor agent. We will also examine agents which may increase SOD activity: SOD analogues and retinol (see Preliminary Results). Because of the direct clinical relevance we will also examine the effect of light and darkness on the development of neovascularization in the ROP model. There is both clinical evidence and evidence from in vitro experimentation in tissue culture that light levels may have an effect on ROP(Glass, et al, 1985; Dorey, et al, 1990).