VASCULAR CELL IMMATURITY IN RETINOPATHY OF PREMATURITY

早产儿视网膜病变（ROP）是一种致盲性疾病， 目前还没有办法预防这种疾病。 ROP 与早产以及O2毒性高度相关， 发育中的脉管系统的分化前沿在ROP中受到影响， 而不是成熟的血管 然而，关于这一角色的研究很少 视网膜内皮细胞（RCE）在疾病过程中的作用。这项建议 解决了发病机制和潜在治疗的问题。我们 将使用RCE分化的体外模型来检查超氧化物 SOD作为RCE能力的部分反映， 不同的辨证点，帮助解毒一些自由基 O2代谢产物; SOD可能是这一过程中的重要酶。 解毒和分化。 在这个模型中，我们还将 检查可能改变分化的试剂对SOD的影响。 尽管体外模型使我们能够检验这一假设， 分化程度决定了EC中SOD的水平，我们需要 体内条件的全面复杂性，以进一步探索发病机制 并评估潜在的干预措施。 我们发明了一种老鼠 可量化的氧诱导血管病变模型，并将使用该模型 研究超氧化物歧化酶（SOD）酶活性和碱性成纤维细胞生长因子（bFGF） 通过免疫组织化学在整个视网膜中的定位， SOD和bFGF mRNA表达（原位杂交）。 我们将比较 我们的ROP模型中的发现与正常发育中的发现相比， 鼠视网膜 此外，我们还将比较已知药物的效果 抑制血管生成：（1）α-干扰素，一种已知抑制血管生成的药物， EC在培养物中的增殖以及目前在用于 治疗血管肿瘤和（2）AGM-1470，一个非常有前途的 血管生成抑制剂现在作为抗肿瘤剂在临床试验中。 我们将 还研究了可能增加SOD活性的药物：SOD类似物， 视黄醇（见初步结果）。 由于直接的临床 相关性，我们还将研究光和黑暗的影响， ROP模型中新血管形成的发展。 既有 临床证据和组织体外实验证据 光水平可能对ROP有影响的培养（Glass等，1985; Dorey等人，1990）。

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).