REDOX CONTROL OF FGF GENE EXPRESSION IN AGING RPE

视网膜外层细胞的氧化应激可能直接参与年龄相关性黄斑变性（AMD）的发病机制。在体外，氧化应激直接升高视网膜色素上皮（RPE）中的FGF-2基因表达，并且在体内，包括毒性光损伤和创伤的各种应激也升高视网膜外层中的FGF-2基因表达。由于FGF-2是一种营养因子，它可以从氧化应激引起的损伤中拯救外视网膜细胞。几项研究表明，衰老细胞对氧化应激的转录反应发生了改变。因此，老年RPE对氧化应激反应中FGF-2基因表达升高的能力降低可能在AMD的发病机制中具有直接的功能作用。我们假设FGF-2在氧化应激反应中的表达是通过FGF- 2基因启动子的AP-1位点调节的，并且由于AP-1复合物的功能降低，这种反应在衰老细胞中减弱。本研究的第一个目的是探讨氧化应激与FGF-2基因表达之间的定量关系。第二个目标将研究调节氧化应激反应中FGF-2基因启动子活性的DNA反应元件和转录因子，第三个目标将具体探索体内RPE衰老如何减少氧化应激反应中FGF-2的表达。我们的假设提供了一个合理的联系细胞死亡的外部视网膜和事件的氧化应激和RPE老化，并可能提供新的方法来理解和治疗AMD。

Oxidative stress to cells of the outer retina may be directly involved in the pathogenesis of age-related macular degeneration (AMD). In vitro, oxidative stress directly elevates FGF-2 gene expression in the retinal pigment epithelium (RPE) and in vivo a variety of stresses including toxic light damage and trauma also elevate FGF-2 gene expression in the outer retina. Because FGF-2 is a trophic factor, it may rescue cells of the outer retina from damage caused by oxidative stress. Several studies have shown that aged cells have an altered transcriptional response to oxidative stress. A diminished ability of aged RPE to elevate FGF-2 gene expression in response to oxidative stress might therefore have a direct functional role in the pathogenesis of AMD. We hypothesize that the expression of FGF-2 in response to oxidative stress is regulated through the AP-1 site of the FGF- 2 gene promoter, and that this response is diminished in aged cells due to the reduced function of the AP-1 complex. In the first aim of this proposal, we will investigate the quantitative relationships between oxidative stress and FGF-2 gene expression. The second aim will investigate DNA response elements and transcription factors which regulate the activity of the FGF-2 gene promoter in response to oxidative stress, and the third aim will specifically explore how RPE aging in vivo diminishes the expression of FGF-2 in response to oxidative stress. Our hypothesis provides a plausible link between cell death in the outer retina and the events of oxidative stress and RPE aging and may provide new approaches for the understanding and treatment of AMD.