REDOX CONTROL OF FGF GENE EXPRESSION IN AGING RPE

外视网膜细胞的氧化应激可能直接参与老年性黄斑变性（AMD）的发病机制。在体外，氧化应激可直接提高视网膜色素上皮（RPE）中FGF-2基因的表达，在体内，包括毒性光损伤和创伤在内的各种应激也可提高外视网膜中FGF-2基因的表达。因为FGF-2是一种营养因子，它可以拯救外层视网膜细胞免受氧化应激引起的损伤。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，衰老的RPE在氧化应激反应中提高FGF-2基因表达的能力下降，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位点进行调节的，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。在本提案的第一个目的，我们将研究氧化应激和FGF-2基因表达之间的定量关系。第二个目标将研究在氧化应激下调控FGF-2基因启动子活性的DNA应答元件和转录因子，第三个目标将具体探讨体内RPE老化如何减少氧化应激下FGF-2的表达。我们的假设提供了外视网膜细胞死亡与氧化应激和RPE老化事件之间的合理联系，并可能为理解和治疗AMD提供新的方法。

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.