Retinal Iron Health in Transport and Disease

项目总结 铁在健康和患病的视网膜中都起着至关重要的作用。的长期目标 建议的研究是为了了解视网膜铁通量的调节，确定为什么铁 在视网膜疾病中积累，并发现如何防止视网膜铁中毒。铁是 视网膜中氧化磷酸化、膜生物发生和视黄醇的必需 异构化，但当调控不当时，它会成为氧化应激的中心生产者。 铁的毒性在视网膜疾病中很明显：它会在进入视网膜后引起快速的视网膜退化 由眼内异物携带的眼睛。视网膜中也发现了铁的积聚。 包括AMD在内的疾病，在那里它可能会加剧氧化应激。此外，患有这种疾病的患者 遗传性无球蛋白血症，由铜蓝蛋白铁氧合酶突变引起 (CP)，视网膜铁蓄积伴RPE色素异常，偶有早期 发作性黄斑变性。CP及其同系物Hephestn(Heph)基因敲除小鼠 有年龄依赖性的视网膜铁超载以及光感受器和RPE的退化。 来自其他器官的证据表明，CP或HEPH可以与唯一的血浆协同作用 膜铁输出器，铁蛋白(FPN)，从细胞中导出铁。然而，来自 先前的资金支持表明，视网膜特异的FPN基因敲除对视网膜没有影响 当视网膜特异性基因敲除HEPH时，铁水平会导致视网膜铁积聚。这些数据 指出铁氧合酶CP和HEPH对保持眼内铁的重要性 (Fe3+)态。我们将在没有FPN的情况下使用AAV-CP基因治疗来验证这一假设，因为 以及一种抗氧化形式的脂质DHA，将进行视网膜保护测试 对抗Fe2+产生的活性氧物种。

PROJECT SUMMARY Iron plays a critical role in both the healthy and diseased retina. The long term goals of the proposed studies are to understand regulation of retinal iron flux, determine why iron accumulates in retinal disease, and discover how to protect against retina iron toxicity. Iron is necessary in the retina for oxidative phosphorylation, membrane biogenesis and retinol isomerization, but becomes a central producer of oxidative stress when improperly regulated. Iron toxicity is evident in retinal disease: it causes rapid retinal degeneration following entry into the eye carried by an intraocular foreign body. Iron accumulation has also been noted in retinal diseases including AMD, where it may exacerbate oxidative stress. Further, patients with the inherited disease aceruloplasminemia, caused by mutation of the ferroxidase ceruloplasmin (Cp), have retinal iron accumulation with RPE pigment abnormalities, and occasionally early onset macular degeneration. Mice with knockout for Cp and its homolog hephaestin (Heph) have age-dependent retinal iron overload and degeneration of photoreceptors and RPE. Evidence from other organs suggests that Cp or Heph can cooperate with the sole plasma membrane iron exporter, ferroportin (Fpn), to export iron from cells. Yet, results from the previous funding period indicate that retina-specific knockout of Fpn has no impact on retinal iron levels while retina-specific knockout of Heph leads to retinal iron accumulation. These data point to the importance of ferroxidases Cp and Heph for keeping intraocular iron in its ferric (Fe3+) state. We will test this hypothesis using AAV-Cp gene therapy in the absence of Fpn, as well as an oxidation resistant form of the lipid DHA, which will be tested for retinal protection against reactive oxygen species produced by Fe2+.